EASD 2021 (European Association for the Study of Diabetes)

September 27-October 1, 2021; Virtual; Full Report – Draft

Executive Highlights

  • EASD 2021 marked the second virtual meeting for the European Association for the Study of Diabetes, which, once again, went off without a hitch. The conference included 45 symposia, 47 oral sessions with a remarkable 260 presenters plus 65 short oral sessions with 441 presenters. There were also 162 invited symposia speakers and 53 invited symposia chairs, rounding out this year’s incredible faculty.
  • In therapy, we learned from exciting real-world evidence of SGLT-2 and GLP-1 use. Notably, we saw RWE on SGLT-2 use in people with type 1 diabetes, which we see as a next step for the field and are excited to learn more about as data becomes available. Other notable topics at this year’s EASD meeting include Lilly’s dual GLP-1/GIP receptor agonist tirzepatide, which was recently submitted to the FDA and EMA for the management of type 2 diabetes with approval expected in mid-2022. We attended three new SURPASS program readouts, including a CGM sub-study, an extended analysis highlighting CV safety, and a patient-reported outcomes study all of which demonstrated strong A1c, Time in Range, and weight control benefits, not to mention improved patient reported outcomes.
  • In technology, AID systems took center stage with a wealth of new real-world evidence, especially from Medtronic’s MiniMed 780G system, which launched in Europe last year. Excitingly, RWE from MiniMed 780G shows users have been able to achieve similar Time in Range to those enrolled in the pivotal trial indicating the system is effective at managing every-day fluctuations in glycemic levels in daily life. Elsewhere in tech, we continue to hear about the benefits of decision support technologies for both providers and patients as well as using technology to help patients on MDI therapy improve their glycemic control and outcomes. As the majority of patients on insulin continue to use MDI over pump-based therapy, we certainly see a benefit to providing increased technology support and leveraging existing algorithms and decision support systems to help patients improve their diabetes management.
  • In big picture, population level health was a hot topic at EASD 2021 with a number of presentations investigating long-term outcomes and risk assessments for people with diabetes across various geographies. We also continued to learn about the relationship between diabetes and severe COVID-19 outcomes with more data supporting the recognition that patients with diabetes are at a higher risk for severe COVID-19 cases.

EASD 2021 took place virtually from September 27 – October 1, 2021. See the conference website as well as our day-of coverage from Day #1, Day #2, Day #3, Day #4, and Day #5. New content is highlighted in blue.

Table of Contents 

Themes

Diabetes Therapy

Real-world evidence: SGLT-2s in type 1, efficacy of SGLT-2s and GLP-1s, and improving consistency and duration of medication use

We were excited to see an emphasis on real-world data at EASD 2021, featuring learnings that both reaffirmed findings from randomized controlled trials and shed light on differences in the consistency and duration of use between medications. These studies captured information that is difficult to gather in RCTs, such as medication use across continents and disappointingly low rate of consistency and duration of medication use even on newer therapies like once-weekly GLP-1s. However, observational studies come with their own limitations, which were also explored. 

  • We were thrilled to see a real-world, retrospective study from Spain and Belgium on SGLT-2 use in people with type 1 diabetes. This study of 199 people with type 1 found that SGLT-2s led to modest reductions in A1c, body weight, and daily insulin dose, but, as expected, diabetic ketoacidosis was a large concern. Among participants, 6% reported DKA, despite education and ketone monitoring. Importantly, participants using SGLT-2s on-label (ie. BMI ≥27) saw greater reductions in A1c than those using it off-label (BMI <27), and no DKA episodes occurred in participants with on-label use of SGLT-2s. These results for on-label SGLT-2 use were certainly encouraging, suggesting that specific patient selection for use of SGLT-2s can help minimize DKA.  
  • Two presentations featured real-world evidence on the efficacy and safety of SGLT-2 empagliflozin (EMPRISE study) and of once-weekly subcutaneous semaglutide (SURE trials). The EMPRISE study, enrolling 134,280 people with type 2 diabetes in Israel, Europe, and East Asia, showed that empagliflozin compared to DPP-4s demonstrated a 29% risk reduction for hospitalization for heart failure, a 26% risk reduction for stroke, a 45% risk reduction for all-cause mortality, and a 51% risk reduction for acute kidney injury requiring dialysis. However, empagliflozin increased the risk of diabetic ketoacidosis by 82% compared to DPP-4s, a disparate finding from the EMPA-REG trial that found no increased DKA risk with empagliflozin compared to placebo. However, the clinical trial setting of EMPA-REG may have enabled closer monitoring and better implementation of DKA risk mitigation strategies. Turning to GLP-1 semaglutide, a pooled analysis of the first four SURE trials included 1,212 patients with type 2 diabetes in Canada, Denmark, Sweden, Switzerland, and the UK and reaffirmed the A1c and body weight benefits of once-weekly semaglutide seen in SUSTAIN 1. However, discontinuation rates were higher in the real-world SURE trials than in SUSTAIN 1 (9.5% vs. 5%-6%) due primarily to gastrointestinal side effects.    
  • Two presentations highlighted improved consistency of medication use among patients on once-weekly GLP-1s and insulin glargine-300. The observational STAY study found that once-weekly injectable GLP-1 compared to once-daily injectable GLP-1 resulted in significantly improved adherence (+35% after 12 months) and a 20% reduced risk of discontinuation, leading to improved glycemic control. However, overall adherence rates were disappointingly low for both once-weekly and once-daily GLP-1s (46% and 34%, respectively). We would be curious to see a real-world study on the consistency of use and persistence with once-daily oral GLP-1 Rybelsus, particularly given some of the opportunities and constraints associated with Rybelsus. Turning to insulin, Dr. Eugene Wright (Duke University) presented a real-world study comparing insulin glargine-300 to first-generational basal insulin. Insulin glargine-300 led to significantly improved adherence and persistence over first-generation basal insulin along with greater reductions in A1c; while both groups had disappointingly low overall rates of adherence (43% vs 38%) and persistence (46% vs 42%), it was very good to get the status quo given all the most recent thoughts on this subject.  
  • Though observational studies can shed light on real-world dynamics that RCTs cannot, they can also be associated with considerable limitations, as Dr. Jesper Krogh (Rigshospitalet, Denmark) argued in a systematic review of SGLT-2 randomized and observational trials. Dr. Krogh compared the effect of SGLT-2s on mortality and heart failure in RCTs and observational studies, and he concluded that SGLT-2 observational studies are burdened by biases that can lead to inflated results.

Two is better than one: Tirzepatide and other multi-receptor agonists take center stage

Dual GLP-1/GIP receptor agonist tirzepatide certainly stole the show at EASD 2021, with three new SURPASS program readouts, including a CGM sub-study, an extended analysis highlighting CV safety, and a patient-reported outcomes study. Other novel combination agonists also featured prominently, including a phase 2a RCT of AstraZeneca’s GLP-1/glucagon receptor agonist cotadutide and a phase 1 trial of Lilly’s GIP/GLP-1/glucagon receptor agonist. Combination agonists appear to be raising the bar for glycemic control and weight loss, with strong potential in NASH, as well. 

  • The highly anticipated SURPASS 3-CGM readout showed significant improvements in Time in Range for patients on tirzepatide vs. insulin degludec at one year. A greater proportion of patients on tirzepatide achieved consensus Time in Range targets; patients in the tirzepatide group also saw significant improvements in hypoglycemia. In addition to these exciting outcomes, we were pleased that the study included a pre-planned CGM analysis and we hope this will become more common going forwards with the validation of Time in Range and growing use of CGM in diabetes therapy clinical trials.
  • Tirzepatide continued to deliver strong results in the SURPASS-4 readout showing continued benefits in A1c and weight control for up to two years with a clean safety profile. We were especially intrigued by the 26% reduction in CV events at 104 weeks in the tirzepatide group. Though this risk reduction was not statistically significant, we’d argue that it lends further support to the early signs of CV benefit seen at 52 weeks in the initial SURPASS readout.
  • Rounding out the positive evidence for tirzepatide, a patient-reported outcomes analysis (SURPASS-5) found that the two higher doses (10mg and 15mg) led to substantial improvements in total treatment satisfaction. Specifically, patients on tirzepatide reported improvements in overall health status, self-perception of body weight, and ability to perform daily tasks relative to those on placebo.
  • Elsewhere in the field of combination agonists, we learned about AstraZeneca’s GLP-1/glucagon dual receptor agonist cotadutide as well as Lilly’s novel GIP/GLP-1/glucagon triple receptor agonist. In a phase 2a RCT, cotadutide exhibited significant glucose-lowering effects in patients with overweight and obesity and type 2 diabetes, while phase 1 data found robust weight loss with Lilly’s triple receptor agonist. Beyond weight loss, these combination agents appeared to reduce liver fat and may play a key role in NASH. While we’ll be very eager to see results from larger RCTs in both obesity and NASH going forwards, the obesity will come far sooner, and it’s the obesity CVOT, SELECT, that we’re most eager to see at this point. On NASH, we’re not even close to moving through a phase 3, so that’s in a very different spot.   

Evolving insulin: next-generation basal insulin, insulin co-formulation, once-weekly insulin, oral insulin, glucose-sensitive insulin, and beta-cell replacement

100 years after the discovery of insulin in 1921, it’s clear that there is tremendous insulin innovation. EASD 2021 featured several talks reflecting on the past and future of insulin therapy. We heard talks highlighting the benefits of recent insulin advancements (next-gen insulins and the insulin/lixisenatide co-formulation) and looking ahead to the potential of insulins in development (once-weekly insulin, oral insulin, and glucose-sensitive insulin) along with a further-down-the-road “cure” for people with diabetes (stem cell therapy).

  • Two talks emphasized the benefits of currently available, relatively new insulins: insulin/GLP-1 lixisenatide co-formulation (iGlarLixi) and next-generation insulins (insulin glargine 300 U/mL and insulin degludec). Dr. Julio Rosenstock (UT Southwestern) shared patient reported outcomes from the SoliMix trial of iGlarLixi (Sanofi’s Soliqua) versus premixed insulin. Patients on iGlarLixi reported reduced treatment burden and improved perception of treatment, while exhibiting improved A1c reduction, no weight gain, and reduced hypoglycemia risk. In a Sanofi-sponsored session, Dr. Alice Cheng (Trillium Health Partners, Toronto, Canada) reviewed the benefits of next-generation insulins over first-generation basal insulins. Broadly, next-generation insulins have similar A1c lowering benefits, but significantly reduced rates of hypoglycemia and nocturnal hypoglycemia, compared to older formulations.     
  • Looking ahead, a Novo Nordisk-sponsored session and a talk by Dr. Tina Vilsboll (Steno Diabetes Center, Denmark) highlighted the development of once-weekly insulin, oral insulin, glucose-sensitive insulin, and beta-cell replacement. In the Novo Nordisk-sponsored session, Dr. Ronald Goldenberg dove into once-weekly insulin icodec, the furthest once-weekly insulin in development, which is about to enter phase 3 trials with expected readouts in 2022. Both Dr. Goldenberg and Dr. Vilsboll touched on Lilly’s once-weekly insulin-FC (BIF) antibody currently in phase 2 trials and oral insulins (Biocon’s phase 2 insulin tregopil and Oramed’s phase 2 ORMD-0801), while briefly noting the potential of glucose-sensitive insulin and beta-cell replacement to dramatically change the diabetes landscape. 
  • In novel therapies, Dr. Gregory Meiffren (Adocia, Lyon, France) shared results of a study investigating an insulin/pramlintide co-formulation. We were excited to hear that this novel insulin/pramlintide co-formulation improved Time in Range along with body weight and prandial insulin dose reductions in people with type 1 diabetes compared to insulin aspart. These results complement a growing number of studies investigating amylin combination agents for obesity.

Weight management is the way forward: KOLs highlight semaglutide’s impressive weight loss effects, call for “weight-centric” approach to diabetes management

This year’s conference brought a lot of enthusiasm for semaglutide’s weight loss effects and its potential to transform clinical approaches to obesity and diabetes. Perhaps most excitingly, KOLs called for a shift from “gluco-centric” diabetes management to a more comprehensive strategy that prioritizes weight loss alongside glucose control and cardiovascular risk reduction. At diaTribe’s Solvable Problems in Obesity panel, we learned of another intriguing shift, this time in the obesity paradigm, which now focuses more on environmental and genetic causes of obesity.

  • While diabetes management has traditionally employed a “gluco-centric” approach, the field appears ripe for a shift to weight-centric management, particularly for patients with adiposity-related diabetes. Under such an approach, patients undergo anti-obesity pharmacotherapy, regardless of baseline A1c, with a target of 15% weight loss – a goal that is now achievable with oral semaglutide.
  • Beyond its impressive double-digit weight loss, we heard time and again that semaglutide supports lifestyle changes through appetite suppression. Given its impressive glucose and A1c lowering effects, KOLs recommended patient education on insulin dose reduction and even hinted that the GLP-1 may one day replace insulin for some patients. Overall, we were happy to hear KOLs advocate for the use of semaglutide as part of a four-part framework that also includes glucose control, CV risk reduction, and overall disease burden reduction.
  • Elsewhere in weight management, diaTribe’s Solvable Problems in Diabetes panel taught us that the obesity paradigm is also shifting rapidly, with greater emphasis on environmental and genetic causes of obesity. The panelists also asserted that obesity does not cause type 2 diabetes and highlighted that while the two conditions are strongly correlated, there are lots of other factors at work. We were also glad to hear discussion of mental health, with panelists acknowledging the role of stigma and stress in obesity. 

Precision medicine: going beyond one size fits all and bringing individualized care to patients with diabetes

Precision medicine was certainly a hot topic of conversation at this year’s conference, though it manifested in many different forms. One of the most widely accepted definitions of precision medicine is giving the right therapies to the right patients at the right time – every time. While no one necessarily argued that a one size fits all approach is the best way to treat diabetes, there were a range of perspectives about what the optimal approach to diabetes management may be. Specifically, positions ranged from genetic analysis of people to determine treatment based on biological pathways to population-level stratification of patients. It was interesting to hear precision medicine becoming a greater part of the conversation in presentations across the conference, even if it wasn’t explicitly named, with many providers thinking about assessing the root cause of a patient’s disease as part of the treatment. One prime example is Dr. Ildiko Lingvay’s presentation on a weight-centric approach to diabetes management, which argues patients with adiposity-related diabetes should be treated with first-line weight management medications, while patients with isolated hyperglycemia and diabetes with CVD utilize alternative first-line treatments that are gluco-centric and cardi0-centric, respectively. 

  • The results of the TriMaster study, the first dedicated precision medicine RCT, showed that eGFR and BMI accurately predict a differentiated drug response of DPP-4s, SGLT-2s, and TZDs. Despite the drugs showing overall similar glucose-lowering abilities across the entire cohort, certain drugs worked better in specific clinical strata of patients. Important to note, the study only utilized elements of routine clinical care to determine optimal treatment for patients making this a low-cost, achievable mechanism of attaining more personalized care, should providers choose to utilize it.
  • A lively debate between Professor Simon Griffin (University of Cambridge), Dr. Miriam Udler (MGH, Harvard), and Dr. John Dennis (University of Exeter) suggested that the field is still far from a consensus on the role of precision medicine in diabetes care. Dr. Miriam Udler (MGH, Harvard) offered very interesting data on the potential different genetic pathways that could cause diabetes, arguing that molecular-based precision medicine helps treat the cause of the disease rather than the symptoms. On the other hand, Dr. John Dennis (University of Exeter) and Professor Simon Griffin (University of Cambridge) argued that there are more cost-effective measures that can be utilized to achieve the best possible care. Dr. Dennis highlighted new research showing patients can be sorted to optimal treatment based on routinely measured clinical features, while Professor Griffin argued that there is no evidence precision medicine is more cost-effective than the current standards of care, and instead that resources should be devoted to population level interventions to address the diabetes epidemic.
  • In the 36th Annual Camillo Golgi Lecture, Dr. Hiddo Heerspink (University Medical Center Groningen, Netherlands) argued for greater use of precision medicine in patients with diabetic kidney disease. With a growing number of therapies now approved for the treatment of DKD, including ACEs, ARBs, SGLT-2s, and finerenone, Dr. Heerspink advocated for personalized medicine and combination therapy to maximize a patient’s response and improve outcomes for DKD. Of note, Dr. Heerspink said that as a field, we do a “poor job” identifying and distinguishing “non-responders” from “responders” and that it’s the clinicians’ “duty and responsibility to find the optimal combination of drugs for each patient.”

Diabetes Technology

Bounty of real-world evidence on AID systems focuses on two systems that launched in last year in Europe (MiniMed 780G and Diabeloop/Roche/Dexcom)

In our EASD 2020 report, we said that the bounty of real-world evidence on AID systems presented at the 2020 sessions was the sign of a maturing AID field. This year’s EASD sessions were certainly a confirmation of that signal, as they focused heavily on real-world AID system data in a combination of large and small datasets. The real-world data focused on the two AID systems that launched most recently in Europe: MiniMed 780G (launched in Europe in October 2020) and the Diabeloop DBLG1/Roche Accu-Chek Insulin pump/Dexcom G6 AID system (launched in Europe in March). With Omnipod 5, Tidepool Loop, MiniMed 780G, and Tandem’s smartphone bolus control function all awaiting FDA clearance, we hope that ATTD 2022 (in Paris, France on March 8-11, 2022) will see an even greater variety of real-world AID studies with a mixture of methodologies and systems studied.

  • Much of the real-world AID data presented at EASD 2021 focused on MiniMed 780G. In a Medtronic-sponsored symposium, Professor Ohad Cohen (Medtronic Diabetes) presented data from three real-world MiniMed 780G studies, including a large cohort (n=12,870) that achieved 76% Time in Range  and a 6.8% GMI on the system. He also presented a real-world crossover study (n=2,977 crossover between closed-loop and open-loop), demonstrating that users who initiate MiniMed 780G witness a +11.4% improvement (+2.7 hours/day) in Time in Range. The final readout of the session was a longitudinal cohort study (n=2,566) showing that the glycemic improvements are observed in the first month after initiating MiniMed 780G and sustained over six months. Elsewhere at EASD 2021, Dr. Pilar Beato-Víbora (Badajoz University Hospital) presented real-world data (n=52) showing that participants saw a +13% Time in Range improvement to 80% after three months on MiniMed 780G, as well as a 0.5% A1c reduction to 6.7% and improved quality of life outcomes. It was hugely exciting to see this bounty of real-world data for 780G less than a year after the system launched in Europe.
  • We also got our first look at data on the Diabeloop DBLG1/Roche Accu-Chek Insulin pump/Dexcom G6 AID system. As background, the partnership between these three companies was announced in December 2020, and the combined system launched in March. During a Diabeloop-sponsored session at EASD 2021, Professor Pierre-Yves Benhamou (Centre Hospitalier Universitaire de Grenoble) read out real-world data from Germany (n=998) showing that participants spent an average of 73% of Time in Range, only 1% of time <70 mg/dl, and almost no time <54 mg/dl (0.1%). In the same session, Drs. Chico and Corcoy Pla shared real-world DBLG1 data from a small cohort (n=26) in Barcelona, Spain that found a +3.6 hour/day improvement in Time in Range to 77% after one month of use.
  • Elsewhere in insulin delivery, we saw real-world data on Omnipod DASH. While not exactly real-world AID system data, the Omnipod DASH data was nevertheless impressive. The retrospective real-world study, which built on preliminary analysis read out at ATTD 2021, included a record sample of 3,341 adults and 1,397 children with type 1 diabetes and found a 0.9% A1c reduction during the first 90 days of Omnipod DASH use.

Increasing use of Time in Range and other CGM-derived metrics in analysis of new therapies

EASD 2021 saw several studies utilizing CGM-derived metrics and Time in Range to assess new therapies. For us, these studies were hugely exciting not only because they showed that the new therapies lead to strong CGM-based outcomes, but also because the use of Time in Range and other CGM-derived metrics is a sign of the broadening acceptance of CGM and CGM-derived metrics – if not plans, yet, for widespread use outside of wealthy countries. These studies’ use of CGM and Time in Range builds upon those that used CGM and were read out at ADA 2021, including a study on Time in Range benefits with cotadutide, Lilly’s once-weekly basal insulin-FC, and glucagon receptor agonist antibody Volagidemab (REMD-477).We hope that this will become increasingly common with the validation of Time in Range and increasing use of CGM. The use of CGM-derived metrics in therapeutic analyses follows increased advocacy for the use of Time in Range and CGM-derived metrics as research outcomes. In his ATTD 2020 presentation, Dr. Roy Beck argued that the growing validation of Time in Range’s correlation with long-term outcomes is a compelling case for the use of TIR and CGM measurements as meaningful endpoints in clinical trials. Later in September at EASD 2020, Dr. Rich Bergenstal argued that CGM-derived metrics like Time in Range could be much more powerful in evaluating various therapies and intervention strategies, rather than relying exclusively on topline A1c results. These studies certainly back up this claim, as the use of CGM-derived metrics makes clear the strong advantage of certain treatments in improving glycemic control beyond A1c.

  • A major highlight of EASD 2021 was the readout of SURPASS-3 CGM, a prespecified CGM analysis from SURPASS-3. Read out by Dr. Tadej Battelino, the data found that type 2s (n=243) spent 3.8 more hours/day in Range on tirzepatide (10 mg or 15 mg) relative to insulin degludec at one year (91% vs. 75%, respectively). Likewise, while 90% of those on tirzepatide achieved TIR/TAR/TBR targets, only 45% in the insulin degludec arm achieved these consensus goals. These data show additional benefits on top of the 2.4% relative A1c improvement previously published and showcase the holistic glycemic benefit of tirzepatide.
  • EASD 2021 also saw post-hoc CGM data on once-weekly insulin icodec. Two posters compared once-weekly insulin icodec vs. once-daily insulin glargine U100 (Gla-100) in insulin-naïve patients with type 2 diabetes (SO 508) and in people with type 2 diabetes on basal insulin at baseline (SO 509). The studies found that once-weekly insulin icodec was noninferior to once-daily insulin glargine U100 in insulin-naïve people with type 2 diabetes (n=205) and in insulin-treated people with type 2 diabetes (n=154). Furthermore, the study that included participants switching from a once-daily insulin to once-weekly insulin icodec found that an initial increase in the dose (a loading dose) was essential to seeing short-term and long-term improvements in Time in Range and to avoiding an initial increase in time above range with the initiation of insulin icodec. Without CGM-based analysis, this short-term rise in hyperglycemia seen without the loading dose would not have been observed, furthering the value of this post-hoc CGM analysis.
  • Another analysis utilized fingerstick-derived Time in Range in a post-hoc analysis of the SUSTAIN trials. Read out by Dr. Vanita Aroda (Brigham and Women’s Hospital), the pooled analysis from SUSTAIN 2-4, 7, 8, and 10 (n=5,680) found that semaglutide saw impressive improvement in fingerstick-derived Time in Range relative to active comparators. Specifically, by the end of the trials, fingerstick-derived Time in Range had increased to 74%-83% for the comparator groups and 76%-91% for semaglutide. Notably, the increase in dTIR was statistically greater for semaglutide 1.0 mg compared to every active comparator except insulin glargine in the SUSTAIN 4 trial, where it was only marginally greater. While CGM-derived Time in Range is preferrable, we are thrilled to see the expanding use of Time in Range, even when utilizing BGM-derived values.
  • More broadly, EASD 2021 saw a greater focus on the integration of diabetes technology and diabetes therapy. Sanofi in particular has given a great deal of attention to the intersection of diabetes technology and diabetes therapy in recent scientific meetings. Its EASD 2021 session on CGM, Time in Range, and holistic views of diabetes control follows similarly tech- and Time in Range-focused Sanofi-sponsored sessions at EASD 2020 and ISPAD 2020 and was followed by a Sanofi-sponsored session at ISPAD 2021 on the relationship between Time in Range and diabetes distress. We look forward to further efforts to integrate learnings across diabetes technology and therapy and further investment in leveraging diabetes technology to make treatment decisions, and we applaud Sanofi for its investment in this work.

Decision support and smart insulin pens: growing emphasis on providing connected care solutions for patients on MDI

Connected care solutions for patients on MDI continues to be an emerging topic in diabetes technology and EASD 2021 was no exception. We saw new data on Medtronic’s InPen and the association between the frequency of on-time meal boluses and increased Time in Range. We also learned more about Lilly’s connected Tempo Smart Button, which the company expects to receive CE-Mark “later in 2021” and heard from leading KOLs Drs. Moshe Phillip (Schneider Children’s Medical Center of Israel) and Tadej Battelino (University Medical Center Ljubljana) who discussed the future of connected care and decision support for MDI users highlighting DreaMed’s Advisor Pro decision support software for MDI users building on initial data read out at ATTD 2021. While we are excited about the potential of connected solutions and smart pens for patients on MDI, as we saw at ADA 2020, even with smart pen technology, MDI therapy is extremely challenging (to get to numbers that are satisfying, to avoid hypoglycemia and associated hyperglycemic swings) a MDI users continue to see lower Time in Range values than those on AID systems raising the question of what else is necessary to support patients using insulin injections (here, we think of things we’ve heard in the past – “Avoid having poor parents, being poor, going to a poor doctor…”).

  • Drs. Moshe Phillip and Tadej Battelino discussed the future of diabetes technology emphasizing the importance of insulin dosing support for patients on MDI. Specifically, Drs. Phillip and Battelino provided an overview of data from the AdvisorPro insulin dosing decision support software for MDI users which indicated that insulin regimen changes recommended by the AdvisorPro system were non-inferior to those from expert providers (ATTD 2021). Given these results, Dr. Phillip argued that decision support tools like AdvisorPro are a “genie in the pocket” and could dramatically alter how providers, especially those in primary care or those who are less familiar with insulin therapy, help patients manage their diabetes. Additionally, for patients using smart insulin pens in combination with CGMs, Dr. Battelino emphasized the power of technology to give patients actionable information in real-time. Specifically, Dr. Battelino shared his view that the past can’t be changed and thus diabetes data should be used to support and encourage behavior change and therapy modification for patients moving forward to drive sustainable improvements in glycemic control.
  • Dr. Robert Vigersky (CMO, Medtronic Diabetes) shared new data from InPen users demonstrating a relationship between the frequency of on-time insulin meal boluses and Time in Range. Data from 1.2 million meals across 257,177 patient days from InPen users also on CGM were analyzed and found that increased frequency on-time boluses (up to 30 minutes ahead of meal or within 15 minutes after a meal) was significantly associated with higher Time in Range (p<o.oo1, r=0.59). However, of the 1.2 million meals analyzed in this study, only 56% had on-time meal boluses suggesting that patients in this population were unlikely to be achieving the International Consensus Clinical Targets for Time in Range goal of 70% time between 70 mg/dl – 180 mg/dl. Given this data, it is clear to us that there is still more than can be done to leverage technology to help improve outcomes for patients on MDI and we are excited to follow Medtronic’s progress in this arena building on integrations between Guardian 4 and InPen to “close the loop” for patients on MDI with nutritional and meal identification software Nutrino and Klue. We’re very intrigued about this although we are also aware that we have said this for multiple years.
  • Lilly is entering the smart insulin pen arena with its Tempo Smart Button compatible with Tempo insulin pens. Lilly’s Tempo insulin pens build on the company’s existing KwikPen infrastructure and maintain the same form factor, but when paired with a Tempo button can automatically store and transmit data to compatible apps on insulin dose amount, timing, and type of insulin. To date, Lilly has data partnerships with Roche, Glooko, myDiabby, and Dexcom allowing patients to view their Tempo data across a range of platforms. Though Lilly’s Tempo Smart Button is not yet available, the company expects it to receive CE-Marking “later this year” and when the system launches it will join NovoNordisk’s NovoPen6 and NovoPen Echo Plus as a smart insulin pen system from the major insulin developers. We are encouraged to see Lilly taking such a significant step in supporting patients on MDI using Lilly insulins and we look forward to seeing real-world data on the Tempo Smart Button system following its launch.

Big Picture

An abundance of new data highlights the connection between diabetes and severe COVID-19 outcomes

The relationship between COVID-19 and diabetes left a lasting impression on us following several informative sessions at EASD. Most notably, it became clear that patients with diabetes are at higher risk for severe COVID-19 cases. The increased risk was particularly prominent in older patients with type 1 diabetes, as well as patients with comorbidities, including higher glucose levels, higher A1c, more hypoglycemia, and older age. There was also much discussion about how the pandemic has interrupted the management of diabetes even in patients who haven’t been diagnosed with COVID-19. Moreover, several providers expressed dismay at the lifestyle changes resulting from the pandemic, including a more sedentary lifestyle and increased weight gain, which they fear will lead to increased rates of obesity and diabetes in the near future.

  • Professor Naveed Sattar (University of Glasgow) attributed the increased risk of severe COVID-19 in older patients with type 1 diabetes to prolonged exposure to hyperglycemia. He noted that this difference is in stark contrast to younger patients with type 1 diabetes (<40 years) who have virtually no increased risk of severe COVID-19. He argued that while the compounding effects of hyperglycemia could lead to vascular damage which contributes to COVID-19 disease course, at this point it is still unclear whether hyperglycemia per se is causing severe COVID or whether it is simply a marker associated with severity. He also argued that exposure to diabetes risk via complications leads to more severe COVID-19. Patients with prior DKA, hypoglycemia, and micro and macrovascular complications all had significantly greater rates of hospitalization and death.
  • Dr. Gillian Booth (St. Michael’s Hospital, Toronto) reviewed a new meta-analysis which found that older age, higher A1c, and other comorbidities are associated with worse COVID-19 outcomes in patients with diabetes. Like Professor Sattar, Dr. Booth noted that certain patient characteristics, such as those mentioned above, are associated with greater disease severity.  In the analysis of more than 300 studies, Dr. Booth found a 59% greater risk for severe COVID in patients with diabetes. Notably, thanks to the breadth of the analysis, Dr. Booth was able to show this increased risk was relatively stable across many different IDF world regions.
  • Interestingly, a meta-analysis showed that patients with type 1 diabetes actually saw a slight improvement in glycemic control in the pandemic lockdown. More than 72% of patients in the pooled analysis saw significant improvements in glycemic outcomes, spending an additional 54 minutes per day in range, on average. Unfortunately, according to the meta-analysis patients with type 2 diabetes actually fared worse during the lock down, with more than 50% of patients reporting a deterioration in their A1c and time in range. This is in contrast to another presentation by Ms. Lisa Ludwig (ILCV Lorraine University, France), whose presentation of the CONFI-DIAB study showed that patients with type 1 and type 2 diabetes both saw improvements in their glucose control.
  • Diabetes management was severely disrupted due to the COVID-19 pandemic. Ms. Ludwig noted that of the 870 patients in her study, more than 49% did not consult their general practitioner and 92% did not consult their diabetologist during lockdown. Professor Kamlesh Khunti (Leicester Diabetes Centre, UK) described several clinical considerations in addressing these disruptions. In particular, he advocated for the continuation of glucose-lowering medications following COVID-19 infection, as well as the need to “make up for lost time” by identifying which patients have fallen the furthest behind due to the pandemic. Professor Khunti also advocated for more resources devoted to mental health in patients with diabetes following the pandemic. 

ADA/EASD 2021 Consensus Report on the Management of Type 1 Diabetes in Adults: guidelines span diagnosis to future of diabetes management with emphasis on patient-centered care

EASD 2021 marked the official publication of the 2021 ADA/EASD Consensus Report on the Management of Type 1 Diabetes in Adults in Diabetes Care and Diabetologia. A draft of the report was initially presented at ADA 2021, which was then available for ten days of public comment before feedback was integrated into the final, and now published, report. The report is designed to provide physicians and other healthcare providers with essential information on type 1 diabetes care from diagnosis to management similarly to the landmark 2018 ADA/EASD consensus report on type 2 diabetes management. Though the final draft of the report presented at EASD 2021 was similar to the draft from ADA 2021, all feedback from the comment period was integrated and largely related to “clarifying the wording of certain sections.” We are encouraged to see such robust guidelines for type 1 diabetes management especially related to increased use of adjunctive therapies in type 1 management and are hopeful that these guidelines can have a meaningful impact on clinical practice for providers to help patients see improved glycemic control and reduced diabetes burden. First things first, the guidelines have to impact choices and care – for now, as one example, there aren’t really any adjunctive therapies that have been approved and are widely available, but we certainly hope this changes in the future. We expect to see SGLT-2 tested for T1D, and would hope that a CKM (continuous ketone monitor) becomes available to wear alongside for safety.

  • Sections of the final report include a dozen different areas: (i) type 1 diabetes diagnosis; (ii) schedule of care and therapy initiation; (iii) diabetes self-management education; (iv) glucose monitoring; (v) insulin therapy; (vi) hypoglycemia management and prevention; (vii) psychosocial care; (viii) DKA management and prevention; (ix) pancreatic and islet cell transplantation; (x) adjunctive therapies; (xi) special populations with type 1 diabetes; (xi) emergent and future perspectives on type 1 diabetes management; and (xii) key knowledge gaps in the field. Across these subsections, the report maintained a strong emphasis on behavioral, psychosocial, and mental health components of diabetes management advocating for patient-centered care.

Emphasis on reducing diabetes distress and improving psychosocial outcomes; faculty call for greater integration of PROs into therapy evaluation and clinical practice

Throughout EASD 2021, presenters and faculty made a point to highlight the importance of addressing diabetes distress and patient reported outcomes as key components of diabetes management. This theme was apparent as early as Day #1 when Dr. Rich Bergenstal (International Diabetes Center) called for diabetes distress scores to be integrated with CGM and other diabetes-related data to create a broader definition of diabetes control. We also attended a number of sessions with new data on patient-reported outcomes (PROs)associated with the use of diabetes technology including insulin pumps, digital health, and CGMs. Additionally, psychosocial care held a prominent position in the published ADA/EASD Consensus Report on the management of type 1 diabetes recognizing the significant impact diabetes can have on patient’s mental well-being. We certainly appreciate this focus and are excited to see how clinicians and researchers continue to integrate PROs into the validation of devices and therapies.

  • Dr. Bergenstal argued in favor of a greater emphasis on diabetes distress in clinical practice building on data demonstrating a relationship between diabetes distress and glycemic control. Specifically, Dr. Bergenstal highlighted data published in Diabetic Medicine in July, which found that higher diabetes distress scores among young adults with type 1 diabetes (n=423) were associated with a significant 1% increase in A1c values compared to young adults not demonstrating signs of diabetes distress. While technology use was associated with lower A1c values among the study population, Dr. Bergenstal pointed out that while technology was beneficial, the largest indicator of reduced A1c was reduced diabetes distress, highlighting the importance of prioritizing diabetes distress management and behavioral health among patients. Given this data, Dr. Bergenstal called for an integration of diabetes distress scores into patient AGP reports. While we think this is a novel perspective, and could certainly have meaningful clinical implications for providers who would be able to see more of a patient’s diabetes-related data in a single location, we are curious how this integration might come about as diabetes distress is not a metric measured (at present) via CGM like the other components of current AGP reports. Excitingly, as we learned in a separate conversation with Dr. Bergenstal, the IDC is already considering ways to achieve this integration by leveraging its EHR and LibreView integration.
  • The ADA/EASD 2021 consensus report on the management of type 1 diabetes includes a section dedicated to psychosocial care. In this section, the authors emphasize that psychosocial care should be an integral and consistent component of diabetes care and that providers should periodically evaluate and discuss “psychosocial health and barriers to self-management” with their patients. Dr. Richard Holt, one of the panel co-chairs, shared his perspective on the report stating “one of the strengths of this report is that we have paid particular attention to the psychological and social aspects of diabetes and the needs for us to incorporate psychosocial care and support within the holistic management of type 1 diabetes.”
  • We learned about new data on patient-reported outcomes (PROs) from patients using diabetes technology demonstrating an overall improvement in PROs and quality of life associated with diabetes technology use. Specifically, PRO data from Roche’s Accu-Chek Solo Micropump found that patients on the micropump system experienced reduced diabetes burden compared to prior MDI use. We also heard from Dr. Ramzi Ajjan (University of Leeds, UK) during an Abbott-sponsored symposium about the importance of putting positive PROs front and center when evaluating technology alongside data on glycemic improvements and cost-savings. That said, we also understand that diabetes technology can also generate a sometimes-overwhelming quantity of data which could actually increase stress and diabetes distress among some patients. To mitigate this, Dr. Linda Gonder-Frederick (University of Virginia) discussed the importance of applying the right technology to meet patient-specific needs, which she argued has the greatest potential to significantly improve psychosocial outcomes including diabetes distress. We certainly agree with this sentiment and see technologies as a key way to help reduce diabetes distress for some patients.

EASD 2021’s program devoted lots of space to discussions about foot care in diabetes. This area has drawn a lot of interest from speakers at recent conferences, especially at ADCES 2021 where Dr. Gary Rothenberg (University of Michigan) talked about his experiences triaging patients virtually during the pandemic and developing the Podimetrics in-home telemedicine system that can remotely monitor and analyze temperature asymmetries in the foot with a wireless “SmartMat.” Much like Dr. Rothenberg, speakers at EASD called for increased prevention strategies for diabetes-related foot ulcer recurrence, and mused on cost considerations, incidence levels, and concerning statistics about the scope of the issue at hand.

  • Across multiple presentations, some salient statistics emerged, chief among them that every 30 seconds, worldwide, a limb is lost to diabetes. Concerningly, people with diabetes are 10-20 times more likely to experience an amputation compared to people without diabetes. In a session overviewing different perspectives on the diabetic foot syndrome, various speakers stressed the high prevalence of diabetic foot ulcers, with an estimated one in seven people with diabetes developing a foot ulcer at some point in their lifetime.
  • As for how diabetic foot care evolved during the pandemic, we learned that HCPs “turned a problem into an opportunity.” Speakers during a Tuesday symposium on diabetic foot syndrome emphasized the growing role of telemedicine in managing and triaging patients, ensuring that those at high risk for developing an ulcer can be redirected into the clinic while those at lower risk can be managed using telemedicine.
  • We’ve heard a lot in the past about preventing diabetic foot ulcers, but at EASD 2021 we got some details behind its potential cost savings. Dr. Jaap van Netten, PhD (Academic Medical Center, Amsterdam) emphasized the cost-effectiveness of at-home temperature monitoring as evidenced from the DIATEMP study. In a poster presented at ADA 2021, Dr. van Netten and his colleagues showed that use of preventative temperature-monitoring led to significantly decreased foot care costs compared to standard treatment (p=0.033). However, given that the daily burden of temperature monitoring might lead to a decrease in quality of life, Dr. van Netten called for providers to carefully consider before prescribing this intervention to patients.
  • We saw data about the incidence of diabetic foot ulcers in Spanish primary care centers. Dr. Judit Llussà Arboix (Primary Health Care Center Sant Roc, Badalona, Spain) presented data from an observational prospective study (n=256) assessing the incidence of diabetic foot ulcers in primary care centers. This first-of-its-kind study estimated the incidence of new diabetic foot ulcers at 0.42% in Catalonia, Spain, and common risk factors included hypertension (81%), hyperlipidemia (69%), and obesity (43%). Given that 80% of diabetes related amputations are preceded by ulceration, Dr. Arboix stressed the importance of primary care to provide: (i) early diagnosis of ulcers through careful evaluation; (ii) personalized treatment to prevent ulcer progression; and (iii) referral to specialists who can “save legs, and lives.”

Insulin Delivery Highlights

Three MiniMed 780G real-world studies: Large cohort (n=12,870) achieves 76% Time in Range, 6.8% GMI; crossover study (n=2,977) boasts +11% Time in Range (+2.7 hrs/day) with one fewer bolus per day; longitudinal cohort (n=2,566) sustains glycemic improvements over six months

Professor Ohad Cohen (Medtronic Diabetes) presented three illuminating real-world studies from MiniMed 780G users and explained how to use these data to optimize glycemic outcomes. As a reminder, Prof. Cohen gave us our first look at real-world data (n=4,120) from MiniMed 780G users at ATTD 2021 after the system’s OUS launch in October 2020 and CE-Marking in June 2020. In the US, MiniMed 780G is still “under active review” with the FDA after being submitted in February, and Medtronic said that “things [were] on track” despite neglecting to commit to a specific timeline during its 2Q21 update. During today’s session, Prof. Cohen overviewed three separate cohorts whose data were gathered across 16 countries, including the UK, Netherlands, Italy, Belgium, Sweden, Switzerland, Finland, Czech Republic, Poland, South Africa, Ireland, Turkey, Iceland, Greece, Slovakia, and Slovenia.

  • Turning to the first study, Prof. Cohen shared data from 12,870 MiniMed 780G users, who achieved a 76% Time in Range and 6.8% GMI. Referring to the results as “striking,” Prof. Cohen explained that 76% of users achieved a GMI <7%, 76% achieved a Time in Range >70%, and 82% saw a Time Below Range (<70 mg/dl) <4%. Putting these together, 72% of participants achieved both a TIR >70% and a GMI <7%, and 58% managed to secure all three: GMI <7%, Time in Range >70%, and Time Below Range (<70 mg/dl) <4%. Although this is hugely impressive, we would have loved to see baseline data, although we understand that this was not available.
    • In another notable update, Prof. Cohen broke down the participants by country of residence, and showed that glycemic profiles were roughly stable across all geographies, while also commenting that he has a slight theory for why there were subtle differences between some regions (he didn’t share why, and we remain curious!).
    • Prof. Cohen then dove into an analysis of system settings as predictors of Time in Range quartiles (1st quartile ≤70.3%, 2nd quartile (70.3-76.5]%, 3rd quartile (76.5-82.3]%, 4th quartile >82.3%), in which he noted that those with a lower active insulin time (2 hours) and low glucose target (100 mg/dl) are overrepresented in higher quartiles of Time in Range post-780G. We found this to be most interesting, and a nice follow-up from earlier this year at ATTD 2021, when we learned that participants in the first MiniMed 780G real-world study spent approximately half their time at the most aggressive glucose setting of 100 mg/dl and that the most popular active insulin time setting was 2.5-3 hours, the second most aggressive setting. Prof. Cohen explained that those who used these “optimal system settings” (i.e., the most aggressive ones) in this cohort achieved an 81% Time in Range (+5%, or +1.2 hours/day compared to the whole cohort) and 6.6% GMI.

 

MiniMed 780G (n=12,870)

Time in Auto Mode

92%

Mean Sensor Glucose

145 mg/dl

GMI

6.8%

Time in Range

76%

Time <70 mg/dl

2.5%

Time <54 mg/dl

0.6%

Time >180 mg/dl

22%

Time >250 mg/dl

4.5%

  • Prof. Cohen then presented a second real-world crossover study (n=2,977 crossover between closed-loop and open-loop), demonstrating that users who initiate MiniMed 780G witness a +11.4% improvement (+2.7 hours/day) in Time in Range. At baseline, 41% of participants achieved a GMI <7% and 36% achieved a Time in Range >70%, which improved to 75% achieving a GMI <7% and 75% achieving a Time in Range >70% after MiniMed 780G initiation. Turning to the topic of user interventions, Prof. Cohen explained that the number of average daily manual boluses per participant in the cohort decreased by one, which he referred to as a “clinically and statistically significant” result (p<0.0001). Furthermore, the cohort’s total daily dose of insulin increased by four units per day, and users received a greater percentage of their TDD from the system, up from 46% to 56%. As Prof. Cohen put it, with more automation by the system producing demonstrably better glycemic control, it is clear that future AID systems like MiniMed 780G will enable users to feel less burdened by their daily self-management and use less insulin to achieve better results. We certainly hope his vision becomes a reality, although we know that many still struggle to initiate AID use and that there are many people with diabetes for whom AID might not be the right choice.

 

Pre-MiniMed 780G (n=2,977)

Post-MiniMed 780G (n=2,977)

Change

Time in Auto Mode

-

93%

-

Mean Sensor Glucose (mg/dL)

161

146

-15

GMI

7.2%

6.8%

-0.4%

Time in Range

64%

76%

+11.4%

Time <70 mg/dl

2.7%

2.3%

-0.4%

Time <54 mg/dl

0.6%

0.5%

-0.1%

Time >180 mg/dl

33%

22%

-11%

Time >250 mg/dl

8.2%

4.3%

-3.9%

Manual boluses

6.0

5.0

-1.0

Total Daily Dose (u)

38

42

+4

  • In his final remarks of the day, Prof. Cohen shared data from a longitudinal cohort (n=2,566) showing that the glycemic improvements are observed in the first month after initiating MiniMed 780G and sustained over six months. We are certainly encouraged by these results, as they show that the real-world improvements seen by the other two cohort studies are, as Prof. Cohen put it, “sustainable” so long as individuals diligently use their systems and initiate boluses appropriately. On this last point, Prof. Cohen shared a graph showing that a higher number of boluses is associated with higher Time in Range, although this correlation dissipates around five or six boluses after which the graph (see below) plateaus.

 

Month 1 (n=2,566)

Month  2 (n=2,566)

 Month 3 (n=2,566)

Month  4 (n=2,566)

Month 5 (n=2,566)

Month 6 (n=2,566)

Time in Auto Mode

95%

95%

95%

95%

94%

94%

Mean Sensor Glucose (mg/dL)

143

143

143

143

144

144

GMI

6.7%

6.7%

6.7%

6.7%

6.7%

6.8%

Time in Range

77%

77%

77%

77%

77%

76%

Time <70 mg/dl

2.5%

2.4%

2.4%

2.4%

2.5%

2.4%

Time <54 mg/dl

0.5%

0.5%

0.5%

0.5%

0.5%

0.5%

Time >180 mg/dl

20%

20%

20%

21%

21%

21%

Time >250 mg/dl

3.8%

3.9%

3.9%

4.0%

4.1%

4.3%

Nine-month extension of Omnipod 5 pivotal finds that pivotal A1c and Time in Range improvements are sustained out to twelve months: Adults/adolescents spent +2.3 hours/day in Range (73%) and children spent +3.5 hours/day in Range (67%) compared to baseline; plus, Insulet business and pipeline updates

In a hugely exciting short oral presentation, Dr. Anders Carlson (International Diabetes Center) presented nine-month extension phase data from the Omnipod 5 pivotal study (SO 561), which was read out at ENDO 2021 in March and published in Diabetes Care in June. As a reminder, the three-month pivotal single-arm trials included 128 adolescents/adults (ages 14-70) and 112 children (ages 6-13) and relative to baseline, saw a 2.2 hour/day improvement in Time in Range to 74% among adults and adolescents and a 3.7 hour/day improvement in Time in Range to 68% among children. Nearly all (95%) of the pivotal participants continued through the first nine months of the extension phase (n=108/110 children (ages 6-13) and 99/114 adults (ages 14-70)). All participants had had type 1 diabetes for ≥six months, had a baseline A1c <10%, and had prior insulin therapy experience (pump or MDI; 12% of children and 17% of adults on MDI at baseline). Notably, an additional three months of data will be collected, bringing the extension phase to a full year – we appreciate the attention to durability of use by Insulet; this is so important.

  • A1c improvements seen after the three-month pivotal were sustained out to twelve months in both the adult/adolescent and the child cohorts. Adults and adolescents saw a significant 0.4% A1c reduction from 7.2% at baseline to 6.8% at 12 months, flat with the improvement seen after the three-month pivotal. The three-month pivotal improvement seen among children was also sustained out to twelve months with children’s average A1c falling 0.7% from 7.7% at baseline to 7% at 12 months. At twelve months, 44% of children and 58% of adults and adolescents achieved an A1c <7%, up from only 23% and 42% at baseline. Based on the data presented in the poster’s associated abstract, these twelve-month figures are down from those at three months, when 53% of children and 65% of adults/adolescents achieved an A1c <7%, and at six months, when 54% of children and 73% of adults/adolescents achieved an A1c <7%. This might suggest that a portion of participants’ A1c improvements were not sustained out to 12 months - this was not discussed in the abstract or poster or by Dr. Carlson. We look forward to following up on this to better understand what prompted the original better results and the slightly worse final 12-month results.

Table 1: Insulet - pivotable trial A1c summary – HORIZON (2020 – 2021)

 

Children

Teens/Adults

0 Months [Baseline]

7.7%

7.2%

3 Months

7.0%

6.8%

6 Months

6.9%

6.7%

9 Months

7.0%

6.7%

12 Months

7.0%

6.8%

Table 2: Insulet - pivotable trial Time in Range summary – HORIZON (2020 – 2021)

 

Children

Teens/Adults

0 Months [Baseline]

52%

64%

3 Months

68%

74%

6 Months

67%

73%

9 Months

67%

73%

12 Months

67%

73%

  • Similarly, Time in Range improvements were sustained across the twelve-month period. Adults and adolescents saw a 2.3 hour/day improvement in Time in Range from 64% at baseline to 73% at twelve months. Children saw an even greater improvement in Time in Range, which increased 3.5 hours/day from 53% at baseline to 67% at twelve months. For both adults and children, the twelve-month improvement was statistically equivalent to that of the three-month pivotal trial.

  • Among adults and adolescents, the 0.7% reduction in time in hypoglycemia that was seen in the pivotal was maintained out to twelve months (fell from 2.1% at baseline to 1.1% at 12 months). Although it’s notable that the adults and adolescents were already doing so well coming into the trial – just 2.1% time < 70 mg/dL or roughly three and a half hours a week. In children, surprisingly, there was no significant difference in time in hypoglycemia after the pivotal or at any three-month assessment in the extension phase, but rates of hypoglycemia were consistently low at all time points (1.3 - 1.5%). During the extension phase, there was one case of treatment-related DKA, which was associated with a suspected infusion set failure and no cases of severe hypoglycemia.

  • Dr. Carlson argued that the findings are particularly impressive given that the study population was already well-managed at baseline. The adolescent and adult cohort had a baseline A1c of 7.2% and spent 64% of Time in Range at baseline. Children had a baseline A1c and Time in Range of 7.7% and 52%, respectively. The pivotal results suggested that those with higher baseline A1c values saw even greater improvements, and we wonder if this trend held out to 12 months. Dr. Carlson also noted that the extension phase was “more hands-off” than the three-month pivotal, which makes the sustained A1c and Time in Range improvements even more significant – we were happy to hear this.
  • In Q&A with session chair Prof. Roman Hovorka (Cambridge, UK), Dr. Carlson shared that time in closed loop remained “fairly consistent” during the extension phase as compared to the three-month pivotal. While he didn’t share specific data, he noted that nearly everyone who continued into the extension phase had a high percentage of time in closed loop. As a reminder, during the pivotal trial, participants spent 95% of time in closed loop; if this impressive level of time in closed loop was continued out to a year, this would be very positive. As closed loop systems become more reliable, we expect that time in closed loop will continue to increase – as a reminder, patients have no reason not to be extremely motivated to have a very high “time in closed loop,” as generally speaking, life is much harder without it! Still, the metric is particularly important to track comparisons to systems on at least a high level; looking back, studies like that of Lal et al. have seen stark drop-offs in long-term time in closed loop. In that trial, for example, “time in closed loop” dropped from 74% one week after starting on MiniMed 670G to 35% after one year on the system (Lal et al. 2019) – this likely reflected both some lack of reliability with the system as well as lack of accuracy that impacted motivation and interest in being on the system.
  • During Q&A, Prof. Hovorka had a different take on the results, noting that to characterize them as improvements reflecting the Omnipod 5 system wasn’t apt. In fact, throughout the session, he relayed his conviction that without randomization and control comparison, a study cannot officially support an intervention’s benefits or improvements. He posited that because the Omnipod pivotal trials (and the extension phase) were single-arm studies without comparison groups, presenting these data as improvements [due to Omnipod 5] “is misleading and not justified.” Dr. Carlson acknowledged the critique’s validity, noting that an RCT would offer more robust data, and also argued that given the durability of the results beyond the three-month pivotal data, the results support the strength of the Omnipod 5 system. This conversation became even more interesting as the time of the short oral continued; during his review of the Omnipod 5 pivotal study, Dr. Gregory Forlenza (Barbara Davis Center) noted that creating control groups for AID system studies is becoming increasingly difficult as more patients initiate AID use. He shared that at Barbara Davis, a third to half of patients are on AID systems, making it challenging to find patients that are interested in participating in a trial and willing to be on sensor-augmented pump therapy rather than an AID system: “We’re getting to the point where everyone who would want to do a study is on HCL (hybrid closed loop).”
    • This is not a complication we have been thinking about readily; of course, the patients in these systems are very fortunate and one wouldn’t need to go far to find other people with diabetes who would love to have this problem. Of course, in the race to the top, time needed for trial enrollment is a very big deal and delays are generally to be avoided at virtually any cost.
  • Per Insulet’s 2Q21 call in August, Omnipod 5 is slated for FDA clearance and a limited launch “later in Q4.” This delay is expected and due to FDA feedback on smartphone control (Tandem received similar feedback). Given the quick turnaround timeline between expected clearance and expected launch, Insulet appears to be highly prepared for the eventual launch, suggesting that it may be able to ramp up the launch more quickly ahead of the “later in 2022” goal for the full launch - of course, there’s many factors that will impact that, and CEO Shacey Petrovic made no promises on that front given that the limited launch can be a learning opportunity. Given this impressive extension phase data, we look forward to seeing the Omnipod 5 system in action in the real world though don’t have any assumptions when that will be the case.
  • During Day #1’s Insulet-sponsored session, CMO Dr. Trang Ly shared several Insulet updates. First, Insulet’s Omnipod is now available in 21 countries and recently launched in Turkey and Australia, ahead of schedule based on the timeline shared in Insulet’s 2Q21 call. Dr. Ly also reiterated that “35%-40%” of new users in the US are people with type 2 diabetes, in line with previously stated figures.

Medtronic pipeline updates: MiniMed 780G update w/Guardian 4 CGM + EWIS to launch in Europe “this fall”; InPen Basal smart insulin pen cap in development; next generation “personalized closed loop”

Mr. Ali Dianaty (Vice President, Product Innovation, Medtronic Diabetes) provided and overview of Medtronic’s product pipeline reiterating plans to launch an updated version of the MiniMed 780G AID system introducing compatibility with the company’s Guardian 4 CGM and extended wear infusion set (EWIS) in Europe “this fall.” According to Mr. Dianaty, the updated system will be available once Medtronic scales its volume and manufacturing of the extended wear infusion set which is currently available for patients in Finland and Belgium. With this update, Mr. Dianaty highlighted that patients on MiniMed 780G will be able to reduce their hardware changes by more than half from once every three days to once every week. As a reminder, EWIS data was read out at ADA 2021 and demonstrated strong survival of 75% sets at seven days.

  • Mr. Dianaty shared that Medtronic is currently developing an InPen Basal smart insulin pen cap. While Mr. Dianaty did not share many details about the system, it is our understanding that this basal pen cap would integrate into the InPen system and allow users to see all of their insulin dosing data in the InPen app. Additionally, we anticipate that the pen cap would include basal dose reminders, which InPen already offers, and also integrate with Guardian 4 CGM data. Offering patients on InPen a connected basal delivery device would certainly be a substantial step toward a closed data loop for patients on MDI, removing the need to manually enter basal doses every day.
  • InPen received CE-mark back in May 2021 with European launch expected “this fall.” Based on Mr. Dianaty’s language, it is our understanding that InPen has yet to launch in Europe, but will do so soon. When InPen does launch, it will include compatibility with Guardian 4 allowing for integration with CGM and insulin dosing data in a single InPen Insights report. Additionally, Mr. Dianaty was emphatic in his discussion of InPen that Medtronic is taking steps to ensure that it can offer similar levels of insulin dosing support and glycemic control to patients on MDI as to those on AID systems sharing that Medtronic is working to incorporate AID features into InPen “as much as possible.”
  • Mr. Dianaty discussed other future upgrades to the MiniMed 780G system including meal estimation and food library features to reduce carb counting, plans to develop a smartphone app allowing for remote bolusing which we first heard about at ATTD 2021, as well as bolus reminders on patient’s connected smart watches via Klue meal detection technology, which Mr. Dianaty previously discussed at ADA 2021. In addition to MiniMed 780G pipeline updates, Mr. Dianaty reiterated Medtronic’s plans to develop a next generation “personalized closed loop” system to provide users with increased flexibility and customization in regards to features such as insulin to carb ratio, insulin sensitivity, active insulin time, glucose targets, and meal bolus preferences among others.
  • Mr. Dianaty also discussed Medtronic’s Synergy CGM, which has faced delays in its FDA submission timeline, which was most recently pushed back to the third quarter of Medtronic’s fiscal year (i.e., November 1, 2021 – January 31, 2022). We have yet to hear any OUS approval timelines for Synergy, but given that Medtronic often launches products in OUS markets ahead of the US we wouldn’t be surprised if Synergy has already been submitted or is close to submission with European regulatory bodies. Once approved, Mr. Dianaty expressed that Synergy will be compatible with the MiniMed 780G system as well as InPen, providing users with a smaller, fully disposable CGM option.

Real-world data from Germany shows strong Time in Range (73%) with Diabeloop’s DBLG1/Roche’s Accu-Chek Insight pump/Dexcom G6 AID system; small real-world study (n=26) in Spain sees Time in Range increase 3.6 hours/day to 77% after one month; plus, Diabeloop’s robust pipeline includes algorithm enhancements, MDI efforts, and indication expansions

In a powerful thirty-minute industry symposium, Diabeloop’s Mr. Erik Huneker (co-founder and CEO), Prof. Benhamou Pierre Yves (Centre Hospitalier Universitaire de Grenoble) and Drs. Ana Chico and Rosa Corcoy Pla (Hospital Santa Creu i Sant Pau, Barcelona, Spain) shared new real-world data from Germany and Spain on the DBLG1 AID system with Roche’s Accu-Chek Insight pump and Dexcom G6. As a reminder, Roche and Diabeloop announced their partnership in December 2020, successfully integrated the system in early March, and launched their combined AID system in March in Germany, Spain, Italy, and the Netherlands. Since then, the system has launched in Switzerland, as of Roche’s 2Q21 update. Diabeloop’s DBLG1 algorithm incorporates predictive low-glucose suspend, basal rate adjustment automation, and automatic correction boluses and is housed in a locked-down handset. Diabeloop previously launched its DBLG1 algorithm with the Kaleido patch pump in a limited launch in France and, as of June 2020, was working to expand into the German market, according to management. In addition to the first real-world data of the Roche/Diabeloop/Dexcom AID system in Germany and Spain, the session also featured Mr. Huneker’s outline of Diabeloop’s pipeline projects to enhance its algorithms, expand its indications, and provide support for those with type 2 diabetes and those on MDI (see more on this below).

  • Prof. Benhamou began the session by sharing real-world DBGL1/Insight/ Dexcom G6 system data from Germany. Using data collected via Diabeloop’s YourLoops provider-facing data visualization platform from 998 patients on the DBLG1 System between April to September 3, 2021, Prof. Benhamou showed that participants spent an average of 73% Time in Range, only 1% time <70 mg/dl, and almost no time <54 mg/dl (0.1%). Participants were in closed loop 87% of the time, slightly lower compared to other commercially available systems in the real world (97% after one month of MiniMed 780G, 89% after one month on MiniMed 670G, 94% after one year of Control-IQ). Although baseline CGM metrics and A1c values after initiation were not collected, Diabeloop researchers used baseline A1c to estimate baseline Time in Range and on-system Time in Range to calculate post-initiation A1c among the 152 participants with baseline A1c data available. Using this method, the researchers estimate that A1c fell 0.4% with the DBGL1 system and Time in Range increased four hours/day (17%). These are hugely exciting findings, and we look forward to publication of this and similar data from Diabeloop that will validate the findings.

  • Drs. Chico and Corcoy Pla shared real-world DBLG1 data from a small cohort (n=26) in Barcelona, Spain. The cohort included all patients with type 1 diabetes who had used DBGL1 for at least one month and had “suboptimal glycemic control” and problematic hypoglycemia or high glucose variability (age 45, 23 years of diabetes). At baseline, 17 were on MDI and FreeStyle Libre, eight were on pump therapy with FreeStyle Libre, and one was on sensor-augmented pump therapy. At the point of analysis, 26 participants had at least one month of data, and seven had at least three months of data. Although median glucose did not see a significant reduction (although there was a downward trend), participants did see significant improvements in Time in Range, time <70 mg/dl, time >180 mg/dl, time >250 mg/dl, GMI, and glycemic variability. Specifically, Time in Range increased 3.6 hours/day to 77% at one month and increased 4.8 hours/day to 82% at three months. Time <70 mg/dl fell 56 minutes/day from 5.3% at baseline to 1.4% at one month, a reduction that was maintained at three months. About two-thirds (65%) of participants achieved both the Time in Range goal of >70% and time below range goal of <4% in the first month of use. Particularly impressive, time >250 mg/dl fell 1.9 hours/day from 9% to 1% by three months, a hugely exciting finding. Likewise, GMI fell from 7.1% at baseline to 6.9% at one month and to 6.6% at three months, and glycemic variability fell from 39% at baseline to 27% and 28% at one and three months, respectively. These findings are generally in line with real-world published on MiniMed 780G and Control-IQ (see table below), although we do caution against a direct comparison given the differences in populations studied (e.g., the Control-IQ data includes type 2s).

 

Diabeloop DBLG1/Roche Accu-Chek Insight/Dexcom G6

Tandem Control-IQ

Medtronic MiniMed 780G

 

Baseline

One month

Baseline

One month

Baseline

One month

Time in Range

62%

77%

64%

75%

67%

80%

Time >180 mg/dl

23%

17%

23%

18%

29%

17%

Time >250 mg/dl

9%

1%

12%

6%

7%

3%

Time <70 mg/dl

5%

1%

1%

1%

3%

3%

Time <54 mg/dl

0.8%

0.4%

0.1%

<1%

1%

1%

GMI/A1c

7.1%

6.9%

7.3%

-

7%

6.5%

    • The speakers believe that these impressive results are in part due to the tunability of the system that allowed for increased aggressiveness. Specifically, they showed that only 12% of participants maintained the 110 mg/dl target glucose at three months (the rest lowered their target glucose value from 110 mg/dl, which some perceive as already on the aggressive end for AID systems). Likewise, 65% of participants had increased their insulin dose by one month, and all participants had increased the aggressiveness of the system in hyperglycemia by three months.

  • To close the session, Mr. Erik Huneker (co-founder and CEO of Diabeloop) discussed Diabeloop’s pipeline, which includes algorithm enhancements, indication expansions, and new products to support MDI users. Specifically, he shared that Diabeloop is working on several improvements to its DBLG1 algorithm, the first of which Diabeloop expects will increase its Time in Range outcomes by 4%-5% “next year.” Further down the line, Diabeloop is also working on incorporating neural network AI technology into its algorithm to further optimize glycemic control (+7%-10% additional Time in Range benefit per Diabeloop estimates). Also on the algorithm, Diabeloop aims to further optimize the system so that users do not have to announce meals and exercise and so that the algorithm takes into hormonal effects (e.g., menstrual cycle) and short-term insulin sensitivity. Simultaneously, Diabeloop is working to expand its indications to underserved populations (e.g., those with highly unstable diabetes), to children and teenagers, and to all insulin types. Diabeloop is also invested in developing algorithms that are optimized to support type 2s on insulin and to support those on MDI through its “DBL-4pen.” DBL-4pen is an app that hosts the Diabeloop algorithm and is connected to a CGM and a connected insulin pen and sends data to YourLoops. Mr. Huneker claimed that the system will provide “80% of the results [seen with the AID algorithm] for 30% of the costs,” making it a much more affordable option. While he didn’t share details about the algorithm or the support it would provide, we are excited to see the increasing interest in providing decision support to those on MDI and look forward to learning further about this system.

KidsAP02 Study: Four-month RCT finds very young children (ages 1-7) spend +2.1 hours/day in Range (72%) with CamAPS FX relative to sensor-augmented pump; Dr. Julia Fuchs advocates for AID as standard of care in age group

Kicking off a session on building the evidence base for new devices, Dr. Julia Fuchs (University of Cambridge) read out the findings of the KidsAP02 study, a four-month RCT that evaluated the CamAPS FX system in very young children (ages 1-7). This is hugely exciting, as Dr. Fuchs asserted that this is the longest AID study in this age group to date (the other major AID trial in very young youth that comes to mind is the three-month single-arm MiniMed 770G study in 46 children age 2-6 , which was read out at ATTD 2019). This multicenter randomized, crossover study included 74 patients ages 1-7 (average 5.6 years) from seven centers across Europe, 74 of whom were included in the primary analysis. At baseline, all participants had had type 1 diabetes for at least six months (average 2.6 years), had been on a pump for at least three months, had an A1c <11% (average 7.3%), and had not used an AID system in the previous two months. The vast majority had previously used a CGM (91%) and were white (89%). Following a run-in period, participants were randomized to the CamAPS FX system (n=39) or sensor augmented pump (SAP; n=35) arm for 16 weeks, which was followed by a washout period and then 16 weeks of the other treatment arm. At the beginning of both treatments, participants received CamAPS FX training or SAP refresher training. As a reminder, the CamAPS FX system was CE-Marked for use in type 1s in March 2020 and uses an Android app (including smartphone control), Dexcom G6, and either the SOOIL Dana Diabecare RS pump or the Dana-i pump. The algorithm modulates insulin delivery every 8-12 minutes, requires a simple setup of body weight and total daily dose, and is “highly adaptive” based on daily insulin needs, diurnal insulin needs, postprandial insulin needs independent of pump basal, insulin-to-carb ratio, and correction factor settings. Notably, the algorithm is housed on the app, which means that unlike Omnipod 5 or Control-IQ, CamAPS FX users need to keep the app in range of the system to stay in closed loop. In this study, parents were able to adjust their child’s glucose target between 79 mg/dl and 198 mg/dl. The study used non-diluted U100 NovoLog rapid-acting insulin based on previous evidence showing that diluted insulin did not provide additional benefits relative to non-diluted insulin in the CamAPS FX system in this age group (Tauschmann et al. 2019).

Hierarchical endpoints

CamAPS FX (n=73)

Sensor-augmented pump (n=73)

Mean adjusted difference

P-value

Time in Range

72%

63%

+2.1 hours/day

<0.001

Time >180 mg/dl

23%

32%

-2 hours/day

<0.001

A1c

6.6%

7%

-0.4%

<0.001

Mean glucose

146 mg/dl

159 mg/dl

- 13 mg/dl

<0.001

Time <70 mg/dl

4.9%

4.5%

+1 minute/day

0.74

  • Children spent 2.1 more hours/day in Range on the CamAPS FX system relative to sensor-augmented pump and saw a significant adjusted A1c drop of 0.4% to 6.6%. Specifically, participants spent 72% of Time in Range compared to 63% with SAP (p<0.001). The relative improvement in Time in Range in the CamAPS FX group was observed at one month and sustained through four months. Most of the Time in Range benefit of CamAPS FX was due to -2 hour/day adjusted relative improvement in time in hyperglycemia in the CamAPS FX arm relative to the SAP arm (23% vs. 32%). Although there was a significant improvement in standard deviation, there was no statistically significant improvement in glycemic variability, which remained quite high (41% for both; p=0.07). During the discussion, Dr. Fuchs stated that she believes that given these outcomes, AID technology should be the standard of care for very young children with type 1, as it is significantly more effective than the “current gold standard” of sensor-augmented pump technology.

  • Notably a significant reduction in hypoglycemia was not observed. Participants spent 4.9% and 4.5% of time <70 mg/dl on CamAPS FX and SAP, respectively (p=0.74) and spent a statistically equivalent amount of time <54 mg/dl (1% vs. 0.9%, respectively; p=0.63). During the discussion, Dr. Fuchs suggested that this is potentially because of the high rates of hypoglycemia at baseline and is “reflective of this particular parent population in Europe.” She also noted that she and her fellow researchers hope that ultra-rapid-acting insulins may help reduce rates of hypoglycemia in this age group of CamAPS FX users and that they are currently conducting a study using ultra-rapid-acting insulin in CamAPS FX systems in very young children with type 1 diabetes.
  • The CamAPS FX arm had a lower median glucose through all hours of the day. Overall, participants had a -13 mg/dl lower mean glucose on the CamAPS FX system than on SAP (146 mg/dl vs. 159 mg/dl). Although lower at all hours of the day, the relative improvement with CamAPS FX was particularly significant during the night.

  • Participants spent 95% of time in auto mode, which was sustained over the four months, and adverse events were generally low. The percentage of participants reporting adverse events in the CamAPS FX arm was comparable to the percentage in the SAP arm with 73% and 76% reporting no adverse events in the arms, respectively. There were 0.4 adverse events per participants in both arms. There was one severe hypoglycemia event in the CamAPS FX group (incidence rate of 4.5 events per 100 person years) and one other severe adverse event (hospitalization for gastroenteritis) in the SAP group. There was no DKA in either group.
  • Although there was no difference in participants’ total daily dose, the user was responsible for administering a smaller proportion of insulin when on CamAPS FX than on SAP. This relative improvement was seen across the entire 24-hour spectrum but was particularly notable during the night. Between 10pm and 6am, almost all insulin was administered by the CamAPS FX system in the treatment arm. Dr. Fuchs noted that this might suggest a lower burden of insulin delivery for parents with the CamAPS FX system, particularly at night. We’d love to see PROs on parent sleep quality and general quality of life, as that could support this important claim.

  • Back at ATTD 2021, Professor Roman Hovorka (University of Cambridge) shared CamAPS FX AID system research updates, including four ongoing studies: (i) four-year use in newly diagnosed adolescents; (ii) four-month use in adults ages 60+; (iii) use in pregnant women through pregnancy; and (iv) two-month use of a fully closed-loop system (i.e., no administered boluses) in type 2s. 2021 has already seen much data from CamDiab with an RCT in youth ages 6-18 read out at ADA 2021, data on app usage by age group read out at ATTD 2021, a study on CamAPS HX in type 2s with end-stage renal disease requiring dialysis published in Nature Medicine, and now this study in very young children. We look forward to seeing the results of the ongoing trials, all of which are in high-need populations in which there is less AID data available.

Sub-analysis from MiniMed 780G real-world study (n=12,780): lower active insulin time and glucose target correlate with higher Time in Range; only 12% of participants used most aggressive system settings

In addition to sharing the findings of three real-world studies from MiniMed 780G users, Professor Ohad Cohen (Medtronic Diabetes) presented additional analysis correlating aggressive active insulin time and glucose target settings with increased Time in Range. These analyses were in line with Prof. Cohen’s presentation from ATTD 2021, when he showed that participants in the first MiniMed 780G real-world study spent approximately half their time at the most aggressive glucose setting of 100 mg/dl and that the most popular active insulin time setting was 2.5-3 hours – the second most aggressive setting. The analysis was conducted on the large cohort (n=12,780) who achieved an average 76% Time in Range and 6.8% GMI after initiating MiniMed 780G. For the analysis, participants were broken down into Time in Range quartiles: (i) ≤70.3%; (ii) 70.3-76.5%; (iii) 76.5-82.3%; and (iv) >82.3%.

  • Users who opted for lower active insulin times and glucose targets had better Time in Range outcomes than those who didn’t. According to Prof. Cohen, this finding is in line with MiniMed 780G’s pivotal trial results, which found two-hour active insulin time and 100 mg/dl glucose target settings to be the optimal system setting to improve glycemic outcomes. Prof. Ohan’s analysis showed similar trends, with those using more aggressive targets (i.e., lower active insulin times and glucose targets) overrepresented in the fourth Time in Range quartile, as opposed to those who used the most relaxed targets, a plurality of whom were in the lowest Time in Range quartile.

Analysis of MiniMed 780G system settings, stratified by Time in Range (TIR) quartile

TIR post-MiniMed 780G

First TIR Quartile
≤70.3%

Second TIR Quartile
(70.3-76.5]%

Third TIR Quartile
(76.5-82.3]%

Fourth TIR Quartile
>82.3%

(n=3,247)

(n=3,248)

(n=3,247)

(n=3,247)

Active Insulin Time, number (%) of users using a given AIT ≥95% of the time

2h

817
(17.79%)

1,072
(23.34%)

1,240
(27%)

1,463
(31.86%)

2 – 3h

1,765
(28.5%)

1,604
(25.9%)

1,525
(24.63%)

1,298
(20.96%)

3 – 4h

374
(37.93%)

262
(26.57%)

197
(19.98%)

153
(15.52%)

Glucose Target, number (%) of users using a given target ≥95% of the time

100 mg/dL

447
(13.26%)

736
(21.84%)

919
(27.27%)

1,268
(37.63%)

110 mg/dL

279
(23.52%)

314
(26.48%)

320
(26.98%)

273
(23.02%)

120 mg/dL

434
(34.44%)

364
(28.89%)

294
(23.33%)

168
(13.33%)

  • Even though using an active insulin time of two hours and glucose target of 100 mg/dl conferred the best Time in Range, only 1,482 users from the cohort (12% of participants) used the optimal system settings. Users of the most aggressive system settings attained an 81% Time in Range and 6.6% GMI. One-fourth of the cohort (26%; n=3,316) opted for a target of 100 mg/dl, and a third (35%; n=4,507) used an active insulin time of two hours. These groups attained a Time in Range/GMI of 79%/6.6% and 78%/6.7%, respectively. Prof. Cohen noted that further investigation is necessary to understand why participants were less likely to use the most aggressive and effective settings. However, he suspects that HCP inertia plays a large role and that providers want to limit Time Below Range for their patients. Granted, those using the most aggressive system settings also had the highest Time Below Range (2.9%) of any cohort in the group, albeit still less than the international consensus guidelines of Time Below Range <4%. Nevertheless, the high Time Below Range for those using aggressive settings might play a large role in explaining the lack of users who elect for them, especially given the dangers of hypoglycemia.

  • Users of “optimal settings” achieved a Time in Range of 81%, which is 5% (+1.2 hrs/day) higher than that reached by the total cohort. As Prof. Cohen mentioned in a different section of his presentation, glycemic outcomes are also correlated with those who administer mealtime boluses around 5-6 times per day. Putting it all together, Prof. Cohen shared that those who used optimal system settings and administered five to six mealtime boluses per day achieved a Time in Range of 82% – only slightly higher (+1%) than those who just use the optimal system settings.

 

Prof. Pratik Choudhary argues in favor of single-hormone AID systems over dual-hormone AID systems based on glycemic outcomes, quality of life, cost, and additional burdens of dual-hormone systems

In a late-afternoon session, Prof. Pratik Choudhary (University of Leicester) advocated for single-hormone AID systems over dual-hormone AID systems. He made four core arguments based on the key methods by which AID systems are evaluated: (i) the glycemic benefits are already strong (enough) with single-hormone systems; (iii) single-hormone systems show positive quality of life outcomes and tolerability; (iii) single-hormone systems are cost effective; and (iv) dual-hormone systems have significant downsides. Comparing open-loop, single-hormone, and dual-hormone AID systems to cars, Prof. Choudhary argued that a single-hormone system is very capable, costly but also cost-effective, reliable, and comfortable while a dual-hormone system is like a luxury vehicle with amazing control and balance that can push the boundaries, but is less practical, costly, less reliable, and less comfortable on a daily basis.

  • On glycemic outcomes, Prof. Choudhary argued that the currently available single-hormone AID systems are already achieving or close to achieving target Time in Range (>70%). Pulling on real-world evidence on MiniMed 780G and Control-IQ, which achieved 80% and 74%% Time in Range in one month and 12 months, respectively. He argued that given the association between the 70% Time in Range threshold and long-term microvascular and macrovascular outcomes, the glycemic benefits achieved with single-hormone systems are strong enough and that future iterations of the systems that use even more effective AI technology could further improve these outcomes without an additional hormone administered via insulin pump.
  • On quality of life, Prof. Choudhary argued that the quality-of-life outcomes for single-hormone AID systems are particularly impressive. He highlighted data from Musolino et al. 2019 that showed that 95% of users are satisfied with their glucose control, 90% of caregivers have less trouble sleeping, and parents and children saw particularly strong benefits. Similarly positive results have been seen in the real-world CLIO study on Control-IQ, which saw greater patient-reported satisfaction with their insulin delivery device and its impact on their diabetes management (7.06 vs. 8.77, baseline and three months respectively, p<0.001) and a significant reduction in the perceived negative impact of diabetes across all dimensions (4.79 vs. 3.26; p<0.001).
  • On cost, Prof. Choudhary highlighted analysis from the UK and Sweden that supports the cost-effectiveness or currently available single-hormone AID systems. In the UK HCL cost-effectiveness study (Roze et al. 2021), use of MiniMed 670G (n=124 adults and adolescents with type 1) led to a quality-adjusted life expectancy of +1.7 QALY years relative to pump therapy at a cost of €23,844/QALY gained, at/meeting the threshold for NICE in the UK. In the Swedish cost-effectiveness study, Jendle et al. found that the use of MiniMed 670G was associated with a QALY gain of 1.90 relative to pump therapy with a cost of €16,197/QALY, meeting the willingness-to-pay threshold in Sweden.
  • Prof. Choudhary bolstered his argument with musings on the specific disadvantages of dual-hormone systems. Prof. Choudhary acknowledged the challenges that persist with single-hormone systems, including meals, exercise, sensor errors, insulin delivery failure, user interface challenges, connectivity, and regulatory requirements. However, most of these challenges would not be solved with a dual-hormone system. In fact, later in his presentation, Prof. Choudhary argued that the challenges seen with insulin-only systems, including device bulkiness, connectivity challenges, and intrusive alarms (Musolino et al. 2019), would only become more challenging with additional pumps, infusion sets, and hormones. Likewise, he argued that many of the burdens of use that lead people to discontinue use of AID systems (Messer et al. 2020) would be exacerbated by dual-hormone systems, including too many alarms/alerts, hassle of wearing devices, device interference with daily life, and how the device feels and looks on one’s body. Furthermore, he shared concerns about the tolerability of a dual-hormone glucagon-insulin or pramlintide-insulin system, as both glucagon and pramlintide are associated with nausea and pramlinatide is also associated with bloating (Boughton et al. 2021). Given these downsides, Prof. Choudhary is unsure that the benefits of a dual-hormone system would outweigh the disadvantages, especially for patients already achieving >70% Time in Range and low rates of hypoglycemia.
    • Based on a back-of-the-envelope calculation, Prof. Choudhary calculated the cost of a dual-hormone system to be significantly higher than that of a single-hormone system and suggested that the significantly higher costs across the pump, reservoirs and cannulas, and glucagon means that dual-hormone systems are likely not cost-effective. Although that will depend on how effective dual-hormone systems are once they reach commercialization and it particularly depends on costs of glucagon or other hormones included – glucagon in particular, we imagine there are alternatives available besides the current price. Of course, we look to see further analysis on this, but Dr. Choudhary’s calculation certainly makes the added costs clear. However, we’d note that if dual-hormone systems are able to achieve significantly better outcomes in the long-term, these higher costs may be counterbalanced by increased effectiveness, making the dual-hormone system cost-effective.

  • In an interesting side note, Prof. Choudhary discussed single-hormone AID system + adjunctive SGLT-2 or GLP-1 as a potential “third option” beyond single-hormone vs. dual-hormone systems. Prof. Choudhary shared data from two proof-of-principle, in-clinic studies that found that Time in Range and mean glucose improved when using a single-hormone AID system with dapagliflozin and liraglutide, respectively, (Biester et al. 2020 and Ilkowitz et al. 2016) primarily due to reductions in post-prandial hyperglycemia following unannounced meals. Using this data, Prof. Choudhary argued that an adjunctive therapy may be effective in further improving the efficacy of insulin-only AID systems to avoid having to add another hormone. While not currently as relevant in the US given that SGLT-2s and GLP-1s are not approved for use in type 1s (although they are used off-label), this option is clinically meaningful in Europe where Forxiga (dapagliflozin) is approved as an adjunctive therapy for type 1 diabetes with BMI >27 (see this talk from yesterday; as well as the talk above from Dr. Chantal Mathieu). We’re certainly curious about this option (seldom discussed!), and we hope to see further and more robust investigation.

Drs. Moshe Phillip and Tadej Battelino discuss future of diabetes technology highlighting improved outcomes, decision support, and automated insulin delivery

Dr. Tadej Battelino (University Medical Center Ljubljana) and Dr. Moshe Phillip (Schneider Children’s Medical Center of Israel) presented components of their EASD e-learning course on “New Technologies for the Treatment of Diabetes” highlighting improved outcomes from AID systems and the need for decision support at the patient and provider levels. EASD e-learning is an online platform providing free educational content on diabetes management that had nearly 6,000 users from 153 countries as of August 2021. In this abbreviated version of their course on diabetes technology, Drs. Battelino and Phillip pulled from their wide-ranging knowledge of diabetes technology to discuss recent advancements with the more than 200 attendees. Dr. Phillip began the presentation by expressing hope that one day there will be a cure for diabetes – certainly our dream as well! – but that until that dream is realized, diabetes technologies can help those living with the disease improve outcomes and reduce burden, especially for patients with insulin treated diabetes. Highlighting data from the SWEET registry, which was read out at ATTD 2021, Dr. Battelino expressed that technology uptake has been associated with improved glycemic control. Furthermore, Dr. Battelino discussed results from the MOBILE study, also read out at ATTD 2021 and published in JAMA, which demonstrated that CGM use was associated with improved diabetes management among type 2s on basal-only therapy. Not to mention the substantial improvements in diabetes control that have been seen across automated insulin delivery systems including MiniMed 780G, Control-IQ, and Omnipod 5. Discussing the implications of these results collectively, both Dr. Battelino and Dr. Phillip argued in favor of increased technology uptake among people living with diabetes, but also recognized that patients will have different preferences for the types of technology they will choose to use and that, regardless of a patient’s technology usage, they should still have access to the highest quality of care. 

  • Recognizing that not all patients will want to use AID systems, Drs. Battelino and Phillip discussed new data presented at ATTD 2021 from the DreaMed Advisor Pro platform for MDI. As a reminder, this study demonstrated that the AdvisorPro system offered non-inferior dosing advice for treatment decisions and insulin titration compared to medical experts for patients on MDI. Highlighting these results, Dr. Phillip argued that decision support tools like AdvisorPro are like a “genie in the pocket” and could dramatically alter how providers, especially in primary care or those less familiar with insulin therapy, help patients manage their diabetes.
  • During Q&A, Dr. Battelino and Dr. Phillip addressed a question on how decision support tools like AdvisorPro, as well as other technical advances such as AID systems, will change the education paradigm for diabetes management. Dr. Phillip shared that he hopes decision support tools will reduce the amount of education that needs to go into the specifics of diabetes management during clinic visits instead making more time for providers to discuss other aspects of diabetes management with their patients. For his part, Dr. Battelino agreed that decision support tools can reduce the burden of diabetes for patients, but that education must still emphasize the rationale behind treatment so patients understand why medication and treatment adherence is important.
  • Both Dr. Phillip and Dr. Battelino argued against transitioning patients from pediatric to adult care until the patient is ready, expressing their views that it is acceptable for patients in their late teens to early twenties to continue seeing their pediatric endocrinologist whom they have likely been working with for a number of years. In Dr. Battelino’s system, patients are not transferred to adult care until they reach the age of 24 after completing their education and noted that pediatric providers often play an active role in supporting patients as they transition and become comfortable with a new care team.
  • Also in Q&A, Dr. Battelino and Dr. Phillip discussed AID use during pregnancy. Session moderator Professor Pratik Choudhary (University of Leicester) clarified that only the CamAPS AID system is approved for use in pregnancy despite the fact that many women will use other systems such as Control-IQ or MiniMed 780G to help manage their glucose levels. Both Dr. Phillip and Dr. Battelino expressed that though the glucose set points of some AID systems are above the tight control recommended during pregnancy, they can still be very beneficial for women who are struggling to bring their glucose levels down. Additionally, during especially stressful times of pregnancy including labor and delivery, Dr. Phillip emphasized that women should use whatever diabetes management method they are most comfortable with.
  • Discussing behavior modifications, Dr. Battelino emphasized the power of technology to give patients actionable information in real time instead of focusing on retrospective data. Specifically, Dr. Battelino expressed that the past can’t be changed and so using data to support and encourage patients moving forward has the largest potential to drive sustainable improvements.

Insulet- and Tandem-sponsored symposia highlight provider bias in patient selection for tech: “Challenge your assumptions about who will do well with technology”

In both Insulet and Tandem’s sponsored symposia, KOLs advocated that providers challenge their assumptions about who will do well with technology. The Tandem-sponsored session featured Dr. Gregory Forlenza (Barbara Davis Center) and Dr. Katharine Barnard-Kelly (Barnard Health), and the Insulet-sponsored session showcased the expertise of Dr. Alice Cheng (University of Toronto, Canada) and Dr. Peter Jennings (Birmingham City University, UK). A growing body of evidence, including that included in the sessions’ presentations, indicates that provider biases impact which patients are offered AID, pump, and CGM technology, and these biases often align with pre-existing health disparities, hurting those who might most benefit from diabetes technology use. We were hugely appreciative of Tandem and Insulet’s focus on this important issue. While likely not planned, the coordination between the two sessions and their reinforcement of the importance of this issue made the message much more impactful. We hope that this important topic will continue to receive increasing airtime and hope that discussions will consider best practices in addressing these biases and assumptions.

  • Dr. Forlenza advocated for AID technology regardless of whether a patient is adhering to recommendations: “Rather than waiting for patients to adhere to recommendations before prescribing T1D technologies, T1D technologies can be used to drive success in meeting recommendations.” Dr. Forlenza shared data from a survey of 192 Pediatric Endocrine Members who prescribe insulin pump therapy to patients with type 1, which investigated their adherence to guidelines, eligibility criteria, and objective and subjective factors that influence insulin pump prescription. The study found that 70% of respondents reported using personal guidelines to guide patient selection and that only 22% reported following any written guidelines. The only standard objective criteria used was glucose monitoring, and subjective factors used by providers included patient lifestyle, risk of hypoglycemia, patient and family motivation. Reflecting on his own practice, he noted that many of his and his colleagues’ criteria for prescription included >4 BGM measurements/day or wearing a CGM, understanding carbohydrate counting, bolusing 3+ times/day, an A1c <10%, having diabetes for more than six months, and a certain level of knowledge, skill, education, or sophistication. He then went on to share patient cases that refute the necessity of these criteria, in particular the need to bolus and the requirement of an A1c <10%. Arguing success begets success, he strongly advocated that patients are offered AID technology regardless of their adherence to recommendations, whether that be bolusing, glucose monitoring, or carbohydrate counting, as the benefits of AID technology can help some overcome the barriers they face in achieving glycemic control.
  • Dr. Barnard-Kelly reflected on the socioeconomic, racial, and ethic disparities in diabetes technology use and argued that HCPs have are essential to facilitating access to the best care options and must work to not act as gatekeepers. Dr. Barnard-Kelly highlighted CLIO data read out at ADA 2021 that showed that Control-IQ was effective in improving A1c across White, Latinx, Black, and Asian participants and noted that AID technology is effective irrespective of age, SES, and duration of diabetes. Although it is effective in broad populations, US and UK audit data show “consistent and widening” disparities in access to AID technology. For example, in the UK, children of low SES or from minority backgrounds are 10 times less likely to access insulin pumps that their white, high SES counterparts. Similarly, retrospective data read out at ISPAD 2020 showed stark disparities in CGM initiation and continuation. Dr. Barnard-Kelly argued that there are five major hidden barriers to AID uptake, including: (i) lack of universal access; (ii) health literacy; (iii) poor understanding of systems and individual suitability; (iv) HCP unconscious bias; and (v) awareness of availability. She also acknowledged the needs and pressures that HCPs face and suggested that they actively reflect on the barriers they face in prescribing AID technology and how to support a broader range of patients.
  • Similarly, Dr. Cheng advocated that HCPs reflect on their pre-existing biases about “who is the ‘right person’ for pump therapy.” Leaning on data from the first 90 days of Omnipod use in 13,389 adults with type 1 and 6,034 children with type 1, Dr. Cheng showed that Omnipod was effective improving outcomes irrespective of age, baseline A1c, or prior mode of insulin delivery (pump vs. MDI). Based on the slew of data she shared, Dr. Cheng argued that the question should not be: “What are the criteria for the ‘right’ patient for CSII?” but rather should be: “Is there anyone who would not benefit from CSII?”
  • Following Dr. Cheng’s presentation, Dr. Jennings shared an example of his own bias in supporting an elderly, 82-year-old patient with type 1 with her diabetes management and his uncertainty of whether Omnipod DASH would be right for her given that she didn’t have a mobile phone. Although he had these pre-existing conceptions of whether Omnipod DASH would work for her, he found that when he initiated her on Omnipod DASH, she thrived, particularly enjoying the lack of tubing when she was sleeping and doing chores around the house. Using this example he noted, “My own prejudices have been challenged. We are gatekeepers to diabetes technology, and we should be more open-minded about who would benefit.”

Small (n=52) real-world analysis of MiniMed 780G use shows +13% Time in Range increase (+3 hours/day) to 80% Time in Range; A1c reduction of 0.5% to 6.7%; improved quality of life outcomes; results reproduced in larger cohort (n=143) since initial analysis

Dr. Pilar Beato-Víbora (Badajoz University Hospital) presented real-world data (n=52) on glycemic outcomes and patient satisfaction after three months on the MiniMed 780G system demonstrating a 0.5% A1c reduction to 6.7% and a 13% Time in Range increase (+3 hours/day) to 80% Time in Range (SO-553). Patients in the study population had an average age of 42 and were all on the MiniMed 640G SAP-PGLS at baseline and were upgraded to the MiniMed 780G system when their MiniMed 640G warranties expired. For participants capillary A1c and 2-week system data were downloaded at baseline and three-month follow-up. After three months on MiniMed 780G, patients saw significant improvements in A1c from 7.2% at baseline to 6.7% (p<0.001) and Time in Range from 67% at baseline to 81% (p<0.001). These results are especially impressive given the relatively strong glycemic control patients demonstrated at baseline – a trend also seen in Insulet’s Omnipod 5 pivotal read out at ENDO 2021 with nine-month extension data presented earlier this week here at EASD 2021. Patients also saw reductions in mean sensor glucose from 155 mg/dl at baseline to 137 mg/dl on MiniMed 780G (p<0.001). Additionally, similarly to in the MiniMed 780G pivotal trial (read out at ADA 2020) and other real-world investigations (published in DT&T and read out earlier this week at EASD 2021), patients spent a higher proportion of time using their CGM sensors from 85% at baseline to 90% after three months (p=0.001) and spent 94% of the time in automode. At three months, Dr. Beato-Víbora also reported an increased percentage of patients achieving an A1c <7% of 69% up from 46% at baseline (p<0.001). Additionally, 89% of patients achieved Time in Range >70% compared to only 46% at baseline (p<0.001) and 60% of patients achieved both targets of Time in Range 70mg/dl – 180mg/dl >70% and time <70mg/dl less than 4% compared to 31% of patients achieving these goals at baseline (p<0.001).

  • Patients saw significant improvement in quality-of-life metrics after three months on MiniMed 780G compared to baseline. Dr. Beato-Víbora detailed results from the Hypoglycemia Fear Survey, Diabetes Quality of Life index, Glucose monitoring experience questionnaire, and Pittsburgh sleep quality index, all of which indicated significant improvements at three months. Specifically, patients experienced reduced fear of hypoglycemia scores from 46 at baseline to 37 at three months (p=0.001), improved diabetes quality of life scores from 81 at baseline to 76 at three months (p=0.036), increased satisfaction with glucose monitoring scores from 3.8 at baseline to 4.0 at three months (p=0.007), and improved quality of sleep scores from 6.6 at baseline to 5.9 at three months (p=0.047).

  • During Q&A, Dr. Beato-Víbora addressed a question about patients inputting “fake carbs” to deliver an extra bolus as some providers have seen on the MiniMed 670G system. While Dr. Beato-Víbora recognized this was an issue for many patients on MiniMed 670G and knew many of her patients to do this, she had not seen similar behavior among patients using MiniMed 780G due to the system’s automatic correction bolus feature that helped improve glycemic control and keep patients in range.

Small retrospective study (n=136) finds AID systems demonstrate improved glycemic control over PLGS and SAP with 71%, 62%, and 59% Time in Range, respectively; reduced severe hypoglycemia among AID users compared to patients on PLGS or SAP

Dr. Paola Morpurgo (ASST Fatebenefratelli Sacco) presented data from a small retrospective, cross-sectional study among patients with type 1 (n=136) comparing outcomes between patients on sensor-augmented pump therapy (SAP), predictive low-glucose suspend (PLGS), and automated insulin delivery (AID) systems demonstrating improved glycemic control for those on AID (SO-555). Among study participants, 24 were on SAP with Dexcom G5 sensors, 49 used PLGS systems including Tandem’s Basal-IQ (n=17), MiniMed 640G (n=19), MiniMed 670G with automode disabled (n=10), and MiniMed 780G with SmartGuard disabled (n=3), and 63 used AID systems including Control-IQ (n=6), MiniMed 670G (42), and MiniMed 780G (n=15).  At baseline there was no significant difference in demographics across the three groups with average ages of 47, 48, and 48 for the SAP, PLGS, and AID cohorts, respectively. Comparing glycemic control across the three groups, Dr. Morpurgo found that Time in Range increased progressively from the SAP cohort with 59% Time in Range, to the PLGS cohort with 62% Time in Range, to the AID cohort which achieved 71% Time in Range with the difference being significant between the SAP and AID cohorts (p=0.002). Dr. Morpurgo also identified a progressive decrease in time <54mg/dl from 1.4% for those on SAP to 0.5% for those on PLGS, and 0.2% for those on AID (PLGS vs SAP p=0.0001; AID vs SAP p=0.0001). Additionally, 56% of patients in the AID cohort achieved Time in Range >70% compared to 33% for PLGS (p=0.003) and 21% for SAP (p=0.003). Interestingly, while psychosocial analysis of convenience, social restrictions, and psychological distress showed higher numeric values for patients on AID compared to those on PLGS or SAP (indicating better QoL), there was no statistical difference between the quality-of-life outcomes among the three groups. However, this could have been due to the small sample size of the study. 

Retrospective real-world Omnipod DASH study with record sample size: Type 1 adult (n=3,341) and pediatric (n=1,397) participants see 0.9% A1c reduction during first 90 days of use; greater improvements in those formerly on MDI or with higher baseline A1c

Dr. Grazia Aleppo (Northwestern Feinberg) shared results from a real-world, retrospective study (n=4,738) on the first 90 days of Omnipod DASH use in US individuals with type 1 diabetes. As a reminder, Dr. Aleppo presented preliminary data from this same study at ATTD 2021, and explained that the final results mark the largest cohort study of people with type 1 diabetes initiating therapy with the Omnipod DASH system. Much like the preliminary results, participants saw significant glycemic improvement, with pediatric participants achieving a 0.9% A1c improvement to 7.7% at day 90 and adults seeing a 0.9% A1c drop to 7.6% (p<0.0001 for both). Unsurprisingly, those with higher A1cs at baseline achieved the greatest change over 90-days of DASH use. MDI patients made up a majority of the study sample (79% of children and 61% of adults) and saw statistically greater A1c improvements than the overall population. In adults, these A1c improvements were achieved with a 20% decline in total daily dose, whereas in children the A1c reductions were achieved without a change in total daily dose. The number of self-reported hypoglycemic events decreased in both pediatric and adult participants, from 2.8 events/week to 1.5 events/week and from 2.9 events/week to 1.3 events/week in children and adults, respectively. Notably, those with lower baseline A1cs had the greatest reduction in hypoglycemic event rates after initiating DASH.

 

A1c Outcomes

 

Pediatric

Adult

N

Baseline

Follow-up

Change

N

Baseline

Follow-up

Change

Total cohort

1,397

8.6%

7.7%

-0.9%*

3,341

8.5%

7.6%

0.9%*

Prior MDI

1,098

8.6%

7.6%

-1.0%*

2,048

8.6%

7.7%

-0.9%*

Prior pump therapy

133

8.5%

8.1%

-0.4%

719

8.0%

7.4%

-0.6%*

A1c <6%

58

5.7%

6.1%

+0.4%**

137

5.6%

5.8%

+0.2%**

A1c 6% to <7%

210

6.5%

6.8%

+0.3%

536

6.5%

6.6%

+0.1%

A1c 7% to <8%

356

7.4%

7.4%

0%

878

7.4%

7.2%

-0.2%*

A1c 8% to <9%

318

8.4%

7.9%

-0.5%*

706

8.4%

7.8%

-0.6%*

A1c 9% to <10%

172

9.4%

8.2%

-1.2%*

432

9.4%

8.3%

-1.1%*

A1c ≥10%

283

11.9%

8.4%

-3.5%*

652

11.7%

8.8%

-2.9%*

*Significant change from baseline, p<0.0001

**Significant change from baseline, p<0.001

Professor Neale Cohen and Dr. Martin de Bock on Android APS and DIY hybrid closed-loop: importance of provider education and calls for more RCT data

In this Ypsomed-sponsored session, Professor Neale Cohen (Baker Heart & Diabetes Institute, Australia) and Dr. Martin de Bock (University of Otago, New Zealand) provided their insights on how to optimize the use of Android APS technology in a clinical setting, and how health care providers can be most helpful in supporting patients who decide to invest in this DIY automated insulin delivery technology. Android APS, which is an open-source AID system launched in 2013 and provides a viable (yet technically complex) alternative to commercial systems. As a reminder, rather than relying on self-learning artificial intelligence, Android APS makes its dosing calculations using the OpenAPS algorithm to regulate automated insulin dosing based on the user’s carbohydrate intake and dosage history. This open-source app has garnered strong support within the diabetes community, since, as Prof. Cohen noted, it was “developed by people with diabetes, for people with diabetes.” As we heard during this session, although over 40 million hours of DIY Closed Loop Experience (for both AndroidAPS and its Apple counterpart Loop for iOS) have been reported without any major concerns for safety, the system’s technical complexities, combined with a lack of randomized controlled trial data (the CREATE trial, the first RCT with a DIY automated insulin delivery system, is set to report primary outcome results in December 2021), federal regulation, and perceived limited support from health care providers has largely limited its utilization. Therefore, in order to support patients who choose to use DIY AID systems, both speakers called on providers to (i) maximize their learning on the benefits and complexities of DIY loop and (ii) engage with the most up-to-date studies on DIY systems in order to inform responsible decision-making in this rapidly-changing landscape.

  • Professor Cohen highlighted how the OpenAPS algorithm can provide users the flexibility and personalization of insulin delivery to meet their personal diabetes management needs. Professor Cohen touched on some of the algorithm’s most advanced features, such as (i) automation, which allows users to program in automatic responses to specific events, and (ii) autosensitivity mode, which can be adjusted based on the timeframe of the sensitivity calculations. As a sidenote, we had heard about some of the advanced features of OpenAPS at EASD 2020, with founder Dana Lewis noting the power of her own personal open-source algorithm, which no longer requires bolus or meal announcements, allowing her to spend less time managing her diabetes. Prof. Cohen asserted that even though OpenAPS gives clinicians and users the power to adjust “almost everything” (allowing for precise control), a scarcity of RCT data on open source closed loop systems continues to limit the scaled implementation and use of DIY diabetes management.
  • Echoing Prof. Cohen’s point about a “lack of RCT,” Dr. Martin de Bock (University of Otago, New Zealand) introduced his team’s CREATE RCT (n=100), the first RCT to date investigating the safety and efficacy of Android APS compared to a sensor-augmented insulin pump therapy. Participants in the study were randomly allocated to receive either AID or sensor-augmented pump therapy, with an allocation ratio of 1:1. The primary outcome measure is Time in Range, and results are on track to be published in December 2021. As Dr. de Bock described, the CREATE Trial will bring real-life, robust data on the use of DIY systems to patients and providers, and many patients enrolled in the trial have already seen “positive results.”
    • Reflecting on the progress of the CREATE RCT so far, Dr. de Bock advocated in support of open-source algorithms, arguing that while it is not a “plug and play” technology, consistent practice and patience can make it feasible for users to navigate. Additionally, Dr. de Bock highlighted the strength of the diabetes community engaged in the DIY arena. This is a common theme that we continue to hear, most recently in June at the Friends for Life conference, we learned more about the #WeAreNotWaiting movement, which was launched by people with diabetes in 2013 to push for this consumer-led technology. Since then the movement has supported patients who have the opportunity to learn from each other and share personal experiences using DIY technology.
  • During Q&A, both speakers shed light on the general pros and cons of Android APS, pointing to accessibility as a key benefit. This point goes hand-in-hand with the strong community support among users of DIY loop. As Dr. de Bock explained, for many low-and-middle income countries that lack commercialized systems, open-source DIY technology can arguably be more convenient since it provides users with access to an international community of users. However, “no technology is infallible,” cautioned Dr. de Bock, and DIY systems, just like any pump, rely on careful hardware management and interoperability. On the topic of safety, given that this technology is largely unregulated, the speakers supported the idea of autonomy; as long as the risk is well-documented and pre-acknowledged, “it’s up to the patient.” Additionally, increasing provider comfort with these systems has the potential to help mitigate risk among users.

Frequency of on-time meal boluses significantly associated with Time in Range across 1.2 million meals for InPen + CGM users (r=0.59, p<0.001); only 56% of meals had on-time boluses, 32% of meals had missed boluses

Medtronic Diabetes CMO Dr. Robert Vigersky presented eye-opening data on the relationship between on-time meal boluses and Time in Range among InPen users. Data from 1.2 million meals across 257,177 patient days from InPen users also on CGM were analyzed and categorized as either (i) on-time bolus (up to 30 minutes ahead of meal or up to 15 minutes after the meal), (ii) late bolus (15-60 minutes after meal), or (iii) missed bolus (no bolus or bolus ≥60 minutes after meal). Across these categories, the frequency of on-time bolus delivery was significantly correlated with increased Time in Range (p<0.001, r=0.59). Using this linear correlation to extrapolate Time in Range values for specific percentages of on-time boluses, Dr. Vigersky outlined three examples. In the first, meal boluses were on-time 29% of the time which was associated with a Time in Range of 36%. In the second, meal boluses were on time 51% of the time resulting in 49% Time in Range. Finally, in the third, meal boluses were on-time 74% of the time, which was correlated with 70% Time in Range. Unfortunately, of the 1.2 million meals analyzed, only 56% had on-time boluses while 12% had late boluses, and a striking 32% had missed boluses, suggesting that the patients in this population were unlikely to be achieving the International Consensus Clinical Targets for Time in Range goal of 70% time between 70mg/dl – 180mg/dl.

  • Dr. Vigersky also discussed data from 6,393 InPen and CGM users that investigated fasting morning glucose targets and changes in overnight glucose levels. This study population was predominantly type 1 (73%) and 60% of participants used CGM while the other 40% used BGM. Of these two groups, only 12% of CGM users met fasting glucose goals of 70mg/dl – 120mg/dl which was only marginally better than the 10% of BGM users meeting the same fasting glucose goal. While this data is certainly concerning and indicates patients were not receiving optimized diabetes management to meet their needs, many patients were also experiencing significant overnight glucose fluctuations that Dr. Vigersky argued were indicative of non-optimized basal insulin dosing. Specifically, among patients using CGM, over 30% experienced a decrease in glucose of ≥30mg/dl with a mean overnight decrease of 76mg/dl. 30% of CGM users also experienced overnight glucose increases of ≥30% with the average overnight glycemic increase of 80mg/dl. While this overnight data was only available for CGM users, we expect patients in the BGM cohort were experiencing similar fluctuations that could be extremely dangerous, particularly since severe hypoglycemia isn’t identified with any sort of system – nor are rebounds, nor is what we’ve taken to calling severe hyperglycemia. By identifying non-optimized basal rates as a potential cause for this fluctuation, Dr. Vigersky argued that InPen and CGM data could be used to help providers identify patients who could benefit from intensified/adjusted therapy.

  • Referencing a presentation from ADCES 2021, Dr. Vigersky discussed results indicating that increased bolus frequency is associated with increased Time in Range among InPen and CGM users. We first heard this data presented by Ms. Hope Warshaw (Hope Warshaw Associates, LLC) at ADCES 2021 showing that among patients using InPen and CGM (n=1,721), those bolusing >6 times per day saw the highest Time in Range value at 67%. Notably, in her discussion of these data, Ms. Warshaw explained that among those bolusing more frequently, they were often delivering smaller bolus doses reducing the risk for hypoglycemia and insulin stacking.

  • Dr. Vigersky also discussed the patient population he sees as best suited to InPen and who will be able to derive the most benefit from the technology. Starting with providers, Dr. Vigersky advocated for InPen use among providers who: (i) are data driven and want methods to evaluate CGM in the context of insulin dosing; (ii) want to verify if patients are adhering to their therapies and insulin dosing guidelines; and (iii) want to understand potential factors impacting patients’ glycemic control to identify the root causes of frequent hypoglycemia and/or high A1c. Moving on to patients, Dr. Vigersky emphasized the benefits of InPen for patients who: (i) want guidance on bolus calculations and assistance tracking when and how much insulin was given; (ii) are struggling to adhere to their therapies and could benefit from InPen basal and bolus reminders; and (iii) want to improve their glycemic management  and avoid frequent hypoglycemia and/or high A1c levels. We heard similar patient populations addressed in a Medtronic symposium at Keystone 2020 during which Ms. Janice MacLeod (Medtronic Diabetes) and Ms. Nicole Schneider (Barbara Davis Diabetes Center) discussed the InPen system and how it can address and help patients overcome many of the common barriers to improved glycemic control for patients on MDI.

Lilly Tempo Smart Button compatible with Tempo insulin pens for Abasaglar, Humalog, and Lyumjev; data integrations with BGM and CGM via partnerships with Roche, Glooko, myDiabby, and Dexcom

In an evening Lilly symposium, Dr. Hood Thabit (Manchester University NHS Foundation Trust) walked the session’s >150 attendees through the new Lilly Tempo Smart Insulin Pen system. Consisting of a Tempo Smart Button, Tempo Pen, and compatible apps, Lilly’s Tempo system builds on the company’s existing KwikPen infrastructure and stores and transmits data on patient’s insulin dose, timing, and type of insulin delivered. When launched, Lilly’s Tempo smart button will be compatible with Tempo Pens for Abasaglar 100 units/mL, Humalog 100 units/mL, and Lyumjev 100 units/mL. Lilly has also already secured partnerships with Roche, Glooko, myDiabby, and Dexcom to integrate Tempo data across these platforms giving patients multiple options for how they may choose to view their Tempo pen data. During his presentation, Dr. Thabit ensured providers that they do not need to be concerned about technological literacy as a barrier to using the Tempo Smart Pen system as Lilly’s Tempo Pens are the same pen design as the company’s currently available KwikPen, with the only difference being Tempo Smart Button compatibility in which the button snaps into the top of the pen and can then store and transmit insulin dosing data. According to comments from Lilly in May the company is expecting CE-Mark for the Tempo Smart Button “later in 2021,” which we assume will be followed by a product launch. With the launch of Lilly’s Tempo smart insulin pen system in the EU expected in the coming months, there will soon be three large players in the European smart pen arena including Novo Nordisk’s NovoPen 6 and NovoPen Echo Plus and Medtronic’s Inpen, not to mention smaller players including Biocorp’s Mallya smart pen cap, which just signed a partnership agreement with Novo Nordisk to develop a smart pen cap for the company’s FlexTouch insulin pens.

  • Dr. Thabit walked attendees through interpreting data from Lilly’s connected Tempo system providing examples of integrations with BGM and CGM data. Starting with BGM, Dr. Thabit explained that patients using digital BGM logbooks, such as those from mySugr and myDiabby, will be able to integrate their insulin dosing data directly into their logbooks providing a centralized location for their diabetes management data. Via this data integration, patients and their providers will also be able to identify specific periods of hypo or hyperglycemia and associated insulin dosing behaviors to mitigate future glycemic excursions. Turning to CGM, Dr. Thabit highlighted the increased level of data available from CGM sensors over BGM providing additional insight into patient behaviors, glycemic control, and insulin dosing patterns. Specifically, Dr. Thabit highlighted the ability of Tempo + CGM data to highlight periods of potentially unrecognized hypoglycemia based on CGM values and prior insulin doses. This mirrors similar sentiments we’ve heard from other smart pen developers including Medtronic for its InPen system. While Dr. Thabit walked attendees through the graphics and data below for fictional patient Joanna to demonstrate the utility of integrated glucose and insulin dosing data, it is unclear if this is the design for the Tempo app itself or a surrogate design as patients will be able to access their data across multiple app platforms.

  • Dr. Thabit identified key populations of patients he believes would benefit from smart pen technology. Specifically, Dr. Thabit highlighted those with prior experience on MDI looking to improve management without switching to a new insulin delivery method, patients who are experienced using diabetes management software and digital tools to track their blood glucose levels, patients with busy schedules who could benefit from the easy data collection from Tempo, and patients who want to improve their diabetes control.

Pre-post analysis of high hypoglycemia risk subgroup from Control-IQ pivotal shows improved patient-reported outcomes at week 26 of AID use; impact of technology on QoL “more profound when it can reduce personal problem areas”

During a session on the psychological challenges raised by diabetes technology, Dr. Linda Gonder-Frederick, PhD (University of Virginia) presented a subgroup analysis (n=41) on patient-reported outcomes from the Control-IQ pivotal trial. Dr. Gonder-Frederick explained that this pre-post analysis studied participants who were at high risk for hypoglycemia at baseline, and saw how behavioral outcomes changed after 26 weeks of Control-IQ use. The analysis found a statistically significant improvement in behavioral health outcomes across the cohort: (i) mean score on the Hypoglycemia Fear Survey decreased from 2.6 to 2.3 (p<0.001); (ii) mean score on the Diabetes Distress Scale decreased from 1.8 to 1.7 (p=0.007), and from 2.0 to 1.6 on the hypoglycemia distress component (p<0.001); and (iii) mean score on the Hypoglycemic Confidence Scale increased from 3.3 to 3.5 (p=0.001), and from 2.8 to 3.3 on the sleep component of the survey (p<0.001). Similar associations were observed in the high hypoglycemia risk subgroup from children and parents in the Control-IQ pivotal trial (n=24), with parents also reporting better sleep at night as measured by the PSQI score (p=0.013).

  • Dr. Gonder-Frederick emphasized that the impact of technology on quality of life will be more profound when it can reduce personal problem areas. Dr. Gonder-Frederick turned to a 2017 DT&T study analyzing the patient-reported behavioral outcomes from the full cohort of the Control-IQ pivotal trial. While this study did find an improvement in Hypoglycemia Fear Survey scores in those on Control-IQ compared to those on sensor-augmented pump therapy, there was no statistically significant association between AID use and reduced diabetes distress. Comparing these data to the high hypoglycemia risk subgroup analysis, Dr. Gonder-Frederick emphasized the need to ensure that diabetes research involving behavioral outcomes is conducted on appropriate study samples. Specifically, while the analysis of all participants in the pivotal trial showed limited improvements in patient-reported outcomes after AID use, the analysis of the subset of patients at high risk for hypoglycemia showed an improvement after AID initiation, which Dr. Gonder-Frederick argued reflects the greater impact that AID has for those prone to hypoglycemia. Were this more granular sample not used, however, the results from the whole pivotal trial sample might suggest that AID does not improve Diabetes Distress scores, which Dr. Gonder-Frederick emphasized is not the case for all subsets of people.
  • Dr. Gonder-Frederick called for more individualized approaches to reducing diabetes technology related burden. Dr. Gonder-Frederick cited Dr. Korey Hood’s (Stanford) paper from the Journal of Diabetes Science and Technology titled “From Wary Wearers to d-Embracers: Personas of Readiness to Use Diabetes Devices,” which proposes five distinct profiles of patients adopting diabetes devices: (i) “d-Embracers” who had few barriers to device use and had the highest rates of device use; (ii) “Free Rangers” who had negative attitudes towards diabetes devices; (iii) “Data Minimalists” who were on pump therapy but had low CGM use and did not want more diabetes information; (iv) “Weary Wearers” who had low overall device use and tended to be younger, more distressed, and have higher A1cs; and (v) “High Distress” individuals who had the most barriers to device use and had the worst patient-reported outcomes. Notably, this study identifies the lowest device uptake and highest level of diabetes distress in the 18-25 year old cohort of participants – a rather concerning result considering T1D Exchange Data showing that this same subgroup has the worst average A1c relative to all other age groups. Ultimately, Dr. Gonder-Frederick invoked this study to emphasize that there is a spectrum of “health technology readiness,” and that there must be more training, support, and intervention program development to facilitate adoption, maintenance, and positive outcomes – and these approaches must be tailored to the unique needs of the individual.

Omnipod 5 significantly associated with improvement in hypoglycemia confidence among adults (n=115) and insulin delivery satisfaction among caregivers of children (n=82), caregivers of teens (n=42), and adults (n=115)

Dr. William Polonsky (UC San Diego) discussed quality of life data from Omnipod 5 users collected during the Omnipod 5 pivotal trial demonstrating improved QoL outcomes following system initiation. These data were initially presented as posters at ADA 2021 (704-P and 709-P) and compliment additional data from Dr. Korey Hood (Stanford University) also presented at ADA 2021 on the impact of Omnipod 5 on QoL outcomes for children and teenagers with diabetes and their parents, which found that Omnipod 5 was significantly associated with improved QoL outcomes across multiple QoL scales. Starting with diabetes distress among adults (N=115), as measured by the Type 1 Diabetes Distress Scale (T1DDS), Omnipod 5 use was associated with a 0.16 point reduction from 1.64 to 1.48 with scores >2 points indicating severe diabetes distress. In Dr. Polonsky’s analysis, he remarked that this reduction, which had a moderate effect size of 0.42, did strike him as impressive given that patients started with relatively low to moderate levels of diabetes distress, suggesting that the Omnipod 5 system was effective at alleviating diabetes burden even when not severe to begin with. Notably, the largest reduction in distress according to the T1DDS subsections came from reductions in hypoglycemia distress with an effect size of 0.44 (p<0.0001). Additionally, adult users of the Omnipod 5 system saw significant improvements in their hypoglycemic confidence scale scores going from 3.52 to 3.65 (p<0.05)) with higher scales indicating higher levels of confidence.

  • Turning to device satisfaction, adults and caregivers of teens and children all experienced significant increases in device satisfaction after initiating the Omnipod 5 system compared to baseline therapy. Specifically, caregivers of teens (n=42) experienced a 0.3 point increase in insulin delivery satisfaction from 3.8 to 4.1 points on the Insulin Delivery Satisfaction Scale (IDSS) (p<0.05). Caregivers of children (n=82) saw a 0.34 point increase in satisfaction from 3.8 to 4.1 points (p<0.0001), while adults (n=115) saw the smallest increase in satisfaction of 0.16 points from 3.9 to 4.1 points (p<0.05). Across subscales, all participants saw significant improvements in satisfaction related to burden and inconvenience of insulin delivery. Additionally, analyzing data collected from the Diabetes Treatment Satisfaction Questionnaire (DTSQ), adults (n=114), caregivers of teens (n=39), and caregivers of children (n=73) all reported increased satisfaction with the Omnipod 5 system compared to baseline therapy.

  • In the same session, Dr. Polonsky discussed the importance of QoL metrics for assessing diabetes technologies, outlining the three aspects of QoL outcomes that he views as most relevant to people living with diabetes. Firstly, Dr. Polonsky discussed how many patients feel out of control with their diabetes and feel like they are struggling to control their glucose levels which can contribute to high levels of stress and diabetes distress, which has been associated with adverse outcomes. Secondly, patients express that never feeling free from the demands of diabetes can also contribute to diabetes distress. Finally, Dr. Polonsky very insightfully highlighted the experience patients can sometimes have of feeling unsafe in their own bodies due to unexpected changes in glycemic levels. Recognizing these three components as potential factors in diabetes distress, though certainly not the only ones, Dr. Polonsky called for more research into how to mitigate these experiences and reduce diabetes distress for patients and also urged researchers to ensure they are collecting relevant QoL outcomes related to these three categories when conducing QoL analysis.
  • During Q&A, Dr. Polonsky shared his belief that the greatest QoL improvements for patients over the next few years will be driven by systems that allow patients to think less about their diabetes while still seeing improved glycemic outcomes. Specifically, Dr. Polonsky highlighted the growing field of automated insulin delivery as a key player in improving QoL outcomes for patients, but did also acknowledge that there are still patients who can feel overwhelmed by the data generated by their diabetes tech raising the issue of how technology manufacturers, providers, and ultimately patients, can find a sustainable balance of data integration and interpretations without feeling overwhelmed by it.

Older age and CGM use associated with improved glycemic control among type 2s using Omnipod or Omnipod DASH; average glucose of 172 mg/dl for CGM users vs. 180 mg/dl for BGM users

Retrospective assessment of glycemic profiles and insulin treatment patterns of 3,358 patients with type 2 diabetes using the Omnipod or Omnipod DASH systems found that across age-groups, patients using CGM had lower average blood glucose readings than those using SMBG (SO-563). For this analysis, data from type 2s using the Omnipod or Omnipod DASH systems between January 2015 and August 2021 were collected (n=3,358). Of this study population, 1,989 patients used SMBG and reported ≥14 days of blood glucose meter data and 596 patients used CGM reporting a minimum of 14 days’ worth of data over a three-month period. At baseline, the average patient age was 57 years old, and the study population was 54% female. Patients had an average total daily insulin dose of 61 units with an average of 3.2 boluses per day that aligns well with the expected number of meal-time boluses patients with type 2 on basal-bolus insulin therapy would be performing. However, while nearly all (96%) of Omnipod and Omnipod DASH users bolused at least once per day, basal insulin still comprised ≥50% of patient’s total daily insulin dose for 78% of users and ≥70% of patient’s total daily insulin dose for 26% of users.

  • Among BGM users, those in the older age brackets (65 to ≤75 years old (n=411) and ≥75 years old(n=90)) had the lowest average glucose levels at 170 mg/dl and 166 mg/dl, respectively. This was in comparison to average glucose levels of 182 mg/dl among users ages 50 to <65 years old (n=1,014), 187 mg/dl among users 18 to <50 years old (n=465), and 218 mg/dl among users <18 years old (n=8). Additionally, older users in the ≥75 year old age bracket reported the highest number of blood glucose readings per day at 3.7 readings per day, which still falls well below the ADA recommended seven fingersticks per day for insulin-requiring patients.
  • Among CGM users, average glucose was lower than for BGM users at 172 mg/dl compared to 180mg/dl. Similarly to BGM users, older patients on CGM in the 65 to ≤75 years old age bracket (n=131) and ≥75 years old age bracket (n=25) had the lowest average glucose levels of 167 mg/dl and 158 mg/dl. Additionally, while the CGM population was smaller than the BGM population in this study, representing 18% of users analyzed, we were excited to see that many type 2 patients were on CGM. However, baseline glycemic control was not available for either group, somewhat limiting our ability to compare between the BGM and CGM subgroups
  • During Q&A, study author Dr. Tina Kader (The University of Vermont Health Network) shared her thoughts on the results, raising a question around what other agents patients in the study may have been taking such as metformin, GLP-1s, or SGLT-2s and how these agents may have also influenced glycemic outcomes. Additionally, discussing potential age-related factors and the improved glycemic control seen among older patients, session moderator Professor Roman Hovorka (University of Cambridge) questioned whether there may have been some level of self-selection leading older patients in better glycemic control to have increased longevity and thus over-representation in the study. While Dr. Kader did not have data to answer these questions, they certainly provide additional research topics for further study.

Three-month European dQ&A survey finds no significant difference in confidence rating of virtual vs. in-person device training for insulin pumps (53% vs. 59%) and CGM (59% vs. 64%); data suggest lack of confidence among new-to-pump users

Three-month dQ&A survey data found no significant difference in participant confidence ratings with virtual vs. in-person pump (n=178) and CGM (n=261) training experiences, suggesting virtual device training could be a compelling substitute for in-person guidance (SO 530). This survey was fielded with patients from dQ&A’s European patient panel between October 2020 and November 2020, specifically seeking the experiences of those who recently initiated pump and/or CGM technology and reported being trained by an HCP either virtually or in-person. Respondents were asked to rate their level of confidence in using their new device (either an insulin pump or CGM) on a scale of one to ten immediately after participating in either virtual or in-person training from a professional. In the CGM arm of the survey data, 85% were trained in-person, 91% had type 1 diabetes, the mean age was 41 years old, and 41% of respondents were new to CGM. In the insulin pump group, 81% were trained in-person, 99% had type 1 diabetes, the mean age was 38 years old, and 35% were new to pump therapy.

  • The researchers found that confidence ratings did not differ significantly between in-person and virtual training methods for both pump users (53% vs. 59%, p=0.58) and CGM users (59% vs. 64%, p=0.58). During the poster presentation, Ms. Emily Ye (Senior Research Analyst, dQ&A) explained that these data show virtual training could be a suitable alternative for in-person training. We imagine that some may like to substantiating this claim with additional clinical data that correlates in-person and virtual device training with A1c, Time in Range, or other health-related measures. Some examples of such data include two RCTs that we saw last year at EASD 2020 that showed that mixed remote/in-person visits are non-inferior to standard, in-person care with A1c as a primary outcome. Additionally, a study published in DT&T in July 2020 showed that virtual training for MiniMed 670G during COVID-19 had comparable glycemic results and better patient satisfaction compared to in-person training. From our view, it was all fantastic to see such corroborating data showing what is possible virtually!
  • In a most interesting result, new-to-pump users were significantly less confident than pump-switchers directly after device training (41% vs. 62%, p<0.01). This trend was not observed with CGM trainings, as both new-to-CGM users and CGM-switchers were equally confident (60% vs. 63%, p=0.61). As we understand it, this finding speaks to the complexities of onboarding patients to insulin pump therapy and might suggest that current education methods are insufficient. This is certainly not the first we’ve heard of difficulties with training patients on insulin pumps. At ATTD 2021, Dr. Laurel Messer argued that current AID system training is not adequate to meet patients’ needs when initiating system use: “It is NOT standardized, NOT consistent, and NOT sufficient.” Specifically, Dr. Messer argued that patients, providers, and industry members must set reasonable expectations on: (i) the learning curve; (ii) the workload and actions needed to keep the AID system working; (iii) giving up some personal control to the system; (iv) expected glycemic outcomes; and (v) the need to maintain basic diabetes self-management skills. We see great value in ensuring that education for new-to-pump users is both comprehensive and encouraging, as we know that improving early experiences and outcomes with pump/AID systems might prevent discontinuation down the line.
  • Although confidence ratings were consistent following in-person and virtual trainings, participant engagement with supplemental online materials was greater in the those who received virtual training than in those trained in person. Specifically, participants who completed virtual device training were significantly more likely to watch online training videos and complete online tutorials than those who were trained in person. The investigators propose that this finding might suggest virtual training is not comprehensive enough for new device users. We also wonder about the degree to which virtual training primes one to utilize ancillary online resources, a factor that could potentially play a large role in explaining these data.

Accu-Chek Solo Micropump associated with reduced diabetes burden as measured via DTQ and PAID surveys compared to MDI for patients with type 1

Dr. Katharine Barnard-Kelly (BHR Limited) presented new data on patient-reported outcomes from 181 patients with type 1 diabetes on the Roche Accu-Chek Solo micropump. Patients were divided into three parallel groups using either MDI (n=61), the Omnipod 2 patch pump (n=58), or Roche’s Accu-Chek Solo patch pump (n=62) for 26 weeks followed by an additional 13 weeks of follow-up. At baseline, patients had an average A1c of 8.0% and diabetes duration of 15 years. At six months, patients on the Accu-Chek Solo micropump scored significantly higher on the Diabetes Technology Questionnaire than those on MDI (p=0.001) demonstrating greater satisfaction with their treatment technologies. Additionally, patients on the Accu-Chek Solo micropump also experienced a reduction in problem areas of diabetes compared to those on MDI with the two cohorts scoring an average 6.3 and 7.6, respectively, on the Problem Areas in Diabetes survey. That said, participants in the Accu-Chek Solo and Omnipod 2 arms saw no significant differences in patient-reported outcomes which is likely due to similarities between the two systems in terms of form factor, pump use, and ease of bolus delivery. Turning to the most frequently cited benefits of the Accu-Chek Solo micropump from patients enrolled in the study, most patients enjoyed the pump’s tubeless form factor, lack of injections, bolus calculator, ease of use, and discreet insulin delivery. For system shortcomings, patients noted that there was not a compatible smart phone app for the Accu-Chek Solo system and that the pump was not waterproof. Notably, newer designs of patch pumps, including Omnipod DASH and Omnipod 5, are waterproof, which can give patients greater flexibility while wearing their devices. Omnipod 5 will also be the first patch pump, when approved, to support smartphone bolusing, which, based on the results of this study, patients would enjoy using. We are curious if Roche has plans to bring smartphone bolusing to its Accu-Chek Solo pump following the successful launch of smartphone boluses via mySugr for Accu-Chek Insight insulin pump users in Europe this spring – it certainly is perceived as an area of differentiation.

  • These data are reminiscent of similar data presented earlier in the week at EASD 2021 demonstrating improved quality of life outcomes for patients using the Omnipod 5 sysytem. We continue to see strong data in this area supporting improved quality of life and PROs among insulin pump and patch pump users demonstrating the potential of diabetes technologies to reduce diabetes distress and burden. Also on Day #1 of EASD 2021, we heard from Dr. Rich Bergenstal (International Diabetes Center) on the importance of reducing diabetes distress to improve glycemic control and outcomes, and we remain hopeful that diabetes technology can help enable this.

Glucose Monitoring Highlights

In a jam-packed and highly anticipated Abbott-sponsored session, Dr. Tadej Battelino (University of Ljubljana, Ljubljana, Slovenia), Dr. Partha Kar (NHS England), and Dr. Ramzi Ajjan (University of Leeds, UK) shared their enthusiasm for FreeStyle Libre CGM technology, an abundance of data, and their perspectives on the use of FreeStyle Libre CGMs in the real world. This powerhouse of KOLs summarized the long list of benefits of isCGM as: (i) improved diabetes control; (ii) improved Time in Range; (iii) reduced time in hypoglycemia; (iv) reduced DKA; (v) reduced severe hypoglycemia; and (vi) reduced diabetes distress. To support these major benefits, they drew upon what can only be called a plethora of data – not only were the results shared impressive, but also the sheer quantity and variety of data highlight how far we’ve come in the CGM arena and how much we’ve learned in just the past few years about this revolutionary technology. While the session covered basically anything and everything related to CGM technology, we found the following to be particularly powerful sections of the session:

  • In a major highlight of the session (and day!), Dr. Kar shared that over 50% of type 1s in England are on CGM. Specifically, he shared that England has “crossed 50%,” up from 47% of people with type 1 diabetes in England in June and only 11% of type 1s in April 2019. Furthermore, he noted that in June 2020, over 20% of the people with type 1 diabetes in each county in England were on CGM, a much better image that the huge geographical disparities and variation seen in April 2019. We applaud England, the NHS, and the many ­– including Dr. Kar – who worked so hard to get us to this point, and we hope that there will continue to be progress. We hope that similar progress can be made in the US and around the world, although the methods and systems within we all are working are different.

  • Both Dr. Battelino and Dr. Kar highlighted the RELIEF study, which was published in Diabetes Care. The retrospective data review included 74,011 patients with type 1 and type 2 diabetes on FreeStyle Libre CGMs, 98% of whom continued usage out to at least a year. Participants with type 1 saw a 49% reduction in diabetes-related acute events (i.e., DKA, severe hypoglycemia, coma, severe hyperglycemia) and those with type 2 saw a 39% reduction. In both type 1s and type 2s, the reduction in DKA was particularly impressive with the rate of DKA falling 56% and 52%, respectively, one year after initiating use of FreeStyle Libre. Both Dr. Battelino and Dr. Kar highlighted the benefits seen among type 2s, who saw significant reductions in all subcategories (DKA, hypoglycemia, hyperglycemia, and coma) as well as the total rate of diabetes-related acute events, providing further support for the use of CGM in type 2s.

  • Dr. Ajjan emphasized the need to pay more attention to the positive PRO and quality of life benefits of CGM technology. He argued that although most major trials report on PROs and quality of life and show impressive benefits, these are often overlooked as the attention instead centers on the impressive glycemic and cost savings benefits. Although this was a sidenote of his talk, we found it particularly meaningful that he mentioned it and reminded the audience of the importance of these factors – for a person with diabetes, their relationship with their diabetes and its impact on their quality of life is incredibly important and improvements to one’s diabetes experience is powerful and incredibly meaningful.
  • Dr. Battelino closed out the session with a few case studies showing how he has used CGM to support his patients. After taking the audience through several patient cases, he summarized his approach to supporting patients: (i) discuss the AGP together with the person with diabetes; (ii) identify challenges and areas of concern and their sources; (iii) discuss potential solutions; (iv) set clear glucose targets that are related to their specific challenges; and (v) schedule additional (remote) contacts with the diabetes team. We’re always interested to hear from KOLs about their approach to data-based patient discussions and their approach to using data to optimize patient self-management and care. We appreciate Dr. Battelino’s focus on personalizing the metrics discussed to the patient’s particular area of concern – something that differs from the methods of Dr. Bergenstal and Dr. Isaacs, although we also appreciate Dr. Bergenstal and Dr. Isaacs’ more established, algorithm-like approach to diabetes data discussions, as this may make their approaches more scalable.

Dexcom-sponsored symposium: Advancing device and data interoperability to improve patient outcomes; plans for OUS expansion of real-time APIs; reiteration of OUS G7 launch by year-end

In a Dexcom-sponsored session, Dr. Pratik Choudhary (University of Leicester, UK) and Ms. Geraldine Gallen (Kings College Hospital, London, UK) advocated that devices and data interoperability is the foundation for patient choice and success in diabetes management. Specifically, the dynamic duo emphasized that safe, secure, and effective exchange of medical data among numerous devices, products, technologies, and health systems is a hallmark of medical device interoperability. As Dr. Choudhary explained it, this idealistic vision of free data flow among different entities is far from the status quo despite the fact that “device interoperability” is slowly becoming a reality. Instead, Dr. Choudhary proposed that our medical data exists in data “silos” that deny free data flow. He listed four discrete sample buckets that are relevant to diabetes: (i) patient data (e.g., severe hypoglycemia episodes as recorded by the individual, patient reported outcomes, and days off work); (ii) industry data (e.g., CGM data, insulin pump data, smart pen data, and connected meter data); (iii) hospital data (e.g., A1c, blood work data, retinopathy data, medication dosage, hospital admission data); and (iv) primary care data (e.g., multi-morbidities, prescriptions, HCP contacts, and disjoint logs across different healthcare providers). Using this illustration, Dr. Choudhury argued that it is difficult for patients to convey a comprehensive picture of the current state of their diabetes along with a thorough history of care when they are being seen by an HCP, potentially leading to unoptimized care. He concluded that as interoperability becomes a hallmark of diabetes technology and patients can choose the ACE pump, iCGM, and iController algorithm that best suits them, we must prioritize data interoperability by linking data between devices and systems – especially at the policy level – to improve patient outcomes. And, as data becomes interoperable, Dr. Choudhary argued that so-called “big data” – the aggregation of patient profiles – can be used to make actionable intelligence that can later inform analytics and decision support.

  • Dr. Choudhary noted that interoperability itself empowers patients to choose the right devices for them, which will drive better patient care and outcomes. In a discussion of how to fit the right technology to the right person, Dr. Choudhary took a step back and asked attendees: of all the diabetes technologies that exist, whose choice dictates what a patient ultimately gets? He argued that there are many stakeholders who govern the process of matching technology to the patient, including patients themselves, HCPs, and health care systems and payers, to name a few. Besides these three key stakeholders, there are so many other factors to consider including: (i) criteria/reimbursement; (ii) training and education; (iii) onboarding; (iv) support/troubleshooting process; (v) policy; and (vi) service planning and delivery. However, Dr. Choudhary suggested that with the increasing number of interoperable devices, diabetes devices may become less like pharmaceutical drugs that are governed by indications, prescriptions, and reimbursement structures and instead begin to resemble ordinary consumer devices. That is, patients can choose the iCGM, ACE pump, and iController algorithm that is best suited for their individual needs, from the company that resonates with them the most. Ultimately, Dr. Choudhary reiterated his belief that interoperability, which provides a high degree of flexibility to consumers, will ensure that patients are receiving the devices that they want and that work best for them, leading to better health outcomes.
  • Dexcom CTO Mr. Jacob Leach followed Dr. Choudhary’s presentation, contending that Dexcom is a category leader of interoperability and sharing intentions to expand Dexcom’s real-time APIs to additional geographies. In an especially enlightening illustration, Mr. Leach presented a diagram showcasing all of Dexcom G6’s integrations across the entire spectrum of diabetes technology, arguing that the Dexcom G6 CGM is central to diabetes management for patients, caregivers, and HCPs around the globe. Mr. Leach added that the company’s Partner Web API, which was cleared by the FDA in July, further makes the Dexcom ecosystem attractive to its commercial pump, smart pen, digital health, and AID partners. As a reminder, Dexcom previously did support an API, but FDA restrictions prohibited real-time data sharing meaning patients could only access their data on a three-hour delay. With real-time APIs, third party app developers who are invited to and interested in integrating Dexcom CGM data into their app will be able to do so in real-time, opening the door for numerous CGM data integrations across diabetes coaching, wellness, fitness, and other apps. In an exciting pipeline update, Mr. Leach shared that the company intends to bring real-time APIs to Europe, the Middle East, and Africa over the coming months, eventually expanding worldwide. Given that a real-time API for CGM data is unprecedented, we’ll be watching to see how its use plays out for patients, partners, and providers and how Dexcom leverages this clearance to further invest in software and digital health.

  • Concluding the session, Mr. Leach reiterated remarks from the company’s 2Q21 earnings report that Dexcom G7 has been submitted for CE-Mark approval and is slated for an OUS launch “by the end of 2021.” Mr. Leach highlighted many features of the Dexcom G7 CGM, most notably: (i) the fully disposable sensor and transmitter design; (ii) the redesigned app experience; and (iii) the 30-minute warmup speed. Mr. Leach also touched on preliminary pre-pivotal data on Dexcom G7 (n=91) from ATTD 2021, showing strong accuracy with an overall MARD of 8.7%. In the US, the pivotal trial is complete (as we had guessed based on Mr. Sayer’s language at Keystone 2021). Dexcom is currently processing the pivotal data and “working toward preparing” the regulatory filing for iCGM submission.

24-month results from FUTURE study of FreeStyle Libre in type 1s: significant reduction in severe hypoglycemic events and work absenteeism; 30% patients achieved <4% of time <70mg/dl

Dr. Sara Charleer (KU Leuven) presented 24-month results of the FUTURE study on FreeStyle Libre use among Belgian patients with type 1 diabetes demonstrating improved quality of life outcomes and reduced hypoglycemia following CGM initiation. In July of 2016, Belgium approved reimbursement of FreeStyle Libre 14-day CGMs for all people with type 1 diabetes, after which point the FUTURE study (n=1,906) was conducted across three diabetes centers to assess the impact of CGM use on quality of life and glycemic control. At 24 months, there was a small amount of attrition with 237 people discontinuing FreeStyle Libre CGM use bringing the study population to 1,577 patients with type 1 diabetes. At baseline, patients had an A1c of 7.8% and the vast majority (77%) used MDI therapy while 22% used insulin pump therapy. While there was no statistically significant improvement in A1c after 24 months, patients did experience fewer episodes of severe hypoglycemia down from 314 hypoglycemic events that required assistance from others in the six months prior to CGM initiation to 150 events between 18-24 months post CGM initiation (p<0.001). Patients also experienced fewer hypoglycemic comas down from 67 in the six months prior to CGM use to 18 events 18-24 months after initiating CGM (p<0.001). While we are very aware of work absenteeism, and potential improvements from technology, the data on the substantial decrease in work absenteeism from 134 events in the six months prior to CGM use to only 39 events 18-24 months after CGM initiation (p<0.001) was quite startling and very positive.  These reductions have huge implications for health care costs and also serve a good reminder of the often-overlooked non-healthcare related benefits from using CGM technology.

  • At 24-months, a significantly higher percentage of patients met Time in Range consensus targets compared to baseline, building on 12-month results. Specifically, 30% of patients achieved <4% of time <70mg/dl at 24-months compared to 24% at baseline (p<0.001), 12% achieved >70% of time between 70mg/dl – 180mg/dl compared to 10% at baseline (p<0.05), 20% achieved <25% of time >180mg/dl compared to 19% at baseline (p<0.05), and 21% achieved <5% of time >250mg/dl compared to 15% at baseline (p<0.001). While these numbers do demonstrate improvement over 24-months, the improvement is relatively modest and indicates there is still an extremely high percentage of people who are struggling to meet consensus Time in Range targets.
  • Participants also saw improvements in quality-of-life outcomes at 24-months, namely on the Diabetes Technology Questionnaire satisfaction subsection with initial improvement seen at 12-months and maintained out to 24-months (p<0.001). Participants in the FUTURE study also completed the Problem Areas in Diabetes survey and hypoglycemic fear survey worry subsection at baseline, 12 months, and 24 months, but no significant differences were found between the scores.

FreeStyle Libre use associated with 0.6% A1c reduction in type 1s (n=138); differences in A1c reductions by reason for use with greatest reductions of 0.9% among patients with high A1c (n=22)

Dr. Puja Thandani (University Hospital Coventry and Warwickshire, UK) presented data from a retrospective study on FreeStyle Libre use among 138 patients in the UK demonstrating improved A1c and reduced hospitalizations for DKA, hyperglycemia, and severe hypoglycemia six months after system initiation (SO-537). In the UK, FreeStyle Libre is available to patients with type 1 diabetes granted they meet one of the following criteria: (i) frequent monitoring (>8 times per day); (ii) pregnancy; (iii) disability; (iv) occupational or psychosocial circumstances; or (v) frequent hypoglycemia or hypoglycemia unawareness. Given these five indications, Dr. Thandani investigated whether there was a differential impact of FreeStyle Libre use due to patients’ reason for use. Patients identified for the study initiated FreeStyle Libre use on the 14-day CGM between August 2019 – March 2020 and had data available at six-month follow-up. The average patient age was 43 years old with an average diabetes duration of 19 years and baseline A1c of 8.6%. Of the patient population, 28% used FreeStyle Libre due to frequent hypoglycemia, 35% for occupational reasons, 22% because of high A1c, 17% due to psychosocial factors, 16% for hypoglycemia unawareness, and 9% for frequent testing. Six months after FreeStyle Libre initiation, patients experienced an average A1c reduction of 0.6% to 8.0% (p=0.001). Notably, as has been seen in other studies, the largest improvements were seen in those with higher baseline A1cs. Specifically, patients with a baseline A1c between 8.6%-11.3% (mean 9.6%) saw an average 0.8% A1c reduction (p<0.05). For patients with a baseline A1c >11.3% this reduction was an even larger 3% to an average A1c of 9.6% (p<0.05).

  • By indication, patients who initiated FreeStyle Libre due to high A1c, frequent hypoglycemia, or occupational reasons all saw significant reductions in A1c. Specifically, patients with high baseline A1c (n=22) experienced an average A1c reduction of 0.9% to 8.3% at six months (p=0.033). Patients with frequent hypoglycemia (n=39) saw a 0.6% reduction to 7.5% (p=0.004) and patients with occupational indications, such as those with irregular work schedules or physically demanding jobs, saw a 0.4% reduction in A1c to 8.1% after six months (p=0.028). While FreeStyle Libre use for other indications, namely psychosocial reasons (n=17), hypoglycemia unawareness (n=16), and frequent SMBG (n=9) was not associated with significant A1c reductions, Dr. Thandani suggested this may have been due to the smaller study group size for these subpopulations.

  • Notably, patients on FreeStyle Libre experienced fewer hospitalizations for hyperglycemia, DKA, and hypoglycemia in the six months following system initiation compared to the prior six months – this is a big deal. For hyperglycemia and DKA, patients in the study population experienced 52 recorded events prior to FreeStyle Libre use, and this value declined substantially to only two events in the six months following FreeStyle Libre initiation. Hypoglycemic events were less common than DKA in the study population prior to FreeStyle Libre use with only five reported events. And, in the six months following FreeStyle Libre initiation, this declined to zero events – we’re sure patients were hugely grateful for fewer severe events and imagine this could contributed meaningfully to improved productivity and quality of life and presumably, at least potentially, even cost savings.

DPV registry analysis finds that CGM use reduces adjusted A1c by 0.2% in type 1s (n=2,994) and in type 2s (n=1,440) after three to six months of use; improvements maintained past six months

In a mid-day session on therapeutic advances, Dr. Stefanie Lanzinger (Ulm University, Germany) shared DPV registry analysis from Germany and Austria (SO 300) that found that CGM use reduced adjusted A1c in both type 1s and type 2s after three to six months of use. The study included 4,434 adults with type 1 and type 2 diabetes who started using CGM after 2015 and used CGM for at least three months. At baseline, type 1s (n=2,994) and type 2s (n=1,440) had a mean A1c of 7.7% and 7.2%, respectively, a median age of 18 years and 68 years, respectively, and had had diabetes for 11 and 13 years, respectively. While “the majority” of type 2 participants were on insulin or other “pharmacological” medications (likely oral or injectable medications),Dr. Lanzinger noted that some participants were not on any pharmacological medications and notably not all participants were on insulin. The researchers compared baseline to two follow-up points: (i) three to six months after CGM initiation; and (ii) more than six months after initiation.

  • Participants with type 1 (n=2,994) saw a significant 0.2% adjusted A1c reduction from 7.7% at baseline to 7.5% after three to six months of CGM use, which was maintained at the second follow-up (>6 months; p<0.001). Likewise, type 1s saw a significant reduction in adjusted severe hypoglycemia event rates (11/100 patient years vs. 8/100 patient years) after at least six months, although this was not seen at the earlier follow-up point (p<0.001). Participants with type 1 did not see a change in BMI at either follow-up point (p=0.151).

  • As with type 1s, participants with type 2 diabetes (n=1,440) saw a significant 0.2% adjusted A1c reduction from 7.2% at baseline to 7% after three to six months of CGM use, which was maintained past six months (p<0.001). Although type 2 participants did not see a reduction in adjusted severe hypoglycemia event rates, this was already quite low compared to type 1s (~1-2 events/100 patient years). Notably, unlike type 1s, those with type 2 diabetes did see a significant reduction in adjusted BMI z-score, although the reduction was not large (p<0.008).

  • This real-world evidence adds to the growing body of evidence supporting the use of CGM in people with type 2 diabetes. As Dr. Lanzinger highlighted in the beginning of her talk, the RCT MOBILE study, which was read out at ATTD 2021 and published in JAMA, provided evidence supporting the use of rt-CGM in type 2s on basal-only therapy who are treated in primary care. The same issue of JAMA published a real-world retrospective study from Kaiser Permanente that showed that type 2s (97% of whom were on basal-bolus therapy) saw a 0.6% A1c drop after initiating real-time CGM compared to non-users. Likewise, at ADA 2021, Dr. Thomas Grace (Blanchard Valley Diabetes Center) read out results from a six-month prospective, single-arm study found that Dexcom G6 drove an A1c drop from 10.1% to 7.1% after six months in type 2s on basal-only or non-insulin therapy (n=28). We’d love to see sub-analysis of this DPV dataset breaking down the type 2 participant population based on their baseline medication use, in particular comparing improvements for insulin users and non-insulin users, as it might provide further support for the expansion of CGM into broader type 2 populations. Either way, certainly at this starting point of 10.1%, we are very happy to see these patients in trials and getting some attention.

The future of CGM: New systems face technical and physiological challenges

In a session on how devices can support diabetes treatment, Dr. Guido Freckmann (IfDT, Ulm, Germany) argued that developers of next-generation CGMs will face many challenges to successfully bring devices to market. Dr. Freckmann prefaced his exploration of the CGM-frontier with a history of the glucose monitoring arena, highlighting the development of BGMs and CGMs while weighing the advantages and drawbacks of several commercial systems. Turning to the product horizon, Dr. Freckmann surveyed various approaches to non-invasive glucose monitoring (e.g., Raman spectroscopy, etc.) and provided history on past projects to detect glucose in various body compartments, with a spotlight mention of Verily’s discontinued glucose-sensing contact lens. Dr. Freckmann explained that early prototypes of noninvasive CGMs have undergone testing and performed similarly to early CGMs from when the technology was still in its infancy. As an example, he touched on DiaMonTech’s D-Base, which was revealed to have a MARD of 11.3% in early clinical tests that were published in the Journal of Diabetes Science and Technology and shared at DiabetesMine’s D-Data Exchange in June. While this degree of accuracy is an accomplishment given significant complexities inherent in noninvasive glucose monitor development, it is still significantly higher than other BGMs and CGMs currently on the market and well-above the accuracy needed to qualify for an iCGM designation or run an AID system. We share Dr. Freckmann’s excitement for the future of CGM and how noninvasive wearables might fit into the market in due time, and we know that there are a number of companies also working to develop noninvasive CGM technology, including recently-funded Biolinq, among others less well known but that may have some opportunities depending largely on the regulatory landscape – see our CGM competitive landscape for the full list.

  • Specifically, Dr. Freckmann argued that next-generation CGMs will face both technical and physiological challenges. On the technical side, challenges include: (i) method specificity to glucose; (ii) signal-to-noise ratio; (iii) inter-individual variability; and (iv) calibration. Physiological challenges include: (i) detection limits or influencing factors, both physiological (e.g., skin color) or non-physiological (e.g., skin cleanliness or temperature); and (ii) compartment differences. Dr. Freckmann underscored the difficulties of compartment differences by showing the difference in glucose concentrations in blood, interstitial fluid, saliva, sweat, and tears. While each of these concentration ranges can be correlated to capillary glucose measurements, developers must gather enough clinical data to build algorithms that can translate the compartment measurement into a blood glucose value, also compensating for any time lags between these values that might affect clinical decision making.

  • Dr. Freckmann concluded with musings on the future of the CGM market, predicting that glucose sensors will penetrate additional indications beyond diabetes. As an example of how CGM can be useful to people beyond those with just diabetes, Dr. Freckmann referred back to his poster from ATTD 2019, which showed that meal composition affects post-prandial glucose concentrations in people without diabetes, and that these people experienced considerable glucose fluctuations under daily-life conditions. As a result, Dr. Freckmann argued that CGM data can add value when thinking about nutrition, obesity, general lifestyle, and sports. We’ve already seen CGM begin to penetrate the athletics market, with companies such as Supersapiens marketing CGM as a “sports biosensor” that provides athletes with personalized insights to optimize their performance. We remain eager to see how consumer CGM performs in “wellness” markets over the coming months, and certainly agree with Dr. Freckmann’s thoughts on the power of CGM data to improve glycemic management for everyone – not just people with diabetes.

Q (Armaan Nallicheri, Close Concerns): Regarding your last point, while many, including us, believe that CGM has great potential to flourish in the wellness and sports markets [given the long term benefits of metabolic health], we also wish to see more of the many people with diabetes get access who don’t have it already (e.g., basal-only type 2s). Any thoughts on how and when we might see this happen? 

A (Dr. Guido Freckmann, IfDT, Ulm, Germany): That will depend on the costs, and ultimately on what payers are willing to pay. We will see more sensors come to market in the coming years, and the question is, how accurate do those sensors need to be to draw good conclusions out of them?

First-ever LifeScan BGM real-world study: 4,154 type 1s and 13,623 type 2s see +8% and +11% improvements in results in range at 90 days, respectively; engagement with OneTouch Reveal app improves glycemic outcomes; 180-day data forthcoming

Dr. Mike Grady, PhD (LifeScan) unveiled a first look at real-world evidence (n=4,154 type 1s and 13,623 type 2s) on users of LifeScan’s OneTouch Verio Reflect meter and Reveal mobile app (App StoreGoogle Play). LifeScan reigns as a BGM giant, with over 20 million users confirmed in August 2021. As a reminder, LifeScan recently announced a wave of new integrations to support its upcoming LifeScan Solutions portal that will launch later this Fall, partnering with Cecelia Health, Fitbit, Noom, and Welldoc. Through LifeScan’s partnerships, the company provides further opportunities to pull insights from BGM data, which we are thrilled to see. LifeScan also differentiates its OneTouch Reveal app from other BGM apps by including a Time in Range feature, similar to what we have grown accustomed to with CGM, bringing a valuable series of metrics to millions of BGM users. We see value in offering people with diabetes a more comprehensive understanding of how lifestyle factors can affect blood glucose levels, whether BGM or CGM users.

  • In the real-world study, people with type 1 and type 2 diabetes using OneTouch Verio Reflect BGM and Reveal app saw an 8% and 11% improvement in results in range at day 90, respectively. While it’s hard to analyze these results through the same lens as Time in Range data, these improvements are directionally favorable, especially given the large samples, even if these are not controlled trials. The improvement in results in range across both arms of the study was due in large part to a reduction in hyperglycemia though hypoglycemia did increase to slightly over 5% (this was a 10% increase overall and whether severe hypoglycemia was present was not noted). Mean glucose readings at day 90 decreased by 15 mg/dl to 160 mg/dl in type 1s and by 18 mg/dl to 140 mg/dl in type 2s.

People with Type 1

(n=4,154)

Baseline (first 14 days)

Day 90 (last 14 days)

Change (Baseline to day 90)

Mean glucose (mg/dl)

175

160

-15

% <70 mg/dl

4.8

5.3

+0.5

% results in-range (70 mg/dl – 180 mg/dl)

58

66

+8

% >180 mg/dl

37

28.5

-8.5

 

People with Type 2

(n=13,623)

Baseline (first 14 days)

Day 90 (last 14 days)

Change (Baseline to day 90)

Mean glucose (mg/dl)

158

140

-18

% <70 mg/dl

1.2

1.3

+0.1

% results in-range (70 mg/dl – 180 mg/dl)

72

83

+11

% >180 mg/dl

26.5

15

-11.5

  • Notably, engagement with the OneTouch Reveal mobile app improved results in range in both type 1s and 2s. Dr. Grady explained that engagement could be measured either as number of sessions on the app per week over 90 days or as minutes spent per week on the app over 90 days, and both are included as independent variables in the study’s analysis. Type 1s saw a 4% improvement with one session per week (n=622), a 7% improvement with two to three sessions per week (n=702), and a 12% improvement with 4-10 sessions per week (n=1,107). As a function of minutes on the app, type 1s saw a 3% improvement in results in range with three to five minutes per week (n=514), 8% with 11-20 minutes (n=721), and 14% with >1 hour (n=802). Type 2s saw similar results in range improvements, with a 5% increase at <1 session per week (n=1,673), 11% at two to three sessions per week, and 13% with >10 sessions per week (n=3,469). That translates to a 3% improvement for ≤two minutes per week of app time (n=849), 8% for three to five minutes (n=1,265), and 12% for 11-20 minutes (n=2,439).

  • Furthermore, engagement with the OneTouch Reveal mobile app reduced mean glucose readings across both cohorts. In type 1s, those who had two to three sessions per week on average (n=702) saw a 14 mg/dl decrease in mean glucose, followed by a 21 mg/dl decline for those who had 4-10 sessions (n=1,107), and a 25 mg/dl decline for those with >10 sessions (n=915). Alternatively, those with 6-10 minutes of engagement per week (n=655) had a 6 mg/dl improvement in mean glucose, followed by those who spent 11-20 minutes on the app (n=721; -15 mg/dl) and those spending >1 hour (n=802; -29 mg/dl). Turning to type 2s, those who had less than one session per week on average (n=1,673) saw a 9 mg/dl decline in mean glucose, followed by those who had two to three sessions (n=2,090; -18 mg/dl) and those with >10 sessions (n=3,469; -22 mg/dl). From the perspective of app time, those with ≤two minutes of engagement per week (n=849) had a 5 mg/dl improvement in mean glucose, followed by those who spent 11-20 minutes on the app (n=2,439; -18 mg/dl), and those spending >1 hour (n=2,641; -22 mg/dl).

  • Dr. Grady shared that 180-days of real-world data from LifeScan’s BGM will be coming “soon.” Given that at 90-days more time on the OneTouch Reveal app (or more “sessions” per week) improved outcomes, we’re looking forward to seeing the extension of this data.

ISCHIA Study: FreeStyle Libre with structured education reduces time in hypoglycemia in adults with type 1 diabetes on MDI (n=102) relative to BGM in crossover RCT

After technical glitches prevented the presentation from playing on Friday, Dr. Takashi Murata (NHO Kyoto Medical Center, Japan) presented the ISCHIA study for on-demand viewing (OP 235). The ISCHIA study assessed the effect of FreeStyle Libre combined with structured education on glycemic control, hypoglycemia, and quality of life in adults (ages 20-74) with type 1 diabetes on MDI in Japan (n=102). All participants had had diabetes for at least five years, a baseline A1c ≤8.5%, and at least three injections/day and three fingerstick measurements/day in the last 30 days. Their average baseline A1c was 7.3% and BMI was 23. Nearly half (46%) were CGM-naïve. The crossover, multicenter RCT included an 84-day FreeStyle Libre period and an 84-day BGM period, during which FreeStyle Libre Pro was used as a blinded CGM. All participants received structured education on how to prevent hypoglycemia using FreeStyle Libre based on the trend arrow and via frequent sensor scanning. The study had a high retention rate with only 9% dropping out (two in the group that started on BGM and four in the group that started on CGM. Dr. Murata did not disclose their reason for dropping out. Participants scanned an average 12 times/day when on FreeStyle Libre, wore FreeStyle Libre 93% of time in the 84-day period, and tested 3 times/day when using BGM.

  • Participants saw a significantly reduction in time below range when on FreeStyle Libre with structured education compared to BGM. Specifically, participants spent 2.4% of time below range (<70 mg/dl) on FreeStyle Libre compared to 3.1% of time below range on BGM (p=0.012). Although statistically significant, this improvement isn’t the most clinically significant, as participants were, on average, already achieving the consensus target of <4% time below range. Participants also had a significantly lower low blood glucose index score on FreeStyle Libre relative to BGM (2.5 vs. 3.3; p=0.013) and fewer had a LBGI score >5 on the FreeStyle Libre relative to BGM (9% vs. 24%; p<0.001). Although LBGI and time <70 mg/dl saw improvements, the frequency of severe hypoglycemia did not differ significantly, although it trended toward improvement with FreeStyle Libre, suggesting that fewer patients were included in the high-risk category when on FreeStyle Libre (2.1% vs. 6.5%; p=0.361). Given these slight but statistically significant improvements in hypoglycemia with FreeStyle Libre and structured education, it would have been interesting to see a similar intervention in those who are at high risk for hypoglycemia or who do not already have strong baseline control.
  • Although participants’ time below range improved on FreeStyle Libre, they did not see a significant Time in Range or time above range improvement with FreeStyle Libre relative to BGM (p=0.45). Likewise, participants actually had a significantly higher mean glucose when on FreeStyle Libre compared to BGM (151 mg/dl vs. 140 mg/dl; p=0.034). While this could be attributed to lower rates of hypoglycemia, the fact that hypoglycemia fell only 10 minutes/day in the FreeStyle Libre treatment relative to the BGM treatment suggests that a reduction in hypoglycemia is unlikely to be the core reason behind this rise in mean glucose.

Accuracy data for small, injectable Lumee CGM (with 3 calibrations/day) demonstrates 92% of paired sensor values fall within Zone A; sensor based on fluorescent technology

Accuracy data from a novel injectable CGM device, Lumee, was read out in a short oral presentation (SO-544) and demonstrated strong correlation to blood glucose reference values with 92% of paired sensor values (n=2,658) falling within Zone A on a Parkes Error Grid. Lumee is a small injectable hydrogel sensor (2.5 x 0.4 x 0.3 mm) that is injected under a patient’s skin for up to 95 days and uses “optical principles” to measure glucose levels. Patients also wear a small wireless optical reader on the surface of their skin to measure the fluorescent signals emitted from the hydrogel sensor that change in proportion to interstitial glucose levels. In this safety and accuracy study, seven patients with type 2 diabetes had two sensors injected in their upper arm and completed nine visits over a period of three months. At each visit, patients underwent six hours of sensor signal monitoring and had capillary blood glucose levels drawn every 15 minutes to serve as reference points. All injected sensors (n=14) were functional out to 95 days when the study was concluded. Patients performed three calibrations per day and 79% of sensor traces demonstrated strong correlation (R2>0.5) with capillary blood glucose reference points. For example, on day 71, the 14 sensors had an average MARD of 5% with an R2 = 0.87 in reference to capillary blood glucose measurements. As is common with many CGM systems, accuracy was weakest on Day #1, but improved over the course of Week 1 and was then stable out to 13 weeks. The investigators also conducted Parkes Error Grid analysis and found that 92% of all paired sensor data points from week 0 to week 13 fell within accuracy Zone A with only 8% in Zone B and 0.2% in Zone C. This demonstrates strong accuracy of the device and is comparable to other systems including Dexcom’s G7 and Medtronic’s Guardian 4 CGM. That said, this is a much smaller study size with a markedly smaller number of paired sensor readings at 2,658 compared to 46,619 for preliminary pre-pivotal data of G7 and 20,612 for Guardian 4. Additionally, three calibrations per day is substantially higher than currently available systems offering users one to zero calibrations, however, we are excited to see another subcutaneous glucose sensor in development as we believe there is certainly a market for fully implantable CGMs.

Retrospective cohort study finds that FreeStyle Libre is as effective and safe as BGM in pregnant women with type 1 on MDI (n=118); minority of women on FreeStyle Libre achieving Time in Range target during pregnancy

In a session on diabetes in pregnancy, Dr. Núria Seguí (Clínic Barcelona Hospital Universitari, Spain) read out the results of a retrospective cohort study (SO 345) that found that FreeStyle libre is as effective and safe as BGM in pregnant women with type 1 on MDI (n=118). The study compared those with FreeStyle Libre data from 2018-2020 (n=60) to those with BGM data from 2013-2018 (n=58). At baseline, the two groups were statistically equivalent, except that the BGM group had a significantly higher proportion who were current smokers when they became pregnant (30% vs. 15%; p=0.047). The CGM group included those with at least 14 days of CGM data from each trimester available on LibreView. When adjusted for confounding variables, there were no significant differences between the CGM and BGM group in obstetric and neonatal complications. Likewise, a statistically equivalent percentage of women in the BGM and CGM groups achieved an A1c <6.5% during each trimester (CGM vs. BGM: 59% vs. 54% in first trimester, 85% vs. 82% in second trimester, 76% vs. 77% in third trimester). This suggests that at a minimum, CGM is as safe and effective as BGM in pregnant women with type 1 diabetes on MDI. Although a small, retrospective study, this contributes to the building body of evidence supporting the use of CGM in pregnant women with type 1 diabetes, the most notable of which is the CONCEPTT study and the CONCEPTT study subanalyses, such as that presented at ATTD 2021 on Time in Range and pregnancy outcomes.

  • The FreeStyle Libre group spent between 60% and 69% of Time in Range during each trimester, rising from 60% in the first trimester to 70% in the third trimester. On average, the cohort did not meet the consensus targets for Time in Range (>70% of time 70 mg/dl-140 mg/dl), nor the target for hypoglycemia (<4% of time <70 mg/dl) during any trimester. In fact, the participants spent a concerning 13% of time <70 mg/dl in the first trimester, 9% in the second trimester, and 10% in the third trimester. Participants on CGM did achieve the consensus target for time above range (<25% of time >140 mg/dl) in the third trimester (23%) but did not achieve the target in the first two trimesters. They used a CGM for ~91%-94% during their pregnancies. This suggests that additional education and support beyond CGM use might be necessary to support pregnant women with type 1 in achieving strong control throughout their pregnancy – from our view, we certainly think that AID for anyone who is pregnant would be outstanding.

Small retrospective cohort study (n=232) finds association between CGM + MDI treatment regimen and reduced risk of poor perinatal outcomes in pregnant women with type 1

During an afternoon short oral session, Dr. Katerina Anderlova (Charles University and General University Hospital, Prague, Czech Republic) presented findings of a small retrospective study on diabetes technology in pregnancy (SO 566). The retrospective cohort study included 232 pregnant women with type 1 diabetes in the Czech Republic. For analysis, participants were split into four cohorts based on their glucose monitoring and insulin delivery technology: (i) CGM + MDI (n=33); (ii) CGM + pump (n=55); (iii) BGM + MDI (n=55); (iv) BGM + pump (n=89). The four cohorts had statistically equivalent BMI, ages, duration of diabetes, and rates of complications at baseline, but those who were on BGM + MDI were significantly less likely to have attended preconception counseling than those on CGM + pump (18% vs. 53%; p=0.002). Women using CGM (either with pump or MDI) had also lower preconception A1c values than did women using BGM (7.2% vs. 7.9%; p=0.005); however, the same did not hold true during any trimester of pregnancy. The researchers found that CGM + MDI use reduced the odds of operative delivery by 71%, large for gestational age by 66%, and umbilical artery pH<7.15 by 96% (all p<0.04); however, notably, these associations did not reach statistical significance when adjusted for maternal age, BMI, diabetes morbidity, and diabetes compensation. Given that this is a retrospective cohort study, it’s challenging to draw any conclusions on the role that CGM use had in improving perinatal outcomes, particularly given the association between CGM and preconception A1c. That said, this data is still noteworthy for its contribution to the expanding body of evidence available on CGM in pregnancy, the most notable of which is the CONCEPTT study and the CONCEPTT study subanalyses, such as that presented at ATTD 2021 on Time in Range and pregnancy outcomes.

Older age and CGM use associated with improved glycemic control among type 2s using Omnipod or Omnipod DASH; average glucose of 172 mg/dl for CGM users vs. 180 mg/dl for BGM users

Retrospective assessment of glycemic profiles and insulin treatment patterns of 3,358 patients with type 2 diabetes using the Omnipod or Omnipod DASH systems found that across age-groups, patients using CGM had lower average blood glucose readings than those using SMBG (SO-563). For this analysis, data from type 2s using the Omnipod or Omnipod DASH systems between January 2015 and August 2021 were collected (n=3,358). Of this study population, 1,989 patients used SMBG and reported ≥14 days of blood glucose meter data and 596 patients used CGM reporting a minimum of 14 days’ worth of data over a three-month period. At baseline, the average patient age was 57 years old, and the study population was 54% female. Patients had an average total daily insulin dose of 61 units with an average of 3.2 boluses per day that aligns well with the expected number of meal-time boluses patients with type 2 on basal-bolus insulin therapy would be performing. However, while nearly all (96%) of Omnipod and Omnipod DASH users bolused at least once per day, basal insulin still comprised ≥50% of patient’s total daily insulin dose for 78% of users and ≥70% of patient’s total daily insulin dose for 26% of users.

  • Among BGM users, those in the older age brackets (65 to ≤75 years old (n=411) and ≥75 years old(n=90)) had the lowest average glucose levels at 170 mg/dl and 166 mg/dl, respectively. This was in comparison to average glucose levels of 182 mg/dl among users ages 50 to <65 years old (n=1,014), 187 mg/dl among users 18 to <50 years old (n=465), and 218 mg/dl among users <18 years old (n=8). Additionally, older users in the ≥75 year old age bracket reported the highest number of blood glucose readings per day at 3.7 readings per day, which still falls well below the ADA recommended seven fingersticks per day for insulin-requiring patients.
  • Among CGM users, average glucose was lower than for BGM users at 172 mg/dl compared to 180mg/dl. Similarly to BGM users, older patients on CGM in the 65 to ≤75 years old age bracket (n=131) and ≥75 years old age bracket (n=25) had the lowest average glucose levels of 167 mg/dl and 158 mg/dl. Additionally, while the CGM population was smaller than the BGM population in this study, representing 18% of users analyzed, we were excited to see that many type 2 patients were on CGM. However, baseline glycemic control was not available for either group, somewhat limiting our ability to compare between the BGM and CGM subgroups
  • During Q&A, study author Dr. Tina Kader (The University of Vermont Health Network) shared her thoughts on the results, raising a question around what other agents patients in the study may have been taking such as metformin, GLP-1s, or SGLT-2s and how these agents may have also influenced glycemic outcomes. Additionally, discussing potential age-related factors and the improved glycemic control seen among older patients, session moderator Professor Roman Hovorka (University of Cambridge) questioned whether there may have been some level of self-selection leading older patients in better glycemic control to have increased longevity and thus over-representation in the study. While Dr. Kader did not have data to answer these questions, they certainly provide additional research topics for further study.

Digital Health Highlights

Integrated Personal Diabetes Management drives improved outcomes; importance of PROs when assessing efficacy of digital health solutions

In a Roche-sponsored symposium, Professor Kamlesh Khunti (University of Leicester) discussed Roche’s Integrated Personalized Diabetes Management (iPDM) platform and the importance of incorporating patient reported outcomes into diabetes data management platforms. Prior data on Roche’s iPDM system indicated that use of the platform was associated with improved glycemic control and cost savings. Walking attendees through this data, Prof. Khunti specifically highlighted the PDM-ProValue study from 2018, which demonstrated use of the Roche’s iPDM was associated with decreases in A1c, decreased hypoglycemic events, increased patient satisfaction, increased consistency of medication use, and increased physician satisfaction. Prof. Khunti also emphasized the ability of Roche’s iPDM to integrate real-world data from patient devices including connected BGMs, CGMs, insulin pumps, and connected smart pen devices. As a reminder, some of the connected devices compatible with Roche’s iPDM include the mySugr app, which was recently integrated with NovoPen 6 and NovoPen Echo Plus and enables smartphone control of Roche’s Accu-Check Insight insulin pump which is also part of a Diabeloop DBLG1-powered AID system.

  • Discussing patient-reported outcomes, Prof. Khunti argued in favor of including PROs when assessing the efficacy and impact of digital health solutions. However, Prof. Khunti did acknowledge that there are many challenges to broader use of PROs including: (i) lack of validation around digital-health specific PROs; (ii) lack of strong association between some PROs and clinical endpoints; (iii) lack of reimbursement for digital health solutions based solely on PROs; and (iv) barriers to integrating PRO reporting mechanisms into digital health solutions. That said, Prof. Khunti advocated to overcome these challenges by developing consensus approaches to evaluating PROs in the context of digital health as well as conducting additional research to investigate potential links between PROs and clinical outcomes. Additionally, Prof. Khunti argued that new PRO measures may need to be developed to match the specific interventions of individual digital health solutions and that when PROs are collected via digital health it must be done in such a way that it does not increase the burden experienced by patients or negatively impact patients’ diabetes management.

Drs. Moshe Phillip and Tadej Battelino discuss future of diabetes technology highlighting improved outcomes, decision support, and automated insulin delivery

Dr. Tadej Battelino (University Medical Center Ljubljana) and Dr. Moshe Phillip (Schneider Children’s Medical Center of Israel) presented components of their EASD e-learning course on “New Technologies for the Treatment of Diabetes” highlighting improved outcomes from AID systems and the need for decision support at the patient and provider levels. EASD e-learning is an online platform providing free educational content on diabetes management that had nearly 6,000 users from 153 countries as of August 2021. In this abbreviated version of their course on diabetes technology, Drs. Battelino and Phillip pulled from their wide-ranging knowledge of diabetes technology to discuss recent advancements with the more than 200 attendees. Dr. Phillip began the presentation by expressing hope that one day there will be a cure for diabetes – certainly our dream as well! – but that until that dream is realized, diabetes technologies can help those living with the disease improve outcomes and reduce burden, especially for patients with insulin treated diabetes. Highlighting data from the SWEET registry, which was read out at ATTD 2021, Dr. Battelino expressed that technology uptake has been associated with improved glycemic control. Furthermore, Dr. Battelino discussed results from the MOBILE study, also read out at ATTD 2021 and published in JAMA, which demonstrated that CGM use was associated with improved diabetes management among type 2s on basal-only therapy. Not to mention the substantial improvements in diabetes control that have been seen across automated insulin delivery systems including MiniMed 780G, Control-IQ, and Omnipod 5. Discussing the implications of these results collectively, both Dr. Battelino and Dr. Phillip argued in favor of increased technology uptake among people living with diabetes, but also recognized that patients will have different preferences for the types of technology they will choose to use and that, regardless of a patient’s technology usage, they should still have access to the highest quality of care. 

  • Recognizing that not all patients will want to use AID systems, Drs. Battelino and Phillip discussed new data presented at ATTD 2021 from the DreaMed Advisor Pro platform for MDI. As a reminder, this study demonstrated that the AdvisorPro system offered non-inferior dosing advice for treatment decisions and insulin titration compared to medical experts for patients on MDI. Highlighting these results, Dr. Phillip argued that decision support tools like AdvisorPro are like a “genie in the pocket” and could dramatically alter how providers, especially in primary care or those less familiar with insulin therapy, help patients manage their diabetes.
  • During Q&A, Dr. Battelino and Dr. Phillip addressed a question on how decision support tools like AdvisorPro, as well as other technical advances such as AID systems, will change the education paradigm for diabetes management. Dr. Phillip shared that he hopes decision support tools will reduce the amount of education that needs to go into the specifics of diabetes management during clinic visits instead making more time for providers to discuss other aspects of diabetes management with their patients. For his part, Dr. Battelino agreed that decision support tools can reduce the burden of diabetes for patients, but that education must still emphasize the rationale behind treatment so patients understand why medication and treatment adherence is important.
  • Both Dr. Phillip and Dr. Battelino argued against transitioning patients from pediatric to adult care until the patient is ready, expressing their views that it is acceptable for patients in their late teens to early twenties to continue seeing their pediatric endocrinologist whom they have likely been working with for a number of years. In Dr. Battelino’s system, patients are not transferred to adult care until they reach the age of 24 after completing their education and noted that pediatric providers often play an active role in supporting patients as they transition and become comfortable with a new care team.
  • Also in Q&A, Dr. Battelino and Dr. Phillip discussed AID use during pregnancy. Session moderator Professor Pratik Choudhary (University of Leicester) clarified that only the CamAPS AID system is approved for use in pregnancy despite the fact that many women will use other systems such as Control-IQ or MiniMed 780G to help manage their glucose levels. Both Dr. Phillip and Dr. Battelino expressed that though the glucose set points of some AID systems are above the tight control recommended during pregnancy, they can still be very beneficial for women who are struggling to bring their glucose levels down. Additionally, during especially stressful times of pregnancy including labor and delivery, Dr. Phillip emphasized that women should use whatever diabetes management method they are most comfortable with.
  • Discussing behavior modifications, Dr. Battelino emphasized the power of technology to give patients actionable information in real time instead of focusing on retrospective data. Specifically, Dr. Battelino expressed that the past can’t be changed and so using data to support and encourage patients moving forward has the largest potential to drive sustainable improvements.

IDF Europe symposium: Data interoperability and personalization in diabetes; differences in application of EMR and user-generated data; emphasis on actionable insights and data

The International Diabetes Federation’s (IDF) afternoon symposium featured a lively, diverse mix of speakers discussing the use of data in diabetes through a patient-centered approach. The panelists came from very different backgrounds that ultimately converged on healthcare, and included Mr. Bastian Hauck (Founder & CEO, Dedoc Labs), Mr. Hugo van Haastert (EU Commission), Dr. José Manuel Boavida (President, Portuguese Diabetes Association), Dr. Kari Kivinen (Education Outreach Expert), Ms. Magda Chlebus (Executive Director, EFPIA), Dr. Niek Klazinga (Head, OECD), Dr. Stan Shepherd (CEO, Instant Medical Access), and Mr. Tanel Ross (Advisor, Supreme Council of Health, Kingdom of Bahrain). Moderator Dr. Niti Pall (Chair, IDF Europe) was sure to ask challenging yet stimulating questions on the use of data in diabetes care, and it certainly made for a very riveting discussion.

  • Dr. Pall began by asking panelists whether there exist any differences between user-generated data and EMR data. Mr. Hauck kicked off the discussion by arguing that there currently does exist a difference in the way EMR data is handled compared to personal data from wearables, but that there shouldn’t be in an ideal world. According to Mr. Hauck, both types of data ought to be owned by the consumer and should be able to be used by third-party players to innovate to support innovation. Dr. Klazinga chipped in that both types of data should be used in the doctor’s office during patient consultations, and that interoperability between different parties (i.e., practitioners, hospitals, pharmacies, etc.) is important to make sense of how communities are doing at large via public health data analyses. The flip side, Dr. Klazinga argued, is that aggregate data must also be disaggregated by social determinants of health (e.g., socioeconomic class, gender, race, etc.) to be relevant to certain sub-populations, with which Dr. Boavida agreed.
  • Ms. Chlebus unpacked why data is important to various healthcare stakeholders. Ms. Chlebus argued that data is important to: (i) patients because they wish to better manage their disease; (ii) healthcare systems because they wish to better manage and allocate their resources; and (iii) researchers because they wish to shape our treatment paradigms with maximum impact. According to Ms. Chlebus, we find ourselves in a unique moment where there is an opportunity to structurally embed data interoperability as a standard in our technology systems as we build and scale them. Ms. Chlebus specifically referenced the European Health Data Evidence Network as an example of an organization that is doing just this – addressing current challenges in generating insights from real-world clinical data, and supporting patients, clinicians, payers, regulators, governments, and the industry in understanding wellbeing, disease, treatments, outcomes, and new therapeutics/devices.
  • Several panelists emphasized that healthcare data must enable accessible and actionable insights for patients. Mr. Ross began by emphasizing that as we digitize patients’ data, patients are still the owners of that data, and that health systems have an obligation to present this data to patients in a comprehensible way so that they can make sense of it and use it to further their own health literacy while also taking charge of their personal care. Dr. Shepherd chimed in, expressing that remote patient monitoring, wearable devices, and other innovations of the sort are going to be a game changer in diabetes as they enable the collection and storage of data. In particular, Dr. Shepherd is excited to see digitization remove the dependency of data on location and institutions. He gave a useful metaphor of the patient’s health record being a credit card, explaining that he’d like to see a world where patients can receive care at any institution they like (or in the case of the metaphor, swipe their credit card) and then have all these visits pop up on a centralized portal. Mr. Hauck couldn’t agree more with this perspective and went so far as to say that he also wishes data sharing was not anonymous so that companies can create technologies and therapies using insights that they gathered from patient data; he compared this process to the way Google might tailor YouTube advertisements based off of one’s search history. This opinion was certainly not held by all others in the group, such as Dr. Kivinen, who cautioned that profit-seeking entities might have ulterior motives at heart and might exploit public data if it is not kept anonymous.
  • In a closing remark, Dr. Shepherd emphasized the need for patients to be able to personalize their own care records. While he understands that there are many valid reasons for EMR data to be standardized, Dr. Shepherd sees no reason why personal care records held by the patient can’t be tailored to that person’s unique health needs. As an example, Dr. Shepherd argued that a person with diabetes has very different health concerns than a person with arthritis, and that a given person might have very different health needs from when they are 20 years old to when they are 70 years old. Dr. Shepherd believes that this level of personalization can be empowering, as it simplifies and streamlines the data that a given patient needs for their care.

GLP-1 Agonist and DPP-4 Inhibitor Highlights

SURPASS-3 CGM: Type 2s (n=243) spend +3.8 more hours/day in Range (91%) on tirzepatide (10 mg or 15 mg) relative to insulin degludec at one year; ~90% of tirzepatide dose groups achieve TIR/TAR/TBR targets compared to ~45% in insulin degludec arm – truly stunning results

In a highly anticipated session, Dr. Tadej Battelino (University of Ljubljana, Ljubljana, Slovenia) read out the results of the SURPASS-3 CGM subanalysis, which compared CGM outcomes with once-weekly tirzepatide to CGM outcomes with insulin degludec in type 2s at 24 weeks and 52 weeks. As a reminder, SURPASS-3 compared tirzepatide as an add-on titrated insulin to insulin degludec, and the impressive results were announced in February, read out at ADA 2021, and published in The Lancet in August. The CGM sub-study included 243 people with type 2 diabetes. At baseline, participants had an average A1c of 8.2%, had had diabetes for nine years, and were 57 years old. Almost three-fourths (70%) of participants were on metformin only. The remaining 30% were on metformin and SGLT-2s (sub-analysis comparing those on metformin vs. metformin + SGLT-2 is ongoing). The three tirzepatide groups (5 mg, 10 mg, 15 mg) and insulin degludec were statistically equivalent at baseline. A blinded Dexcom G6 was inserted ~7-10 days prior to baseline, week 24, and week 52 visits to gather CGM metrics. The sub-study’s primary endpoint was time in tight range (70 mg/dl-140 mg/dl) at 52 weeks. The study also investigated time in tight range, Time in Range, time in hypoglycemia, and glycemic variability outcomes for tirzepatide 5 mg, 10 mg, and 15 mg vs. insulin degludec at 24 weeks and 52 weeks. For us, these results are exciting not only because they show that tirzepatide leads to strong CGM-based outcomes at 24 weeks and one year, but also because this study included a pre-planned CGM analysis, something we hope will become increasingly common with the validation of Time in Range and increasing use of CGM.

 

Insulin degludec

Tirzepatide 15 mg

Tirzepatide 10 mg

Tirzepatide 5 mg

 

Baseline

52 weeks

Baseline

52 weeks

Baseline

52 weeks

Baseline

52 weeks

Time in tight target range (70 mg/dl-140 mg/dl)

22%

48%

21%

73%*

26%

72%*

23%

60%*

Time in Range

54%

75%

50%

91%

61%

91%

52%

85%

Time in hypoglycemia (<70 mg/dl)

0.3%

2.4%

0.3%

0.8%

0.3%

1%

0.3%

0.6%

Glycemic variability (CV)

-

24%

-

16%

-

16%

-

19%

*p<0.05 compared to insulin degludec at the same timepoint

  • Those on tirzepatide saw a significant improvement in Time in Range (70 mg/dl-180 mg/dl) compared to those on insulin degludec at one year. At baseline, there was no significant difference in Time in Range across treatment groups (~50%-60% Time in Range, which isn’t at the 70% goal, and certainly leaves lots of room for improvement). Those on tirzepatide 10 mg and 15 mg saw their Time in Range increase from 61% and 50% at baseline, respectively, (statistically equivalent) to 91% at one year, compared to a rise from 54% to 75% with insulin degludec (p<0.001 relative to insulin degludec). Likewise, those on tirzepatide 5 mg saw a statistically significant adjusted improvement relative to insulin degludec, increasing from 52% at baseline to 85% at one year (p<0.05).

  • A significantly greater proportion of participants in the tirzepatide groups achieved the consensus Time in Range (>70%), time below range (<4%), and time above range (<25%) at one year compared to the insulin degludec group. In fact, a whopping ~90% of participants in the tirzepatide group achieved the three target goals at one year compared to only ~45% in the insulin degludec group. These are all up from a baseline of ~25%-35% of participants in each group achieving the three targets. 

  • At 52 weeks, those on tirzepatide 10 mg or 15 mg saw a 5.9 hour/day adjusted improvement in time in tight target range (70 mg/dl-140 mg/dl) relative to those on insulin degludec (p<0.001). Specifically, those on tirzepatide 10 mg or 15 mg increased their time in tight target range from 23% at baseline to 73% at one year while those on insulin degludec saw an improvement from 22% to 48% at one year. This improvement relative to insulin degludec was already apparent at 24 weeks. Those on tirzepatide 5 mg saw a +2.8 hour/day improvement in time in tight target range relative to those on insulin degludec at 52 weeks (p=0.031), although the difference was not significant at 24 weeks.

  • Participants also saw significant hypoglycemia improvements with tirzepatide relative to insulin degludec. At one year, those on tirzepatide 5 mg and 15 mg saw a 26 minute/day and 23 minute/day relative reduction in time in hypoglycemia (<70 mg/dl), respectively, relative to insulin degludec (p<0.001), and those on the 10 mg dose saw a 20 minute/day relative reduction (p=0.003). Similar trends held for time in severe hypoglycemia (<54 mg/dl), although the difference compared to insulin degludec was only significant for tirzepatide 10 mg (four minute/day relative reduction; p=0.03). Overall, those in the tirzepatide 10 mg grew spent 2.5 times less time in hypoglycemia and three times less time in severe hypoglycemia than the insulin degludec, although even the insulin degludec group achieved the consensus targets (<4% <70 mg/dl; <1% <54 mg/dl). Additionally, participants’ glycemic variability was 0.9%-3.4% lower with every dose of tirzepatide relative to insulin degludec (p<0.001 for all doses). Specifically, those on insulin degludec had a glycemic variability of 24% while those on tirzepatide 5 mg, 10 mg, and 15 mg had CV of 19%, 16%, and 16%, respectively, at 52 weeks.

Dr. Stefano Del Prato presents additional data from SURPASS-4 showing consistent benefits in A1c and weight control for up to two years, further evidence of CV risk safety; first mechanism study suggests tirzepatide may act via improved insulin sensitivity

During a morning session on dual GLP-1/GIP agonist tirzepatide, Dr. Stefano Del Prato (University of Pisa, Italy) presented updated results from the SURPASS-4 trial demonstrating continued benefits in A1c and weight control for up to two years in people with type 2 diabetes. As a reminder, initial results from SURPASS-4 showed statistically superior reductions in A1c and body weight with tirzepatide (5, 10, and 15 mg) compared to insulin glargine at 52 weeks. The updated analysis found that benefits in A1c, fasting plasma glucose, body weight reduction, and lipid profiles were maintained at two years. In particular, Dr. del Prato emphasized the 26% reduction in CV events at 104 weeks, which, though not statistically significant, he argued “suggests or supports the CV safety of tirzepatide.” Dr. Del Prato explained that the SURPASS-4 study was designed with an extended variable treatment period, beyond 52 weeks, up to 104 weeks to “favor the collection of CV events” (leaving more time to accrue more events). In our view, the extended trial and apparent divergence of the curves in the Kaplan Meier plot (below) lend further support to the early signs of CV benefit seen at 52 weeks, suggesting, if data from future studies will support, that tirzepatide may potentially lead to CV risk reduction in addition to its favorable glycemic and body weight control. We remain eager for the results from the ongoing SURPASS-CVOT study, which will deliver more data regarding CV safety and/or benefit of tirzepatide. Dr. Del Prato also highlighted the sustained reductions in triglycerides and non-HDL cholesterol, noting that this was an important finding given that these patients are at high CV risk. The extended study also confirmed tirzepatide’s safety profile, with a higher number of adverse events occurring in the tirzepatide vs. glargine group, though Dr. Del Prato stressed that these events were consistent with those seen with the GLP-1 drug class. We look forward to a full readout on the complete CV outcomes in the SURPASS-CVOT, as well as the CV meta-analysis of the SURPASS phase 2-3 clinical development program. We continue to follow closely for updates on Lilly’s intended submission of tirzepatide to the FDA and to global regulatory authorities by the end of the year.

  • Prof. Jan Eriksson (Uppsala University, Sweden) presented the commentary on the updated SURPASS-4 results, highlighting the “striking consistency” in A1c and body weight reductions and speculating on tirzepatide potential in obesity (presumably high). Overall, he emphasized that the A1c and body weight reductions seen with tirzepatide in the SURPASS program are greater than those seen with other antidiabetic drugs, suggesting that “SURPASS” is indeed an appropriate name for the study. Dr. Eriksson also speculated on the potential of tirzepatide for obesity, pointing to the wide dose response for weight loss compared to A1c reduction in SURPASS-2. He suggested that higher doses of tirzepatide are probably needed to achieve meaningful weight loss and even went so far as to speculate that the agent might one day “compete” with bariatric surgery. Given the impressive double digit weight loss seen with semaglutide (presented at ADA 2021), GLP-1s may be started earlier in economies with good reimbursement systems where investment in prevention is encouraged. We’re also happy to see GLP-1 agonists being used more often with bariatric surgery. Certainly weight loss alone with GLP-1 is approaching the level of weight loss with bariatric surgery (see our competitive landscape for more).
  • Later in the session, we learned about one of the first mechanistic studies of tirzepatide from Dr. Tim Heise (Neuss, Germany), which found significant improvements in insulin sensitivity in patients on tirzepatide vs. semaglutide and placebo (n=117). The primary endpoint was the clamp-derived disposition index, which is a measure of both insulin sensitivity and insulin secretion. Dr. Heise described an “impressive” six-fold increase in the disposition index in the tirzepatide group, significantly higher than the three-fold increase observed with semaglutide.
    • Notably, the study also found meaningful increases in whole-body insulin sensitivity (+63% with tirzepatide, +35% with semaglutide, -2% with placebo) as well as clinically relevant improvements in first-phase insulin secretion from baseline to week 28 (+466% in tirzepatide, +298% semaglutide, -20% placebo). Overall, Dr. Heise suggested that these effects of tirzepatide may explain how a large proportion of patients achieved normoglycemia (defined as A1c<5.7%) in the SURPASS program, ranging from 48% in SURPASS-3 to 62% in SURPASS-5. As the data continues to accumulate for tirzepatide and begins to accumulate for other dual agonists, we look forward to more discussion about particularly what outcomes trials might show.

KOLs highlight semaglutide for weight loss in obesity and diabetes, emphasize “four pillars” of treatment strategy, discuss appetite-suppressing mechanism of GLP-1s

In a Novo Nordisk-sponsored session on holistic approaches to type 2 diabetes treatment and weight management in people with obesity, Dr. Vanita Aroda (Harvard, Brigham and Women’s) discussed four pillars to promoting a healthy lifespan in people living with type 2 diabetes and, in discussion with fellow panelists, offered practical suggestions to implement these recommendations. She advocated for treatment approaches that address the following four areas simultaneously: (i) glucose control; (ii) weight management; (iii) CV risk reduction; and (iv) overall disease burden reduction. On the first point, Dr. Juan Pablo Frias (National Research Institute, Los Angeles, CA) reviewed the SUSTAIN FORTE trial (read out at ADA 2021), where semaglutide demonstrated a “robust” A1c reduction in both the 1.0 mg and 2.0 mg groups at 40 weeks and a significantly greater reduction in the higher dose group compared to the lower dose group. On the remaining points, Dr. Aroda emphasized semaglutide’s double-digit weight loss in the STEP program trials (read out at ADA 2021) and the approximately 25% risk reduction in MACE in PIONEER 6 and SUSTAIN 6. She also touted the GLP-1’s potential to improve adherence and reduce overall disease burden in its convenient oral formulation or once-weekly injection. Overall, Dr. Aroda advocated tailoring therapy to support holistic patient-centric goals and highlighted semaglutide’s unique ability to improve eating patterns and thereby contribute to lifestyle changes. During the panel discussion, Dr. John Buse (UNC) stated his belief that “these new drugs are so powerful; I think the future is very bright. Using therapies like GLP-1s early in disease course could potentially mean that a GLP-1 the last diabetes medication a patient needs to experience in their life.” We too are very optimistic about the potential of GLP-1s to reduce the burden of obesity and type 2 diabetes both at the individual patient and health systems level, and we appreciated the panelists’ thoughtful discussion on how to achieve this in the clinic – see more below. 

  • In response to a question by session chair Dr. Tina Vilsbøll (University of Copenhagen, Steno Diabetes Center, Denmark) on how to implement these goals in clinical practice, Dr. Aroda recommended focusing on both short and long-term goals. Discussing her “90-second strategy” for these conversations, she noted that long-term goals are often an area of particular interest to the patient. Dr. John Buse (UNC) agreed, explaining that he often frames treatment goals in context of things patients want to do in their lives – attending major milestones for their children or grandchildren, for instance, can be a key motivator and help the patient get on board. In addition to goal setting, both Dr. Aroda and Dr. Buse discussed the importance of developing an ongoing partnership with the patient that is based on trust and active listening to their individual preferences, concerns, and needs.
  • Dr. Aroda noted that the four-part framework can also lead to de-prescription of drugs, helping combat polypharmacy, simplify treatment regimens, and reduce overall disease burden. Dr. Aroda noted that as patients achieve their A1c goals on GLP-1s, she typically removes medications that are no longer necessary. Dr. Buse added that listening to patients’ concerns about side effects and de-prescribing accordingly is especially important. Dr. Melanie Davies (University of Leicester, UK) conferred, highlighting the importance of stopping medications that are not needed. As Dr. Davies noted, clinical inertia surrounding GLP-1s remains a challenge, but it’s equally important to consider removing unnecessary medications. We were glad to hear this important discussion around de-prescribing medications, which can help reduce pill burden (and therefore improve adherence) while also minimizing cost.
  • Dr. Aroda and Prof. Rachel Batterham (University College London, UK) touched on the mechanisms of GLP-1s, highlighting their appetite-suppressing capabilities. Dr. Aroda argued that GLP-1s are quite unique as a class because they promote healthy eating and physical activity, citing a small 12-week crossover study showing reduction in ad libitum calorie intake, hunger cravings, and consumption of high fat foods among people with obesity (n=30). Likewise, Prof. Batterham discussed the potential of semaglutide 2.4 mg for weight management, noting that GLP-1s act on multiple systems including the brain (promote satiety and reduce energy intake) and stomach (reduce gastric emptying), while also bringing about improved glycemia and CV benefits via action in the pancreas and liver. Prof. Batterham also noted that semaglutide’s effects have been documented across a range of studies (STEP 1-4, STEP 8, and SELECT) in a broad range of populations. Given the extremely positive results of the STEP 1-4 trials, we’re eager for the additional trials in expanded populations, including children and younger teens, as well as in expanded populations like HFpEF and potentially even prediabetes reversal to hopefully expand the use of GLP-1s into even broader populations.

  • Also on the STEP program, Prof. John Wilding (University of Liverpool, UK) described improvements in cardiometabolic risk factors seen alongside weight loss in follow-up analyses of the STEP trials. Prof. Wilding emphasized that greater weight loss leads to greater cardiometabolic benefits, describing how the DEXA substudy of 140 STEP 1 participants identified reductions in body fat alongside the body weight changes in the semaglutide group. Specifically, this exploratory analysis found improvements in the ratio of lean body mass to fat mass, as well as reductions in central adiposity. Prof. Wilding also noted the high proportions of STEP participants who reverted to normoglycemia from prediabetes at baseline. Turning to holistic improvements, he described significant improvements in quality of life and physical functioning in the STEP-2 participants. We are encouraged by these follow-up analyses on the STEP program and are especially glad to see a focus on quality of life, given the stigma and complex psychosocial challenges presented by obesity.

Post-hoc analysis of STEP 2 trial finds higher dose confers greater weight loss; greater weight loss associated with greater reduction in cardiometabolic risk factors

In this short-oral presentation (SO-479), Professor John Deanfield (University College London) outlined a post-hoc analysis of the STEP 2 trial, demonstrating that greater reductions in cardiometabolic risk factors were seen in patients with greater weight loss. As a reminder, the STEP 2 trial enrolled 1,210 participants with type 2 diabetes and obesity or overweight with complications and compared semaglutide 2.4 mg to semaglutide 1.0 mg and placebo. The initial findings showed 9.6% weight loss from baseline of 220 lbs. for patients in the semaglutide 2.4mg arm compared to 7.0% weight loss for semaglutide 1.0 mg and 3.4% weight loss for placebo. Moreover, 46% of patients on semaglutide lost more than 10% of their body weight, compared to 29% of patients on the 1 mg semaglutide dose and 8.2% of patients on placebo. The post-hoc analysis presented by Prof. Deanfield focused on four different cardiometabolic risk factors – systolic blood pressure, triglycerides, non-HDL cholesterol, and C-reactive protein, measured as a change from baseline to week 68. The improvements across these four risk factors were significantly greater for patients who lost more than 10% of their body weight compared to patients who lost less than 10% of their body weight, irrespective of the semaglutide dose they were taking. However, because more patients on the semaglutide 2.4 dose achieved weight loss greater than 10% of their body weight, this group saw overall larger improvements in cardiometabolic risk factors.

  • Professor John Deanfield strongly contends that weight is the primary determinant of which patients with obesity will subsequently develop type 2 diabetes. He argued that with semaglutide, this is the first time clinicians have the ability to “target weight in a dramatic way,” which is especially important given that weight is a determinant in which patients are likely to later develop diabetes. He noted this is chance not only to manage risk, but also an opportunity to “turn back the clock” in people with new onset diabetes or even prevent development in the first place. He also noted that while the reductions in MACE seen in SUSTAIN-6 are the result of complex interactions between glycemic control, weight, inflammation, and the direct effect of the drug on the vessel wall, his “gut feeling” is that the changes in the cardiovascular risk factors are a direct result of the weight loss as opposed to improved glycemic control.

Post-hoc analysis of STEP 1 trial shows that semaglutide vastly improves reversion to normoglycemia in patients with prediabetes

In this presentation, Dr. Leigh Perrault (University of Colorado) and Professor Carel le Roux (University College Dublin) discussed a post-hoc analysis of the STEP 1 trial assessing the effects of semaglutide on glucose metabolism in adults with prediabetes. As a reminder, STEP 1 trial showed that semaglutide conferred 15% body weight reduction (15.3 kg) after 68 weeks, compared to a 2.4% reduction with placebo. This analysis assessed the change from baseline to week 68 on glycemic status, A1c, fasting plasma glucose, HOMA-IR, and HOMA-β. The data suggest that in patients treated with semaglutide, there was a significant reversal of prediabetes. About 45% of patients entered the trial with prediabetes, and by the end of the study, this had dropped to 15%. Conversely, 40% of patients treated with placebo had prediabetes at baseline, which increased to 49% by week 68. Moreover, while 3% of patients in the placebo period progressed to diabetes over the course of the 68-week period, just 0.5% of patients saw a comparable progression on semaglutide. Dr. Perrault semaglutide conferred a 0.35% treatment difference on A1c reduction, a -8.5 mg/dl difference on FPG, and a significant improvement in HOMA-IR (0.72). During Q&A, Professor le Roux noted that because obesity is a lifelong condition, it requires lifelong treatment, and argued that semaglutide can be that treatment. Moreover, Professor le Roux noted that while once weekly semaglutide is currently the “state of the art” therapy, “all of us would be shocked” if five years from now, the injectable once weekly GLP-1 is still the standard of care.

Semaglutide shown to improve seven-point-fingerstick-derived Time in Range relative to active comparators in post-hoc analysis of SUSTAIN trials

In this fascinating short oral session, Dr. Vanita Aroda (Harvard, Brigham and Women’s Hospital) presented a pooled analysis from SUSTAIN 2-4, 7, 8, and 10 (n=5,680), which evaluated the derived Time in Range for semaglutide versus several active comparators. As a reminder, the SUSTAIN trials tested semaglutide against other glycemic lowering agents in head-to-head RCTs and found that semaglutide was consistently superior to other therapies in terms of A1c reductions and weight loss (see SUSTAIN 2, SUSTAIN 3, SUSTAIN 4, SUSTAIN 7, SUSTAIN 8, SUSTAIN 10). Dr. Aroda was careful to point out that the data used in this subanalysis did not come from CGM, but rather was derived Time in Range (dTIR) calculated from self-monitored blood glucose (SMBG) data. To be included in the analysis, patients had to have ≥6 SMBG measurements in their seven-point profile at baseline. The seven-point profile includes glucose measurements taken before and after breakfast, lunch, and dinner, and at bedtime. To extrapolate Time in Range, the number of SBMG measurements 70 mg/dl-180 mg/dL was divided by the total number of SBMG measurements and multiplied by 100. At baseline, the derived Time in Range was low, ranging from 40%-50% across the trials, with significantly more time spent above range than below range. And, notably, following treatment with glycemic lowering agents, Time in Range significantly increased across the board. At the end of the trial (EOT), Time in Range had increased to 74%-83% for the comparator groups and 76%-91% for semaglutide. Notably, the increase in dTIR was statistically greater for semaglutide 1.0 mg compared to every active comparator except insulin glargine in the SUSTAIN 4 trial, where it was only marginally greater. Aside from insulin glargine, the differences ranged from a 1.6 hour/day relative increase compared to exenatide extended-release (GLP-1) to a 2.8 hour/day relative increase compared to DPP-4 inhibitor sitagliptin. Given that 5% is the generally accepted threshold for a clinically relevant change in Time in Range, semaglutide conferred impressive and significant increases in Time in Range over the other agents.

  • Notably, semaglutide appeared to improve glycemic control in both the pre-prandial and post-prandial glucose levels. Dr. Aroda suggested this finding aligns with the glucose-dependent mechanism of action and long half-life of semaglutide. In response to an interesting question from Dr. Tina Vilsboll (Steno Diabetes Center Copenhagen) who wondered why semaglutide outperformed other GLP-1s, Dr. Aroda noted that it was in this post-prandial period that semaglutide showed clear superiority to other agents. She added that this finding speaks to the potency of semaglutide and to its strong effect on glycemic control.
  • We are thrilled to see Time in Range used to evaluate therapies, although we hope that in the future, CGM will be used to measure Time in Range and other CGM metrics. At last year’s EASD conference, Dr. Rich Bergenstal admitted that while it can act as a good proxy, there are certain limitations of derived Time in Range. He called for more large-scale CVOTs to include CGM and TIR as part of their analysis, and we couldn’t agree more. More generally, we strongly support any work to get more access to CGM for patients with type 2 diabetes, particularly those on insulin. The results, including those of the MOBILE study, continue to be exceedingly positive, and we are hearing more and more discussion of CGM use in patients with type 2 diabetes on the conference circuit – see HiD 2021, ESC 2021, Keystone 2021.

Post hoc analysis of SUSTAIN 10 suggests that addition of GLP-1 to SGLT-2 further reduces A1c, body weight, and systolic blood pressure

In this presentation with almost 700 attendees, Dr. Matthew Capehorn (Rotherham Institute for Obesity, UK) compared clinical outcomes in people taking GLP-1s with and without SGLT-2 therapy. This analysis was first presented as a poster at ADA 2021 (647-P) and is based on the SUSTAIN 10 trial, which investigated the safety and efficacy of GLP-1s, semaglutide (1mg once-weekly) or liraglutide (1.2mg once-daily) in people with type 2 diabetes some of whom were already taking SGLT-2s. Dr. Capehorn explained that this study was motivated by results from post hoc analyses of PIONEER 4 (poster as ADA 2020) and SUSTAIN 9 (published in Lancet Diabetes Endocrinology in 2019) that suggested adding GLP-1 semaglutide to SGLT-2s confers additional clinical benefits, namely greater reduction in A1c, body weight, and systolic blood pressure. In this present analysis, semaglutide led to greater reductions in A1C, body weight, and systolic blood pressure than liraglutide over 30 weeks, regardless of baseline SGLT-2 use (with SGLT-2: n=142; without SGLT-2: n=435), though both GLP-1s led to reductions from baseline in all three measures. Notably, there were no unexpected safety concerns in patients receiving both a GLP-1 and SGLT-2 with low discontinuation rates due to adverse events in both the semaglutide and liraglutide groups (without SGLT-2: 13.4% and 6.4%, respectively; with SGLT-2: 5.5% and 7.2%, respectively). In both the with and without SGLT-2 cohorts, baseline characteristics and background medications (metformin or sulfonylureas) were similar. The researchers took this data to indicate that the addition of a GLP-1 to an SGLT-2 treatment may increase reductions in A1c, body weight, and systolic blood pressure without additional safety concerns, expanding the evidence base on the safety and efficacy of combing GLP-1s and SGLT-2s. 

  • Analyzing the graphs below, it appears that taking a GLP-1 with baseline SGLT-2 use actually resulted in smaller reductions in A1c, weight, and blood pressure than taking a GLP-1 alone, but during discussion when our team asked Dr. Capehorn about this he justified his interpretation of the results. Dr. Capehorn explained that patients not on an SGLT-2 at baseline who are given a potent medication like a GLP-1 may receive large A1c and body weight reductions, more so than someone who already had reductions from an SGLT-2 at baseline. We would be interested to know the magnitude of these SGLT-2 driven improvements for the study participants in the SGLT-2 cohort to potentially calculate the combined effect of GLP-1 + SGLT-2 therapy for this patient population.

Post-hoc analysis of SUSTAIN 6 and PIONEER 6 shows that semaglutide reduces CV events, A1c, and body weight regardless of metformin use

Dr. Mansoor Husain (University of Toronto, Canada) presented results from a post-hoc pooled analysis of SUSTAIN 6 and PIONEER 6 demonstrating that the CV and metabolic benefits of semaglutide are independent of metformin use. For background, both SUSTAIN 6 and PIONEER 6 were CVOTs for once-weekly injectable semaglutide and oral once-daily semaglutide (Rybelsus), respectively. SUSTAIN 6 found that semaglutide compared to placebo led to a 26% risk reduction on three-point MACE (CV death, non-fatal MI, and non-fatal stroke), and PIONEER 6 found that once-daily oral semaglutide was noninferior to placebo on MACE with a trend toward relative benefit (note that PIONEER 6 was not designed to demonstrate superiority). In this post-hoc pooled analysis, patients on metformin at baseline (n=4,881) and those not on metformin (n=1,599) had similar reductions in MACE (p-interaction=0.36), A1c (p-interaction=0.42), and body weight (p-interaction=0.51). Overall, for patients with and without metformin at baseline, semaglutide led to a 25% risk reduction on MACE (HR=0.75; 95% CI: 0.61, 0.91), a 0.81% A1c reduction (95% CI: -0.87%, -0.75%), and a 3.58 kg body weight reduction (95% CI: -3.85, -3.31). Furthermore, safety outcomes were comparable with similar rates of severe adverse events (p-interaction=0.99) and severe hypoglycemic episodes (p-interaction=0.97) in the two metformin subgroups. At baseline, patients not on metformin were older (67 years vs. 65 years), had diminished renal function (eGFRs of 62 mL/min/1.73m2 vs 79 mL/min/1.73m2), more concomitant insulin use (71% vs 48%), and less sulfonylurea use (29% vs 41%). Ultimately, these data clearly show that there is no significant difference in oral or injectable semaglutide’s efficacy or safety between metformin subgroups. During discussion, Dr. Mansoor suggested that a “consensus is emerging that baseline metformin use is not critical.” He went on to say that soon patients may not need to take first-line metformin, and instead they may take a first-line SGLT-2 and/or GLP-1. These data, he asserted, can support guideline changes to enable first-line SGLT-2 and GLP-1 use.

Patient-focused management strategy of oral semaglutide results in flexibility in treatment course resulting in GLP-1 therapy persistence

In this presentation, Professor Stephen Bain (Swansea University Medical Center, UK) highlighted the importance of flexibility and patient education in treatment with oral semaglutide (Rybelsus). Using data from PIONEER 6 (n=3,183), Professor Bain showed that discontinuation rates of oral semaglutide are high, with 27% of patients stopping treatment at least once during the trial due to adverse events. Using a patient-focused management strategy, investigators were encouraged to reduce the dosage and then re-escalate if adverse events occurred. The study design also allowed for treatment pauses until any adverse advents were resolved; if the pause was greater than 21 days, re-escalation to a lower dose was recommended to mitigate the adverse events. Additionally, patients were educated to address gastrointestinal tolerability issues to make them as comfortable as possible. Ultimately, this patient-focused management strategy helped many patients complete the course of treatment: 75% of participants who had discontinued the medication due to an adverse event restarted oral semaglutide.

  • Most of the discontinuation events occurred during the initial dose escalation period, as seen in the graph below. As such, providers have to walk a fine line between up titrating to the correct dosage at a rate patients can handle but making sure they are reaching a clinically relevant dosage. At ADCES 2021, Dr. Susan Cornell noted that one of the biggest issues with oral semaglutide is that patients get stuck on the “dating dose” of 3 mg for months, which is not effective for glycemic control, and then get frustrated with the drug when it isn’t showing clinical improvements.

  • Professor Bain offered insightful commentary on how to help patients manage the side effects. Professor Bain noted that patients must be informed of these gastrointestinal effects, but also should be aware that the side effects will likely disappear after the initial dose escalation period. If patients are feeling nauseous, he recommended that patients restrict portion sizes, reduce spicy and fatty foods, or to stop eating when they feel ill. He argued that so long as providers are transparent about the side effects of the drug, patients tend to persist with treatment because of the significant weight loss benefits.
  • Part of the reason for the high discontinuation rates is the complex physiology behind oral delivery. Only ~1% of each oral semaglutide dose is effectively absorbed into the bloodstream, thus requiring a much larger dose (14 mg for Rybelsus compared to 1 mg for Ozempic) to obtain the necessary results. Moreover, oral semaglutide must be taken on an empty stomach because drug release is dependent on the conditions of the stomach, and changes in pH can alter how much of the drug is absorbed, which causes dosage to be volatile. Additionally, the gastrointestinal side effects that are common to GLP-1s are especially prevalent with oral semaglutide, particularly if the dosage is not titrated correctly. Patients must be started on a lower dose to help mitigate adverse events but are gradually titrated up to at least 7 mg, which is the threshold of clinical effectiveness. Thus, although oral semaglutide may facilitate increased access to GLP-1s in diverse clinical settings, helping patients manage the strict treatment regimen is of utmost importance to ensuring the treatment is successful.

First four SURE trials show once-weekly subcutaneous semaglutide is effective in a real-world setting

Dr. Jean-Francois Yale (McGill University) and Dr. Gottfried Rudofsky (Olten Cantonal Hospital, Switzerland) presented data from the first four SURE studies, which investigate the real-world use of once-weekly semaglutide. The pooled analysis includes 1,212 patients with type 2 diabetes in Canada, Denmark, Sweden, Switzerland, and the UK. The SURE studies measure body weight and A1c of a diverse population over a 30-week period in routine clinical practice. Patients were treated with semaglutide and other glycemic-lowering agents at the physician’s discretion. Dr. Rudofsky noted it is “always interesting” to see how a drug works following market entry when the medication is tested in a less controlled setting. Both Dr. Yale and Dr. Rudofsky were pleased with the results of the trial, noting that the real-world results support the use of once-weekly, subcutaneous semaglutide in routine clinical practice in adults with type 2 diabetes. As a reminder, once-weekly semaglutide was initially tested in the SUSTAIN trials. In a closely controlled clinical setting, SUSTAIN 1 compared 0.5 mg and 1.0 mg doses of semaglutide to placebo in 388 drug-naïve patients with type 2 diabetes. The findings showed a weight loss of 3.8 kg with the 0.5 mg dose and 4.6 kg with the 1.0 mg dose, compared to a 1 kg weight loss on placebo. The 0.5 mg dose and 1 mg dose led to A1c reductions of 1.5% and 1.6%, respectively, compared to no change in A1c for the placebo.

  • Baseline characteristics for the overall population in the pooled SURE analysis were reflective of real-world practice. The detailed characteristics are shown in the table below.

Age

60.1 years

Female

473 participants (39%)

Diabetes duration

12.2 years

A1c

8.1%

Fasting plasma glucose

9.2 mmol/L

Body weight

101.5 kg

BMI

34.9 kg/m2

  • Participants saw a 1.1% A1c reduction after 30 weeks, dropping from 8.1% at baseline to 8% at 30 weeks. Participants with a baseline A1c ≥9% (n=231) saw the greatest A1c reduction over the 30-week period at an average of -2.5%. Approximately 53% of the overall population was able to achieve an A1c <7% at the end of the study, including 45% of participants who had an A1c≥7% at the beginning of the study. Notably, there was no difference in A1c reduction between patients who used semaglutide in addition to a DPP-4 inhibitor and patients who switched from the DPP-4 to the GLP-1. In both cases, semaglutide conferred a 1.3% reduction in A1c, findings that suggest DPP-4s do not have an additive benefit, according to Dr. Yale.
  • Both Dr. Yale and Dr. Rudofsky were interested in the additional effect on A1c in patients who switched from an existing GLP-1 to semaglutide. While GLP-1 naïve patients saw a 1.2% reduction in A1c, patients who switched still saw a 0.7% reduction, an impressive drop given GLP-1s share the same cellular mechanism. In Q&A, Dr. Rudofsky attributed this decline to the potency of semaglutide. He referred to the superior efficacy of semaglutide compared to exenatide and dulaglutide, as demonstrated in the SUSTAIN 3 and SUSTAIN 7 trials, respectively. In response to a question asking whether greater A1c and body weight reductions in patients switching from other GLP-1s was due to the once-weekly injection over once or twice daily, Dr. Rudofsky suggested while the ease and accessibility of a once-weekly injection are certainly benefits, the effect is much more likely due to the increased potency.
  • On average, participants saw a 4.7 kg reduction in body weight over the 30-week study period from a mean baseline of 101.8 kg. This finding is remarkably similar to the 4.6 kg weight loss found in SUSTAIN 1, highlighting the efficacy of semaglutide in a real-world setting. Patients with a BMI≥35 at baseline saw the greatest average reduction, around 5.6 kg, but patients in each BMI category still saw statistically significant weight loss. Patients naïve to GLP-1s saw body weight reductions of 5 kg compared to 3.4 kg for patients who switched from a different GLP-1 to semaglutide, but Dr. Yale was still impressed with this reduction for the experienced GLP-1 users. More than 60% of patients had weight loss of greater than 3%, 44% had weight loss greater than 5%, and 14% had weight loss greater than 10%. Patients saw significant weight loss regardless of their baseline A1c, diabetes duration, age, or DPP-4 usage.
  • Dosing varied significantly in the real world. In Q&A, Dr. Yale noted that not all patients reached the maximum suggested dose of semaglutide. The average dose was about 0.8 mg, with 58% on 1 mg, 27% on 0.5 mg, and 11% on 0.25 mg. Notably, the remainder of patients were on dosages between the established levels, which Dr. Yale felt showcased the capacity of the pen to go in between set dosages to help patients get on the optimally tolerated dose.
  • The discontinuation rate of semaglutide was 9.5%, higher than the rates seen in the SUSTAIN trial (the discontinuation rates were 5% and 6% for the semaglutide 0.5 mg and 2 mg, respectively, in the SUSTAIN 1 trial). GLP-1s are somewhat notorious for their gastrointestinal side effects, which are oft cited as the most common adverse effect. In Q&A, Dr. Rudofsky attributed these as the primary reason why patients were stopping the trial early. Clinicians often recommend the importance of slowly titrating the dosage to get patients accustomed to the drug to minimize the side effects, however the higher discontinuation rates suggest that this may not be happening as much in real-world practice.
  • At ADA 2021, we saw several other presentations on the real-world effectiveness of semaglutide. A retrospective study (n=1,842) found that once-weekly subcutaneous semaglutide was associated with a 1.3% drop in A1c from a baseline of 8.4%. Another study found that oral semaglutide was associated with a 0.9% reduction in A1c from a baseline of 8.2%. Patients with a baseline A1c ≥9% saw even greater reductions in A1c – a 2.3% drop, on average.

STAY study, an observational retrospective study, finds better persistence and adherence on once-weekly injectable GLP-1 than once-daily GLP-1

Dr. William Polonsky (University of California San Diego) presented results from the STAY study, an observational, retrospective study that assessed persistence (primary endpoint) and adherence (secondary endpoint) in US patients with type 2 diabetes initiating once-weekly or once-daily injectable GLP-1. This data was first presented as a late-breaking poster at ADA 2021 (83-LB). Persistence was defined as stay time (time on drug), and patients were censored after 360 days if they had not discontinued treatment, which was defined as ≥60 days not covered by medication. Participants with a proportion of days covered ≥0.8 were defined as adherent, so non-adherent patients had less than 80% of days covered by medication. There were 784 participants in each treatment arm with similar baseline characteristics between both groups: mean BMI of 36.5 kg/m2, about 55 years of age, 50% women, and mean A1c of 8.5%. About 45% of participants were on metformin, 23% were on sulfonylureas, 18% were on DPP-4s, and 5% in the daily arm and 12% in the weekly arm were on SGLT-2s. Once-weekly GLP-1 treatment was associated with significantly higher persistence than once-daily treatment (median stay time: 333 days vs. 269 days) with a 20% reduced risk of discontinuation (HR=0.80; 95% CI: 0.71-0.90; p<0.01). Additionally, compared to once-daily GLP-1 treatment, once-weekly treatment was associated with significantly higher adherence at six months (+23%; p<0.01) and 12 months (+35%; p<0.01). We expect this real-world evidence to assist clinicians in considering persistence and adherence when prescribing medications in the GLP-1 class.

  • Improved persistence and adherence were associated with improved glycemic control. Specifically, patients on once-weekly GLP-1s experienced greater mean reduction in A1c over six and 12 months than patients on once-daily GLP-1s (six months: -1.1% vs. -0.9%; 12 months: -0.9% vs. -0.7%). Furthermore, over a year, adherent patients experienced greater mean A1c reductions in both once-weekly (-1.1%) and once-daily (-1.0%) cohorts than non-adherent patients (-0.6% in both once-weekly and once-daily cohorts). Therefore, persistence and adherence have clear clinical benefits.
  • While once-weekly GLP-1s had higher adherence than once-daily GLP-1s, adherence rates were disappointingly low in both groups.  Once-weekly and once-daily GLP-1s were associated with adherence rates at six months of 54% and 44%, respectively; at one year, adherence was 46% and 34%, respectively. It would be great to see additional analysis on what factors drove more than half of patients in both cohorts to have less than 292 days in a year (<80%) covered by medication. During discussion, Dr. Polonsky acknowledged these “tragic” adherence rates. He explained that GLP-1s, like other cardiometabolic medications, prevent complications over the long term, but people often discontinue medications since “they don’t perceive them as worthwhile over the course of time.” He emphasized that improving patient perception of the value of their medications “continues to be an enormous source of interest.” A study comparing adherence on Novo Nordisk’s oral, once-daily GLP-1 Rybelsus to once-weekly injectable GLP-1s would also be informative, highlighting the relative influence of administration method and dosing frequency on patient adherence. Dr. Polonsky expressed that he hoped to see such a study in the future. Of note, Rybelsus may have its own adherence challenges since it must be administered on an empty stomach and patients must wait at least 30 minutes before eating, drinking, or taking other medications.
  • The once-weekly and once-daily cohorts each included 784 propensity-scored individuals with similar baseline characteristics. The study used the IBM MarketScan Explorys Claims-EMR Data from July 1, 2012 to January 31, 2019 and identified insulin-naïve adults with type 2 diabetes who had a claim for an injectable GLP-1 once-weekly (semaglutide, dulaglutide, exenatide extended-release) (n=4,311) or once-daily (liraglutide, exenatide standard-release, lixisenatide) (n=5,639). Patients in the once-weekly and once-daily groups were propensity score-matched 1:1 using baseline age, A1c, weight, Charlson Comorbidity Index score, sex, and antidiabetic medication (metformin, DPP-4, SGLT-2, or sulfonylurea). Many patients were excluded due to missing A1c and weight data, leaving 784 patients per cohort. 

Dr. Vanita Aroda and Prof. Filip Knop highlight oral semaglutide’s robust A1c-lowering and weight loss effects that support lifestyle changes across spectrum of T2D and CKD

In an enthusiastic overview of oral semaglutide and the PIONEER trial program, Dr. Vanita Aroda (Harvard, Brigham and Women’s) and Prof. Filip Knop (Steno Diabetes Center, Copenhagen, Denmark) highlighted the first-in-class oral GLP-1’s strong potential for patients with type 2 diabetes. Reviewing the PIONEER trials, Prof. Knop emphasized that oral semaglutide yielded “robust” dose-dependent reductions in A1c and body weight. Notably, the PIONEER 2 and PIONEER 3 head-to-head studies demonstrated oral semaglutide’s superiority to both SGLT-2 empagliflozin and DPP-4 sitagliptin in terms of the proportion of patients achieving glycemic targets. Echoing yesterday’s session on holistic approaches to weight loss, Dr. Aroda explained that oral semaglutide supports comprehensive lifestyle changes by reducing food intake and consumption of high-fat foods. She cited a small crossover study of oral semaglutide in people with obesity that found a 1,200-kilocalorie reduction in energy intake following an ad libitum meal; participants in the semaglutide group also had a lower preference for fatty foods. Prof. Knop summarized by stating, “Both as a patient and as their caregiver, you want exactly what semaglutide gives – weight loss and improved glycemic control without increased risk of hypoglycemia, plus healthier eating with fewer calories” in order to reduce diabetes complications. Overall, Dr. Aroda called for a shift away from “add-on therapy” to a mindset of “incorporating therapy,” suggesting that frequent re-assessment of a patient’s treatment regimen is key. In particular, she noted that GLP-1s can help patients achieve much of the same glucose-lowering that insulin achieves, stating that it’s important to “lift the foot off the brake to see what the pedal can do.”

  • Both speakers highlighted oral semaglutide’s potential in patients with type 2 diabetes and CKD, with Prof. Knop emphasizing that it can be used across the eGFR spectrum “almost down to where patients need dialysis” – wow! We were very encouraged to hear Prof. Knop speculate that GLP-1s may halt progression into macroalbuminuria in patients with diabetic nephropathy. Currently, GLP-1s are the preferred second-line agent for patients with type 2 and CKD in the latest KDIGO guidelines, though we continue to anticipate GLP-1s being further elevated in treatment recommendations in both DKD and heart failure pending results from FLOW and SOUL.
  • While both speakers emphasized the overall clean safety profile of oral semaglutide, Dr. Aroda stressed the importance of patient education and insulin dose reduction. In particular, Dr. Aroda advocated that providers discuss the mechanism of action and explain that patients will feel fuller faster and therefore, may want to reduce food intake to help reduce GI side effects. Interestingly, Dr. Aroda shared that satiety can be a new sensation for patients and can even be confused with nausea, though these feelings are typically mild to moderate and transient. Because oral semaglutide acts in a glucose-dependent manner, it has a low risk of hypoglycemia, though Dr. Aroda still suggested reducing insulin dose accordingly. For instance, in the PIONEER 8 study, insulin dose was reduced by 20% in the treatment group to account for the GLP-1’s insulinotropic action. We can imagine some degree of patient instruction is required for proper insulin dose reduction, as well. Time and again, we’ve heard KOLs call for patient education to manage adverse effects of GLP-1s and SGLT-2s – we would love to hear further discussion of how to effectively convey information to patients, particularly those with lower health literacy or from lower-resource backgrounds.

New GLP-1 prescriptions in patients with type 2 diabetes from 2014 to 2019 increased modestly but were disappointingly low; 40% of prescriptions from family medicine, <1% of prescription from cardiology

In this short oral presentation (SO 448), Dr. Anne Ersboll (University of Copenhagen, Denmark) shared trends in GLP-1 initiation in US patients with type 2 diabetes from 2014 to 2019, a period encompassing key CVOT publications (2016 LEADER, 2016 SUSTAIN 6, 2019 PIONEER 6, and 2019 REWIND) and an updated label indication (2017 CV indication for liraglutide). Nearly three million (2,966,970) adults with type 2 diabetes were identified using the US Optum’s de-identified Clinformatics Data Mart Database, and of this cohort, 108,541 patients had initiated GLP-1s during the study period. Throughout the five-year period, new GLP-1 users tended to be younger and have a higher mean A1c (8.6% vs. 6.7%) than non-GLP-1 users. New GLP-1 users were also more likely to be taking antihypertensive and lipid-lowering medications. Dr. Ersboll suggested that this increase in concomitant medications among new GLP-1 users indicates that GLP-1s are being prescribed late in the course of type 2 diabetes. From 2014 to 2019, there was a modest three-fold increase in new GLP-1 prescriptions, but absolute numbers of prescriptions were disappointingly low (0.72 prescriptions/100 patient years in 2014 to 2.05 prescriptions/100 patient years in 2019). While disheartening, this is not surprising given NHANES analysis published in NEJM in June found that only 7% of type 2s were on GLP-1s or SGLT-2s in 2015-2018. In a sub-analysis, Dr. Ersboll found that patients with ASCVD and type 2 experienced similarly moderate increases in new GLP-1 prescriptions but overall very low absolute numbers of prescriptions. Family medicine generated nearly 40% of total GLP-1 prescriptions each year, the most out of all specialties, whereas cardiologists contributed <1% of prescriptions each year.

  • These results highlight a lack of adoption of CVOT data- and guideline-recommended therapy for US patients with type 2 diabetes and ASCVD. Overall, trends in prescriptions did not coincide with release of CVOT data for liraglutide and semaglutide or with the FDA approval of a CV indication for liraglutide. During discussion, Dr. Ersboll suggested that these results could be quite different in other countries where reimbursement structures may differ, and we certainly think a similar study in other countries would be worthwhile to better understand the contributing factors for this clinical inertia.

New meta-analysis supports use of GLP-1s in CVD, though benefits on hard renal endpoints are still in question; panelists look ahead to new trials with GLP-1s on the five-year anniversary of first positive CVOT

Dr. Steven Marso (HCA Midwest Health, Kansas City), Dr. Ofri Mosenzon (Hadassah Medical Centre, Israel), and Dr. Ildiko Lingvay (UT Southwestern) highlighted the progress that has been made in five years since the first positive CVOT results were published and looked ahead to the future of GLP-1 therapy. In particular, Dr. Marso homed in on the established cardiovascular benefits from the nine existing GLP-1 CVOTs, while Dr. Mosenzon explored the relationship between GLP-1s and kidney function, where there is not too much primary data yet. Dr. Lingvay assessed the current guideline directed care with GLP-1 inhibitors and highlighted the tremendous amount of work that still must be done to get more patients on this life-saving medication, regardless of the guidelines. All three providers turned an eye towards the future, noting the continued research and development that is furthering GLP-1 discoveries.

  • Much of the discussion focused on a new GLP-1 meta-analysis from Professor Naveed Sattar (University of Glasgow). The study, published in the August edition of The Lancet Diabetes & Endocrinology, assessed eight cardiovascular outcome trials with GLP-1 agonists to estimate the overall hazard ratio for MACE and its individual components, all-cause mortality, hospital admission for heart failure, a composite kidney outcome, worsening kidney function, and the odds ratios for key safety outcomes, including hypoglycemia, retinopathy, pancreatitis, and pancreatic cancer. Professor Sattar’s work builds on previous meta-analyses, such as the oft-cited 2019 analysis, with the inclusion of the AMPLITUDE-O study. Recall that AMPLITUDE-O, which was presented at ADA 2021 and published simultaneously in the NEJM, found that efpeglenatide delivered a 27% relative risk reduction on MACE, making it the first exendin-based GLP-1 to find CVOT success in patients with type 2 and CV/renal disease. The meta-analysis also includes data from ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY-Outcomes, REWIND, and PIONEER 6.
  • Dr. Marso outlined the positive cardiovascular results from the pooled meta-analysis (n=60,080). Dr. Marso noted that, across the board, the data strongly demonstrates a clear cardiovascular benefit for patients with type 2 diabetes. Specifically, Dr. Marso highlighted the effectiveness of GLP-1 agonists irrespective of diabetes duration or baseline A1c. The primary CV outcomes from the pooled meta-analysis outlined by Dr. Marso are highlighted in the table below. When looking at this table, recall that five years ago, there was little expectation that GLP-1s would benefit the heart (LEADER was first presented in 2016) – they were simply being tested to prove non-inferiority on CV safety (not superiority) while establishing beneficial glycemic control. The magnitude of this discovery was not lost on the panelists in today’s session and gave the audience a chance to reflect on the power of scientific discovery.

Outcome

Relative Risk Reduction

Hazard Ratio (95% CI)

p-value

MACE (CV death, MI, stroke)

14%

0.86 (0.80-0.93)

<0.0001

CV death

13%

0.87 (0.80-0.94)

0.0010

Fatal or non-fatal MI

10%

0.90 (0.83-0.98)

0.020

Fatal or non-fatal stroke

17%

0.83 (0.76-0.92)

0.0002

All-cause mortality

12%

0.88 (0.82-0.94)

0.0001

Hospitalization for heart failure

11%

0.89 (0.82-0.98)

0.013

  • While GLP-1s have been shown to maintain their glycemic lowering and cardiovascular benefits in patients with diabetic kidney disease, the direct effect on “hard” renal outcomes (e.g., end stage kidney disease or renal failure) is still unknown.  Dr. Mosenzon highlighted the results of four trials specifically looking at GLP-1s in patients with type 2 diabetes and chronic kidney disease – HARMONY 8, LIRA-Renal, AWARD-7, and PIONEER 5. The studies found that GLP-1s maintained their metabolic effect, shown through reduced A1c and body weight, in patients with moderate to severe chronic kidney disease, though the question of the effect of GLP-1s in patients with end-stage kidney disease remains in question. Dr. Mosenzon also turned to the new meta-analysis, highlighting composite kidney outcomes from ELIXA, LEADER, SUSTAIN-6, EXSCEL, REWIND, and AMPLITUDE-O. Notably, when the composite outcome included reductions in macroalbuminuria, there was a statistically significant 21% relative risk reduction (HR=0.79, 95% CI: 0.73-0.87, p<0.0001) across the six studies. However, when looking at outcomes without macroalbuminuria, the positive effect is smaller and not statistically significant. Dr. Mosenzon argued that while evidence supporting reducing macroalbuminuria is quite positive, more evidence is needed to show there is a firm benefit of GLP-1s on clinically significant kidney outcomes.
  • Despite benefits and integration into guidelines, uptake of GLP-1s remains low, presumably in part due to side effect profile, in part due to cost. Dr. Lingvay pointed out that there was a relatively quick uptake of GLP-1 medications into clinical guidelines. For instance, she noted that 2018 was a “banner year” for the therapy when the ADA/EASD jointly released the consensus report for glycemic management in type 2 diabetes, which included the findings from several positive CVOT trials. Dr. Lingvay also highlighted the 2019 ESC guidelines for the treatment of type 2 diabetes, which suggested that high risk patients be treated with SGLT-2 or GLP-1s, independent of metformin use – that’s definitely the first we would’ve pointed to. Despite the positive data and guideline recommendations, Dr. Lingvay highlighted new research showcasing the lack of clinical uptake of GLP-1s. Only 9.9% of patients with type 2 diabetes and ASCVD were treated with an SGLT-2 or GLP-1 between April 2017 and April 2018. Moreover, Dr. Lingvay said, the overall yearly incidence of new GLP-1 prescriptions in the US is barely topping 1.5%. Global use of GLP-1s remains low as well – with just 3% of patients with type 2 diabetes taking a GLP-1 in a cohort of more than 15,000 people across 38 countries.
  • The future of GLP-1s is bright, with a number of ongoing trials examining their use within and beyond diabetes. Dr. Lingvay highlighted the ASCEND-PLUS trial, which will enroll 20,000 patients without cardiovascular disease to assess the ability of oral semaglutide to prevent CVD. She also discussed the much anticipated SELECT trial, which is the largest CVOT ever designed for anti-obesity medication (and practically the only). Moreover, Dr. Lingvay highlighted the SELECT-LIFE trial, which will follow patients enrolled in SELECT for 10 years following the completion of the initial five-year trial period – we are so glad to hear this. Dr. Marso specifically praised the SURPASS-CVOT trial, noting that there is an intense need for active comparator CVOTs in the GLP-1 arena. Dr. Lingvay concurred, expressing that she is “eagerly awaiting the results of this next-generation CVOT.” So is the entire world of researchers. The trial is expected to complete in October 2024. Dr. Mosenzon looked ahead to the FLOW trial, which is the first and only ongoing kidney outcome trial (KOT) with a GLP-1. The trial has enrolled 3,508 patients with type 2 diabetes and CKD and is measuring time to first occurrence of composite kidney endpoints (≥50% eGFR reduction compared to baseline, onset of persistent eGFR <15mL/min/1.73 m2) for patients on 1 mg semaglutide versus placebo. FLOW is an event-driven trial that will close when enough information collected to show clear result of the study, which is expected in August 2024, per clinicaltrials.gov. We were also excited to hear Dr. Lingvay mention the EVOKE and EVOKE+ trials, which are ongoing trials assessing the efficacy of semaglutide in patients with dementia and with Alzheimer’s disease. She noted that the data is accumulating to support the potential benefit in these patients who have few therapeutic options.

Patient-reported outcomes sub-analysis of SURPASS-5 shows that tirzepatide 10 mg and 15 mg leads to improvements in overall health status, self-perception of body weight, and ability to perform daily tasks relative to placebo; majority more satisfied with treatment than at baseline

In an afternoon session on the advantage of dual agonists, Ms. Maria Yu (Eli Lilly) read out the patient-reported outcomes of SURPASS-5. As a reminder, SURPASS-5 was a 40-week RCT comparing 5 mg, 10 mg, and 15 mg tirzepatide to placebo, the results from which were announced in February and presented at ADA 2021. All three tirzepatide doses saw significantly greater A1c and BMI reductions from baseline relative to placebo and were well tolerated with most common adverse events being mild to moderate gastrointestinal side effects. This patient-reported outcome(PRO) sub-study included any randomized participant who received at least one dose of the study drug (n=419) and reported on the change in four PRO measures from baseline to 40 weeks: (i) EQ-5D-5L (measures overall health status); (ii) Impact of Weight on Self-Perception Questionnaire (IW-SP); (iii) Diabetes Treatment Satisfaction Questionnaire (DTSQ) status and change scores; and (iv) Ability to Perform Physical Activities of Daily Living Questionnaire (APPADL) All tirzepatide doses saw a significantly higher total treatment satisfaction and perceived frequency of hyperglycemia based on the DTSQ questionnaire. Surprisingly, there was no significant improvement in the perceived frequency of hypoglycemia relative to the placebo.

  • At week 40, the majority of participants in the tirzepatide arms were “much more satisfied” with their tirzepatide treatment than their baseline treatment of metformin or metformin and an SGLT-2 inhibitor (5 mg = 66%, 10 mg = 70%, and 15 mg = 54%). This compared to 44% among those on the placebo. Likewise, a majority of those in the tirzepatide arms were “much more satisfied” with continuing on their present form of treatment compared to their baseline treatment (5 mg = 63%, 10 mg = 70%, and 15 mg = 55%) compared to a minority among the placebo group (40%).
  • Tirzepatide 10 mg and 15 mg saw significant adjusted improvements in overall health status scores (EQ-5D-5L) from baseline to 40 weeks (p=0.002 and p=0.009, respectively). There was no significant difference between tirzepatide 5 mg and the placebo group. Likewise, the tirzepatide 10 mg group saw a significant relative improvement from baseline in health-related quality of life (EQ-VAS scale; p<0.001 relative to placebo group); however, no significant differences were found between tirzepatide 5 mg or 15 mg vs. placebo.
  • Likewise, both tirzepatide 10 mg and 15 mg led to significant improvements in self-perception of body weight relative to placebo (IW-SP questionnaire, 0-100 scale). Specifically, those in the tirzepatide 10 mg and 15 mg arms saw a +10 and +12 score improvement, respectively, relative to placebo (p<0.001), a strong relative improvement. Compared to baseline the tirzepatide 5 mg group also saw an improvement (+5 score); however, this was not significant when compared to placebo (p=0.171).
  • Similarly, those in the tirzepatide 10 mg and 15 mg groups saw significant improvements in ability to perform tasks of daily living relative to the placebo group based on the APPADL questionnaire (p=0.002 and p<0.001, respectively) while the tirzepatide 5 mg did not see a significant improvement.

PIONEER 2 post-hoc analysis shows oral semaglutide increases long-term time in glycemic control (A1c 6.5%-7%) compared to empagliflozin

Using data from the PIONEER 2 trial, Professor Filip Krag Knop (Gentofte Hospital, Copenhagen) and Professor Eduard Montanya (University of Barcelona) showed that patients taking oral semaglutide spent significantly more time with an A1c below 6.5% and 7% compared to patients taking empagliflozin. Recall that PIONEER 2 tested 14 mg oral semaglutide (Rybelsus) in a head-to-head trial with 25 mg empagliflozin in 816 adults with type 2 diabetes on background metformin. The initial results showed a statistically significant reductions in A1c of 1.4% at 26 weeks and 1.3% at 52 weeks with semaglutide compared to compared to 0.9% and 0.8% decreases for the empagliflozin group at 26 and 52 weeks, respectively. Both groups had a baseline A1c of 8.1%. Professor Knop’s analysis assessed the percentage of patients in each treatment arm who spent any time in glucose control (A1c below 7%), who were in control for ≥14 weeks, in control for ≥26 weeks and in control for ≥38 weeks. The study showed that semaglutide outperformed empagliflozin at each of these thresholds.

 

Oral Semaglutide 14 mg

Empagliflozin 25 mg

Patients spending any time ≤7%

78%

61%

In control for ≥14 weeks

65%

48%

In control for ≥26 weeks

56%

38%

In control for ≥38 weeks

46%

28%

Median time in control (weeks)

27±20

19±20

  • While patients taking semaglutide did see a significant A1c reductions compared to empagliflozin, Professor Eduard Montanya noted there were no significant differences in weight loss between the groups. This was somewhat surprising to other speakers in the session, given semaglutide’s historically very impressive benefits on weight loss. Professor Montanya attributed this to the study design, noting that although no difference was seen in the primary endpoint was at 26 weeks, semaglutide had conferred greater weight loss compared to empagliflozin at 52 weeks.
  • Though we appreciate the emphasis on duration in addition to the magnitude, it would have been interesting to see analysis using Time in Range. To us, this move to use “Time in Range-like” metrics like “A1c Time in Range” or this study’s “time in glycemic control” is a signal that the field is more broadly moving toward Time in Range. We’d note however that such A1c-based metrics miss the granularity and day-to-day and within-day glycemic fluctuations that have a major impact on long-term outcomes. Furthermore, while these data do show that semaglutide seems to improve glycemic control, we still don’t know about the effect on glycemic variability, which is a key area of interest.

Novo Nordisk Symposium: Oral semaglutide is safe and effective in weight management, kidney disease, and cardiovascular disease

In this Novo-Nordisk-sponsored session, an all-star panel of KOLs provided a brief overview on three aspects of oral semaglutide – weight management, renal benefits, and cardiovascular benefits. Oral semaglutide, marketed as Rybelsus, has been on the market since its launch in September 2019 when it became the first oral GLP-1 available to patients. Our key takeaways from the session were that, first and foremost, oral semaglutide has consistently proven to be safe and effective across a number of different trials – see a comprehensive list of the PIONEER trials in the table below. Additionally, the speakers praised oral semaglutide for its comparability to subcutaneous once-weekly semaglutide, noting that once the peptide is in your system, it has the same effects regardless of mode of delivery. When asked whether they prefer oral to subcutaneous, the panelists agreed that they don’t consider one to be better than the other given the two modes’ similar efficacy and safety profile, but rather different options to meet different patients’ needs and preferences. They noted while some patients may prefer the ease of taking one injection once a week, needle-averse patients now have the choice of a tablet option. The session concluded with a look to the future with semaglutide, with Dr. Adie Viljoen (Lister Hospital, Stevenage, United Kingdom) highlighting the forthcoming FLOW, SOUL, and SELECT trials. Though FLOW and SELECT are not being tested using Rybelsus, these trials certainly will offer deeper insights into the weight management, renal and cardiovascular aspects of the semaglutide peptide.

  • Weight Management: In their weight management presentation, Professor Tina Vilsboll (Steno Diabetes Center, Copenhagen) and Professor Juris Meier (Augusta Clinic Bochum, Germany) reviewed data from a host of PIONEER studies. Specifically they highlighted PIONEER 1, which showed statistically significant reductions in weight loss (-9 lbs on the 14 mg dose) and A1c (-1.5% on 14 mg dose) compared to placebo. They also highlighted results from PIONEER 4, which showed that oral semaglutide was superior to liraglutide, one of the most established GLP-1s on the market. Professor Meier noted he was “a bit surprised” to see that these impressive results when they first came out, given that absorption of oral semaglutide was thought to potentially be a barrier that could reduce efficacy. Professors Vilsboll and Meier also made sure to highlight the safety profile of semaglutide, which is consistent with the rest of the GLP-1 class. As perhaps is expected, the most common adverse event associated with oral semaglutide was mild to moderate nausea.

Q: If we initiate semaglutide orally, how do we titrate the doses?

Professor Meier: As with most GLP-1s, there is an important dose escalation period. Based on experience with other GLP-1s, we know that slow titration of the doses is the best way to avoid side effects.

Q: Is there really a need to have both an oral and an injectable?

Professor Vilsboll: From a physician’s perspective it is very good to have choices. The injectable version is very easy to use – just once a week with a very thin needle, so some people prefer that method. While others, particularly in injection-naïve patients, may prefer taking a tablet when given the choice.

  • Renal Impairment: Professor Peter Rossing (Steno Diabetes Center, Copenhagen) and Professor Tina Vilsboll (Steno Diabetes Center, Copenhagen) focused on the use of GLP-1s in patients with type 2 diabetes and chronic kidney disease. Notably, Professor Vilsboll highlighted that the progression of CKD varies in patients, with the timeline often depending upon the point of diagnosis. Early screening and intervention can substantially improve outcomes. Professor Rossing reviewed the KDIGO 2020 treatment guidelines, which suggest metformin and SGLT-2s as the first line therapy for patients with CKD and T2D. The guidelines recommend GLP-1 as the second-line therapy if additional glycemic control is still needed in these patients. Results from the SUSTAIN 6 trial were prominently featured, as they showed semaglutide conferred benefits in patients across the spectrum of eGFR. Professor Rossing noted that this is one significant benefit of GLP-1s is that they are safe and effective for use in patients with lower eGFRs, which is not necessarily the case with SGLT-2s. Finally, they highlighted the results from the PIONEER 5 trial, which showed that oral semaglutide effectively improved glycemic control and reduced body weight in patients with type 2 diabetes and moderate renal impairment.

Q: How is the dose taken?

Professor Vilsboll: This is a very important question – oral semaglutide has to be taken exactly as prescribed in order for it to have any effect. It must be taken on a completely empty stomach with a small sip of water and must wait 30 minutes before eating anything else. If patients feel that this is a problem, however, the injectable semaglutide is always an option. I usually start with a tablet, though, and then take it from there.

Q: How do you recommend this be taken with hypothyroid mechanism?

Professor Vilsboll: It is important that patients should take their medications with the thyroid and semaglutide medications separately. So, I sometimes recommend taking thyroxine at night and oral semaglutide right when they wake up in the morning to help separate the doses.

Q: Is semaglutide’s effect on renal impairment a class effect of GLP-1s or is it specific to this molecule?

Professor Rossing: I think we have to be really careful with class effects with GLP-1s, as we’ve seen a broad range of cardiovascular and kidney benefits. With that said, going forward, we should be looking to go with agents that have the proven evidence behind them.

Q: Does the dose have to be adjusted in patients with renal impairment?

Professor Rossing: No – as discussed in the presentation, GLP-1s can be used with an eGFR down to 15 mL/min/1.73m2 and don’t need to be dose adjusted. There is a chance that patients with very low kidney function will see greater side effects, but they can ho up to the maximally tolerated dose.

  • Cardiovascular Disease: Dr. Matt Cavender (UNC School of Medicine) and Professor David Strain (University of Exeter) reviewed the risk of cardiovascular risk in diabetes, suggesting that the significance of ASCVD is often overlooked. Despite clear guidance suggesting that SGLT-2s and GLP-1s be considered as first-line therapy, uptake among patients is still low. Professors Cavender and Strain highlighted results from the PIONEER 6 study which was the first trial to demonstrate cardiovascular benefit with an oral GLP-1. While there was no statistical significance, the data was certainly trending in the correct direction. Moreover, when pooled with SUSTAIN 6, the post-hoc analysis showed a statistically significant 24% RRR on three-point MACE (95% CI: 0.62-0.92) and a 35% RRR on stroke (95% CI: 0.43-0.97). They were particularly impressed by the relative risk reduction on stroke and concluded by saying that GLP-1-based treatment is an effective strategy to reduce the risk of stroke in high-risk individuals.

Cardiovascular Disease Q&A:

Q: Do you think cardiologists are ahead of the curve by saying that high-risk patients don’t even need metformin and are just going right to the newer agents?

Dr. Strain: It is very difficult to say that for certain, as most of the studies were done on top of metformin, but it is an interesting idea. I think that cardiologists are right to think we should look to prevent CVD before it even occurs.

Dr. Cavender: In many ways, the endocrinologists are way ahead of us in using medications. They are still much more likely to prescribe the GLP-1s and SGLT-2s than cardiologists. However, endocrinologists are still using them predominantly for glycemic control. While of course this is very important for patients with diabetes, the mechanism of cardiovascular benefit for GLP-1s is thought to be independent of glycemic control, and so there are benefits that are aside from this that should be considered.

Q: How has the pandemic shifted prescribing of semaglutide?

Dr. Strain: The pandemic has very much hindered our ability to engage with patients. Initiating the first injectable is very difficult in the remote and virtual world, therefore the option for oral semaglutide can help get patients on therapy despite this barrier.

  • PIONEER Trials: The results of the ten-study phase 3 PIONEER program (n=9,543) were read out in 2018 and 2019. See a full table of these studies and their results belowBy and large, PIONEER has supported efficacy and tolerability of oral semaglutide. The combination of glucose-lowering and weight loss efficacy with a remarkable safety profile (especially on hypoglycemia) is unparalleled among oral agents and even offers improvements over some existing injectable GLP-1 agonists.

Trial

Enrollment

Comparator/Design

Timeline

PIONEER 1

704

Placebo

Completed December 2017; Topline results announced February 2018; Full results at ADA 2018

PIONEER 2

816

Lilly/BI’s Jardiance (empagliflozin)

Completed March 2018; Topline results announced May 2018; Full results at ADA 2019

PIONEER 3

1,864

Merck’s Januvia (sitagliptin)

Completed March 2018, Topline results announced June 2018; Full results at ENDO 2019

PIONEER 4

711

Novo Nordisk’s Victoza (liraglutide)

Completed March 2018; Topline results announced June 2018; Full results at ADA 2019

PIONEER 5

324

Moderate renal impairment

Completed May 2018; Topline results announced August 2018; Full results at ADA 2019

PIONEER 6

3,183

CVOT

Completed September 2018; Topline results announced November 2018; Full results at ADA 2019

PIONEER 7

504

Flexible dose escalation

Completed March 2019; Topline results announced June 2018

PIONEER 8

731

Insulin add-on

Completed August 2018; Topline results announced October 2018

PIONEER 9

230

Placebo and liraglutide in Japan

Completed August 2018; Topline results announced November 2018

PIONEER 10

336

Lilly’s Trulicity (dulaglutide) as an add-on to oral agents in Japan

Completed July 2018; Topline results announced September 2018

Small study finds combined dapagliflozin-dulaglutide treatment improves vascular dysfunction and albuminuria vs. DPP-4-s independent of glycemic control in patients with type 2 diabetes (n=37)

Dr. Emmanouil Korakas (National and Kapodistrian University of Athens, Greece) presented results of a small study comparing combination dulaglutide-dapagliflozin treatment vs. DPP-4s on arterial stiffness, endothelial function, and albuminuria in type 2 diabetes. At baseline, all 37 participants were on DPP-4s and had similar cardiovascular markers and an A1c of ~8%. The majority of patients (n=21) were transitioned to dulaglutide and dapagliflozin, while the other 16 remained on DPP-4s. While both groups saw statistically significant decreases in A1c at four months, the combination group showed greater improvements than the DPP-4 group (-1.3% to 6.6% vs. -0.9% to 7.3%). The dulaglutide/dapagliflozin group also saw a significant 9% reduction in carotid-femoral pulse-wave velocity, the gold standard for assessing arterial stiffness of the large vessels. Dr. Korakas also described a significant 9% decrease in perfused boundary region of the sublingual arterial microvessels, an index of glycocalyx stiffness. Those on the combination therapy also saw a significant 6% decrease in systolic blood pressure. Dr. Korakas summarized that these three findings reveal improved arterial stiffness with dulaglutide/dapagliflozin combination therapy. Albuminuria (UACR) was also significantly reduced by 40% in the combination group, compared to a non-significant 15% reduction in the DPP-4 group. We’d note that the combination group had a higher baseline UACR of approximately 413 mg/g vs. 241 mg/g in the DPP-4 group, which may suggest that this combination approach is most effective in patients with more severely increased albuminuria. Based on these findings, Dr. Korakas concluded that dulaglutide/dapagliflozin treatment improves arterial stiffness, endothelial glycocalyx, and albuminuria after four months compared to DPP-4s in patients with type 2 diabetes. Overall, he suggested that early initiation of this combination may prevent disruption in endothelial function, a key component in the pathogenesis of diabetic nephropathy. We are very happy to have seen these early results, which are clearly very promising. We look forward to larger analyses with longer follow-up, as well as mechanism studies, to clarify the precise effects of this novel combination treatment in type 2 diabetes.

“Our time to act is now”: Dr. John Buse highlights six key points to get more people on SGLT-2s and GLP-1s; focus on collaboration and translation of trial data into clinical practice

In this BI/Lilly-sponsored session, Dr. John Buse (UNC School of Medicine) argued that despite “spectacular” results of SGLT-2s and GLP-1s, too few patients are benefitting from the therapies. Using the acronym ACT NOW, Dr. Buse proposed six points to help get more people on these life-changing medications. The points predominantly focus on translating the strong benefits seen in different trials into clinical practice. There is also a strong focus on collaboration – both between patients and providers, as well as across different specialties. Throughout the session, Dr. Buse repeated the phrase, “our time to act is now,” highlighting the relevance of the acronym. Patients are suffering from complications that are preventable with early and intensive treatment with these new therapies, emphasizing the urgency behind this problem.

  • Approach type 2 diabetes in a holistic way – are we thinking beyond commonly predefined targets? Dr. Buse highlighted the closely intertwined cardiovascluar, renal, and metabolic (CRM) systems and the importance of looking at the whole person, rather than a certain system in a silo. In particular, he noted that each dysfunctional organ has the potential to perpetuate disease in the other organs. He argued that type 2 diabetes is not just a risk factor for cardiorenal disease, but also a marker of it. If a person has one CRM condition, there is likely another condition to be found, and if there are two conditions, there will “almost always” be a third. Unfortunately, the compounding cardiorenal abnormalities have a drastic impact on life expectancy. For example, patients who have type 2 diabetes and chronic kidney disease have a life expectancy that is more than nine years shorter than patients without diabetes or CKD.
  • Clinical inertia- what causes it and how can it be overcome? Dr. Buse noted that the two major causes of clinical inertia are habitual prescribing behavior and patient education. For the most part, Dr. Buse believes that it is simply difficult for providers to switch from medications they have been prescribing for years (or decades) to unfamiliar agents, though there may be some providers who simply aren’t aware of the compelling SGLT-2 and GLP-1 data. Moreover, Dr. Buse noted that change is often instigated by patients, but that many patients haven’t been adequately educated by their providers about the benefits of the new therapies. He added that anecdotally, his patients really want to use these drugs once they have been educated about them.
  • Treatment benefits – how can early treatment impact the management of type 2 diabetes? Dr. Buse argued for early and intensive glycemic control to prevent irredeemable complications. He highlighted results from the Diabetes and Aging Study, which showed that patients with an A1c≥6.5% in the first year after diagnosis had increased microvascular and macrovascular complications.
  • New paradigm – how have type 2 diabetes treatment guidelines evolved following positive results from CVOTs? Dr. Buse noted that many aspects of the treatment guideline have been updated to include reflect cardio-renal-metabolic interactions in type 2 diabetes care. For example, the updated ADA standards of care recommend patients with high risk or established ASCVD, CKD, or HF to consider SGLT-2s or GLP-1s, independent of metformin use. At recent conferences, we’ve heard calls for even stronger and earlier usage, including at ADA 2021 when Dr. Julio Rosenstock called for semaglutide as a first-line therapy in newly diagnosed patients, and at Keystone 2021, when Dr. Ralph DeFronzo advocated heavily for the aggressive first-line triple therapy of pioglitazone, a GLP-1, and an SGLT-2.
  • Optimal patient care – are we adopting the guidelines into our clinical practice? Dr. Buse noted that there are obstacles in translating proposed guidelines into clinical practice. Even in places that have exceptionally strong healthcare systems, like Denmark, the proportion of patients receiving an SGLT-2 or GLP-1 are still remarkably low. In 2018, less than 20% of patients were treated with a new glucose-lowering therapy within one year after diagnosis of CV disease and established type 2 diabetes. According to Dr. Buse,there is still a great deal of work to that needs to be done to get proportions we are proud of.”
  • Work together – how can we work in collaboration across disciplines to provide holistic care for our patients with type 2 diabetes? Dr. Buse was adamant that patients are treated using team-based innovative care. Treating diabetes is no longer just about glycemic control, but also about using organ-protective therapies, as well as treating other metabolic targets, including blood pressure and lipids. He noted the importance of utilizing dieticians, diabetes care and education specialists, as well as cardiologists and nephrologists to ensure holistic patient care.

Phase 2a RCT finds GLP-1/glucagon receptor dual agonist cotadutide exhibits significant glucose-lowering effects via increased insulin secretion and delayed gastric emptying

Dr. Rajna Golubic (MRC Institute of Metabolic Science, UK) highlighted data from a randomized, double-blind phase 2a trial assessing the effect of GLP-1/glucagon receptor dual agonist cotadutide in adults with overweight or obesity and type 2 diabetes. As background, cotadutide is currently in development by AstraZeneca for the treatment of patients with type 2 diabetes and diabetic kidney disease, as well as patients with NASH. This phase 2a study measured glucose homeostasis with a mixed-meal tolerance test and frequently sampled IV glucose tolerance in patients on subcutaneous cotadutide versus placebo. Patients with type 2 diabetes (A1c ≤8.0%) and BMI 28-40 kg/m2 were randomized 2:1 between the cotadutide group (n=19) and the placebo group (n=9). Patients were started on a cotadutide dose of 100 µg, which was up-titrated every four days to 300 µg daily. Patients were assessed with the mixed meal tolerance test or the glucose tolerance test over a 60-day evaluation period.

  • Baseline characteristics:

Parameter

Placebo (n=9)

Cotadutide (n=19)

Age (years)

62.6

59.5

Male

7 (77.8%)

18 (94.7%)

Female

2 (22.2%)

1 (5.3%)

Weight

101.36

99.30

BMI

34.52

32.23

A1c

6.7

7.0

Duration of diabetes

8.7

7.3

  • The mixed meal tolerance test showed a significant decrease in glucose and significant increase in insulin among patients on cotadutide. No significant change in fasting insulin was observed.

 

Cotadutide

% change vs placebo

p-value

Glucose AUCo-4 h

35.5 → 26.9 mmol/L*h

-12.3%

p=0.010

Insulin AUC 0-4 h

889.6 → 985.7 hr.pmol/L

29.6%

p=0.085

  • The frequently sampled IV glucose tolerance test saw a marked reduction in glucose and an increase in insulin in the cotadutide group relative to placebo. Patients in the cotadutide group also saw an increase in the first phase insulin response, while there was no significant effect on insulin sensitivity or glucose effectiveness. Patients on cotadutide also saw significantly longer gastric emptying time in patients on cotadutide.

 

Cotadutide

Placebo

p-value

First phase insulin response

117.4 → 1966.9 min* mU/L

489.4 → 441.8 min*mU/L

p=0.003

Gastric emptying time

6.7 hours

2.6 hours

p=0.019

  • There was no significant change in fasting insulin with cotadutide relative to placebo. In Q&A, Dr. Golubic noted that patients on cotadutide also saw significant weight loss compared to placebo. Patients on the GLP-1/glucagon dual agonist saw an average 4 kg relative decrease in weight, corresponding to a 2.3% decrease in body weight. According to Dr. Golubic, this weight loss is comparable to other studies with cotadutide.
  • Dr. Golubic concluded that cotadutide achieved a significant glucose-lowering effect in patients with overweight and obesity and type 2 diabetes. Based on these findings, the predominant glucose-lowering effects are due to an increase in insulin secretion and delayed gastric emptying rather than a change in insulin responsiveness. She noted that there is likely an additive effect between the delayed gastric emptying and the increased insulin secretion, as they have different mechanisms of glycemic control.
  • Data presented at past conferences has showed the benefits of cotadutide on weight loss and NASH. At ADA 2020, the data showed that patients taking cotadutide saw significant reductions in postprandial hepatic glycogen content (-100.2 mmol/L vs. +5.5 mmol/L, p=0.023), a 27% relative reduction in fasting hepatic glycogen content (p=0.003), and a 33% relative reduction in liver fat (p=0.006). These are all significant biomarkers for NASH, which is a significant area of unmet need, suggesting cotadutide has great promise as a NASH therapy. At ADA 2021, data from a phase 2a trial showed cotadutide significantly increased time in range compared to placebo for patients with type 2 diabetes and stage 3 chronic kidney disease. Moreover, another trial showed patients on cotadutide lost significantly more weight than those on placebo. Data from a NASH phase 2b trial is expected to be read out later this year.

SGLT-2/GLP-1 combo therapy slows eGFR decline in type 2 diabetes patients with rapidly progressing CKD

In a short oral session on nephropathy interventions, Dr. Koji Kashima (Kiryu Kosei General Hospital, Kiryu, Japan) evaluated the renal impact of GLP-1/SGLT-2 combination therapy in type 2 diabetes patients with advanced chronic kidney disease (CKD, Stages 3 and 4) (SO 607). Dr. Kashima specifically investigated how GLP-1 receptor agonist liraglutide affected eGFR decline – an indicator of how fast CKD is progressing – with concurrent or staggered treatment with an SGLT-2 inhibitor. Benefits of the combination regimen were seen across all subgroups, regardless of whether the GLP-1 and SGLT-2 were initiated simultaneously or one after the other. Most impressively, while the slope of eGFR decline was -14.6 mL/min/1.73 m2/year without either therapy, it improved to -5.4 mL/min/1.73 m2/year (p<0.05) and -2.6 mL/min/1.73 m2/year (p<0.05) when a GLP-1 and an SGLT-2 was added, respectively. Dr. Kashima also separated the patients into “rapid decliners” (eGFR slope>-10 mL/min/1.73 m2/year) and “responders” (eGFR slope ratio reduced >1.0 mL/min/1.73 m2/year after SGLT-2 inhibitor). The percentage of “responders” increased as the severity of CKD increased, with an impressive 89% of stage 4 CKD patients seeing improvements in eGFR. These data suggest that GLP-1/SGLT-2 combination therapy may have significant benefits for patients with type 2 diabetes who are rapidly progressing to diabetic kidney disease (DKD).

Budget neutrality of GLP-1 use driven by decreased inpatient and outpatient costs among high-risk type 2s with CVD; GLP-1 use associated with 12-month hazard ratio of 0.85 for re-hospitalization for CVD events

Health care expenditure analysis of 1,712 people with type 2 diabetes with prior CVD events in the OFFSET study found that treatment with GLP-1s was budget neutral compared to standard of care treatment (SO-268).  Given recent recommendations that advocate for GLP-1 use as an add-on to metformin or as first-line therapy in patients with type 2 diabetes and cardiovascular disease or high CVD risk, the OFFSET study was conducted to investigate the health systems cost of GLP-1 use among patients with type 2 diabetes and prior hospitalization for CVD events. Data collected between September 2012 and September 2019 from the IBM MarketScan database of patients with type 2 diabetes and prior hospitalizations for cardiovascular disease were compared for those prescribed a GLP-1 (n=1,712) and those on standard therapy (n=122,334) through one year of follow-up post CVD event. Costs were broken down into three categories: (i) drugs; (ii) inpatient costs; and (iii) outpatient costs. While patients receiving a GLP-1 did experience higher drug costs one year post CVD event hospitalization averaging $1,046 per patient per month compared to $675 for those on standard therapy (p<0.001), patients prescribed a GLP-1 saw significantly lower inpatient and outpatient costs than those on standard therapy ultimately leading to budget neutrality between the two groups. Specifically, inpatient costs for those prescribed a GLP-1 totaled $1,147 per patient per month compared to $1,458 per patient per month for those on standard therapy (p<0.001). Additionally, outpatient costs were also lower among those prescribed a GLP-1 at $1,660 per patient per month compared to $2,155 per patient per month for those on standard therapy (p<0.001). Collectively, total healthcare costs of patients with type 2 diabetes prescribed a GLP-1 following hospitalization for a CVD event were $3,853 per patient per month which was not significantly different than costs for patients receiving standard of care following hospitalization for a CVD event at $4,288 per patient per month ultimately demonstrating that though GLP-1 use is associated with increased up-front cost, these costs are offset by subsequently reduced inpatient and outpatient expenditures.

  • Patients prescribed a GLP-1 following hospitalization for a CVD event had a lower risk of re-hospitalization within 12-months than patients on standard of care therapy. Specifically, a lower percentage of patients on GLP-1s were re-hospitalized with a 10% re-hospitalization rate at three months, 18% at six months, 23% at nine months, and 28% at 12-months compared to patients on standard therapy with re-hospitalization rates of 13% at three months, 22% at six months, 29% at nine months, and 35% at 12-months. Additionally, overall risk of re-hospitalization was lower among patients on GLP-1s with a hazard ratio of 0.85 compared to patients on standard therapy (p<0.001). These differences in re-hospitalization risk also help contextualize the lower costs associated with inpatient care for patients prescribed a GLP-1 following initial hospitalization for a CVD event, once again supporting the long-term budget neutrality of GLP-1 use. Not to mention, fewer re-hospitalization is indicative of an overall healthier patient population demonstrating that GLP-1s have the potential to improve health outcomes without increasing health care expenditures.

Lilly’s novel GIP/GLP-1/glucagon triple receptor agonist LY3437943 shows robust weight loss in preclinical and phase 1 study; preclinical results also point to promising liver fat reductions in obese mouse model

In a mid-morning session on novel agents, Drs. Charles Benson (Eli Lilly) and Tamer Coskun (Eli Lilly) presented the results from both a phase 1, first-in human single-ascending dose study and a preclinical trial of GIP/GLP-1/glucagon triple receptor agonist LY3437943. Dr. Benson shared that the triple agonist was developed based on dual GIP/GLP-1 receptor agonist tirzepatide’s significant reductions in A1c and body weight in the SURPASS trials, and the hypothesis that glucagon may further reduce appetite and modulate energy expenditure to confer additional weight loss. Dr. Benson presented the results of a phase 1 study in healthy participants (n=45), which found dose-dependent weight loss that was sustained over the 43 days of the study. Participants also had reduced appetite, as indicated by an increased visual analog scale (VAS) score, which is a measure of hunger, fullness, satiety, and prospective food intake, where greater scores indicate lower appetite. In a preclinical study of diet-induced obese mice, Dr. Coskun demonstrated the efficacy of LY3437943 in reducing body weight through decreased food intake and increased energy expenditure; this was largely driven by an impressive 80% loss of fat mass. He described significant reductions in fasting glucose and fasting insulin, indicative of improved insulin sensitivity; these findings echo those of a first mechanistic study of tirzepatide presented by Dr. Tim Heise earlier in the conference. LY3437943 also appeared to have beneficial effects in the liver of the obese mice, including reductions in liver triglycerides and improved biomarkers of liver health, all of which Dr. Coskun suggested may result from the reductions in body weight. Overall, Dr. Benson and Dr. Coskun highlighted the sustained weight loss seen in both the preclinical and phase 1 studies of LY3437943, which support further clinical evaluation of the triple receptor agonist in type 2 diabetes, obesity, and NAFLD. These studies add to the substantial body of evidence showing significant reductions in body weight with next-generation incretins and help elucidate the mechanism of action of GIP, GLP-1, and glucagon on weight loss and liver health. While tirzepatide is currently leading the way in the field of multi-agonist incretins, competition will certainly intensify as further studies of dual and triple agonists commence.

SGLT-2 Inhibitor Highlights

Real-world, two-center retrospective study of SGLT-2s in people with type 1 diabetes (n=199) finds modest reductions in A1c, body weight, and insulin dose; 6% of participants report DKA “despite additional educational measures”

Dr. Falco van Nes (UZ Leuven, Belgium) presented the results of a retrospective safety and efficacy study that found modest reductions in A1c, body weight, and daily insulin dose with SGLT-2 use in people with type 1 diabetes, especially among those with higher baseline A1c and BMI. The real-world study examined healthcare records from patients in Spain and Belgium (n=199) on dapagliflozin, empagliflozin, and canagliflozin. At 12 months, A1c was reduced by 0.5% from a baseline of 8.2% to 7.7%. This improvement in glycemic control appears to be driven largely by A1c reductions in those with higher baseline A1c, as reductions in the lowest baseline A1c group were not statistically significant. Moderate reductions in weight loss (-3.5% from 84 kg to 81 kg) and total daily insulin dose (-8.5% from 0.67 IU/Kg to 0.61 IU/Kg) were also seen over the 12 months of follow-up. While these findings are encouraging, Dr. van Nes noted that adverse events occurred frequently – in over one-third (39%) of patients – with 12% ultimately discontinuing SGLT-2 treatment due to adverse events. Genital infections were the most commonly reported adverse event, occurring in 29% of participants. As expected, diabetic ketoacidosis was a large concern, with 6% of participants reporting DKA “despite additional educational measures” including ketone measuring. In the Q&A, Dr. van Nes called for proper patient selection and patient education to manage adverse events, echoing Dr. Chantal Mathieu’s commentary at Keystone 2021. As we wrote yesterday in our coverage of a five-year risk reduction study of SGLT-2s in type 1 diabetes, widespread use of these agents in type 1 will likely continue to be an uphill battle until CKM (continuous ketone monitoring) is approved; at that point, there will be a “disease modifying” technology to address ongoing risks associated with DKA. We’re happy to see further research devoted to this field; while in the meantime, of course patient selection and education will undoubtedly help prevent this very preventable risk, we believe that the right technology is on its way. Meanwhile, there is no question that people with T1D will continue to take this therapy off-label – so more visibility about the risks, in the meantime, also bode well for patient safety. We look forward to real-world outcomes data that may also be helpful as the field moves toward where it can and undoubtedly should be – preventing adverse effects.

  • Currently, Forxiga (dapagliflozin) is the only adjunctive therapy approved for type 1 diabetes in Europe and Japan, and it is indicated for people with a BMI over 27. In this study, patients using SGLT-2s “on label” (i.e.BMI ≥27) saw greater reductions in A1c than those using it “off-label” (BMI <27), suggesting that heavier patients are most likely to benefit from adjunctive use. In the Q&A, Dr. van Nes noted that no DKA episodes occurred in patients with on-label use of SGLT-2s. We’re certainly extremely encouraged to hear that “on-label” use in Europe resulted in no DKA episodes and while we hope that proper patient selection for “off-label” use will help minimize DKA, as well, we also look forward to the technology that can help prevent DKA when the wrong patients get it and take it.

Baseline A1c

A1c at 12 months

Reduction in A1c

p-value

8.8

8.1

-0.7

<0.0001

7.6

7.4

-0.2

0.001

6.7

6.6

-0.1

0.064

 

BMI

Baseline A1c

A1c at 12 months

Reduction in A1c

p-value

<27

8.1

7.8

-0.3

<0.0001

≥27

8.3

7.7

-0.6

<0.0001

 

VERTIS CV INSULIN sub-study finds that SGLT-2 ertugliflozin added to insulin significantly reduced A1c, body weight, and systolic blood pressure at 18 weeks in patients with type 2 diabetes and ASCVD

Dr. Ildiko Lingvay (UT Southwestern) presented results from VERTIS CV INSULIN, a substudy of the VERTIS CV study that was read out at ADA 2020 and published in NEJM. Full results of VERTIS CV INSULIN were published March 2021 in Diabetes, Obesity and Metabolism. For background, VERTIS CV was a CVOT investigating Merck/Pfizer’s SGLT-2 ertugliflozin (Steglatro), and as reported multiple times earlier this year, ertugliflozin only demonstrated non-inferiority, not superiority, to placebo on the primary endpoint of three-point MACE. Presumably, like with Bydureon before it, and with other therapies before that, we infer from multiple conversations with multiple thought leaders that this is less likely to be something mechanistically different with ertugliflozin and probably more likely to be due to some combination of chance as well as more aggressive trial design definitions, etc. As many KOLs emphasized, ertugliflozin had pronounced effects on exploratory outcomes, including hHF and renal outcomes.

As background, as reported last year, VERTIS CV INSULIN was an 18-week study enrolling patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) with inadequate glycemic control on insulin, with or without metformin. 1,065 participants received either oral, once-daily ertugliflozin (5mg or 10mg) or placebo, and 979 participants (91.9%) completed 18 weeks of treatment. Ertugliflozin, at both doses, demonstrated a significant placebo-corrected ~0.6% A1c reduction over 18 weeks compared to placebo (5mg: -0.58%; 95% CI: -0.71, -0.44; p<0.001) (10mg: -0.65%; 95% CI: -0.78, -0.51; p<0.001). This result did not differ significantly by baseline A1c, age, sex, race, ethnicity, or background therapy (either insulin only or insulin + metformin since patients with other agents were excluded). Ertugliflozin also demonstrated significant reductions on the secondary outcomes of fasting plasma glucose, body weight, and systolic blood pressure. Body weight had not plateaued at 18 weeks, suggesting weight decreases may continue beyond 18 weeks. As expected for the SGLT-2 class, genital mycotic infections were the most common adverse events, and other adverse events including hypoglycemia were similar across groups. These results suggest ertugliflozin, along with the rest of the SGLT-2 class, may be useful treatment options in patients with type 2 diabetes on insulin who need additional glycemic control.

  • Baseline characteristics. The participant population was primarily male (68%) with an average age of 65 years. 12% of participants were Hispanic/Latino. At baseline, 60% of participants used metformin, and participants had an average A1c of 8.5%, BMI of 32 kg/m2, and mean duration of type 2 diabetes of 16.5 to 17 years. Dr. Lingvay asked attendees to remember when interpreting results that these patients generally had long durations of diabetes with advanced diabetes and comorbidities, forming a generally harder-to-treat patient population.
  • SGLT-2s as a class are effective as add-ons to insulin in patients with inadequately controlled type 2 diabetes. Providing context for these results within the SGLT-2 class, Dr. Lingvay shared similar results from five other studies of empagliflozin or dapagliflozin as add-ons to insulin. She also noted that SGLT-2s have a complementary mechanism of action with exogenous insulin – SGLT-2s decrease reabsorption of glucose and insulin promote cellular uptake of glucose in peripheral tissues. Additionally, SGLT-2s counterbalance the weight gain associated with insulin therapy. Dr. Lingvay concluded, “For those of you who may not be convinced, I want to remind you of VERTIS-CV results and the overall SGLT-2 effect on decreasing HF and decreasing progression of CKD, which are quite significant.”

Two VERTIS CV subanalyses: SGLT-2 ertugliflozin’s efficacy in patients with stage 3 CKD and cardiorenal outcomes by baseline glucose-lowering agent

In back-to-back presentations on SGLT-2 ertugliflozin, Dr. Samuel Dagogo-Jack (University of Tennessee) discussed ertugliflozin’s efficacy in patients with stage 3 CKD, ASCVD, and type 2 diabetes (SO26-438), and Dr. Bernard Charbonnel (University of Nantes, France) reported cardiorenal outcomes with ertugliflozin by baseline glucose-lowering agent (SO26-439). Both analyses were first presented as posters at ADA 2021 and were based on the VERTIS CV study, read out at ADA 2020 and published in NEJM. As a reminder, in the VERTIS CV CVOT, ertugliflozin showed neutral impact on three-point MACE (non-fatal MI, non-fatal stroke, and CV death) but a significant benefit on the secondary outcome of hospitalization for heart failure (HR=0.70, 95% CI: 0.54-0.90). Ertugliflozin also showed a 34% risk reduction on an exploratory kidney composite outcome defined as sustained ≥ 40% decrease in eGFR, dialysis/transplantation, or kidney death (HR=0.66; 95% CI: 0.50, 0.88). In his subanalysis, Dr. Dagogo-Jack reported that ertugliflozin at both 5 mg and 15 mg doses led to significant A1c, body weight, and systolic blood pressure reductions in patients with stage 3 CKD, atherosclerotic cardiovascular disease (ASCVD), and type 2 diabetes. In the other subanalysis, Dr. Charbonnel reported that ertugliflozin’s cardiorenal outcomes in patients with type 2 diabetes were consistent regardless of baseline glucose-lowering agent (metformin, insulin, sulphonylurea, and/or DPP-4). These two subanalyses followed Dr. Ildiko Lingvay’s (UT Southwestern) presentation during EASD 2021 Day #1 on the VERTIS CV INSULIN sub-study, which showed that ertugliflozin added to insulin significantly reduced A1c, body weight, and systolic blood pressure in patients with type 2 diabetes and ASCVD.

  • Ertugliflozin led to modest A1c reductions, typical for SGLT-2s in people with stage 3 CKD, along with blood pressure and body weight reductions and preservation of renal function. Dr. Dagogo-Jack reported that over 18 weeks, ertugliflozin at both 5 mg and 15 mg doses yielded significant placebo-subtracted reductions in A1c (5mg: -2.9; p<0.001) (15mg: -3.0; p<0.001), body weight (5mg: -1.4 kg; 15mg: -1.5 kg), and systolic blood pressure (5mg: -2.9 mmHg; 15mg: -3.2 mmHg) in the 1,776 patients in VERTIS CV who had stage 3 CKD (eGFR between 30-<60 mL/min/1.73m2). Dr. Dagogo-Jack noted that ertugliflozin’s modest A1c reduction in this population was similar to that of other SGLT-2s, and the magnitude of body weight and systolic blood pressure reductions were similar to the overall VERTIS CV population. Interestingly, the 1,319 participants with stage 3A CKD (eGFR 45-<60 mL/min/1.73m2) experienced significant placebo-corrected A1c reductions at both 5 mg and 15 mg ertugliflozin, but the 457 participants with more severe stage 3B CKD (eGFR 30-<45 mL/min/1.73m2) only had significant placebo-corrected A1c reductions with 5 mg ertugliflozin (p=0.006), not with 15 mg ertugliflozin (p=0.064). Typical of the SGLT-2 class, patients on ertugliflozin experienced a dip in eGFR after treatment initiation, followed by a rebound without any apparent worsening of function. This eGFR dip plus rebound is tantamount to preservation of renal function on ertugliflozin, whereas those on placebo experienced deterioration of renal function. Safety outcomes (overall adverse events, hypoglycemic events, and kidney-related adverse events) were similar between patients with stage 3 CKD receiving ertugliflozin and those receiving placebo, except ertugliflozin significantly increased genital infection, as expected for the SGLT-2 class.
    • During discussion, Dr. Dagogo-Jack explained why A1c reductions are modest in patients with stage 3 CKD. Patients with stage 3 CKD have a low eGFR, so filtration through the glomerulus is substantially impaired, leading less glucose to pass through the glomerulus. As a result, there is a limited amount of glucose in the renal tubule to block from being reabsorbed, which is the primary mechanism by which SGLT-2s lower blood glucose. Therefore, Dr. Dagogo-Jack stated, “An SGLT-2 is not going to be a first line drug for lowering blood glucose in CKD patients. These patients ought to be on other agents.” However, he emphasized that the glycemic benefits and cardiorenal benefits of SGLT-2s are uncoupled. Even though patients with stage 3 CKD have impaired kidneys and modest A1c reductions on SGLT-2s, Dr. Dagogo-Jack was adamant that they deserve to receive the well-shown cardiorenal benefits of SGLT-2s.
  • Ertugliflozin’s effect on cardiovascular and kidney outcomes was not modified by baseline use of metformin, insulin, sulfonylureas, or DPP-4s, though ertugliflozin only conferred a significant benefit on hHF and an exploratory kidney composite outcome. Of the 8,246 participants in VERTIS CV, 76% took metformin, 47% took insulin, 41% were on a sulfonylurea, and 11% were on a DPP-4 at baseline. Those on insulin tended to have a longer duration of diabetes. Those who took DPP-4s were less likely to have heart failure at baseline. Those on insulin were less likely to be on a sulfonylurea and vice versa. The effect of ertugliflozin on MACE, hHF/CV death, CV death, hHF, kidney composite (death from renal causes, renal replacement therapy, or doubling of serum creatine), and exploratory kidney composite (≥ 40% decrease in eGFR, dialysis/transplantation, or kidney death) was not modified by baseline glucose lowering agents (all p-interaction > 0.05). There was a positive, non-significant trend suggesting that participants on ertugliflozin and either metformin or insulin at baseline had a lower risk of hHF and the exploratory kidney composite outcome. Interestingly, ertugliflozin was not associated with an increased risk of symptomatic or severe hypoglycemia regardless of baseline glucose lowering agent. In a similar session at ADA 2021, Dr. David Cherney (University Health Network, Canada) presented a subanalysis of VERTIS CV examining cardiovascular outcomes by baseline use of cardiorenal therapies, and he concluded that ertugliflozin with baseline use of diuretics increased heart failure protection.

VERTIS-CV sub-analysis reveals consistent cardiorenal benefits of ertugliflozin in patients ≥65 and ≥75 years vs. younger comparators; small RWE study demonstrates safety and efficacy of various SGLT-2s

During a jam-packed oral presentation session on SGLT-2 trials, Dr. Richard Pratley (AdventHealth Translational Research Institute, Orlando, Florida) presented the results of an analysis of over 4,000 elderly patients in VERTIS-CV that demonstrated ertugliflozin’s consistent benefits, safety, and tolerability in older patients with type 2 diabetes and CVD. The analysis of over 4,000 elderly patients found that the effects of ertugliflozin on cardiovascular and kidney outcomes were consistent between subgroups of patients ≥65 and <65 years and subgroups of patients ≥75 and <75 years; the results in both subgroups were also consistent with those of the overall VERTIS-CV cohort. Dr. Pratley emphasized that despite the older patient subgroup having a higher incidence of CKD and coronary artery disease, the older patients gained benefits of ertugliflozin consistent with those in the younger group. No new safety concerns were identified in this analysis of older patients, though the incidence of urinary tract infections were higher in both the >65 and >75 subgroups compared to their younger counterparts. Based on this “robust” analysis of large numbers of elderly patients (n=4,145 ≥65 years, n=903 ≥75 years), Dr. Pratley concluded that ertugliflozin is effective, safe, and generally well-tolerated in older patients. Given that usage of guideline-directed medication therapies remains concerningly low in patients with type 2 diabetes and CVD, we’d hope this analysis and others that may follow will lead to greater usage of these powerful cardiorenal protective agents, particularly in older populations. We’d imagine this study may spur similar research of other agents in older populations, which will become especially important as patients with type 2 diabetes live longer thanks to advances in diabetes therapy and technology.

  • Addressing the study rationale, Dr. Pratley argued that it’s especially important to study SGLT-2s in older patients because they tend have a longer duration of diabetes and are therefore likely to have multiple comorbidities and develop CV and kidney complications. Indeed, the older patient subgroups had double the incidence of CKD compared to the younger subgroup, with 30% of patients ≥65 years vs. 13% of those <65 years presenting with CKD stage 3 and approximately 43% of patients ≥75 years vs. 20% those <75 years presenting with CKD stage 3. Despite these differences in kidney function, Dr. Pratley noted that the benefit of ertugliflozin was maintained in the older patient group. While the incidence of adverse events, serious adverse events (including deaths), and discontinuations due to an adverse event were higher in the older vs. younger patient subgroups, Dr. Pratley stressed that rates did not differ between the ertugliflozin vs. placebo groups. In the Q&A, he advocated for preferential use of SGLT-2s in older patients with high CV risk, stating that “this is one of the most likely groups to benefit.”
  • Earlier in the session, Dr. Maria Lunati (ASST FatebeneFratelli-Sacco, Milan, Italy) presented findings from a small real-world study examining the safety and efficacy of various SGLT-2s in 450 patients 70 years of age over one year of follow-up. The retrospective analysis found that SGLT-2s were effective in older patients, conferring statistically significant reductions in A1c and fasting plasma glucose, alongside non-statistically significant reductions in BMI. While discontinuation occurred in approximately 7% of subjects at 12 months, primarily due to intolerance and urinary tract infections, no cases of DKA or amputation were recorded. Dr. Lunati concluded that these findings demonstrate safety, efficacy, and tolerability of the SGLT-2 class in older patients, though she recommended some caution in more frail patients and advocated individualization of therapy. Overall, both Dr. Lunati and Dr. Pratley emphasized the lack of data on SGLT-2s in older patients, especially those over 75 years. In our view, this represents a clear shortcoming in the field given that these patients tend to be at higher risk of CV, kidney, and other complications, and we hope to see more studies of SGLT-2s, GLP-1s, and other new agents in older patients going forwards.

New data from EMPEROR-Preserved on patient population, efficacy endpoints, and safety of empagliflozin by diabetes status + commentary from Karolinska Institute’s Dr. Anna Norhammar

Esteemed cardiologist Dr. Gerasimos Filippatos (University of Athens) presented new EMPEROR-Preserved analyses evaluating the efficacy of BI/Lilly’s SGLT-2 Jardiance (empagliflozin) in HFpEF by diabetes status. As a reminder, EMPEROR-Preserved found that empagliflozin demonstrated a 21% risk reduction on the primary composite outcome of CV death or hHF, a 27% risk reduction on total heart failure hospitalization, and a significant reduction in slope of eGFR decline (1.36 mL/min/1.73 m2/year slope difference) in HFpEF patients (ejection fraction > 40%) with diabetes (n=2,938) or without diabetes (n=3,050). It was first read out at ESC 2021, was published in NEJM accompanied by an editorial by Dr. Mark Drazner (University of Texas), and led to Jardiance receiving FDA Breakthrough Therapy designation for HFpEF. In today’s session, Dr. Filippatos broke down the study results by diabetes status, which led him to conclude that the decision to use empagliflozin to treat HFpEF “should not be influenced by glycemic status,” and Dr. Anna Norhammar’s discussed her takeaways from the trial and a meta-analysis published this week in The British Journal of Diabetes on 10 SGLT-2 trials that included EMPEROR-Preserved in its analysis. 

  • Baseline characteristics by diabetes status. Dr. Filippatos highlighted multiple differences at baseline between patients with and without diabetes. Patients with diabetes had a significantly higher A1c (7.3% vs. 5.7%), increased hHF in last 12 months (25% vs 21%), increased hypertension (94% vs 87%), and decreased atrial fibrillation (46% vs 56%). Patients with diabetes were also more likely to take ARBs (42% vs. 36%), beta blockers (88% vs. 85%), and MRAs (39% vs. 36%). As expected, those with diabetes were more likely to be on any glucose-lowering therapy (80% vs. 1%). Of those with diabetes, 54% were on biguanides, 29% were on insulin, 21% were on sulfonylureas, 13% were on DPP-4 inhibitors, and 2% were on GLP-1 agonists.
  • Heart and renal outcomes by diabetes status. As shared at EMPEROR-Preserved initial readout, which Dr. Filippatos reiterated, empagliflozin reduced the primary composite endpoint of time to first hHF or CV death similarly in patients with and without diabetes (p-interaction=0.9224). The components of the primary endpoint did not differ significantly by diabetes status. Baseline A1c did not impact the effect of empagliflozin on composite CV or hHF. Additionally, empagliflozin’s reduction in total hHF was similar in patients with and without diabetes (p-interaction=0.9697). Turning to the main renal outcome, empagliflozin slowed the rate of decline in eGFR in both patients with (+1.77 mL/min/1.73m2/yr) and without (+0.98/mL/min/1.73m2/yr) diabetes, but this reduction was significantly greater in those with diabetes (p-interaction=0.01).

  • Insulin initiation by diabetes status. In patients who were not on insulin at baseline, empagliflozin decreased the risk of sustained insulin initiation by 31% in patients with diabetes or prediabetes (HR=0.69; 95% CI: 0.49, 0.98; p=0.04), but not in participants with normoglycemia. Sustained insulin initiation was defined the maintenance of insulin treatment for two or more study visits. We aren’t so familiar with this unit as a measure.
  • A1c, vital signs, and biomarkers by diabetes status. Empagliflozin significantly reduced A1c in patients with diabetes but not in patients without diabetes. Compared to those without diabetes, patients with diabetes on empagliflozin experienced more weight reduction (-1.7 kg vs. -1.1 kg; p-interaction=0.0175) and a greater reduction in the natriuretic peptide NT-proBNP (-31 pg/mL vs. -27 pg/mL; p-interaction=0.0308). Interestingly, uric acid reduction was more pronounced in those without diabetes (-0.74 mg/dL vs. -1.06 mg/dL).

  • Safety by diabetes status. Safety outcomes were similar for both patients with and without diabetes. Importantly, patients with diabetes did not have a substantial increase in diabetic ketoacidosis (0.3% vs. 0%), hypoglycemia events (4.3% vs. 0.4% prediabetes vs. 1.1% normoglycemia), or severe hypoglycemic events (1.5% vs. 0.1% prediabetes vs. 0.2% normoglycemia). There were also no differences in hypotension or lower limb amputations between patients with and without diabetes.
  • Dr. Anna Norhammar (Karolinska Institute, Sweden) had glowing remarks on EMPEROR-Preserved and referenced a meta-analysis published in the British Journal of Diabetes this week that incorporated EMPEROR-Preserved, entitled, “Effect of sodium-glucose linked transporter-2inhibitors on heart failure end points in people with type 2 diabetes mellitus: a systematic review and meta-analysis.” In her commentary on EMPEROR-Preserved on today’s session, Dr. Anna Norhammar borrowed from Dr. Drazner’s editorial, saying that these results are “truly a win against a formidable foe” and adding, “This is a game changer for heart failure patients, for patients with type 2 diabetes, and for us healthcare providers. It will simplify treatment choices for patients.” She emphasized that clinicians should not delay starting patients on empagliflozin since the reduction in CV death or hHF to which it leads is seen incredibly early at only 18 days. Dr. Norhammar concluded that SGLT-2s clearly have a consistent effect on hHF, citing a meta-analysis of SGLT-2s on heart failure endpoints that found a 31% risk reduction on hHF across ten RCTs including EMPEROR-Preserved. She encouraged clinicians to focus on treatment implementation rather than discussion about ejection fraction cutoffs and SGLT-2 mechanisms, given what she termed the disappointing uptake of SGLT-2s. 

EMPRISE real-world study shows that SGLT-2 empagliflozin is associated with significantly reduced risk of hHF and AKI (-29% and 51%, respectively) compared to DPP-4s in patients with type 2 diabetes in Israel, Europe, and East Asia; risk of all-cause mortality reduced by 45%

In this short oral presentation (SO27-445), Dr. Avraham Karasik (Sheba Medical Center, Israel) presented results on empagliflozin’s CV effectiveness and safety outcomes from the international, real-world EMPRISE study. The study included 134,280 adults with type 2 diabetes from Israel, Finland, Germany, Spain, Sweden, South Korea, Taiwan, or Japan, who initiated either empagliflozin or a DPP-4 in a 1:1 ratio. Participants were followed from 2014 to 2019, though the specific study period varied by country. Baseline characteristics were similar across countries, except 27% of the Japanese study population had congestive heart failure at baseline compared to single digit percentages in the other countries. This disparity arose because the Japanese cohort only included hospitalized patients, whereas this was not the case in other countries. After pooling event rates from all eight countries, empagliflozin compared to DPP-4s demonstrated a 29% risk reduction on hHF (HR=0.71; 95% CI: 0.60-0.82), a 26% risk reduction on stroke (HR=0.74; 95% CI: 0.62-0.88), and an astounding 45% risk reduction in all-cause mortality (HR=0.55; 95% CI: 0.45-0.67). Empagliflozin also demonstrated significant risk reductions on two composite outcomes: (i) hHF and all-cause mortality, and (ii) myocardial infarction, stroke, and all-cause mortality. The benefits on hHF, all-cause mortality, and the two composite outcomes were independent of baseline CV disease status. Empagliflozin also conferred a significant 51% risk reduction on acute kidney injury requiring dialysis (HR=0.49; 95% CI: 0.34-0.69) along with no significant change in risk of bone fracture compared to DPP-4s. Dr. Karasik concluded that these real-world results complement those from the EMPA-REG randomized controlled trial, read out at EASD 2015 and published in NEJM, which found that empagliflozin significantly reduced risk of CV death, hHF, all-cause hospitalization, and all-cause mortality in adults with type 2 diabetes and CV disease. Ultimately, he argued, these real-world results lend greater support to the use of SGLT-2s in patients with type 2 diabetes to reduce hHF, CV events, and death.

  • Empagliflozin increased the risk of diabetic ketoacidosis by 82% compared to DPP-4 (HR=1.82; 95% CI: 1.12-2.95). While SGLT-2s increase the risk of DKA in patients with type 1 diabetes (dapagliflozin, empagliflozin, and sotagliflozin received CRLs from the FDA due to DKA concerns in patients with type 1 diabetes), only patients with type 2 diabetes were enrolled in this study. DKA is still a risk with SGLT-2 in patients with type 2 (SGLT-2 FDA labels include a DKA warning), and it is a higher risk in certain cases like when people with T2D take it before a surgery and are on insulin – we look forward to better understanding this. To date, when there is “perfect information,” the DKA has been preventable – here, such a large increase in DKA risk is worrisome, and while the confidence interval for this point estimate is big, we look forward to more perspectives and input. Notably, the EMPA-REG trial found no significant increase in DKA with empagliflozin over placebo, but the clinical trial setting may have enabled closer monitoring and better implementation of DKA risk mitigation strategies. When asked about the risk of DKA with empagliflozin, Dr. Karasik stated that no sub-analysis of EMPRISE has been done yet to identify which patients were at highest risk of DKA or why the DKA rate was so high. He encouraged physicians and patients to discuss the risk of DKA along with risk mitigation strategies before initiating an SGLT-2.
  • Just yesterday at EASD 2021, we heard from Dr. Jesper Krogh (Rigshospitalet, Denmark) who urged caution when interpreting observational studies of SGLT-2s and warned of inflated and biased results. Dr. Krogh conducted a systematic review of SGLT-2 randomized trials and observational studies and found that the heterogeneity between results on all-cause mortality, CV mortality, and heart failure were explained by study type. Specifically, he found that the pooled RCTs showed a 14% risk reduction on all-cause mortality, while the pooled observational studies showed a 45% risk reduction on all-cause mortality. He argued that the observational results were inflated due to immortal-time bias and residual confounding. If Dr. Krogh’s analysis of EMPRISE is published in more detail, we would be interested to learn how such biases and confounding were mitigated. We expect the 1:1 propensity score matching procedure used in EMPRISE to have mitigated these concerns to some extent. Of note, however, empagliflozin is the only SGLT-2 to show a significant risk reduction on all-cause mortality in an RCT – in EMPA-REG, empagliflozin conferred a 32% risk reduction on all-cause mortality. Compared to a 32% reduction, the 45% risk reduction on all-cause mortality found in EMPRISE is not as surprising.

EMPRISE study finds that patients on SGLT-2 empagliflozin had lower healthcare resource utilization in both inpatient and outpatient settings than those on a DPP-4

In this short oral presentation (SO 27-444), Dr. Leo Niskanen (University of Eastern Finland) presented sub-analysis from the EMPRISE study, one of the first real-world studies on the effect of SGLT-2s on healthcare resource utilization by European patients with type 2 diabetes. Although the EMPRISE study has a broader scope, the sub-analysis presented by Dr. Niskanen was limited Sweden, Finland, Norway and Spain and focused on healthcare resource utilization. For background, EMPRISE was conducted throughout Europe and Asia and assessed efficacy, safety, and healthcare resource utilization of empagliflozin compared to DPP-4s in real-world routine clinical settings. In Dr. Niskanen’s analysis, the study population consisted of adults with type 2 diabetes who had initiated empagliflozin or a DPP-4 between May 2014 and December 2018 (Nordic countries) or April 2015 to December 2018 (Spain). Empagliflozin and DPP-4 cohorts were matched 1:1 using propensity scores, and Sweden, Finland, Norway, and Spain identified 15,785, 11,801, 6,344, and 5,865 matched patient pairs, respectively. In a meta-analysis of data from all four countries, patients on empagliflozin compared to those on a DPP-4 had a 17% reduced risk of first hospitalization, a 25% reduced risk of all-cause hospitalization, a 20% reduced risk of an emergency room visit, and an 11% reduced risk of a non-ER outpatient visit. In each country, there were significant risk reductions for all four of these outcomes with empagliflozin relative to a DPP-4, except in Sweden where empagliflozin did not significantly reduce risk of emergency room visitation. Furthermore, results indicated that patients on empagliflozin in all countries had fewer inpatient days than those on a DPP-4. These results trended in the same direction regardless of patients’ CVD or HF status at baseline in the four countries. Taken together, these results strongly support that empagliflozin reduces inpatient care need and outpatient visits for patients with type 2 diabetes in routine European clinical practice compared to DPP-4s. These findings provide real-world context to the landmark EMPA-REG randomized controlled trial, read out at EASD 2015 and published in NEJM, which found that empagliflozin significantly reduced risk of CV death, hHF, all-cause hospitalization, and all-cause mortality in adults with type 2 diabetes and CV disease.

EMPA-REG OUTCOME subanalysis finds that Jardiance reduces total burden of events leading to or prolonging hospitalization by 22%

In a midafternoon session, Dr. Silvio Inzucchi (Yale) presented subanalysis from EMPA-REG OUTCOME (SO 489), which found that Jardiance (empagliflozin) reduced the total burden of events leading to or prolonging hospitalization by 22%. As background, EMPA-REG OUTCOME included people with type 2 diabetes and established ASCVD who were randomized to receive Jardiance or placebo treatment for 206 weeks (~four years) and found a 14% relative risk reduction of three-point MACE with Jardiance relative to placebo. Previous analysis found that Jardiance reduced the risk of total (first + recurrent) events leading to all-cause hospitalization by 17% and the composite of all-cause mortality and all-cause hospitalization by 19% vs. placebo. In the subanalysis presented by Dr. Inzucchi in today’s presentation, researchers evaluated the impact of Jardiance on the risk of events leading to or prolonging hospitalizations for any cause and found an even greater risk reduction with Jardiance relative to placebo. Specifically, the researchers found a 12% relative risk reduction in the rate of first events leading to or prolonging hospitalization (95% CI=0.81-0.95; p=0.002) and a 22% relative risk reduction in total events (first + recurrent) leading to or prolonging hospitalization with Jardiance relative to placebo. This benefit was observed almost immediately from the onset of treatment. Overall, only six patients were needed to treat to prevent one event leading to or prolonging hospitalization over three years. During Q&A, Dr. Inzucchi noted that the researchers observed a trend toward a reduction in all subtypes of hospitalizations studied with Jardiance (gastrointestinal, pulmonary, cardiovascular hospitalizations, etc.), not just in cardiovascular hospitalizations, although not all subtypes achieved statistical significance individually.

  • Empagliflozin was also correlated with a 24% relative risk reduction of the composite of total events leading to or prolonging all-cause hospitalization and all-cause mortality. Although both the mortality and hospitalization components contribute to the composite risk reduction, much of this benefit was due to reductions in the risk of recurrent hospitalization-related events, as relative risk reduction of the composite of all-cause mortality and first events leading to or prolonging hospitalization was only 14%. As with hospitalizations alone, this benefit was observable within six months of randomization. Only five patients are needed to treat to prevent one composite event over three years. Looking at all-cause mortality alone, the relative risk reduction with empagliflozin was a whopping 31%.

SGLT-2 inhibitors confer impressive CVD and ESKD five-year risk reduction in type 1 diabetes study: Results from Steno Diabetes Center Copenhagen

In a striking presentation, Dr. Elisabeth Buur Stougaard (Steno Diabetes Center Copenhagen) evaluated how the risks of cardiovascular disease (CVD) and end-stage kidney disease (ESKD) are modulated by SGLT-2 inhibitor treatment in type 1 diabetes (SO 606). Dr. Stougaard’s research was based upon clinical data from type 1 diabetes patients treated at Steno’s outpatient clinic (n=3,660). Using the Steno T1 Risk Engine, she assessed the extent to which certain risk factors – notably A1c, systolic blood pressure (SBP), and urine albumin-to-creatinine ratio (UACR) – were modified with SGLT-2 inhibitor treatment to ultimately affect 5- and 10-year CVD and ESKD risk. Impressively, SGLT-2 inhibitors conferred a 6.1% relative risk reduction (RRR) on the endpoint of five-year CVD risk and a 5.3% RRR on the endpoint of five-year ESKD risk. For both endpoints, the magnitude of the risk reduction seen was greater in those with albuminuria (11.1% on five-year CVD risk, 7.6% on five-year ESKD risk). These results potentially suggest a significant benefit for SGLT-2 inhibitors in type 1 diabetes, particularly in higher risk patients with albuminuria.

  • SGLT-2 use in patients with type 1 diabetes is a complicated issue – while several KOLs are supportive of the off-label use, there are safety concerns that patients must be aware of. In her 2019 ATTD talk, Dr. Chantal Mathieu framed SGLT-2s as a “promising adjunct therapy” while cautioning that “we have to strike the right balance between benefits and side effects.” The impetus for patients with type 1 to take SGLT-2s is much the same as it is for patients with type 2 diabetes – the impressive cardiovascular and renal benefits. However, the primary concern, of course, is diabetic ketoacidosis. At ENDO 2020, Dr. Anne Peters noted that even the most well-educated and wealthy patients struggle to completely eliminate DKA risk. Notably, the three largest trials for SGLT-2 use in patients with type 1 diabetes – DEPICT (for AZ’s SGLT-2 dapagliflozin), inTandem (for Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin), and EASE (for Lilly/BI’s SGLT-2 empagliflozin) – have each resulted in a CRL from the FDA – sotagliflozin in March 2019, dapagliflozin in July 2019, and empagliflozin in March 2020 – largely due to failure to mitigate concerns about DKA. Ultimately, it remains an uphill battle for widespread SGLT-2 use among type 1 patients, but we greatly appreciate new research in the field, as seen above, to help someday give patients this choice.

Dr. John Wilding and Dr. Michael Nauck debate whether SGLT-2s or GLP-1s will prevail in 100 years for type 2 diabetes treatment, considering glycemic, weight loss, CV, and renal benefits, plus cost-effectiveness

In a stirring debate about which new class of diabetes drugs will prevail in 100 years for the treatment of type 2 diabetes, Dr. Michael Nauck (St. Josef-Hospital, Germany) argued in favor of GLP-1s while Dr. John Wilding (University of Liverpool, UK) argued for SGLT-2s. Of course, it’s possible that in 100 years both therapies become foundational and widely used for diabetes and other conditions, and neither speaker suggested otherwise, instead arguing that one drug class may be better under some circumstances than the other. In this spirit, the chair of the session Dr. Robert Semple (University of Edinburgh, UK) concluded, “The answer is that these are two wonderful medicines.” Both Dr. Nauck and Dr. Wilding agreed that many more people should receive both medications – by some estimates, only 9% of patients receive SGLT-2s, 8% receive GLP-1s, and only 7% receive guideline-directed therapy.

We found that pitting GLP-1s (including GIP/GLP-1 dual agonist tirzepatide) and SGLT-2s against each other was an incredibly informative way to compare and assess available data for each class even though, of course, both will prevail. Much of Dr. Nauck’s argument was based on an unpublished meta-analysis he wrote that compared GLP-1 glycemic control, body weight reduction, and CV and renal risk reduction to basal insulins and SGLT-2s. Ultimately, Dr. Nauck concluded that GLP-1s have a slight advantage over SGLT-2s due to A1c lowering, body weight reduction, and the eventual development of small-molecule GLP-1 tablets. On the other hand, Dr. Wilding asserted that SGLT-2s stand out due to their reduction of kidney outcomes and hHF, and he countered that small molecule GLP-1s or oral biologic GLP-1s (Rybelsus, oral semaglutide) will not be as effective as the most potent injectables, GLP-1 semaglutide and GIP/GLP-1 tirzepatide. Dr. Wilding added that SGLT-2s are more cost-effective than GLP-1s, as shown by guidelines for SGLT-2 use instead of GLP-1 use by the UK’s National Institute for Health and Care Excellence

  • Dr. Nauck asserted that GLP-1s have better A1c lowering, body weight reduction, and risk reduction on stroke than SGLT-2s, but he acknowledged that SGLT-2s demonstrate greater risk reduction hHF and kidney outcomes. To argue that GLP-1s yield greater A1c and body weight reductions than SGLT-2s, Dr. Nauck cited SUSTAIN 8, which found that once-weekly semaglutide compared to canagliflozin demonstrated a significantly greater A1c reduction (-0.49% difference; 95% CI: -0.65, -0.33; p<0.0001) and body weight reduction (-1.06 kg difference; 95% CI: -1.76, -0.37; p=0.0029). On CV and renal events, Dr. Nauck references his unpublished meta-analysis, which showed that GLP-1s tend to have a greater reduction in stroke than SGLT-2s, whereas SGLT-2s have significantly greater reduction in hHF and kidney-related outcomes. While CV mortality risk reductions are similar for both classes, Dr. Nauck suggested that the mechanisms of CV death reduction could be different. GLP-1s may reduce CV mortality by reducing ischemic events, whereas SGLT-2s may act by reducing heart failure events. Dr. Nauck concluded by scoring the characteristics of GLP-1s and SGLT-2s and found that overall they were relatively equal, except GLP-1s came out on top after he accounted for eventual widespread availability oral GLP-1s (which we recognize is a big assumption).

    • Dr. Nauck highlighted that orally active GLP-1s could change the game for the GLP-1 class. He cited PIONEER 4, which showed that oral semaglutide (Rybelsus) has similar A1c reductions and greater body weight reductions that subcutaneous liraglutide. Rybelsus has been available since late 2019 and its sales are growing rapidly. However, Dr. Nauck was more interested in the potential for small molecule GLP-1 tablets that have greater bioavailability than Rybelsus, which is burdened with bioavailability issues and cannot be taken with other drugs or food. He references multiple compounds in developments and highlighted Pfizer’s compound, danuglipron, which completed a phase 2 trial in July 2021. Over 28 days, danuglipron compared to placebo demonstrated significantly greater reduction in A1c (-0.7%) and body weight (-5.4kg). Dr. Nauck added that steady state had not been reached at 28 days, suggesting greater A1c and body weight reductions with longer duration of treatment.

  • Dr. Wilding argued that SGLT-2 will be around 100 years from now in large part because they have impressive reductions on hospitalizations of HF and kidney-related outcomes and have benefits in patients with HF regardless of diabetes status.  Dr. Wilding did less direct comparison of GLP-1s and SGLT-2s, opting to do an in-depth review of SGLT-2 outcomes data and trials, but he cited a 2019 meta-analysis in Circulation showing that SGLT-2 are superior to GLP-1s in reducing hospitalization for heart failure (hHF). Reviewing four SGLT-2 trials, one for each of the four approved drugs in the class, he summarized that all the trials show a >27% risk reduction on hHF and three out of the four trials showed a >39% risk reduction on kidney outcomes. He reviewed impressive CKD benefits of SGLT-2s from CREDENCE and DAPA-CKD and referenced real-world evidence from CVD-REAL 3 and a Scandinavian cohort study, showing substantial risk reductions on kidney events compared to other glucose lowering therapies. Citing the ADA 2021 Standards of Care, he acknowledged that where ASCVD predominates GLP-1sd may be better, but asserted that where HF and CKD predominate, SGLT-2s are certainly the way to go.

    • Dr. Wilding also took a practical, cost-based approach to supporting the superiority of SGLT-2s over GLP-1s. He referenced guidance on treating patients with type 2 diabetes from the UK’s National Institute for Health and Care Excellence (NICE). According to these guidelines, patients at high risk of CVD, with congestive heart failure or ASCVD, or with CKD should receive an SGLT-2. Dr. Wilding explained that in these scenarios NICE considered SGLT-2s to be cost-effective interventions, which was not the case with GLP-1s.

New DAPA-CKD cardiorenal sub-analyses demonstrate consistent benefit of dapagliflozin across glycemic levels, CKD stages (including stage 4), and in patients with and without HF, PAD, and AF; further evidence for prevention of new-onset diabetes

In a stirring symposium on new data from DAPA-CKD, Profs. David Wheeler (University College London, UK), John McMurray (University of Glasgow, UK), and Silvio Inzucchi (Yale University) presented results from several sub-analyses demonstrating dapagliflozin’s consistent benefits across a range of cardiorenal patient subgroups. Taken together, these substudies indicate that dapagliflozin provides strong cardiorenal risk reduction benefits to a range of patients, from those with advanced CKD or underlying CV conditions to those with normoglycemia. We hope these powerful results can assuage any doubts that HCPs harbor concerning prescription of SGLT-2s (in particular to patients with low eGFRs) and lead to further uptake of these impressive risk-reducing agents.

  • Prof. Wheeler focused on the nephrology analyses, highlighting the consistent benefits of dapagliflozin in patients with CKD stage 4 (eGFR 25-30, n=624). Examining the graph of eGFR trajectories, he noted that the acute dip at two weeks was “remarkably similar” among patients with stage 2/3 and those with stage 4 CKD. He also stated that there were no major safety concerns in the stage 4 group. Prof. Wheeler suggested that these findings (published in the Journal of the American Society of Nephrology) should address any remaining doubts about dapagliflozin’s efficacy and safety in patients with lower eGFRs, emphasizing that the SGLT-2 can be used even in patients with advanced kidney disease. Prof. Wheeler also pointed to further substudies demonstrating that the benefits of dapagliflozin were consistent across CKD etiologies (both diabetic and non-diabetic nephropathy) and by baseline albuminuria. These results expand upon the impressive initial findings from DAPA-CKD and provide a strong endorsement for using the SGLT-2 in a broad range of patients, even those with severe renal impairment.

  • Offering a cardiology perspective, Prof. McMurray emphasized that dapagliflozin’s beneficial effects were not modified by the presence of heart failure (HF), peripheral arterial disease (PAD), or atrial fibrillation (AF), despite the fact that each of these conditions were associated with higher event rates. Results from an HF sub-analysis (published in the Journal of the American College of Cardiology), as well as preliminary data from PAD and AF sub-studies, revealed that these conditions were associated with higher risk of the primary composite outcome (eGFR decline ≥50%, ESKD, or kidney or CV death) and especially risk of the secondary CV composite outcome (CV death or HF hospitalization), which occurred at four to six times the rate in patients without these conditions at baseline. Interestingly, dapagliflozin conferred an increased benefit for patients with AF on the secondary CV composite outcome, with the p-value for interaction approaching statistical significance (p=0.07). Noting that AF is a “powerful driver” for the risk of CV death and greatly elevates risk in CKD patients, Prof. McMurray suggested that dapagliflozin may confer an especially powerful benefit in those with AF and CKD. While much remains unknown about the mechanisms of action of SGLT-2s, we’d imagine further mechanism studies could help explain how these agents confer increased risk reduction for those with AF.

  • On the cardiometabolic front, Prof. Inzucchi highlighted results from a pooled analysis of DAPA-CKD and DAPA-HF showing a 33% risk reduction in new-onset diabetes in patients without diabetes at baseline (n=4,003). These results corroborate those of an initial DAPA-CKD subanalysis presented at ADA 2021, suggesting that dapagliflozin may prevent development of diabetes, in addition to reducing CV and renal outcomes. An additional study (published in Diabetes Care) found consistent risk reduction across patients with normoglycemia, pre-diabetes, or diabetes (n=4,304), providing further support for dapagliflozin’s preventative benefits in patients without diabetes. Given that no significant differences in A1c were found between the placebo and active-therapy groups in DAPA-CKD and DAPA-HF, Dr. Inzucchi noted that dapagliflozin’s beneficial effect likely goes beyond mere “glycemic masking” and may suggest a more underlying effect on the pathogenesis of type 2 diabetes.

SGLT-2/GLP-1 combo therapy slows eGFR decline in type 2 diabetes patients with rapidly progressing CKD

In a short oral session on nephropathy interventions, Dr. Koji Kashima (Kiryu Kosei General Hospital, Kiryu, Japan) evaluated the renal impact of GLP-1/SGLT-2 combination therapy in type 2 diabetes patients with advanced chronic kidney disease (CKD, Stages 3 and 4) (SO 607). Dr. Kashima specifically investigated how GLP-1 receptor agonist liraglutide affected eGFR decline – an indicator of how fast CKD is progressing – with concurrent or staggered treatment with an SGLT-2 inhibitor. Benefits of the combination regimen were seen across all subgroups, regardless of whether the GLP-1 and SGLT-2 were initiated simultaneously or one after the other. Most impressively, while the slope of eGFR decline was -14.6 mL/min/1.73 m2/year without either therapy, it improved to -5.4 mL/min/1.73 m2/year (p<0.05) and -2.6 mL/min/1.73 m2/year (p<0.05) when a GLP-1 and an SGLT-2 was added, respectively. Dr. Kashima also separated the patients into “rapid decliners” (eGFR slope>-10 mL/min/1.73 m2/year) and “responders” (eGFR slope ratio reduced >1.0 mL/min/1.73 m2/year after SGLT-2 inhibitor). The percentage of “responders” increased as the severity of CKD increased, with an impressive 89% of stage 4 CKD patients seeing improvements in eGFR. These data suggest that GLP-1/SGLT-2 combination therapy may have significant benefits for patients with type 2 diabetes who are rapidly progressing to diabetic kidney disease (DKD).

Systematic review compares the effect of SGLT-2s on mortality and HF in randomized trials and observational studies, warning of biased and inflated results in observational studies

In this short oral presentation (SO 26-442) Dr. Jesper Krogh (Rigshospitalet, Denmark) suggested that the reported effects of SGLT-2s on all-cause mortality and CV mortality in observational studies are inflated due to methodological considerations, such as immortal-time bias and residual confounding. Dr. Krogh explained the motivation for this study by highlighting the apparent disparity between SGLT-2 RCT results that found modest risk reductions on mortality and the results from observational studies that found close to 50% risk reductions on mortality. This disparity is concerning, especially with the push to use observational studies in regulatory approval; in 2018, the FDA launched the Real-World Evidence Program to support the use of real-world evidence in drug approval applications. As a result, the research team aimed to assess and compare results from RCTs and observational studies of SGLT-2s, focusing on all-cause mortality, CV mortality, and heart failure (HF). Through PubMed, the research team identified 398 articles and ultimately included seven randomized controlled trials (RCTs) and 23 observational studies in their analysis. They found that study type explained the heterogeneity between results on all-cause mortality (p-interaction<0.001), CV mortality (p-interaction < 0.001), and to less of an extent heart failure (p-interaction=0.018). Specifically, the pooled RCTs showed 14%, 15%, and 32% risk reductions on all-cause mortality, CV mortality, and HF, respectively. In contrast, the pooled observational studies found 45%, 41%, and 36% risk reductions on all-cause mortality, CV mortality, and HF. Ultimately, Dr. Krogh urged caution when using observational studies to guide type 2 diabetes treatment. Dr. Krogh and the session chair, Dr. Naveed Sattar (University of Glasgow), acknowledged that pharmacoepidemiologic studies can be important in some circumstances, but they questioned the need for observational studies with SGLT-2s given the abundance of data from large randomized controlled trials across the SGLT-2 class.

  • Dr. Krogh suggested that observational study results were inflated due primarily to residual confounding along with immortal-time bias. Immortal-time bias could have arisen because patients in the SGLT-2 arm had to survive treatment with the comparator drug prior to starting on an SGLT-2, potentially making the SGLT-2 group less frail than the comparator group. As a result, immortal-time bias can confer a survival advantage to the SGLT-2 group, leading to lower mortality rates. Residual confounding is a data distortion that occurs when confounding variables are not considered, perhaps because data could not be collected, which is often the case in observational studies. Dr. Krogh was especially concerned that many observational studies left out a major confounding variable: socioeconomic status. He characterized this shortcoming as “highly problematic.”

A new health economics modelling approach for type 2 diabetes treatment strategies finds that SGLT-2-based therapeutic approach saves $24,514 in incremental costs and results in +0.71 QALYs relative to DPP-4s

Gengshi Chen (Health Economics Manager, AstraZeneca) presented results from her health economic modelling study (SO 488) evaluating the cost-effectiveness of SGLT-2 inhibitors in type 2 diabetes. Ms. Chen’s model was a significant update from traditional approaches to modelling the health economic effects of treatment sequences in type 2 diabetes – what she describes as the status quo modelling approach. In contrast to the status quo approach, Ms. Chen’s contemporary model reflect how treatment is currently being intensified for people with type 2 diabetes in clinical practice, particularly capturing the greater utilization of SGLT-2 inhibitors. By incorporating data from various SGLT-2 inhibitor CVOTs (DECLARE, DAPA-HF, DAPA-CKD) as well as the UK THIN database, Ms. Chen’s model revealed that SGLT-2 inhibitors are correlated with significant cost savings and increased quality-adjusted life years (QALYs). Specifically, relative to DPP-4-based approaches, SGLT-2-based approaches saw a 0.71 incremental QALY improvement and $24,514 (€20,994) in incremental cost savings. The magnitude of these positive findings was particularly impressive for type 2 diabetes patients with comorbid heart failure, chronic kidney disease, and end-stage renal disease. In addition, the older status quo model underestimated these benefits compared to Ms. Chen’s contemporary model, as the status quo model shows only +0.11 QALYs and $6,549 (€5,608) in incremental cost savings with SGLT-2-based approaches relative to DPP-4-based approaches, compared to +0.71 incremental QALYs and $24,514 (€20,994) in incremental cost savings with the contemporary model. Overall, Ms. Chen’s study gives proof-of-concept to a superior way of modelling the cost-effectiveness of diabetes treatment sequences, while also highlighting the longitudinal health economic benefits of SGLT-2 inhibitors. We hope that such a model can be used moving forward to generate evidence that supports expanding access to and coverage of SGLT-2s – the long-term cost-savings are particularly impressive and should provide the evidence necessary to push insurers to support SGLT-2 use.

Two CREDENCE and CANVAS pooled subanalyses: SGLT-2 canagliflozin decreased risk of total hHF regardless of baseline eGFR and reduced risk of MACE regardless of baseline UACR

In back-to-back short oral presentations, Dr. Mikhail Kosiborod (St. Luke’s Mid America Heart Institute, Kansas) shared data on the effects of canagliflozin on hHF by baseline eGFR (SO26-440), and Dr. David Wheeler (University College London, UK) reported canagliflozin’s MACE risk reduction by baseline UACR (SO26-441). Both analyses were based on pooled data from CREDENCE, read out at WCN 2019 and published in NEJM, and CANVAS, read out at ADA 2017. As a reminder, in CANVAS, canagliflozin showed a 14% risk reduction on MACE (CV death, nonfatal MI, and or nonfatal stroke) and 33% risk reduction on heart failure hospitalization (hHF), and in CREDENCE, canagliflozin showed a 21% risk reduction on MACE and 39% risk reduction on hHF. Participants in CREDENCE (n=4,401) had type 2 diabetes and CKD, while participants in CANVAS (n=10,142) had type 2 diabetes and high CV risk. Pooling patient-level data from both studies, Dr. Kosiborod shared that canagliflozin decreased time to first hHF, total number of hHF events, and total events of CV death and hHF without significant differences in relative risk reduction between baseline eGFR subgroups. Similarly, Dr. Wheeler reported that canagliflozin reduced the risk of MACE and its components with consistent benefits regardless of baseline urine albumin-to-creatinine ratio (UACR). Safety outcomes for canagliflozin were also similar across eGFR and UACR subgroups. It is certainly reassuring that canagliflozin has consistent efficacy and safety across eGFR and UACR ranges, but we do not expect these data alone to substantially impact clinicians’ decision making since canagliflozin is already indicated to treat adults with diabetic nephropathy with albuminuria. That said, there seems to be more awareness about the different groups of late and we do think that having a broader range is considered very helpful.

  • Across eGFR subgroups, canagliflozin had consistent relative risk reductions but varied absolute risk reductions. Across the three baseline eGFR subgroups (<45 mL/min/1.73m2, 45 mL/min/1.73m2-60 mL/min/1.73m2, and >60 mL/min/1.73m2), canagliflozin significantly decreased time to first hHF (HR=0.58; 95% CI: 0.48, 0.70; p-interaction=0.84), total number of hHF events (event ratio=0.63; 95% CI: 0.54, 0.73; p-interaction=0.51), and total events of hHF events and CV death (event ratio=0.72; 95% CI: 0.65, 0.80; p-interaction=0.82). While having consist relative benefits across the range of eGFR, canagliflozin had larger absolute benefits in participants with lower eGFR at baseline. Unsurprisingly, as baseline eGFR decreased, there was an increase in the prevalence of hypertension, history of HF, diabetes duration, and age. Arguing for the value of total event analysis, Dr. Kosiborod explained that first-event analyses generally underestimate absolute risk reduction. He also suggested that the entire SGLT-2 class likely delivers hHF benefits regardless of baseline eGFR.
    • Importantly canagliflozin’s label cautions against use in adults with an eGFR <30 mL/min/1.73m2, and Dr. Kosiborod’s analysis did not specifically study this range of eGFR. The lowest baseline eGFR range included in Dr. Kosiborod’s analysis was <45 mL/min/1.73m2, so while canagliflozin demonstrate efficacy and safety in that range there is still no direct evidence that canagliflozin has consistent efficacy and safety at eGFRs <30 mL/min/1.73m2. However, as Dr. Silvio Inzucchi (Yale) observed at CEU 2021, the lower bound eGFR for SGLT-2 use in CKD continues to be pushed lower. While CREDENCE only included patients with an eGFR ≥30 mL/min/1.73m2, DAPA-CKD with dapagliflozin had a reduced threshold of eGFR ≥25 mL/min/1.73m2. The ongoing EMPA-KIDNEY trial with empagliflozin (estimated completion 2022) has an even lower threshold of eGFR ≥20 mL/min/1.73m2. We are interested in seeing data that shows canagliflozin has consistent efficacy and safety even at these lower eGFR ranges.  
  • Canagliflozin reduced the relative risk of MACE compared to placebo similarly across UACR subgroups, but the rates of MACE increased with both canagliflozin and placebo as baseline UACR increased. Of the 14,542 patients in the integrated data set, 14,434 had baseline UACR measurements of which 49% had a baseline UACR <30 mg/g, 32% has a UACR between 30-300 mg/g, and 19% had a UACR >300 mg/g.  Across the three UACR subgroups, canagliflozin significantly reduced the risk of MACE (HR=0.83; 95% CI: 0.75, 0.92; p-interaction=0.42). Additionally, as baseline UACR increased, the rates of MACE increased. Specifically, in the CANVAS program, the number of participants on canagliflozin with a MACE event per 1,000 patient-years in each UACR range was 22, 35, and 54 participants (from lowest to highest UACR range). In CREDENCE, the number of participants on canagliflozin with a MACE event per 1,000 patient-years in each UACR range was 33, 41, and 63 participants.

Meta-analysis of SGLT-2 CVOTs finds that SGLT-2s consistently reduce the risk of CVDHHF so long as a patient has either type 2 diabetes, HF, or CKD

Dr. Konstantinos Charalampidis (Aristotle University of Thessaloniki, Greece) closed out a session on cardiovascular complications and drugs with a meta-analysis of SGLT-2 CVOTs that explored subgroup differences in cardiovascular death and heart failure hospitalization (CVDHHF) based on baseline presence of type 2 diabetes, HF, and CKD (SO 689). The meta-analysis included 10 studies: EMPA-REG Outcome, DECLARE-TIMI 58, CREDENCE, EMPEROR-Reduced, CANVAS, DAPA-HF, VERTIS-CV, DAPA-CKD, SCORED, and SOLOIST-WHF, which assessed, empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and sotagliflozin with follow-ups ranging from nine months to four years. In the overall population across the ten studies, SGLT-2s reduced CVDHHF by 24%. When stratified by the presence of diabetes, the meta-analysis found no difference in the SGLT-2-derived CVDHHF risk reduction in those with and without diabetes (HR=0.76 vs. 0.75; p=0.96). The same was true when stratified by the presence or lack of baseline HF (HR =0.75 vs. 0.77; p=0.78) and when stratified by the presence or lack of baseline CKD (HF=0.73 vs. 0.79; p=0.33). Thus, overall, the meta-analysis found that as a drug class, SGLT-2s consistently reduced the risk of CVDHHF so long as a patient has at least type 2 diabetes, HF, or CKD (eGFR<60 ml/min/1.73m2, but that the SGLT-2 CVDHHF benefit was not predicated on having all of these conditions. In his conclusion, Dr. Charalampidis was sure to note that the meta-analysis does not provide evidence by which the specific SGLT-2s can be compared, but rather provided evidence supporting the strong class effect irrespective of HF, type 2 diabetes, and CKD. Similar findings were recently published in JAMA Cardiology by Maguire et al., which assessed the association between SGLT-2s and CV and renal outcomes in patients with type 2 diabetes based on the outcomes data of six SGLT-2 trials (EMPA-REG Outcome, DECLARE-TIMI 58, CREDENCE, CANVAS x2, and VERTIS-CV).

Insulin Highlights

Drs. Alice Cheng and Jeremy Pettus discuss next-generation insulin and its role in clinical practice: Benefits over first-gen basal insulins, plus barriers to proper use of insulin in type 2s and how to address them

In this compelling Sanofi-sponsored session, Dr. Alice Cheng (Trillium Health Partners, Toronto, Canada) highlighted the range of clinical evidence supporting the use of next-generation basal insulin and the primary barriers to its use. In particular, Dr. Cheng focused on the benefits of second-generation basal insulin over older products. The BEGIN study showed that over the course of 52 weeks, the reductions in A1c and fasting plasma glucose were clinically identical between the first-generation glargine-100 group and the second generation insulin degludec group, but that degludec showed an 18% lower rate of hypoglycemia and a 36% lower rate of nocturnal hypoglycemia. Moreover, comparing second-generation insulins head-to-head highlights the importance of lowering A1c while also reducing the risk of hypoglycemic events. Similar to last year’s EASD 2020 session, Dr. Cheng once again summarized the results from the BRIGHT trial, a Sanofi-sponsored head-to-head trial of Toujeo (glargine-300) vs. Novo Nordisk’s Tresiba (insulin degludec). During the titration phase (first 12 weeks), participants randomized to Toujeo experienced significantly less hypoglycemia <70 mg/dl (HR=0.74, p=0.03) and <54 mg/dl (HR=0.63, p=0.044) than those on insulin degludec, though there was no difference in hypoglycemic events in the following periods or the study period as a whole. Dr. Cheng was particularly interested in two sub-group analyses of the BRIGHT study in patients with moderate to severe renal impairment (eGFR <60 mL/min/1.73m2) and in patients older than 70 years. The subanalysis found that patients age 70+ had 0.3% lower A1c values on Toujeo than on insulin degludec and had a statistically equivalent rate of hypoglycemia. Likewise, patients with moderate/several renal impairment saw a 0.4% A1c reduction on Toujeo relative to those insulin degludec, again without an increased risk of hypoglycemia. Some have expressed questions about the BRIGHT trial related to reporting out, like, the decision to categorize “elderly patients” as older than 70, given that there was no significant interaction between age above/below 65 and A1c decline in a pre-specified subgroup analysis. That is interesting from our view and makes us wonder about hundreds of other trials assessed – that one is hard to call, since it’s not something usually assessed. Furthermore, the decision to frame the “titration period” as clinically relevant for hypoglycemia was also questioned – this is also something we haven’t much background on. For some, the results of the trial suggest that Tresiba and Toujeo may actually be more similar than different – we will look more closely at the results. While some may say they don’t see superiority of one, we’d look at the duration of action – it does go without saying from our view that both of these second-generation insulins are superior to the older basal insulins, certainly in terms of stability.

  • Dr. Cheng highlighted the importance of minimizing “dysglycemic legacy,” which can be thought of as the complications arising due to excess area under the A1c curve. Dr. Cheng noted the key differences between the smooth, declining convex trajectory of A1c in randomized controlled trials compared to the spiky, undulating waves of real-world glucose measures. Failure to control and maintain glucose levels is a major contributor to the glycemic variability that results in harmful complications. However, insulin, when used properly, can be used to flatten the curve of glycemic variability. Unfortunately, Dr. Cheng notes that insulin titration is often inadequate, resulting in microvascular and macrovascular complications for patients down the line.
  • According to Dr. Cheng, ineffective insulin titration can be attributed, in part, to fear of hypoglycemic events. Dr. Cheng noted this happens on both sides, with providers often hesitating to start type 2 patients on insulin treatments for fear of causing hypoglycemic events, and with some patients being reluctant to be aggressive with their insulin, due to their understanding of the dangers of severe hypoglycemic events. These concerns are warranted: despite the common misconception that patients with type 2 diabetes are not at risk for severe hypoglycemia, any patient taking insulin is at risk for hypoglycemic events. Dr. Cheng highlighted data from the iNPHORM study, which offered real-world evidence that hypoglycemic events are more common than many people think. The retrospective annual incidence proportion of severe hypoglycemia was 37% – 51% among patients with type 1 diabetes and 33% among patients with type 2 diabetes. Notably, an important sub-analysis found that patients on a first-generation basal insulin had significantly more hypoglycemia than patients on a second-generation product (IRR=2.70, 95% CI: 1.07-6.84).
  • Despite positive data for insulin, there remain several barriers to proper usage of insulin in a clinical setting. In a roundtable discussion, Dr. Jeremy Pettus (UC San Diego) joined Dr. Cheng to discuss the major reasons why patients are failing to receive adequate treatment on insulin therapy:
    • Physician Factors: Dr. Pettus argued that, first and foremost, physicians are key to improving the implementation of insulin therapy in type 2s. He acknowledged that helping patients start insulin can be a challenging process that requires time and a significant amount of education. Because many patients with type 2 diabetes are diagnosed and treated in their primary care clinic, where their provider has to cover a number of bases in a short amount of time, it can be easier to just continue down the “path of least resistance” with diet, exercise, and oral agents. Dr. Cheng also added that providers may not always be fully knowledgeable about the types of insulin that are on the market, particularly the newer agents, and so hesitation to prescribe may be in part due to their discomfort with medications they haven’t previously worked with.
    • Patient Factors: Both Dr. Pettus and Dr. Cheng acknowledged there can often be significant hesitation around starting insulin on the part of the patient; however, they argued that this hesitation is more than a fear of injection, to which the hesitation is commonly attributed. They agreed that patients often feel starting insulin is akin to “failure,” which is absolutely not the case. Given this barrier, the speakers advocated that providers work with patients to reframe how the patient thinks about insulin therapy. Dr. Pettus noted he sometimes describes insulin as a “natural therapy” – our body produces insulin, and the injections are simply supplementing insulin because the body needs help. Dr. Cheng shared that she frames diabetes as a “progressive disease” from the time of diagnosis, so patients know that eventually insulin will likely be part of their treatment course, not because they failed but simply because that is how the disease functions.
    • Technological Factors: In response to a question about technology, Dr. Pettus emphasized the need for CGM use as the standard of care for patients on basal insulin, which he called the “next frontier” and which is supported by the outcomes of the MOBILE study read out at ATTD 2021 and published in JAMA in June. He commented on the huge impact that CGM has had on the care he provides his patients and in improving the quality of their interactions and the evidence from which he can draw insights to optimize care. Moreover, using CGM, Dr. Pettus noted that he can more easily figure out whether patients are having trouble with their insulin because the dosing and titration is off, or simply because they aren’t taking it. These are different problems with different solutions that were previously difficult to distinguish.

The future of basal insulin therapy: once-weekly insulin icodec, oral insulin, glucose sensitive insulin, and stem cell therapy

In this Novo-Nordisk sponsored session with over 650 attendees, Dr. Ronald Goldenberg (LMC Diabetes & Endocrinology, Canada) discussed the unmet needs and exciting developments in basal insulin therapy. He first acknowledged that administration of daily basal insulin can be burdensome and inconvenient, resulting in clinical inertia, delays in insulin initiation, and poor self-management and adherence in patients with type 2 diabetes. In contrast, Dr. Goldenberg argued that once-weekly insulin could provide greater convenience, improved self-management, improved quality of life, and reduced treatment burden for patients and care takers. Dr. Goldenberg largely focused his presentation on the once-weekly insulin furthest in development, Novo Nordisk’s injectable insulin icodec. Insulin icodec has completed three phase 2 trials against insulin glargine U100: a head-to-head study read out at ADA 2020 and published in NEJM in November 2020, a titration study published in Diabetes Care April 2021, and study on switching to insulin icodec or glargine U100 published in Diabetes Care April 2021. Following positive results from all three phase 2 trials, the phase 3 ONWARDS program began in 4Q20. Notably, on the digital health front, Dr. Goldenberg highlighted that an app is in development to assist in insulin icodec dosing and glucose monitoring. He indicated that blood glucose monitors and insulin pens would connect to the app to record glucose readings and dosing data, and the app would provide dose guidance to support patients with titration. We imagine this could be especially helpful if dosing the once-weekly insulin is more complicated than current basal formulations or if patients may need reminders to take their once-weekly doses. Additionally, for patients transitioning from current basal formulations, we anticipate additional titration and dosing support could also be beneficial to ensure the correct dose size is delivered. Looking beyond insulin icodec, Dr. Goldenberg highlighted Lilly’s once-weekly basal insulin Fc (BIF) antibody in phase 2 trials, oral insulins (Biocon’s phase 3 insulin tregopil and Oramed’s phase 2 ORMD-0801), glucose-sensitive insulin, and stem cell therapy.

  • Insulin icodec has a unique structure that allows for once-weekly dosing. Insulin icodec has three amino acid substitutions, removal of a terminal threonine, addition of a spacer, and a 20 carbon icosane fatty diacid that collectively contribute to high and reversible albumin binding, reduced enzymatic degradation, and reduced insulin receptor-mediated clearance all of which facilitate its week-long action. Pharmacokinetic and pharmacodynamic data presented in a poster at EASD 2020 indicated that insulin icodec’s half-life is approximately 1 week (196 hours) with a consistent glucose lowering effect over a week. Additionally, Dr. Goldenberg noted that clinicians would be happy to know that steady state is achieved after three to four once-weekly injections. 
  • The ONWARDS program consists of six phase 3 trials with expected readouts in 2022. The ONWARDS program includes three trials enrolling insulin-naïve patients with type 2 diabetes (ONWARD 1, ONWARD 2, ONWARD 3), two trials enrolling insulin-treated patients with type 2 diabetes (ONWARD 4, ONWARD 5), and one trial (ONWARDS 6) enrolling patients with type 1 diabetes. Majority of the phase 3 trials likely enroll patients with type 2 diabetes since, as some KOLs like Dr. Julio Rosenstock (Dallas Diabetes Research Center) have expressed, insulin icodec is likely to be more transformative in patients with type 2 diabetes, given less flux in insulin need.     
  • Another once-weekly insulin of note is Lilly’s phase 2 basal insulin Fc (BIF) antibody, for which positive phase 2 results were shared at ENDO 2021 and ADA 2021. The presentation at ENDO 2021 shared that BIF achieved non-inferiority compared to insulin degludec on the primary endpoint of A1c change from baseline after 32 weeks of treatment. Building on these results, the data readout at ADA 2021 showed that BIF resulted in similar Time in Range, time ≤70 mg/dL, and time >180 mg/dL compared to insulin degludec, but BIF remarkably yielded a 30% risk reduction on hypoglycemia.
  • The most advanced oral insulins are Biocon’s phase 2 insulin tregopil and Oramed’s phase 3 ORMD-0801, but both face poor bioavailability, leading to preclinical investigations of oral insulin technologies to increase bioavailability. Dr. Goldenberg highlighted four investigational technologies that can mitigate oral insulin’s poor bioavailability: (i) Self-orienting millimetre-scale applicator from Brigham and Women’s Hospital, MIT, and Novo Nordisk; (ii) high velocity liquid injection from Baywind Bioventures; (iii) passive hooking method from Biograil; and (iv) dissolvable microneedle in enteric capsule from Rani Therapeutics. 

KOLs discuss the enduring legacy of insulin, praising its modern-day versatility while emphasizing ongoing problems with severe hypoglycemic events for patients on basal insulins

In a Sanofi-sponsored session, Dr. Jay Skyler (University of Miami, FL), Professor Hertzel Gerstein (McMaster University, Ontario, Canada), Dr. Stewart Harris (West University, Ontario, Canada), and Dr. Emma Wilmot (University Hospitals Derby and Burton NHS Foundation Trust, UK) spoke on the enduring power of insulin, from its very first clinical use to its current hypoglycemia-related challenges. Mr. Gerstein kicked off the presentation with an energizing overview of the tumultuous history of insulin—from the first difficulties of isolating it from a pancreas to its first successes in treating children with type 1 diabetes, for whom diabetes had previously been a death sentence. He emphasized how far we have come today, with a range of different formulations and chemistries for insulin delivery, which are generally well-tolerated. Still, he explained that severe hypoglycemia “remains a key unmet need” when it comes to insulin treatment.

  • Dr. Stewart Harris provided a real-world perspective on the challenges of basal insulin and hypoglycemia, emphasizing that fear of hypoglycemia is a major barrier to optimal insulin initiation and titration. Specifically, he explained that fear of hypoglycemia can lead to deterioration of glycemic control as patients discontinue basal insulin, intentionally keep their levels high, or are less willing to intensify their treatment plans. Healthcare providers similarly tend to fear hypoglycemia: over 70% of surveyed providers in one study agreed that they would treat their patients more aggressively if there were no concern about hypoglycemia.
  • Just as alarming, Dr. Harris reported on data from the real-world iNPHORM study showing that there is a high incidence of severe hypoglycemia occurring in individuals with type 1 and 2 diabetes taking insulin in the US (see below). iNPHORM data reports an average of 3.5 severe hypoglycemia incidents per person-year for those with type 1, and a rate of 2.2 severe hypoglycemia incidents PPY among type 2s on insulin, in line with the findings of other studies.  

  • Dr. Wilmot expanded the discussion by considering the adverse consequences of hypoglycemia while on insulin therapy. Specifically, she noted that hypoglycemia during the first three months of initiating basal insulin therapy is predictive of long-term hypoglycemia risk in the following three months to two years. Therefore, particularly for patients with type 2, effective titration of basal insulin is key for short- and long-term outcomes, given that failure to initially control or maintain target glucose levels can lead to a “dysglycemic legacy” of complications, including microvascular and macrovascular complications.

  • To conclude, Dr. Wilmot presented several pieces of complementary evidence from real-world data and RCTs that support the use of 2nd generation basal insulins in adults with type 2 diabetes to achieve effective glycemic control and reduced hypoglycemia risk. She cited several meta-analyses which found that second-generation basal insulins IDeg-100 and Gla-300 have similar reduction of A1c as the first-generation Gla-100, but that the risk of severe hypoglycemia is lower for the second-generation insulins (see below). Follow up studies have confirmed that glycemic improvements for Gla-300 and IDeg are sustained both in clinical contexts, as well as in real-world settings.

Real-world evidence shows insulin glargine-300 leads to better treatment and adherence and greater A1c reductions compared to first-generation basal insulin

In this session, Dr. Eugene Wright (Duke University School of Medicine) highlighted new data from a real-world observational study comparing patients switching from a prior basal insulin to either an alternate first-generation basal insulin or to second-generation insulin glargine U300 (Gla-300). The study was designed to compare five different outcomes for these patients: (i) persistence (days on treatment without discontinuation); (ii) adherence (proportion of days covered >80%); (iii) healthcare resource utilization (all-cause, diabetes-related, hypoglycemia related); (iv) healthcare costs (all-cause, diabetes-related, hypoglycemia-related); and (v) change in A1c. Adult patients with type 2 diabetes who switched from their initial basal insulin between April 2015 and August 2019 were followed from the index date for 12 months, or until plan disenrollment or death. The cohort (n=3,077) was matched on baseline demographic and clinical characteristics using propensity scoring. The baseline characteristics were remarkably well-balanced across each of the variables, with the exception of hospitalization, which was adjusted as a covariate in the analysis. The cohort was 52% female, had a mean age of 68 years, a baseline A1c of 8.9%, and was 45% white. The vast majority (86%) of patients were on Medicare.

  • The results of the study were consistently favored Gla-300. Detailed findings for each outcome are shown in the table below. During Q&A, Dr. Wright attributed the seemingly low rates of treatment persistence and adherence to the observational nature of the study and noted that in real life, many patients don’t take their drugs exactly as they’re prescribed. He argued, however, that “the best medicine for the patient is the one that they will take” and that even these small increases in persistence are very important.

Outcome

Gla-300

1st-gen basal insulin

p-value

Treatment persistence

46%

42%

p=0.0001

Treatment adherence

43%

38 %

p=0.0006

Reduction in A1c (at 12 months)

0.65%

0.45%

p=0.004

Proportion achieving A1c<8%

47%

41%

Not given

All-cause health resource utilization: ER visits per 1oo patient years

112

149

p<0.0001

All-cause healthcare costs: pharmacy (per person, per year)

$13,668

$10, 642

p<0.0001

All-cause healthcare costs: total (per person, per year)

$41,225

$45,316

p=not significant

  • While the observational study design allows us to understand the real-world evidence associated with insulin glargine-300, it also poses some limitations. In particular, we were curious about moderator Professor Tina Vilsboll’s question asserting that the patients she starts on Gla-300 are different than those who she puts on traditional basal insulin. While the propensity scored matching likely controls for some of this variation, it is an interesting thing to consider, particularly in light of the higher pharmacy costs associated with Gla-300. Dr. Wright also noted that the retrospective study design precludes measuring the reasons for improved adherence on Gla-300. However, he hypothesized the greater adherence could be attributed to lower risk of hypoglycemia or simply feeling “better” on the Gla-300 compared to the first-generation basal insulin.

Post-hoc CGM data finds that once-weekly insulin icodec is noninferior to once-daily insulin glargine U100 in insulin-naïve people with type 2 diabetes (n=205) and insulin-treated people with type 2 diabetes (n=154); loading dose is important to the switch from once-daily to once-weekly insulin

In a session on news from new insulins, Dr. Ildiko Lingvay (UT Southwestern Medical Center) and Dr. Harpreet Bajaj (LMC Diabetes & Endocrinology, Canada) read out post-hoc CGM data assessing once-weekly insulin icodec vs. once-daily insulin glargine U100 (Gla-100) in insulin-naïve patients with type 2 diabetes (SO 508) and in people with type 2 diabetes on basal insulin at baseline (SO 509). As a reminder, insulin icodec is a once-weekly basal insulin under development at Novo Nordisk, which has been assessed in a phase 2 study read out at ADA 2020 and published in NEJM and is currently in the phase 3 ONWARDS program that began in 4Q20. In a study that followed the phase 2 study and assessed insulin icodec in insulin-naïve people with type 2 diabetes, three insulin icodec titration methods were assessed: (i) titration A, which was the least aggressive (n=51); (ii) titration B (n=51); and (iii) titration C, which was the most aggressive with the lowest glucose target and the fastest titration scheme (n=52). These groups were compared to those on Gla-100 (n=51), and the main results were published in Diabetes Care in April 2021. A second study assessing insulin icodec in those on insulin at baseline included 154 type 2s who were treated with once-daily basal insulin (10 U/day-50 U/day) and metformin with or without a DPP-4 or SGLT-2 at baseline. This study also assessed the impact of a loading dose, which increases the initial insulin dose given when switching from a daily to weekly insulin to limit the transient rise in glucose that has been seen with the switch from a shorter half-life insulin to a longer half-life insulin. To do so, the 154 participants were divided into three groups: (i) once-weekly insulin icodec with a loading dose (n=54); (ii) once-weekly insulin icodec without a loading dose (n=50); and (iii) once-daily Gla-100 (n=50). The main results were published in Diabetes Care in April 2021. For both post hoc analyses, CGM data was gathered via a double-blinded Dexcom G6 CGM.

  • The study assessing insulin icodec in insulin-naïve people with type 2 diabetes found that generally, once-weekly insulin icodec was noninferior to Gla-100 with all three titration approaches taken. Specifically, there were no statistically significant Time in Range differences between any dose of insulin icodec and Gla-100 over the entire 16 weeks period. That said, all four groups saw a Time in Range improvement from baseline (~50%-60% Time in Range) to 16 weeks (~75%-85% Time in Range), suggesting that the once-weekly insulin icodec groups saw at least noninferior Time in Range improvements compared to those on Gla-100. Likewise, all groups saw a significant reduction in time above range (>180 mg/dl) relative to baseline, falling from ~40%-50% time above range to 25%-15%. However, only icodec titration C saw a significant reduction relative to Gla-100 (p=0.035). Specifically, icodec titration C saw a -1.3 hour/day reduction in time above range relative to Gla-100. All groups also trended toward increased time below range over the 16 weeks; however, all were still well below the consensus target of <4% time below range, ranging from ~0.5%-2% at 16 weeks. Icodec titration A and B did not differ significantly from Gla-100. Icodec titration C had a significantly higher time below range compared to Gla-100 over the entire 16-week period, which makes sense given that icodec titration C was the most aggressive titration scheme and targeted the lowest glucose target of the three doses (p=0.006). That said, time below range was still quite low over the 16-week period, averaging 0.3% in the icodec titration C group vs. 0.2% in Gla-100, suggesting that the difference was not clinically significant.

  • The study assessing once-weekly insulin icodec in patients with type 2 diabetes on a basal insulin at baseline found that at week 16, those on insulin icodec with a loading dose saw a 1.6 hour/day Time in Range improvement relative to those treated with Gla-100 (p=0.005). Specifically, those treated with insulin icodec and the initial loading dose had a Time in Range of 71% at 16 weeks, a 1.6 hour/day improvement relative to those on Gla-100 (64% Time in Range at 16 weeks). Those treated with insulin icodec who did not receive the loading dose saw a Time in Range improvement relative to baseline that was statistically equivalent to that of those treated with Gla-100 (61% vs. 64% at 16 weeks, p=0.323). Dr. Bajaj argued that this suggests that the loading dose is incredibly important to achieving short-term and medium-term improvements in glycemic control. This conclusion was supported by time above range data, showing that the group treated with insulin icodec and the loading dose had a significantly lower time above range compared to the Gla-100 group between weeks 0-6 (-1.8 hours/day, p=0.005) while the group on insulin icodec without the loading dose saw a transient rise in time above range. This time above range improvement in the insulin icodec with loading dose group relative to the Gla-100 group was maintained throughout the 16-week period (p=0.002). It’s worth noting that the insulin icodec + loading dose group did have statistically significantly higher time below range and time <54 mg/dl results than the Gla-100 group did (p<0.001 and p<0.018, respectively); however, these results were not clinically meaningful and were significantly below the consensus guidelines for time below range and time <54 mg/dl. 

ATOS study subgroup analysis shows that insulin glargine U300 is effective with low risk of hypoglycemia in people with type 2 diabetes with and without renal impairment

Dr. Amir Tirosh (Tel-Aviv University, Israel) presented results from a subgroup analysis of the ATOS study that investigated insulin glargine U300’s (Sanofi’s Toujeo) effectiveness and safety in insulin-naïve people with type 2 diabetes with and without renal impairment. This abstract was first presented at ADA 2021. For background, ATOS was a 12-month prospective observational study of insulin glargine 300 U/mL in 18 countries outside the US and Western Europe, and it showed that insulin glargine U300 in people with type 2 diabetes resulted in improved glycemic control with low rates of hypoglycemia and minimal weight change. Over 12 months, patients with (n=581) and without (n=3,841) renal impairment had similar A1c reductions (-1.8% vs. -1.9%) and fasting plasma glucose reductions (-3.8 mmol/L vs. -4.0 mmol/L). Four ranges of individualized A1c targets were set by physicians (<7%, 7% to <7.5%, 7.5% to <8%, or ≥8%). The majority of participants had A1c targets of 7% to <7.5% with over 95% of participants having targets <8%. At six months, 28% of participants with renal impairment achieved their A1c target, and 25% of those without renal impairment achieved their A1c targets. Furthermore, the increase in insulin glargine dose over 12 months was similar between those with and without renal impairment (+0.12 U/kg vs. +0.10 U/kg) along with minimal body weight changes in both groups (95% CI: -0.7 kg, +0.1 kg vs. 95% CI: -0.3 kg, +0 kg). Symptomatic and severe hypoglycemia incidence was low but slightly higher in the renal impairment group. Overall, these real-world results indicate that insulin glargine U300 is effective in people with type 2 diabetes irrespective of renal impairment.

Professor Tina Vilsbøll and Professor Cees Tack celebrate 100 years of insulin: where we are now and where we are headed

To celebrate 100 years of insulin, we heard from Professor Tina Vilsbøll (Steno Diabetes Center, Denmark) and Professor Cees Tack (Radboud University, Netherlands) on the history of insulin discovery, the current state of insulin, including what has changed and what has not, and future directions for further innovation. In thinking about what the future of insulin may hold, Prof. Vilsbøll focused her excitement on (i) once-weekly insulin, (ii) oral insulin, (iii) glucose-sensitive insulin, and (iv) beta cell replacement as potential therapies that will offer convenience, simplicity, safety, and a cure to type 1 diabetes, respectively.

  • Professor Tack began this symposium session with an overview of insulin treatment in the past 100 years, taking a close look at (i) what has changed and what has not since the discovery of insulin in 1921 (ii) the imperfections of insulin treatment, and (iii) how the field is moving towards individualized treatment. At its root, the basic molecular mechanisms of insulin have remained the same – insulin binds to its receptor, which causes post receptor signaling leading to insulin degradation. However, discoveries in recent decades have changed insulin’s absorption profile drastically, resulting in distinct types of insulin, such as long-acting or short-acting insulin. Despite these improvements, Prof. Tack noted that there is still room for improvement in how insulin is delivered.  In theory, insulin should be injected in the portal circulation, rather than subcutaneously for it to truly mimic the effects of endogenous insulin. However, most commercially available insulins are injected into subcutaneous tissue, though Mannkind’s Afrezza is a notable exception. Recall that Mannkind just announced the first patient enrolled in the IHALE-1 study, which is assessing inhalable insulin in pediatric populations. Notably, however, studies comparing a portal versus subcutaneous delivery of insulin have not shown positive outcomes. A systematic review published in April concluded that portal delivery of insulin did not confer statistically significant benefits in absorption, and it resulted in “quite extensive” side effects, such as inflammation and severe abdominal pain. In light of this data, Prof. Tack concluded by noting what works in theory does not always work in practice.
  • Looking to the future, Prof. Tina Vilsbøll illustrated what she believes are the four most exciting avenues of innovation for insulin: (i) once-weekly insulin, (ii) oral insulin, (iii) glucose-sensitive insulin, and (iv) beta cell replacement. Starting off with once-weekly insulin, Prof. Vilsbøll focused on two of the five once-weekly insulins currently in development. First, she spoke about Novo Nordisk’s insulin icodec, citing a November 2020 study by Dr. Julio Rosenstock and colleagues, which found that once-weekly insulin icodec had the same rates of hypoglycemia as once-daily insulin glargine U100. Prof. Villsbøll then turned her attention to Eli-Lilly’s once-weekly insulin-FC (BIF), which showed non-inferioririty to insulin degluec after 32 weeks of treatment results, and the same rates of hypoglycemia, based on data presented at ADA 2021. Prof. Vilsbøll also wondered whether co-formulating once-weekly insulins with once-weekly incretins will be a feasible therapeutic option, and this is something we will most definitely be keeping our eyes out for as tremendous progress is being made in both of these areas.

  • Moving on to oral insulin, Prof. Vilsbøll discussed a report from April on the potential growth of an oral insulin market projecting a global market of $5 billion by 2025. Additionally, Prof. Vilsbøll argued that oral insulin holds promise in improving patient adherence, since it is a simpler, more convenient method of administering insulin compared to a subcutaneous injection. Still, some challenges to this alternative shared by Prof. Vilsbøll include permeability, enzymatic stability, and food effect. Recall that oral GLP-1s (semaglutide) must be taken in a fasting state, however, it is unknown whether the same holds true for oral insulin. There are currently several oral insulins in development, including an agent developed by MIT in 2019 that follows the self-orienting millimeter-scale applicator (SOMA) model, meaning the molecule orients itself to the stomach wall to administer insulin. Oral insulin 338, a long-acting basal insulin analog in development by Novo Nordisk was discontinued in 2019 after being deemed “not commercially viable,” due to it requiring ~58x higher dosage compared to insulin glargine to have the same effects on maintaining glycemic levels.
  • Briefly touching on other (further ahead) future directions for insulin, Prof. Villsbøl seemed very enthralled by the idea of glucose-dependent insulin, a “smart” insulin that would automatically deliver hormonal activity based on blood glucose levels without external monitoring (see our Insulin Competitive Landscape for more on this). Finally, Prof. Villsbøl spoke on the potential of stem cell therapy, pointing to beta cell replacement as a therapeutic cure for people with diabetes. Recall that in March 2021, Vertex received an FDA Fast Track Designation for their stem cell-derived insulin producing cells, based on technology from Semma Therapeutics, which they acquired in September 2019 for $950 million .

Dr. Julio Rosenstock highlights patient reported outcomes from the SoliMix trial; iGlarLixi (Insulin Glargine/Lixisenatide) found to reduce treatment burden and improve patient perception of treatment

Closing out an afternoon Sanofi-sponsored session, Dr. Julio Rosenstock (UT Southwestern) highlighted patient reported outcome (PRO) data from the SoliMix trial. A first look at the PRO data was initially presented in a poster at ADA 2021, coinciding with the full read out of the SoliMix trial. SoliMix was the first RCT head-to-head trial directly comparing a fixed ratio combination of insulin and GLP-1 with a premixed insulin (BIAsp30). As a reminder, the SoliMix trial showed that the fixed ratio combination (iGlarLixi) treatment conferred greater efficacy with respect to weight loss and A1c reductions, with lower incidence of hypoglycemia. Full results from the trial, which Dr. Rosenstock summarized exceptionally well in his presentation, are detailed below. The patient reported outcomes were measured using the TRIM-Diabetes (TRIM-D) questionnaire and the Global Treatment Effectiveness Evaluation (GTEE). TRIM-D focuses on important aspects of day-to-day life, while the GTEE measures perceived treatment effectiveness from and was collected from both patients and providers. Across the board, iGlarLixi was found to generate a significantly larger treatment effect than BIAsp30, with greater improvements in perceived treatment from both patients and physicians. Notably, Sanofi has been pushing a reduced treatment burden as one of the biggest selling points of iGlarLixi over pre-mixed insulin. The vastly improved TRIM-D scores with iGlarLixi are a strong indication that this is true and provide strong support for this claim. Dr. Rosenstock concluded the session by positioning iGlarLixi as an alternative option to advancing therapy for patients who are inadequately controlled on basal insulin and oral anti-diabetic medication. Moreover, Dr. Rosenstock expressed that the improved A1c reductions, absence of weight gain, and lower risk of hypoglycemia all point in favor of the fixed dose combination insulin plus GLP-1 treatment compared to premixed insulin.

  • As a reminder, SoliMix enrolled people with type 2 diabetes and an A1c between 7.5% and 10% who were on a regimen of basal insulin and one or two oral antidiabetic medications, randomizing them to once-daily injections of iGlarLixi –a fixed-dose combination of insulin glargine and GLP-1 agonist lixisenatide (n=443) – or twice-daily injections of the premixed insulin BIAsp30 (n=444) for 26 weeks. iGlarLixi met both of the trial's co-primary endpoints, including non-inferiority to BIAsp30 in A1c reduction (-1.3% vs. -1.1%) and superiority to BIAsp30 for body weight change (-0.7 kg vs. 1.2 kg). iGlarLixi also met all of the trial's key secondary endpoints, including superiority to BIAsp30 in A1c reduction, a greater proportion of participants achieving an A1c <7% without weight gain (27.5% vs. 12.4%), and a greater proportion of participants achieving an A1c <7% without weight gain and without hypoglycemia (19.4% vs. 7.0%). Very importantly, iGlarLixi was also associated with lower incidence of hypoglycemia (6.3% [n=28] vs. 12.9% [n=57]) and severe hypoglycemia (0.2% [n=1] vs. 0.5% [n=2]) compared to BIAsp30. No severe adverse events were reported in the trial, though participants randomized to iGlarLixi experienced more GI side effects (10.4% vs. 2.3%), as is expected with GLP-1 agonist therapy. Overall, the SoliMix results point to iGlarLixi as a better alternative to premixed insulin for people with type 2 diabetes who are not meeting their A1c goals on typical basal insulin/oral antidiabetic medication therapy.
  • Per our interview with Dr. Luigi Meneghini (Vice President & US Medical Head of Diabetes, Sanofi) at ADA, we our curious to see which patient populations Sanofi believes will benefit the most from an fixed ratio combination treatment. We’ve previously heard that elderly populations may be particularly benefitted by Soliqua (iGlarLixi), As older adults are at a higher risk of cognitive decline and institutionalization, the complexity of their diabetes treatment regimens is important to consider. Older adults with type 2 diabetes are also at higher risk of hypoglycemia compared to younger adults. With these considerations in mind, Soliqua is an excellent choice – offering not only improved glycemic control but also fewer injections and lower hypoglycemia risk. We will be curious to see whether any future post-hoc analyses with the SoliMix data are able to support this hypothesis.
  • We want to remind readers that since the FDA approval in 2019 as a first injectable therapy, there have been questions around where FRC therapies should be used.  For example, some KOLs have told us it is counterintuitive to prescribe a “pre-insulin” therapy in combination with insulin, and whether this may contribute to hesitation of the part of the providers. In fact, with many guidelines recommending GLP-1s as a first-line or near first-line therapy, there is some question where exactly the fixed ratio combination medications fit into the treatment algorithm. With that said, we are immensely in favor of any therapy that is easy to dose, shows consistently positive results, and has a strong safety profile.
  • While some ask about the “lack of clarity” around who may benefit the most from this basal insulin/GLP-1 fixed dose combos, of course this class is a poor man’s entry into GLP-1 and a great one at that for many, given the options. While it may not be traded for all once-weekly GLP-1 formulations, we suspect this isn’t always a choice. CEO of dQ&A Richard Wood gave us recently the percentages of those in the dQ&A panel on GLP-1 (many, many hundreds of people with T2D) and the percentage “at goal,” meaning A1c. He’s got heaps of data on duration of diabetes, whether they take insulin, and on it goes – if you’d like to see more and understand GLP-1 better, write dQ&A here. While of course, typical management often includes sequential additions of GLP-1 and insulin therapy for patients with type 2, sometimes inertia emerges. 

Real world data (n=808) from Romania shows that iGlarLixi significantly reduced A1c by 1.4% in adults with type 2 diabetes who were inadequately controlled on oral antidiabetic drugs with and without basal insulin

In this short oral presentation (SO 512), Dr. Cristian Guja (University of Medicine and Pharmacy, Romania) shared results from a study on the effectiveness and safety of Sanofi’s iGlarLixi (fixed-ratio combination GLP-1 lixisenatide and insulin glargine U100) in a routine clinical setting. Over 65 study sites in Romania, 808 adults with type 2 diabetes which was uncontrolled on oral antidiabetic drugs with and without basal insulin initiated iGlarLixi treatment. Participants had a mean age of 63 years, 10-year duration of diabetes, and a baseline A1c of 9.2%. At baseline, all participants were on metformin, 59% were on basal insulin, 27% were on sulfonylureas, and 2%-3% were on DPP-4 inhibitors and SGLT-2 inhibitors. After 24 weeks on iGlarLixi, participants saw a significant 1.4% reduction in A1c (p<0.0001). Those treated with only oral antidiabetic drugs at baseline experienced a greater A1c reduction (-1.8%; p<0.0001) than those on basal insulin at baseline (-0.9%; p<0.0001). Notably, 42% of participants achieved an A1c ≤7.5% after 24 weeks. Participants also experienced a mean weight decrease of 1.6 kg, indicating that lixisenatide abrogated insulin’s weight gain effects. iGlarLixi was well tolerated with only 5% of participants reporting adverse effects. As expected for the GLP-1 class, gastro-intestinal side effects were most common. Only 1.3% of participants reported at least one hypoglycemic event, and there was one severe hypoglycemic episode. These results provide real-world support to the clinical trial results from SoliMix study of iGlarLixi vs. insulin aspart that was read out at ADA 2021. Also see an impressive talk from earlier in EASD 2021 by Dr. Julio Rosenstock (UT Southwestern) on patient reported outcomes from the SoliMix trial, which found that iGlarLixi reduced treatment burden and improved participants’ perception of treatment.

Dr. Umpierrez on the use of sliding scale insulin and DPP-4s as viable alternatives to basal-bolus “gold standard” regimens in non-ICU hospital settings for patients with type 2 diabetes for those with admission blood glucose <180 mg/dl; importance of individualized therapy

During this EASD e-learning session titled “Insulin@100: Insulin in hospital settings,” Dr. Guillermo E. Umpierrez, (Emory University School of Medicine, Atlanta, GA) provided an overview of the current recommendations for administrating insulin in a non-ICU hospital setting and offered his insight on two alternatives to basal-bolus therapy: DPP-4s (specifically sitagliptin with insulin and linagliptin monotherapy) and sliding scale therapy. Given the higher levels of hospital complications seen in PWD (50% more likely to have pneumonia, 1.5x more likely to experience renal failure when undergoing non-cardiac surgery, according to this 2010 study), Dr. Umpierrez argued it is of upmost importance to optimize insulin treatments in a hospital setting, and from what we heard in this talk, personalized medicine will be key in achieving this. Dr. Umpierrez shared that while a basal-bolus insulin regimen remains the “gold standard” (preferred over premixed insulin and sliding scale insulin therapy) we now have new data (2017 Sita-Hospital Trial and the 2019 Lina-Surg Study) supporting the use of sliding scale insulin and noninsulin antihyperglycemic therapies, namely DPP-4 inhibitors, in the hospital. However, when choosing to use these alternative therapies, Dr. Umpierrez noted that the key to successful glycemic management will be based on which patients are chosen to receive these therapies. For example, while DDP-4 inhibitors linagliptin monotherapy and sitagliptin (when complemented with basal insulin) showed statistically equivalent levels of efficacy to a basal-bolus therapy, they were only effective for patients with an admission BG < 180 mg/dl. Likewise, a sliding scale insulin regimen failed to help patients who had significant hyperglycemia at the time of hospital admission, indicated by a BG >180 mg/dl. Dr. Umpierrez’s emphasis on an individualized approach – giving adequate therapies to the right patients based on their characteristics at hospital admission – shed light on the potential of both sliding scale insulin therapy and DPP-4 in-hospital use to help improve outcomes among hospitalized patients with diabetes.

  • Dr. Umpierrez began with an overview of the current “gold standard” method of insulin administration in a non-ICU hospital setting, basal-bolus therapy, which has historically been preferred over sliding scale insulin and premixed insulin based on results from the RABBIT 2 (n=130), RABBIT-SURGERY (n=211), and Belido et al. (n=71) Trials. These studies from 2007, 2010, and 2015, respectively, demonstrated the superiority of a basal-bolus insulin regimen (glulisine before meals and glargine once daily) compared to sliding scale insulin for maintaining glycemic control in non-ICU hospitalized patients with diabetes. From the RABBIT-SURGERY study, basal-bolus therapy was associated with a lower risk of post-surgery hospital complications at 8.6% compared to 24.3% for patients on sliding scale insulin. Dr. Umpierrez noted that this difference in post-surgery complication rates lowered the costs of hospitalizations by 14% per day, per patient, for those on the basal-bolus therapy. In comparison to basal-bolus therapy, premixed 30/70 human insulin (which may be preferred due to its simplicity), showed an alarmingly higher risk of hypoglycemia (~3x more than those on basal-bolus therapy). However, newer data on DPP-4 inhibitors and newer sliding scale insulin has reignited interest around alternative therapies for the inpatient management of patients with diabetes.

    • Dr. Umpierrez referenced four studies that have compared basal insulins (Glargine U100 vs Detemir U100, 2017; Glargine U100 vs Glargine U300, April 2020; Glargine U100 vs Degludec, September 2021) demonstrating that no statistically significant differences in outcomes among hospitalized patients with diabetes have been found between the classes of basal insulins.
  • Turning to newer evidence, Dr. Umpierrez advocated in support of the use of incretin agents and sliding scale insulin regimens as viable alternatives to basal-bolus therapy in a non-ICU hospital setting. Despite basal-bolus therapy being the “insulin gold standard” for 10+ years (and currently the primary recommendation in the ADA 2021 Standards of Care), it requires frequent daily injections, high levels of monitoring, and often results in overtreatment, since hospitalized patients tend to have a reduced appetite meaning they may not always require meal-time boluses. Consequently, incretin agents have emerged as a possible alternative to basal-bolus therapy. Dr. Umpierrez shared that in Israel, about 60-70% of hospitalized patients are given oral antihyperglycemic drugs either with or without insulin, while 30-40% of hospitalized patients in the UK also receive antihyperglycemic medications. Dr. Umpierrez noted, recent data from the 2017 Sita-Hospital Trial and the 2019 Lina-Surg Study have demonstrated the safety and efficacy of sitagliptin and linagliptin (respectively) for the management of hospitalized patients with type 2 diabetes. The Sita-Hospital Trial showed that sitagliptin in conjunction with basal insulin had the same success in maintaining glycemic control as basal-bolus therapy. The Lina-Surg Study tested linagliptin’s efficacy as a monotherapy and reported success as well. Importantly, as Dr. Umpierrez asserted, both these therapies were only successful in maintaining normoglycemia for hospitalized patients with an admission blood glucose less than 180 mg/dl. For patients with blood glucose >180 mg/dl upon hospital admission, DPP-4 therapy, whether supplemented with insulin or not, was not effective. While this means DPP-4s may be effective for patients hospitalized for hypoglycemia or for non-diabetes related reasons, they are unlikely to be successful for patients experiencing DKA or hyperglycemic crises.
  • Drawing from his August 2021 study (n=25,813), Dr. Umpierrez also advocated for the adoption of sliding scale insulin therapy as an alternative to basal-bolus therapy, but only for patients with admission blood glucose <180 mg/dl. Despite its controversy, sliding scale insulin is still widely used; according to a 2007 survey, at 44 US hospitals, 41% of noncritical patients with hyperglycemia were treated with sliding scale insulin alone. Historically (and as mentioned above), sliding scale insulin has been associated with increased duration of hospital stays and poorer glycemic control, but this data has been based on studies that, by the nature of their design, have excluded patients with noncritical hyperglycemia. Therefore, to determine why sliding scale insulin is still widely used despite its reported drawbacks, Dr. Umpierrez and his team collected EHR data from 25,813 adult patients with type 2 diabetes between June 2010 and June 2018. Through this, they identified 8,095 patients who were treated with sliding scale insulin during their hospitalization and subclassified this population into two sub-cohorts: (i) continuous sliding scale insulin patients (those who remained on sliding scale insulin treatment through the entirety of their hospitalization) and (ii) transition to basal (those who transitioned to basal insulin therapy after day two of hospitalization). The study found that the percentage of patients achieving target glycemic control was equivalent among both patient populations. Within the sliding scale insulin group, 86% of patients with blood glucose <140 mg/dL and 83% of patients with blood glucose 140 to 180 mg/dL achieved glycemic control without hypoglycemia when managed with sliding scale insulin alone, compared with 53% of those admitted with blood glucose 180 to 250 mg/dL and only 18% of those with admission blood glucose ≥250 mg/dL. As Dr. Umpierrez noted, this study confirmed that sliding scale insulin therapy can be effective, but only for specific populations of patients with type 2 diabetes.
    • A1c levels were also used as a marker for this study with patients with an A1c< 8% responding well with sliding scale insulin monotherapy. Conversely, patients with an A1C >8% did not experience success via sliding scale insulin monotherapy, and experienced higher levels of hypoglycemic episodes.
  • Dr. Umpierrez summarized the current recommendations from The Endocrine Society for insulin treatment following hospital discharge, highlighting individualized care as a key theme. Dr. Umpierrez also pointed to a study published in February, where GLP-1 receptor agonist liraglutide showed equal levels of safety and efficacy in lowering A1c from baseline compared to Glargine U100 during a 26-week follow up period for patients with type 2 diabetes after hospital discharge. This new data has facilitated the emergence of GLP-1s as a novel alternative to insulin at discharge. However, as Dr. Umpierrez noted, the gastrointestinal side effects of GLP-1s should still be kept in mind. With regards to using GLP-1s during hospitalization rather than insulin, Dr. Umpierrez expressed hesitation because of the adverse GI events associated with this drug class, which could exacerbate the already-reduced appetites of hospitalized patients. Excitingly, Dr. Umpierrez shared that updated guidelines are scheduled to be released later this year and we are curious if they will include recommendations for GLP-1 use following hospital discharge.

Phase 3 study finds that Gan & Lee Pharmaceuticals’ proposed biosimilar insulin aspart is non-inferior to Novo Nordisk’s Novolog with similar safety profiles and immunogenicity

In this short-oral presentation (SO-513), Dr. Jun Yao (Peking University, Beijing, China) shared results from a phase 3, confirmatory study in patients with type 2 diabetes comparing a proposed biosimilar insulin aspart to its reference product, Novo Nordisk’s branded insulin aspart (Novolog).  This study was conducted in 21 hospitals in China and randomized 590 patients with type 2 diabetes with poor glycemic control on oral antidiabetic drugs alone to either Gan & Lee Pharmaceuticals’ proposed biosimilar insulin aspart (GL-ASP) (n=439) or Novo Nordisk’s Novolog (NN-ASP) (n=149) in combination with metformin. Baseline characteristics were similar between both groups – mean diabetes duration was 8.4 years with a mean age of 56 years and A1c of 9.5% – except that the GL-ASP group enrolled more males than the NN-ASP group (56% vs. 44%). After 24 weeks, the primary efficacy outcome of non-interiority of GL-ASP versus NN-ASP was met. The biosimilar GL-ASP led to an A1c reduction from baseline of -2.16% (95% CI: -2.29, -2.03), and the reference NN-ASP led to an A1c reduction of -2.20% (95% CI: -2.40, -2.00), leading to an estimated treatment difference in A1c reduction of 0.04%. Additionally, adverse events (p=0.7), hypoglycemic events (p=0.9) and serious adverse events (p=0.054) were similar between the two treatment groups. The rates of insulin aspart-specific antibody production were similar between those receiving the biosimilar and reference insulins (OR: 0.7; 95% CI: 0.28, 1.93). Looking to secondary outcomes, a similar proportion of patients achieved A1c values <7% (~50%) and ≤6.5% (~30%) in both groups. These results come in the midst of a booming biosimilar and generics market in China – 90% of marketed drugs in China are generics, and there have been 13 biosimilar approvals between 2018 and 2021. As a reminder, in the US the FDA approved Biocon/Viatris’ biosimilar Semglee (insulin glargine-yfgn) in August 2020 and granted Semglee an interchangeability designation in in July 2021.  

Novel Therapy and Precision Medicine Highlights

Professor Per-Henrik Groop offers independent commentary on FIGARO-DKD and FIDELIO; praises “wonderful” results while also noting gaps that warrant further study; calls for three-pillar approach to DKD care

Closing out a fantastic session on finerenone, Professor Per-Henrik Groop (University of Helsinki) offered independent commentary on FIGARO-DKD, FIDELIO-DKD, and the pooled meta-analysis FIDELITY, which compared the oral non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone to placebo in patients with chronic kidney disease and type 2 diabetes. In both trials, finerenone showed significant improvements on cardiovascular and renal outcomes– see below for more detailed results. For the most part, Professor Groop praised the studies, noting the findings offer “very, very good news” for patients with diabetic kidney disease (DKD), whose current treatment options are limited. Professor Groop framed his talk around the severity of the DKD epidemic, noting that at least half of the patients with type 2 diabetes around the world also have DKD. Moreover, the estimated reduction in life-expectancy for patients with early diabetic kidney disease is a whopping 16 years. Given this context, as a nephrologist, Professor Groop is very optimistic about the use of finerenone, suggesting that this new drug is, “exactly what we need.” While his review was very positive overall, Professor Groop also highlighted some gaps in the study which he felt warrant more research. Namely, he was focused on the under-powered sub-analysis of SGLT-2 and GLP-1 therapy in combination with finerenone, as well as the exclusion of patients with non-albuminuric DKD.

  • Prof. Groop argued that nephrologists have new tools at their disposal and should implement a three-pillar approach to care. In Q&A, panelists noted that they felt like they were, “kids in a candy store” with all the new drugs that are available for the treatment of DKD. Professor Groop advocated for a new approach to management that involves three pillars of care – ACEs/ARBs, SGLT-2s, and finerenone – from very early in the disease course, akin to the four pillars of heart failure treatment. This is not the first time we’ve heard this argument. At HiD 2021, Dr. Ralph DeFronzo called for aggressive, early combination therapy with SGLT-2 inhibitors, finerenone, ACEs/ARBs, and even GLP-1 to address the multiple pathophysiologic abnormalities contributing to the development and progression of DKD.
  • Combination therapy with finerenone and SGLT-2s has been a hot topic of debate since these results were first published. Today, we saw a sub-analysis of the data from trials showing the reductions in UACR stratified by baseline use of SGLT-2 inhibitors – see table below.

 

Number of patients

Baseline UACR

Change in UACR with finerenone vs placebo

FIDELIO-DKD

 

 

 

SLGT-2 at baseline

259 (5%)

630 mg/g

-25%

No SGLT-2 at baseline

5415 (95%)

816 mg/g

-32%

GLP-1 at baseline

394 (7%)

749 mg/g

-36%

No GLP-1 at baseline

5289 (93%)

811 mg/g

-31%

FIGARO-DKD

 

 

 

SGLT-2 at baseline

618 (8%)

325 mg/g

-41%

No SGLT-2 at baseline

6734 (92%)

283 mg/g

-32%

While this data suggests that finerenone could have an additive benefit on top of SGLT-2s, Professor Groop argued that one shortcoming of the study was the low number of patients on an SGLT-2 or GLP-1 at baseline. The underpowered sub-analysis makes it more difficult to see obvious effects of combination therapy with finerenone, although Prof. Groop acknowledged that the low baseline numbers are likely a function of the timing of the study, which was designed prior to the flood of research highlighting the cardiorenal benefits of these newer agents. He advocated for more dedicated research to determine whether combination therapy with SGLT-2 and finerenone actually possesses additive – or potentially even synergistic – benefits. This avenue of research is particularly intriguing following pre-clinical data showing mice treated with a low-dose finerenone/empagliflozin combination fared significantly better than placebo controlled mice (93% vs. 50% survival over 50 day period) and the monotherapy-treated group.

  • The effects of non-albuminuric DKD were not explored in these trials, which Professor Groop posits as another gap in the study. He noted that even with the pooled analysis, the finerenone studies did not account for all patients on the DKD heat map. He noted that patients with normal to mildly increased albuminuria were excluded from the study, despite the fact that about 20% of patients with diabetic kidney disease will never develop albuminuria. Professor Groop noted that the FIDELITY trials are not an outlier in this regard. Most studies don’t include these patients due to their lower risk, which would translate into much lengthier clinical trials.  EMPA-Kidney will include patients with non-albuminuric DKD, and he is looking forward to seeing these results, which are expected in June 2022.
  • Professor Groop noted that despite the small increase in hyperkalemia with finerenone, the clinical impact of hyperkalemia was minimal. The maximum difference in mean serum [K+] between the two groups was 0.16 mmol/l in FIGARO-DKD and 0.23 mmol/l in FIDELIO-DKD. He highlighted that while 14% of patients on finerenone in FIDELITY reported any hyperkalemia in the study period relative to 6.9% of patients on placebo, only 1.7% of patients discontinued the trial as a result. Notably, no patients in either trial died from hyperkalemia, suggesting that education and close monitoring can reduce harmful outcomes, although this might be of greater concern outside a clinical trial setting. Dr. Groop argued that these low rates of hyperkalemia should “trigger” people to implement finerenone in clinical practice given the impressive cardiorenal benefits and clean safety profile.
  • According to Professor Groop, FIDELITY is a well-powered, well-designed meta-analysis (n=13,171). Dr. Groop is “not very fond” of most meta-analyses because they can only be hypothesis-generating and are not approved to test hypotheses. With that said, Dr. Groop noted that, “even I believe in FIDELITY because of the numbers and well-done studies.” Recall FIDELITY found that finerenone (10 or 20 mg) demonstrated a 14% risk reduction on the composite CV outcome, defined as time to CV death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure (HR=0.86; 95% CI: 0.78-0.95; p=0.0018) relative to placebo. Finerenone also demonstrated a 23% risk reduction on the composite renal endpoint, defined as time to kidney failure, sustained ≥57% decrease in eGFR from baseline, or renal death (HR=0.77; 95% CI: 0.67-0.88; p=0.0002).
  • As a reminder, FIDELIO-DKD assessed mostly renal outcomes in patients with advanced CKD. FIDELIO-DKD randomized people with type 2 diabetes and chronic kidney disease (n=5,734) to placebo or finerenone. Over a median 2.6 years follow-up, the primary composite endpoint (kidney failure, sustained ≥40% decrease in eGFR, or renal death) occurred in 21.1% of placebo patients (600/2,841) vs. 17.8% of finerenone patients (504/2,833). In other words, finerenone gave a significant 18% relative risk reduction for adverse kidney outcomes (HR=0.82, 95% CI: 0.73-0.93, p=0.0014). Components of the composite endpoint all trended in favor of finerenone: Results showed a 13% relative risk reduction for kidney failure (HR=0.87, 95% CI: 0.72-1.05) and 19% for sustained ≥40% eGFR decline (HR=0.81, 95% CI: 0.72-0.92); there were no instances of renal death over the course of the trial. Finerenone reduced risk for the secondary CV endpoint (CV death, non-fatal MI, non-fatal stroke, or heart failure hospitalization) by 14% vs. placebo (HR=0.86, p=0.0339).
  • FIGARO-DKD, on the other hand, was predominantly a CV outcomes trial and included patients with more moderate chronic kidney disease. FIGARO-DKD randomized patients with type 2 diabetes and chronic kidney disease (n=7,437) to placebo or finerenone. Over a median 3.4 years follow-up, finerenone demonstrated a significant 13% risk reduction on the primary CV composite outcome, defined as CV death, non-fatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure (HR=0.87, 95% ci: 0.76-0.98; P=0.03). Finerenone benefit was driven by a 29% risk reduction of hHF (HR=0.71; 95% CI: 0.56-0.90), as none of the other individual CV components reached statistical significance. Notably, finerenone had a nonsignificant effect on the first secondary composite renal outcome (kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death), which is consistently attributed to the lower eGFR threshold than was used in FIDELIO-DKD. Finerenone, did, however demonstrate a 23% risk reduction on an exploratory renal outcome (kidney failure, sustained ≥57% decrease in eGFR from baseline, or renal death) (HR=0.77; 95% CI: 0.60-0.99; p=0.041).

TriMaster Results: First dedicated RCT to provide evidence for precision medicine in type 2 diabetes: eGFR and BMI accurately predict a differentiated drug response of DPP-4s, SGLT-2s, and TZDs

A first look at the positive results from the TriMaster study were presented this afternoon. The TriMaster study utilized a three-way, randomized, double blind crossover study to measure the attempt to tailor diabetes treatment for patients stratified using common clinical features. This is the first trial to directly test precision medicine and prove that a stratified approach works in type 2 diabetes. The full methods, results, and commentary of the trial are detailed below, but at a high level, the trial found that eGFR and BMI accurately predicted a differential drug response of DPP-4s, SGLT-2s, and TZDs based on A1c reductions. Despite the drugs showing overall similar glucose-lowering abilities, certain drugs worked better in specific clinical strata of patients. This TriMaster study was sorely needed in the field, which has been hesitant to put precision medicine into clinical use, but the researchers feel that the present approach to diabetes management can be improved using an individualized approach to glycemic treatment. With that said, we heard several researchers express that they found the fact that they were studying precision medicine in a dedicated RCT even more meaningful than the results – we’ve been thinking about that too. Some expressed disappointment by the researchers’ decision to use A1c over a 16-week (four-month) period as the primary endpoint, given the substantial long-term benefits that SGLT-2s have on HF and CKD, but that sort of positive long-term outcomes data was nowhere near being announced at that time. We do question the decision to give TZDs to patients with a BMI >30 since weight gain has long been associated with TZDs. While some might question the decision to give patients with reduced eGFRs a DPP-4 over an SGLT-2 in patients, the benefits of SGLT-2s for people with kidney disease were not at all well known at the time. Professor Andrew Hattersley (University of Exeter) acknowledged many of these points in his presentation.

  • Patient stratification and hypotheses: Professor Hattersley highlighted routine clinical data from the CPRD database (n>100,000) showing that BMI differentially impacts A1c response of DPP-4 inhibitors and TZDs. Notably, patients with a higher BMI saw greater A1c responses to TZDs, while patients with a lower BMI see noticeably greater effects on DPP-4 inhibitors. The database also found patients with an eGFR>90 mL/min/1.73m2 saw larger A1c reductions with SGLT-2s, while patients with a lower eGFR (60-90 mL/min/1.73m2) had better A1c responses on a DPP-4. As such, they key hypotheses tested in the trial were that:
    • patients with a BMI>30 kg/m2, compared to patients with BMI≤30kg/m2, will achieve a lower A1c when assigned pioglitazone rather than sitagliptin; and
    • patients with an eGFR 60-90 mL/min/1.73m2 compared to patients with an eGFR>90 mL/min/1.73m2, will achieve a lower A1c when assigned sitagliptin rather than canagliflozin.
  • Trial design: Ms. Catherine Angwin (University of Exeter) discussed the design of the study, which used a three-way, randomized, double blind crossover method to assess the A1c reductions in stratified patients on canagliflozin, sitagliptin, and pioglitazone. Patients with type 2 diabetes on metformin or on metformin+SU were randomly assigned to one of six drug order sequences (see diagram below). Patients completed 16 weeks on each drug before moving to the next drug, with A1c, weight, and patient-reported side effects collected prior to initiation with the subsequent therapy. If a patient was unable to tolerate a drug, they immediately moved to the next drug in the sequence.
    • Ewan Pearson (University of Dundee) outlined the primary advantages of the crossover relative to a traditional RCT. First, it can be powered with a much smaller sample, and second, patients can compare drugs and express their preference. He also noted, however, that potential carryover into future periods, as well as the inability to assess long-term outcomes are downsides of this methodology. In the results, they saw no evidence of carryover between periods, meaning the beneficial effects of one drug did not spill into the following period; however, they did see a period effect where period 2 had a slightly lower A1c compared to the other periods. This was adjusted for in the results using mixed effects models.

  • Study outcomes: The primary outcome was the difference in achieved A1c on the two therapies (sitagliptin vs. pioglitazone for BMI analysis or canagliflozin vs. pioglitazone for eGFR analysis) between each strata (BMI and eGFR). The outcome was valid if patients were on the therapy for at least 12 weeks with greater than 80% adherence. The secondary outcomes were the tolerability of each therapy, weight gain/loss, hypoglycemia on each drug, and the patient preference of each drug. The outcomes were pre-specified in a published statistical analysis plan.
  • Baseline characteristics:

Total subjects

503

Male

383 (73%)

Age

61.9 years

Diabetes duration

8.9 years

BMI

31.7 kg/m2

eGFR

89.7 mL/min/1.73m2

A1c

8.5%

White ethnicity

94%

  • Results: Overall, there were no differences in A1c without stratification, suggesting that the drugs were equally effective glycemic-lowering agents across the study period. However, when stratified by BMI, patients with a BMI<30 kg/m2 saw greater reductions in A1c when treated with sitagliptin, while patients with a BMI>30 kg/m2 saw greater reductions in A1c when treated with pioglitazone. The overall A1c difference was 0.4% (2.92 mmol/mol) suggesting that patients treated with their optimal medication, as determined by the routine clinical marker, saw significant glycemic benefit. Similarly, patients with an eGFR between 60-90 mL/min/1.73m2 fared better when treated with sitagliptin, while patients with an eGFR>90 mL/min/1.73m2 had better glycemic results when treated with canagliflozin. The treatment difference between strata is also 0.4% (2.83 mmol/mol), again highlighting significant treatment benefit on optimal therapy.

  • Patient experience: There weren’t any major surprises when it came to side effects. Pioglitazone led to significantly more weight gain compared to the other agents, while canagliflozin led to passing more urine, increased thirst, and thrush. Across other measures, each of the agents had comparable results. One of the biggest advantages of the crossover design is that participants were able to compare their own experience on each of the three drugs. Interestingly, there was no clear winner among pioglitazone, sitagliptin, and canagliflozin. 26% of patients preferred pioglitazone, 35% preferred sitagliptin, and 39% preferred canagliflozin. Notably, the preferred drug was associated with the lowest A1c and fewest side effects. However, in the discussion, the researchers noted they were surprised that a quarter of participants chose pioglitazone despite the weight gain.
  • Discussion: Professor Hattersley reiterated that this was the first trial to directly test a precision medicine approach in diabetes – and it worked! He noted that these guidelines can inform clinical practice when glycemic management is the priority, although as seen in Dr. Rich Bergenstal’s session on Day #1, this is rarely the case anymore. Professor Hattersley recognized this by saying that as part of individualized treatment, some patients will have specific non-glycemic priorities. In particular, patients at risk for CKD or HF should be prescribed an SGLT-2 regardless of their other clinical markers. Professor Hattersley noted that the mean deterioration of A1c on stable therapy is about 1 mmol/mol/year suggesting that the ~3 mmol/mol benefit conferred by optimal medical therapy will lead to an additional three years of stable treatment. This means that there is reduced cost and diabetes burden for three additional years. Perhaps most notably, this benefit is conferred at absolutely no cost. Because BMI and eGFR are routine clinical markers, Professor Hattersley framed it, as “why would you not use it?” given the accessibility of the clinical markers. This is in stark contrast to the more traditional “omics” that are thought of in precision medicine, which often require expensive, non-routine testing to determine genetic composition.
  • Commentary: Independent commentary was provided by Professor Caroline Kistorp of Rigshospitalet, a highly specialized possible in Denmark. First and foremost, she expressed congratulations to the group on moving precision medicine into the “modern era” of evidence-based therapy using RCTs in patients with type 2 diabetes. She commended the group on their complex study design, particularly since it was planned in 2015, characterizing the study as ahead of its time. While of course, knowing what we know today about the benefits of SGLT2 inhibitors and GLP1 agonists, the optimal trial design would certainly have incorporated long-term cardiovascular and kidney (and perhaps even cognitive outcomes data. Professor Kistorp concurred, noting that even though the trial included patients without established CVD and CKD, they were still 60 years old with a significant diabetes duration, placing them in the high-risk category for each of these conditions. We also might ask whether the patients may have had some CVD and CKD risk that wasn’t measured (we will find out the answer to this and report back.) Additionally, she wondered whether A1c was the most important parameter for these patients but acknowledged the limitations of the short duration of the trial. Despite the fact that CGM was not nearly as accurate or reliable (as a technology) as it is today, what we really wish (!) that CGM would’ve been used at the start and end of the trial so that time in range could have been measured.
  • Despite the shortcomings of the trial, we see this as a significant step forward in the world of precision medicine. This is currently a very hot topic in diabetes – see our debate from earlier today– and the field would surely benefit from dedicated research assessing outcomes of precision medicine. We hope this study will inform more trials in the near future and further out, and that in the future, a greater number of patients will have the option to be treated based on their most optimal medical needs.

Debate on precision medicine centers on question of scale: Should it be approached from a molecular, individual, or population level?; panelists deliberate cutting-edge research, cost-effectiveness, adherence, equity, and the future of diabetes management

More than 800 people tuned in live to watch this refreshing session with Professor Simon Griffin (University of Cambridge), Dr. Miriam Udler (MGH, Harvard), and Dr. John Dennis (University of Exeter) debate the role of precision medicine in diabetes management. In the session, moderated by Dr. Robert Gabbay (ADA) and Professor Paul Franks (Lund University, Sweden), Dr. Udler and Prof. Griffin took on the “pro” and “con” sides of the debate, respectively, and Dr. Dennis proposed a more middle of the road approach. Precision medicine has been defined as giving the right therapies to the right patients at the right time – every time. In theory, this sounds fantastic, and of course, today’s debate on precision medicine really came down to scale: should the emphasis of diabetes management be on the cellular processes or the global population level? Though each of the panelists made it clear that they are not so polarized in clinical practice, Dr. Udler and Dr. Griffin took the management of diabetes to the extreme. Dr. Udler discussed diabetes on the molecular level, highlighting research that focuses on the different physiological pathway disruptions that result in diabetes. Professor Griffin argued that there is a “tidal wave” of patients who are going to be diagnosed with diabetes in the coming decades and that resources should be more targeted at population level interventions. Meanwhile, Dr. Dennis’s argument focused almost exclusively on the individual level, suggesting that treating diabetes should be based on demographic characteristics and routine clinical markers, such as sex, BMI, A1c, and eGFR.

  • Dr. Udler defined precision medicine as the movement away from “one size fits all” disease management and towards individualized care. Each of the panelists agreed that some sort of personalized care is likely the best course of treatment, though each had their own view on what exactly this means. Dr. Udler proposed individualization using clinical, socioeconomic, and “omic” features, which include a patient’s genetic and biologic composition. Focusing on the individual level, Dr. Dennis argued that we are not yet ready for “omics” and should instead focus on routine clinical markers to identify which patients could potentially benefit the most from a given therapy. Professor Griffin, on the other hand, argued in favor of personalized rather than precision medicine, which he takes to mean individualizing care based on a jointly determined course of action between patients and providers to optimize treatment goals and adherence to medication. He argued that precision medicine is too narrowly focused on the individual and not their greater context, instead proposing population health interventions as a the most critical solution to the diabetes epidemic.
  • Looking at the molecular level, Dr. Udler argued that molecular-based precision medicine helps treat the cause of the disease rather than the symptoms. Dr. Udler highlighted research that identified biological pathways underlying diabetes and the four stages of precision medicine where they might be useful. Dr. Udler described five clusters of genetic type 2 diabetes loci, including islet dysfunction and islet development which result in insulin deficiency, and liver/lipid dysfunction, fat distribution, and obesity that result in insulin resistance (Udler et al, 2018 and Mahajan et al, 2018). Building on his talk from EASD 2020, Dr. Udler argued that as more is learned about these clusters and the physiological pathways that define them, they will have greater significant clinical relevance. In the prevention stage of precision medicine, high-risk individuals can be identified using these pathways before they are diagnosed to help prevent the progression of diabetes. For other individuals, in the diagnostic stage, precision medicine can be used to understand why the diabetes developed and which pathways were involved. Much of today’s debate focused on the third stage – treatment – which Dr. Udler called the “crux of precision medicine,” in which the genetic phenotype identified can be used to determine the patient-specific optimal treatment course. Finally, in the prognosis stage, precision medicine can be used to identify the expected disease course and risk of complications or comorbidities.
  • Cost-effectiveness and efficiency underpinned the arguments of both Dr. Dennis and Professor Griffin. Dr. Dennis agreed that while genetic testing is coming in the future, the current state of diabetes does not allow for patients to be managed based on nonroutine biomarker testing, turning instead to individualized care based on routinely measured clinical features. Using his forthcoming algorithm, Dr. Dennis can sort patients to their optimal medical therapy based on these clinical features. This low-cost intervention is a start at bringing individualized treatment to patients. In his talk, Professor Griffin argued that there is no evidence that precision medicine is more cost-effective than the current standards of care. Moreover, he argued that stratification of patients based on certain characteristics into groupings rather than the individual is a much more efficient and cost-effective mechanism. Both Dr. Dennis and Professor Griffin cited a 2019 study, published in The Lancet by Dr. Dennis, which shows that features such as age, sex, BMI, and A1c are actually better predictors of optimal A1c lowering therapies than HOMA-derived clusters.  On the flip side, Dr. Udler argued in Q&A that even if omics features are too costly to be integrated into clinical care at present, it is still incredibly important to understand disease mechanisms underlying the highest risk patients. She hopes that someday, this knowledge will be used to prevent diabetes on a global scale.
  • Conversations around precision medicine and equity were highlighted as potential barriers for scaling precision medicine programs. Unfortunately, it’s a well-known fact that across the board, current management of disease for patients with diabetes is suboptimal. Dr. Udler noted that “even with adherence to treatment, most people are not meeting their A1c targets,” citing a 2014 study that found less that 50% of patients adherent to their medications met glycemic targets. Dr. Udler sees this as an opportunity – precision medicine can be used to fill this ominous treatment gap by connecting patients with their most optimal therapy. On the other hand, Professor Griffin argued that if (or when) precision medicine works, it runs the risk of exacerbating health inequalities, with the wealthy and educated patients benefitting from precision medicine while everyone else is left behind. Professor Griffin highlighted data from the 2018-2019 National Diabetes Audit in England and Wales, showing that a significant portion of patients still are not receiving elements of care with known benefits. Instead, he argued that resources should be used to improve rates of established care, and that these will have much greater effects than precision medicine.
  • Professor Griffin proposed adherence as the key to treatment, noting a patient’s biological pathways are irrelevant if they are not taking the drug. As he so bluntly put it, “adherence is not related to genes.” He cited a 2002 study showing that only 31% of patients prescribed sulfonylurea were adhering to their medication, defined as 90% of days with adequate drug coverage based on labeling. While recent data shows there may have been slight improvements (closer to 41%), overall adherence remains generally low. In Q&A, Professor Griffin added that for the most part, glucose-lowering drugs work in all patients so long as they are taking them. Professor Griffin implied that before you spend billions of dollars figuring out which medication is correct for an individual patient based on their genetics, simply getting them to adhere to a well-established therapy should be the primary goal. On the other hand, Dr. Dennis noted that discontinuation is one of the most predictable features based on patient’s demographic and clinical profile. Using a patient’s individualized features to determine which therapy they are the likeliest to continue on with can increase adherence.
  • According to Professor Griffin, more dedicated clinical research is needed before precision medicine can take center stage. Professor Griffin strongly opposed using molecular pathway markers in clinical practice before there is solid evidence that it is safe and effective. He noted that for any drug, the organization making it available it has to prove it is “safe and cost-effective” before it comes to the market. He called for more research of precision medicine assessing hard clinical outcomes, such as MACE, CV death, CKD, instead of the intermediate glycemic target. Moreover, Professor Griffin noted that the current data on precision medicine comes from post-hoc and sub-analyses, which are susceptible to spectrum bias. Dr. Griffin argued that searching for answers in a population that has a high prevalence of disease may lead to spurious correlation rather than true hypothesis-generating findings. More dedicated studies are needed to show meaningful evidence for precision medicine, but in the meantime, Professor Griffin called for more research on population health initiatives to stem the rising tide of diabetes and obesity.
  • Dr. Gabbay and Professor Franks highlighted the work of the joint ADA/EASD committee, who published a consensus report on precision medicine last summer. The report defines precision medicine and the rationale for its use in diabetes, as well as diagnostics, therapeutics, and equity, among other things. Professor Franks noted the committee is working on an updated consensus, which is set to be published in 2024 and will focus on the strengths and gaps of precision medicine. Dr. Gabbay celebrated the committee for releasing a series of requests for applications to advance precision medicine, which were sent out earlier this year. We are looking forward to more work from this dedicated task force of scientists and clinicians in the coming years on this cutting-edge topic.

36th Annual Camillo Golgi Lecture: Dr. Hiddo Heerspink calls for personalized medicine with combination therapy to improve CKD management in type 2 diabetes, advocates biomarker and tissue-level studies to better understand drug response

During the 36th Annual Camillo Golgi Lecture, Dr. Hiddo Heerspink (University Medical Center Groningen, Netherlands) gave an innovative and compelling presentation calling for greater use of personalized medicine with combination therapy to manage CKD in patients with type 2 diabetes. Dr. Heerspink argued for a “shift away from a ‘one size fits all approach’ to a ‘one size for each person’ strategy,” in which each patient receives therapy based on the drugs that they individually best respond to. With several drugs now approved for the treatment of CKD in type 2 diabetes, including ACE inhibitors, angiotensin II receptor blockers (ARBs), SGLT-2s, and now finerenone, Dr. Heerspink expressed excitement about the potential for improved CKD management via personalized medicine and combination therapy to maximize a patient’s response and improve outcomes for DKD. Given the high burden of CKD and, from a patient perspective, the desire to avoid progression to renal replacement therapy, we’d imagine that Dr. Heerspink’s approach could substantially improve patient outcomes and satisfaction. We hope to see continued progress in biomarker discovery and validation, as well more combination therapy trials going forwards.

  • Dr. Heerspink argued that a personalized medicine approach is necessary to address the high level of residual risk for kidney outcomes seen in landmark CVOTs, which he argued is due to substantial variation in patients’ response to these agents. The field of DKD treatment has made significant progress with the 2019 approval of canagliflozin for CKD associated with type 2, the April 2021 approval of dapagliflozin for the treatment of CKD in patients with and without diabetes, and the July 2021 approval of finerenone for CKD associated with type 2. However, Dr. Heerspink lamented that a substantial amount of residual risk remains in terms of the number of patients experiencing the kidney endpoint in landmark CVOTs (nearly 200 in DAPA-CKD, nearly 250 in CREDENCE, and over 500 in FIDELIO-DKD). Dr. Heerspink proposed that this residual risk may be explained by suboptimal drug response due to a high degree of variation in patients’ response to medications. In other words, he suggested that we do a poor job identifying and distinguishing “non-responders” from “responders” and prescribing optimal treatment accordingly.
    • For instance, the ROTATE study documented a large degree of variation in albuminuria response to various agents between individual patients, seen in the “waterfall plot” below. Each dot represents an individual patient’s albuminuria response (% change in ACR) to a particular drug, with gray dots indicating the patient’s response to their worst three drugs and the colored dots representing the patient’s response to their best three drugs. Dr. Heerspink noted that if every patient were to be on their best drug, this would yield an average 60% reduction in albuminuria –and that’s just a single agent alone. With combination therapy, we assume this percentage is likely to be even higher. 

    • Dr. Heerspink suggested that reliance on systemic, rather than tissue-level, measurements of drug concentration may explain the substantial variation in drug response. Excitingly, he explained that biomarkers and PET-imaging of SGLT-2s can combat this challenge. For instance, Dr. Heerspink explained that he used a radioactive canagliflozin tracer (18F-Canagliflozin) to measure the drug’s pharmacological activity in the kidney. Overall, he called for greater use of biomarker and PET studies to obtain more accurate measurements of drugs at the level of the tissue. While Dr. Heerspink acknowledged that we have a "long way to go" in terms of understanding disease pathophysiology, identifying biomarkers, and validating these biomarkers, we share his enthusiasm for the potential of precision medicine in the CKD landscape.
  • Pushing for combination therapy, Dr. Heerspink asserted that given the large variation in individuals’ response to therapy, it is clinicians’ “duty and responsibility to find the optimal combination of drugs for each patient.” He highlighted three combination therapies, each appropriate for different circumstances: SGLT-2 + GLP-1, SGLT-2 + mineralocorticoid receptor antagonist (MRA), and SGLT-2 + endothelial receptor antagonist (ERA). ERAs are used to treat pulmonary hypertension, but they are also being investigated as treatments for diabetic nephropathy. Dr. Heerspink shared an algorithm (below) to personalize treatment with combination therapy. For patients at high risk of heart failure, he suggested an SGLT-2 with an MRA can yield large risk reductions in the risk of heart failure. Meanwhile, GLP-1s have strong weight loss benefits and therefore should be part of the treatment protocol for patients with obesity. Finally, in patients with high potassium levels, an ERA can be substituted for an MRA because MRA’s are associated with hyperkalemia.
    • Dr. Heerspink referenced completed and ongoing studies investigating each of these three combination therapies. For the SGLT-2 and MRA combination, he cited the ongoing ROTATE-3 study in the EU, assessing the albuminuria-lowering effects of dapagliflozin and steroidal MRA eplerenone; we’ll be eager to see the ROTATE-3 results when they become available in two weeks. For the SGLT-2 and ERA combination, he referenced the ongoing phase 2 ZENITH trial, which is assessing the effect of dapagliflozin with investigational ERA zibotentan on UACR, eGFR, and blood pressure. Dr. Heerspink also cited an analysis of the SONAR study that he published in Kidney International investigating the use of SGLT-2 with investigational ERA atrasentan. Dr. Heerspink’s analysis of SONAR found that SGLT-2s when used with atrasentan enhance albuminuria reduction and abrogate the fluid retention and weight gain that results from ERA use. For the SGLT-2 and GLP-1 combination, he cited a secondary analysis of the DECREASE trial published in Diabetes Obesity Metabolism that found the combination of exenatide and dapagliflozin lead to greater reductions in UACR and  24-hour albumin excretion than placebo or either drug alone.

Small cross-over study investigating pramlintide-insulin co-formulation ADO09G finds improved Time in Range alongside body weight and prandial insulin dose reductions vs. insulin aspart in type 1 diabetes (n=44)

Dr. Gregory Meiffren (Adocia, Lyon, France) presented the results of a small cross-over study comparing novel pramlintide and insulin co-formulation drug AD09G vs. insulin aspart over 24 days in patients with type 1 diabetes (n=44). Participants were divided into two groups based on their total daily prandial insulin dose: Part A included those using less than 40 U insulin per day (n=28), while Part B included those using 40 to 75 U insulin per day (n=16). Both groups saw a significant increase of nearly one hour for Time in Range (70 mg/dl-180 mg/dl) with AD09G relative to aspart (Part A: +51 min; p=0.01; Part B: +58 min; p=0.04) and of >1 hour for Time in Tight Range (70 mg/dl-140 mg/dl) with AD09G relative to aspart (Part A: +70 min, p=0.0017; Part B: +63 min, p=0.01). Time below range (<70 mg/dL) was slightly increased with ADO09, though this increase was only significant in Part A (Part A: +10 min, p=0.046; Part B: +13 min, p=0.15). While total hypoglycemic events were also slightly increased with ADO09 relative to aspart (Part A: 142 vs 115 total events; Part B: 96 vs 79 total events), Dr. Meiffren noted that no severe hypoglycemic events were reported and ADO09 did not increase the risk of nocturnal hypoglycemic events. ADO9G was generally well-tolerated. More gastrointestinal adverse events occurred with ADO09 vs. insulin aspart, though Dr. Meiffren emphasized that these events were transient and consistent with pramlintide’s side effect profile. These initial results for ADO09 complement to a growing number of studies investigating amylin combination agents for obesity. At the moment, Novo Nordisk’s Cagri-Sema (amylin analogue cagrilintide and GIP/GLP-1 semaglutide) appears to be the frontrunner, with a recent publication in The Lancet documenting superior weight loss over rockstar anti-obesity drug semaglutide 2.4mg. We’ll be eager to follow developments from Adocia, Novo Nordisk, and others pursuing amylin analogues as novel agents for obesity and diabetes management.

  • As an amylin analogue, pramlintide improves post-prandial glucose by delaying gastric emptying, reducing glucagon secretion, and promoting satiety. Indeed, Dr. Meiffren noted that gastric emptying was slower with ADO09, as T-maximum (the time a drug is present at maximum concentration in the blood) was achieved approximately two hours following the mixed meal tolerance test with ADO09 in both groups, compared to 30 minutes and 40 minutes with aspart in Parts A and B, respectively. Likewise, Dr. Meiffren noted that both Part A and Part B had significant reductions in glucagon secretion by 70% to 85% with ADO09 vs. aspart.
  • Dr. Meiffren shared that ADO09 also reduced prandial insulin dose and body weight vs. insulin aspart. On day 24, prandial insulin doses were significantly reduced by four units in Part A (-18%, p<0.0001) and 12 units in Part B (-25%, p=0.0004) with ADO09 vs. aspart. Dr. Meiffren also described moderate weight loss, especially among those in Part B, who tended to be heavier at baseline given that they were on a higher insulin dose (average BMI of 31 in Part B. vs. 25 in Part A). Average weight loss was -0.8 kg in Part A and -1.6 kg in Part B, though subjects in Part A with a BMI below 25 did not see any weight reduction. Overall, these results point to promising potential weight loss effects of Adocia’s novel pramlintide/insulin co-formulation agent.

Beyond A1c Highlights

Dr. Rich Bergenstal calls for new diabetes control definition centered on Time in Range, Time Below Range, Diabetes Distress, and CVD/CKD; diabetes technology associated with improved glycemic control among young adults with and without diabetes distress

Dr. Rich Bergenstal (International Diabetes Center) chaired an insightful Sanofi-sponsored symposium providing his perspectives on CGM and Time in Range and calling for greater emphasis on diabetes distress and prevention of CVD/CKD in assessments of diabetes control. We were especially excited to see Sanofi, as one of the three largest insulin manufacturers, take the opportunity to focus its symposium on the value of diabetes technology with Dr. Bergenstal, a visionary in the field of Time in Range adoption and diabetes technology more broadly. Kicking off the session, Dr. Bergenstal advocated for a new definition of diabetes control incorporating Time in Range, Time Below Range, Diabetes Distress, and CVD/CKD risk assessment and prevention with the goal of focusing not only on glucose control, but also patient quality of life and complications. Beginning with Time in Range, Dr. Bergenstal reiterated his “More Green Less Red” mantra for Time in Range representing an increase in time spent between 70mg/dl – 180 mg/dl and less time <70mg/dl. Dr. Bergenstal also reminded attendees of the FNIR mnemonic, which stands for “flat, narrow, and in range” referring to the ambulatory glucose profile graphs generated from patient CGM data. Additionally, as more clinical studies report Time in Range outcomes, Dr. Bergenstal called on the FDA to add Time in Range data to medication and technology indications, and for quality measurement organizations like NCQA to include TIR as a national diabetes quality measure. His contention is that TIR will become more widely adopted as a key management metric if clinical, regulatory and quality measurement bodies are all aligned.  To enable greater use of Time in Range in his new definition of diabetes control, Dr. Bergenstal also advocated in favor of increased diabetes technology use to support remote patient monitoring, data collection, and treatment decision-making. However, should providers continue to ramp the use of diabetes technologies among their patients, Dr. Bergenstal discussed the importance of technology and connectivity assessments highlighting a recent commentary published in the Journal of Diabetes Science and Technology from Dr. David Klonoff (Diabetes Technology Society) et al. titled “Digital Connectivity: The Sixth Vital Sign.” In this commentary, Dr. Klonoff et al. urge providers to assess patients’ technological skills and access to resources as a key component of routine care, noting that as diabetes management continues to become a more digitally supported ecosystem, connectivity represents a significant determinant of health and should be considered in tandem with other social determinants of health such as behavioral, environmental, and psychosocial factors.

  • Dr. Bergenstal argued in favor of a greater emphasis on diabetes distress in clinical practice building on data demonstrating a relationship between diabetes distress and glycemic control. Specifically, Dr. Bergenstal highlighted data published in Diabetic Medicine in July, which found that higher diabetes distress scores among young adults with type 1 diabetes (n=423) were associated with a significant 1% increase in A1c values compared to young adults not demonstrating signs of diabetes distress. Among the study population, technology use of insulin pumps and CGMs was consistently associated with lower A1c even among patients experiencing high levels of diabetes distress. While diabetes technology has previously been discussed as a potential method for mitigating diabetes distress, this study demonstrated the important impact technologies can have on improving glycemic control even among patients experiencing high levels of distress. Conversely, Dr. Bergenstal also pointed out that while technology was beneficial, the largest indicator of reduced A1c was reduced diabetes distress, highlighting the importance of prioritizing diabetes distress management and behavioral health among patients. Given this data, Dr. Bergenstal called for an integration of diabetes distress scores into patient AGP reports. While we think this is a novel perspective, and could certainly have meaningful clinical implications for providers who would be able to see more of a patient’s diabetes-related data in a single location, we are curious how this integration might come about as diabetes distress is not a metric measured (at present) via CGM like the other components of current AGP reports. Excitingly, as we learned in a separate conversation with Dr. Bergenstal, the IDC is already considering ways to achieve this integration by leveraging its EHR and LibreView integration. Specifically, Diabetes Distress scores as well as CVD and CKD risk assessments are stored in patient EHRs, now the same location as patient LibreView AGPs, which enables easy data integration so providers can have access to all their patient data in a single location. This makes a lot of sense from a quality perspective as well and goes right in with the learnings on CGM in the EHR and diabetes distress, both from that meeting. We loved Dr. Bergenstal’s ideas that both could be done – explicitly – as part of pre-visit check-ins, which IDC does routinely now. In his vision, CGM as well as a Diabetes Distress (DD) survey and score would go to the EHR and the latter would also be inserted into the AGP report, increasing the value of this, as well, increasing the visibility and importance of intentional checks on mental health. As well (!), CVD and CKD risk would ideally go there as well, making everything far more actionable.

  • Sanofi’s symposium also featured two roundtable discussions, the first on the use of CGM in pediatric and primary care populations, with Drs. Thomas Martens and Amy Criego, both of the International Diabetes Center where Dr. Martins works in primary care and Dr. Criego in pediatric endocrinology. In their discussion, Drs. Martens and Criego highlighted the differing levels of diabetes technology uptake in their respective patient populations with Dr. Criego seeing much higher technology use among her pediatric population than Dr. Martens sees in the primary care arena. Discussing diabetes management in primary care, Dr. Martens expressed that A1c still “rules the world of primary care,” largely influenced by A1c based pay-for-performance standards. That said, Dr. Martens did acknowledge that CGM “has made inroads” in primary care via growing provider awareness and structured quality improvement initiatives. Discussing her own work, Dr. Criego highlighted the IDC’s successful integration of Abbott’s FreeStyle Libre View platform into EPIC health records, which Dr. Criego presented at ADA 2021, discussing the benefit for providers and clinical workflow of having patient CGM data easily accessible via existing electronic health records.

    • Both Dr. Criego and Dr. Martens presented case studies from their clinical practice demonstrating the power of CGM and Time in Range to support patients and help drive improved glycemic control. Dr. Criego discussed a patient of hers who is a 20-year-old male with type 1 diabetes who, especially at the beginning of COVID-19, struggled to control his glucose levels, but was wearing a CGM. By analyzing his AGP, Dr. Criego was able to identify that he was often taking his basal dose at different times in the morning and other times forgetting to take his basal insulin and had only 27% Time in Range. Using this information, Dr. Criego focused her clinical conversations with this patient around consistency in basal dosing time as well as proactively dosing insulin before meals instead of reacting once glucose levels rose following a meal. Only two weeks later, Dr. Criego followed up with this patient via telemedicine by which time they had already seen a significant Time in Range improvement of +14% (+3.2 hours/day) to 41% Time in Range. Dr. Martens discussed one of his primary care patients with type 2 diabetes and a BMI of 31 kg/m2 who was on a basal-only insulin regimen (52 units/day) and had 34% Time in Range. Based on this patient’s CGM data, Dr. Martens suggested initiating basal-bolus insulin therapy, however the patient was hesitant and decided to instead use his CGM data to help guide behavioral and dietary changes. Nine months later, this same patient had seen a remarkable improvement in Time in Range to 89% without intensification of medication. Notably, while discussing this patient, Dr. Martens also referenced the MOBILE study presented at ATTD 2021 and published in JAMA, which demonstrated similar improvements in glycemic control among basal-only type 2s using CGM.
  • Turning to the second roundtable discussion on connected solutions and telemedicine, Dr. David Kerr (Sansum Diabetes Research Institute) moderated a conversation between Dr. Jeremy Pettus (UC San Diego) and Ms. Lori Berard (Nurse consultant, Diabetes Educator, Winnipeg, Canada) who discussed the continued use of virtual care beyond the COVID-19 pandemic. Kicking off the conversation, Dr. Pettus highlighted the data-driven nature of diabetes management as a key reason for the generally successful transition to virtual care that many patients and providers have experienced in the last 18 months. Specifically in his own practice, Dr. Pettus estimated that he has a 70-80% “success rate” using virtual visits with his patients having roughly two to three patients out of ten who require additional problem solving either related to technology use or treatment that is more easily conducted in person. However, Ms. Berard did raise the important point that virtual visit “success” is highly dependent on the types of patients being served and it can be much harder to provide virtual care for patients not using technologies or not consistently tracking their glucose data.

Discrepancies between GMI and A1c: 14-day GMI and A1c correlation factor R2=0.82; 30-day GMI and A1c correlation factor R2=0.85; GMI consistently lower than A1c

Dr. Paul Fellinger (Medical University Vienna) presented new data on discordances between A1c and GMI values for patients using CGM with GMI indicating stronger glycemic control compared to A1c. In this retrospective analysis, Dr. Fellinger analyzed data from 170 outpatients with diabetes who used CGM and collected data for 14 days and 30 days prior to A1c assessment in order to calculate GMI. Patient GMIs were then compared to their laboratory A1c values to assess deviations between the two measures. For the purpose of the study, Dr. Fellinger identified a deviation between GMI and A1c of >0.4% points to be clinically significant. At baseline patients had a mean A1c of 7.5% and the vast majority of patients used a FreeStyle Libre CGM (n=166). After 14 days of CGM data, patients’ average GMI was 7.19% compared to 7.21% after 30 days of data. Both the 14-day and 30-day GMIs correlated closely with A1c with R2 values of 0.82 and 0.85, respectively (p<0.001) indicating that the 30-day GMI was slightly more closely correlated with A1c. However, when patient-specific data was plotted, a substantial number of datapoints fell outside the previously identified clinical relevance threshold of a 0.4% point divergence in GMI and A1c. Notably, these divergences became more pronounced in patients with A1c >8% and GMI >7.5% with GMI values often falling below those from A1c measurements. While Dr. Fellinger’s data highlight the importance of recognizing and accounting for discrepancies between GMI and A1c, he did not provide a perspective on which measurement he thought provided a more accurate overview of a given patient’s glycemic control.

  • Similar data on GMI and A1c discordance was published in DT&T  in March 2021. In this study, the authors concluded that GMI and A1c deviations indicated that A1c “may not as accurately reflect mean glucose” as was previously thought. Interestingly, this data was highlighted at ATTD 2021 in a debate between Dr. Fergus Cameron (Murdoch Children’s Research Institute) and Dr. Stuart Weinzimer (Yale School of Medicine) on the value of A1c versus CGM derived metrics including Time in Range and GMI. While Dr. Cameron interpreted the study’s results as indicative that GMI may not accurate represent a patient’s glycemic control, Dr. Irl Hirsch (University of Washington), who was serving as the debate moderator and was an author on the DT&T study, joined the conversation to share his view that he had understood the data to mean that A1c may not be as accurate an assessment of risk as it has long been thought to be and that GMI may provide a more accurate surrogate for mean glucose, which both Dr. Hirsch and Dr. Cameron identified as the true metric indicative of long-term outcomes. This last point about finding an accurate surrogate for mean glucose is certainly valuable and we hope to see more research in the future investigating the relationship between GMI and A1c as well as longitudinal studies on the associations between GMI and Time in Range on long-term micro and macrovascular outcomes to help determine which parameters may provide patients the most accurate assessment of their glycemic control and long-term risk.
  • At HiD earlier this month we heard interesting data from Dr. Viral Shah (Barbara Davis Center for Diabetes) on the importance of understanding A1c and GMI discrepancies. During a case study presentation of one of his type 2 patients on oral medications with an A1c of 8.4 who had not tolerated GLP-1s well in the past, Dr. Shah asked the audience what their next steps in management would be providing four options: (i) initiate basal insulin therapy; (ii) try a GLP-1 again; (iii) add an SGLT-2; or (iv) gather more data as A1c alone may not be enough to inform action. While the audience contemplated their own courses of action, Dr. Shah shared that he had chosen the fourth option and opted to put this patient on a FreeStyle Libre CGM for one week to gather more data to inform his clinical decision-making. Notably, when Dr. Shah shared his patient’s FreeStyle Libre AGP, he had an average glucose of 123 mg/dl with a GMI of 5.9% and a remarkable 90% Time in Range. Given the discrepancies between this patient’s A1c and AGP data, Dr. Shah was able to identify that they had a falsely elevated A1c due to iron deficiency suggesting that many of the clinical steps that might have been taken based on their A1c alone (e.g., initiating basal insulin therapy, adding an SGLT-2 inhibitor, etc.) were not actually necessary given the patient’s strong glycemic control. Ultimately, Dr. Shah discussed his experience with this patient as an example of why it is important to use Time and Range and other CGM-derived metrics in conjunction with A1c to ensure providers are getting the full picture of their patients’ glycemic control before making substantial treatment decisions and changes.

Preliminary results from Hypo-RESOLVE offer powerful analysis from 22,071 type 1s and type 2s: Alarming associations between hypoglycemia exposure and subsequent severe hypoglycemia; increased risk of microvascular and macrovascular complications from hypoglycemia exposure

Dr. Joseph O’Reilly, PhD (University of Edinburgh, Scotland) shared preliminary data from JDRF and Novo Nordisk’s Hypo-RESOLVE trial (n=6,976 type 1s and n=15,095 type 2s), showing that increased hypoglycemia exposure in the last 45 days is associated with increased risk of subsequent severe hypoglycemia and microvascular and macrovascular complications (SO 69). As a reminder, the Hypo-RESOLVE (Hypoglycemia – REdefining SOLutions for better liVEs) Project was developed with the intention of developing a better and more universal hypoglycemia classification system that could be integrated into standard guidelines. Backed by €26.8 million from the Innovative Medicines Initiative, JDRF, and Helmsley Charitable Trust, Hypo-RESOLVE also strives to standardize clinical data collection, elucidate the pathology of hypoglycemia, and calculate the financial cost of hypoglycemia in European countries. During today’s session, Dr. O’Reilly read out preliminary data from Work Package Four of the large, collaborative study, which specifically aims to confirm existing predictors and consequences of hypoglycemia while also identifying new associations. Hypo-RESOLVE investigators pooled data from many data sets, totaling 890,350 (!) hypoglycemic events across 22,071 individuals. Using adjusted statistical models, the study mapped the correlation between hypoglycemic events (HEs) and severe hypoglycemia events (SHEs) during the lagged-time period, along with proportional hazard models to associate HE with CVD, nephropathy, and neuropathy.

  • The number of HEs in the past 45 days was positively associated with the probability of subsequent SHEs in participants with both type 1 and type 2 diabetes, regardless of HE severity. In this study, level one HEs were defined as glucose 54 mg/dl-70 mg/dl, level two HEs were defined as blood glucose <54 mg/dl, and level 3 HE or SHE was defined as any HE requiring “third-party assistance.” In type 1s, each level of hypoglycemia was associated with increased risks for further hypoglycemia events at all levels: level 1 HEs increased risk of subsequent HEs at every level (HE levels 1-3 ORs = 1.36, 1.18, and 1.05, respectively), as did level 2 HEs (HE levels 1-3 ORs = 1.21, 1.36, and 1.07, respectively) and SHEs (HE levels 1-3 ORs = 1.19, 1.20, and 1.46, respectively). For type 2s, the researchers observed the same trend: level 1 HEs increased risk of subsequent HEs at every level (HE levels 1-3 ORs = 1.32, 1.19, and 1.09, respectively), as did level 2 HEs (HE levels 1-3 ORs = 1.36, 1.48, and 1.17, respectively) and SHEs (HE levels 1-3 ORs = 1.10, 1.09, and 1.46, respectively). These preliminary data speak to the serious consequences of hypoglycemia exposure regardless of severity. In particular, a strength of this study is that the granularity of the data that the researchers gathered allowed them to standardize a definition of hypoglycemia across their entire data set, regardless of how the studies from which they obtained data chose to define it.

  • Exposure to HEs was also associated with macrovascular and microvascular outcomes in type 1s and type 2s. For type 1s, there was a trend between exposure to hypoglycemic events and elevated risk of a future adverse event (CVD, neuropathy, or nephropathy), but the 95% confidence interval of the hazard ratios encompassed 1 and thus these associations were not significant. Most notably, there was a possible association between SHEs and subsequent CVD events (HR = 1.32, 95% CI lower bound = 0.99), but no other association could be clearly identified – a challenge that Dr. O’Reilly noted could be addressed with additional data. For type 2s, the picture was slightly clearer: there were strong associations between exposure to HEs and future adverse events with a strong association between hypoglycemia and subsequent neuropathy (level 1 HE HR = 1.04, level 2 HE HR =1.36, level 3 HE HR = 1.97) and CVD (level 1 HE HR = 1.58, level 2 HE HR =1.56, level 3 HE HR = 1.67). While no other associations could be identified, Dr. O’Reilly explained that these negative clinical outcomes are deeply alarming: since their data had already demonstrated that any HE exposure is associated with severe hypoglycemia, which is in itself associated with further microvascular and macrovascular outcomes, the preliminary results suggest a cascade of consequences may be initiated by initial exposure to any degree of hypoglycemia.

HARPdoc trial shows efficacy but not superiority of novel psychoeducational program to reduce severe hypoglycemia in type 1 with impaired hypoglycemia awareness (n=96); novel intervention incorporates cognitive behavioral therapy and motivational interviewing

In a stirring session on a new intervention for problematic hypoglycemia, Prof. Stephanie Amiel (King’s College London) presented the results of the Hypoglycemia Awareness Restoration Program for adults with type 1 diabetes and problematic hypoglycemia Despite Optimized Control (HARPdoc) study. The multi-center, two-arm parallel-group trial aimed to investigate the value of addressing unhelpful beliefs in improving awareness of hypoglycemia and preventing severe hypoglycemia specifically among a population of patients who had not responded to other treatment strategies. Specifically, the study compared the novel HARPdoc curriculum with the Blood Glucose Awareness Training (BGAT) educational program that was developed in the late 1980s. Both programs are six-week manualized psychoeducational interventions that involve small group sessions with educators to combat hypoglycemia unawareness. HARPdoc was associated with substantial reductions in the number of severe hypoglycemia events at 12 and 24 months but did not achieve superior reductions to BGAT. On the secondary mental health outcomes, HARPdoc demonstrated significantly greater reductions in diabetes distress, anxiety, and depression than BGAT; these improvements in mental health were sustained over the entire duration of follow-up (as assessed by the Problem Areas in Diabetes Questionnaire and the Hospital Anxiety and Depression Scales). HARPdoc also had a superior impact on the problematic cognitions at both timepoints, as assessed by an Attitudes to Awareness Questionnaire. Overall, Prof. Amiel concluded that HARPdoc offers a novel adjunctive therapy for people struggling with hypoglycemia, with clinically important and sustained improvements in mental health outcomes alongside reduced incidence of severe hypoglycemia.

  • The HARPdoc program addresses problematic cognitions through cognitive behavioral therapy and motivational interviewing. The comparator program, BGAT aims to teach participants new ways of predicting extremes in blood glucose through understanding external cues and paying attention to internal cues. BGAT has been demonstrated to reduce severe hypoglycemia and restore impaired awareness, though Prof. Amiel noted that it has not been widely adopted. HARPdoc grew out of qualitative interview-based research by Nurse Consultant Helen Rogers (London, UK) who identified common cognitions contributing to sustained impaired hypoglycemia awareness in people with low hypoglycemia concern.
    • Mrs. Rogers found four common problematic cognitions among these individuals: (i) normalizing impaired awareness of hypoglycemia, (ii) underestimating the severity of hypoglycemia, (iii) avoiding the sick role, and (iv) overestimating hyperglycemia. Based on these findings, Nicole De Zoysa (King’s College London) developed the HARPdoc educational curriculum, which draws on cognitive behavioral therapy and motivational interviewing to identify and restructure problematic cognitions and support behavior change.
  • Prof. Amiel described a “huge range” of experiences with severe hypoglycemia in the study. At baseline, some participants had experienced as many as 550 events in the previous 12 months and approximately half had been living with problematic hypoglycemia for over ten years. The 99 participants reported nearly 3,000 episodes of severe hypoglycemia during the year prior to their HARPdoc or BGAT course. Given the harmful consequences of severe hypoglycemia at a physiological, psychological, and social level, we are very disheartened by these data. While there has been exciting innovation in the field as of late with the launch of next-generation rescue glucagons (Zealand’s Zegalogue, Xeris’ Gvoke Kit, and Lilly’s Baqsimi), so few people with diabetes have these therapies compared to the number that should – indeed, it’s incredibly concerning to hear that some patients continue to experience these life-threatening events at alarming rates.
  • In a positive commentary, Dr. Ramzi Ajjan (University of Leeds, UK) emphasized HARPdoc’s efficacy in reducing severe hypoglycemia and its advantage over BGAT in improving psychological and mental health outcomes. Although HARPdoc was not superior to BGAT in reducing severe hypoglycemia, Dr. Ajjan emphasized that the novel intervention performed better than expected and congratulated the investigators on a successful, “well-designed” study. In particular, Dr. Ajjan noted that educational programs such as HARPdoc provided a crucial intervention for this treatment-resistant population, given the low engagement with technology documented in trial participants.
    • Shockingly, while nearly all HARPdoc participants were offered and tried insulin pumps or CGM, less than one-third were using pumps or CGM at the start of the trial. Dr. Ajjan asserted that “technology is not the answer” in this group of treatment-resistant patients, explaining that technology should not take over education, which remains “incredibly important” in type 1 diabetes.
    • Looking ahead, Dr. Ajjan suggested that future analyses on the cost-effectiveness, long-term benefits, real-world efficacy of HARPdoc are warranted. We were excited to learn that HARPdoc received high ratings from participants and that another course is scheduled to begin soon. We found the HARP doc analysis to be especially impactful for reducing the mental burden of diabetes and diabetes distress and see great potential for the intervention to address these challenges patients and their loved ones face moving forward.

Diagnosing, Treating, and Preventing Impaired Awareness of Hypoglycemia: Psycho-educational programs prove to be single most effective tool

Dr. Stephanie A. Amiel (King’s College London) gave a compelling presentation on impaired hypoglycemia awareness (IAH), discussing the current health risks associated with IAH as well as strategies to identify, treat, and prevent it. Indeed, she began by defining IAH as loss of subjective awareness of hypoglycemia—that is, a “diminished ability to perceive the onset of acute hypoglycemia,” and a muted stress response during hypoglycemic events. She further cited that IAH is relatively common, affecting 25-40% of patients with type 1 and ~10% of people with insulin-treated type 2 diabetes. Additionally, IAH can increase the risk of severe hypoglycemia 6-fold for patients with type 1, and an astounding 17-fold in patients with type 2. Given this alarming context, Dr. Amiel discussed strategies for properly diagnosing IAH, as well as methods to treat and prevent it. 

  • Dr. Amiel began by identifying the 3-step process that clinicians can use to identify hypoglycemia unawareness among their patients. The first step involves using one of the four currently validated assessments for IAH, including the Gold Score, Clarke Score, DAFNE Tool, and Pedersen-Bjergaard Score. She noted that the Clarke Score is the simplest (and therefore most clinically relevant) assessment, as it asks a single question—“Do you know when your hypos are commencing?”—and asks patients to rate it on a scale of 1 (always aware) to 7 (never aware), with a score of 4+ indicating IAH. The second step then involves checking the person’s glucose records and looking for when the patient had a blood glucose level under 54 mg/dL (i.e., level 2 hypoglycemia) without symptoms. Finally, the third step should involve asking family members how often they recognize hypoglycemia before the person experiencing it does.
  • Turning her attention to prevention and management of IAH, Dr. Amiel emphasized that the best current evidence for its management supports structured psycho-educational programs used alongside technology. Indeed, while she explains that CGM data has undoubtedly reduced severe hypoglycemic events, these devices are “only as good as the person that’s using them”—that is, they do not provide protection against hypoglycemia unawareness when a person isn’t wearing them, or if they malfunction. Studies have corroborated this point by reporting no significant differences in self-reported IAH scores between CGM and non-CGM groups. Diabetes teaching and treatment programs, however, have proven to be the single most effective intervention to date which can reduce IAH scores. By teaching patients to use their insulin more flexibly, and providing them with self-management tools, the UK National Daphne Audit program found that hypoglycemia recognition improved in 43% of those initially reporting unawareness. Notably, they found that structured education programs work well for not only reducing IAH, but for reducing severe hypoglycemic events as well (see graphs below).

  • Finally, Dr. Amiel concluded her talk by presenting some forward-thinking research on how IAH affects the brain’s responses to hypoglycemia. Indeed, a 2018 study by her group found that in patients with IAH, there is differential activation in the brain regions that generate symptomatic responses for hypoglycemia. That, and these patients have differences in cortical responses to hypoglycemia involved in emotional salience which affect their perception of unpleasantness. Drawing from this, Dr. Amiel and colleagues have hypothesized that people with impaired awareness have different neurological response to hypoglycemia, such that they do not perceive it as unpleasant, can struggle to learn that it needs to be avoided, and therefore do not acquire the motivation to reduce these events in the future. Fascinating! Her research group is taking this neuroimaging data one step further by addressing problematic cognition around hypoglycemia through cognitive behavioral therapy and motivational interviewing. See here for more coverage on this innovative intervention, called the HarpDoc Trial.

Big Picture Highlights

10-year and lifetime CVD risk strongly linked with history of CVD in type 2s; 80% of patients with a history of CVD met high risk threshold vs 0.4% without a history of CVD

Dr. Jan Westerink (University Medical Center Utrecht) presented new data from a post-hoc analysis of the CAPTURE study investigating the distribution of CVD risk among patients with type 2 diabetes and found that both 10-year and lifetime CVD risk are strongly linked with patient history of CVD. As a reminder, the CAPTURE study was an international, non-interventional, cross-sectional study of adults with type 2 diabetes (n=9,823). In his analysis, Dr. Westerink and his colleagues used the DIAL model to calculate 10-year and lifetime CVD risk (risk of experiencing vascular mortality, myocardial infarction, or stroke) for participants in the CAPTURE study (n=9,416). The DIAL model was validated in 2019 and incorporates risk factors including age, sex, smoking, systolic blood pressure, body mass index, A1c, eGFR, non-HDL cholesterol, albuminuria, diabetes duration, insulin treatment, and history of CVD. Patients in Dr. Westerink’s analysis were stratified according to baseline CVD status, either they had CVD and were categorized as having a history of CVD (n=2,901) or they did not have CVD and were categorized as having no history of CVD (n=6,515). Patients without a history of CVD were slightly younger with an average age of 61 compared to those with a history of CVD with an average age of 67. According to the results of this analysis, both 10-year and lifetime CVD risk demonstrated wide distributions for patients with type 2 diabetes highlighting the importance of individual risk assessment for patients. Specifically, for patients with a history of CVD, the mean 10-year CVD risk was 40%, substantially higher than the “high risk” cutoff of 10%.  However, while the average risk was 40% there was a large distribution spanning all the way down to a risk of 10% with 96% of patients with a history of CVD experiencing 10-year CVD risk >10%. For lifetime CVD risk, the majority of patients with a history of CVD (80%) met the high-risk threshold of a lifetime 50% risk while the average lifetime risk for patients with a history of CVD was 65%. Turning to patients without a history of CVD, only 14% had a 10-year risk >10% and the average 10-year CVD risk was 5%. For lifetime risk, patients without a history of CVD again saw lower risk profiles with only 0.4% qualifying as high-risk with a lifetime risk >50% and an overall average lifetime risk of 10%, well below the 50% cutoff for high-risk patients. Given these variation in risk, Dr. Westerink strongly encouraged providers to undertake risk assessment for their patients and integrate individualized risk assessment conversations into a shared decision-making model of clinical care.

  • Despite the significant CVD risk among patients with a history of CVD, only 18% of these patients were on an SGLT-2 and only 10% were on a GLP-1. Dr. Westerink did acknowledge that this data was collected pre-2019 ahead of many of the recent trial readouts for these drug classes that showed significant cardioprotective benefits, which could potentially explain why so few patients were taking these medications. Additionally, SGLT-2 and GLP-1 penetration was nearly identical for patients without a history of CVD at 16% and 11%, respectively, further supporting Dr. Westerink’s hypothesis that much of this data was likely collected before providers were prescribing SLGT-2s and GLP-1s for their cardioprotective effects. That said, there were noticeable regional differences in prescribing patterns for SGLT-2s and GLP-1s with much higher SGLT-2 use for patients with a history of CVD in the Middle East and Australia than other regions. Dr. Westerink highlighted these regional differences as an important area of future research.

Michael Berger Debate: Professor Naveed Sattar and Dr. Bairey Merz debate absolute vs relative risk of cardiovascular disease in women with diabetes

Dr. Noel Bairey Merz (Cedars-Sinai Medical Center, Los Angeles) and Professor Naveed Sattar (University of Glasgow) squared off in a lively debate on whether or not women with diabetes have higher cardiovascular risk than men. Dr. Bairey Merz argued that yes, women are at higher risk, in part due to gender and sex differences in detection, treatment, and diabetes mechanisms, while Professor Sattar argued no, men actually have higher risk. While the panelists agreed more than they disagreed, the biggest discussion arose over relative vs absolute risk. Professor Sattar conceded that women tend to have higher relative risk of heart disease but argued that men have higher absolute risk. Dr. Bairey Merz noted, however, that each of the risks are “valuable metrics” for understanding the consequences of cardiovascular disease depending on the situation. She argued that the relative risk is meaningful to “societies, health systems, and population health” while absolute risk refers to the individual patient. Ultimately, both Dr. Bairey Merz and Professor Sattar concurred that risk of CVD is too high in patients with diabetes, and more preventative measures and better utilization of medications must be implemented to reduce the high burden of disease.

  • Dr. Bairey Merz centered her argument on the comparative sex and gender differences related to diabetes mechanisms and treatment in patients with diabetes. Dr. Bairey Merz reviewed a 2019 meta-analysis which showed that the pooled women-to-men relative risk ratio for all-cause mortality, using data from 49 different studies (n= 5,162,654), led to a 13% greater risk of CVD for women with diabetes compared to men. Moreover, women with diabetes had a 58% greater risk of coronary heart disease (CHD) mortality. Notably, however, despite this higher risk, women have lower frequency of medication usage and adherence, as demonstrated in a 2015 report. Dr. Bairey Merz attributed this to the implicit bias associated with weight in women, citing a 2015 editorial suggesting women are more often “shamed” about their weight and are less often given treatment, despite the fact that some medications may be even more effective in women than men. Dr. Bairey Merz also offered a biological explanation for the difference in risk, reviewing several studies suggesting that women with diabetes and central hypogonadism experience a greater risk for cardiovascular disease.
  • Professor Sattar focused on the greater absolute risk of cardiovascular disease in men with diabetes. He noted the “lower denominator” of CVD events in women without diabetes, noting that this automatically confers a higher incidence ratio. Professor Sattar reviewed several studies showing this is the case, including one nationwide registry study in Denmark which found that the rates of MACE-HF was 7.0/1000 person years in women without diabetes and 10.1/1000 person years in men without diabetes, which increased to 19.9 and 24.9 in women and men with diabetes, respectively. Even though this data demonstrates that the number of events was greater in men, the increase corresponds to a 2.8-fold relative increase for women compared to a 2.5-fold increase for men. Professor Sattar also highlighted that there are more men with type 2 diabetes and that these men often have worse glycemic control at diagnosis. Another one of Professor Sattar’s salient points was that to develop diabetes, women have to “travel more distance” from baseline to diagnosis threshold, suggesting that women often have higher weight and further progression of disease at diagnosis ultimately increasing women’s risk of CVD.
  • Professor Sattar argued that there must be greater diabetes risk prevention for men, and that they should be encouraged to take their health more seriously. He noted that despite having higher cardiovascular risk and higher diabetes prevalence, less men are utilizing primary care and prevention programs, which contributes to their overall absolute risk. He argued that improving outreach to men for prevention should be a primary target of diabetes care, citing the need for “better public messaging” to talk with men about their healthy lifestyle. Interestingly, Dr. Bairey Merz has been able to use the fact that women interact more with the health care system, often for reproductive health issues, to her advantage. In her practice, she is working with OB/GYNs and family medicine providers to do more screening for diabetes in women, as these are often women’s most frequent touch points with the healthcare system.
  • Dr. Bairey Merz argued that SGLT-2s and GLP-1s are “not going to be miracles” any time soon, advocating for increased use of statins in the meantime. Dr. Bairey Merz stated, “Right now, the best thing you can do for an adult with diabetes is to put them on a statin.” We were surprised to hear this, especially in light of recent data on SGLT-2s and GLP-1s which continue to demonstrate sizable improvements in glycemic control, not to mention strong cardiorenal and weight loss effects. During Q&A, Dr. Bairey Merz argued in favor of the incontrovertible evidence for statins, citing the 10-year and lifetime risk reductions associated with their use. She noted that right now, SGLT-2s and GLP-1s are simply too expensive and most primary care providers don’t have the ability to get them authorized. As such, she suggested that the primary use at present will be in the hands of specialists and the highest risk patients. Professor Sattar concurred, noting that it is “brilliant” to have these new tools, but that there also needs to be better utilization of “old tools.”

Inside CKD model suggests screening for UACR could prevent close to 250,000 cases of CKD in US and UK in the next 5 years

In this presentation, Dr. Albert Power (North Bristol NHS Trust, Bristol, UK) outlined the enormous economic burden that chronic kidney disease imposes on countries around the world. Using a country-specific, patient-level microsimulation model called Inside CKD, Dr. Power assessed the epidemiologic impact of chronic kidney disease. Inside CKD is built from virtual populations constructed based on published country-specific data of demographics, chronic kidney disease, type 2 diabetes, chronic kidney disease, comorbidities and complications. Specifically, Inside CKD models the implementation of routine urine albumin creatinine ratio (UACR) screening at routine primary care visits in adults greater than 45 years old and the effect of the subsequent pharmacotherapeutic interventions when screening detects abnormalities. The model compares a baseline scenario from current clinical practice patterns to the ideal scenario with routine UACR screening and updates the albuminuria and eGFR status of the virtual population as the simulation progresses over the five-year period.

  • The model assessed preliminary data from the United States and the United Kingdom from 2021 to 2026. Over the course of the 5-year period, the model predicts that UACR screening would prevent nearly 207,428 patients in the US and 32,486 patients in the UK from progression to stages 3b-5 of CKD. The correlates to significant reductions projected cases of heart failure, myocardial infarction, and stroke. Though no explicit cost-savings were made in the presentation, Dr. Power suggested that reductions in CKD will lead to significantly reduced healthcare costs. In Q&A, he argued that the primary avenues of cost-savings will come through the avoidance of renal replacement therapy, as well as reductions of hospitalizations and associated non-kidney events, predominantly cardiovascular events.

  • There are several key assumptions the model makes, which may not translate directly into the real world. The model estimates the eGFR slope based on clinical characteristics and comorbidity status, which of course varies at the individual level. Moreover, the model assumes a 100% chance of agreeing to be screened for albuminuria, and that 100% of individuals will be receive guideline-directed therapy – in this case, RAASi therapy – if they have tested positive for CKD and have a UACR ≥300 mg/g, hypertension, or diabetes with a UACR of 30-300 mg/g.
    • One of the limitations of the study, as pointed out by Dr. Power, is that the model doesn’t account for any major changes in the management of CKD over the projection period, which may not be entirely accurate given the tremendous benefits of SGLT-2 inhibitors in recent years, which have been shown to improve kidney outcomes. Recall that in April, dapagliflozin received FDA approval for the treatment of chronic kidney disease in patients with and without diabetes, and has since been approved in Europe and Japan. Also in the pipeline, the EMPA-KIDNEY trial is expected to complete in June 2022. Empagliflozin has already received a Fast Track Designation from the FDA. Likewise, J&J’s Invokana received FDA approval for the treatment of diabetic kidney disease in September 2019.
  • As an aside, we’ve recently heard much greater discussion of UACR as an important biomarker for kidney disease. In fact, at HiD 2021, Dr. Rajiv Agarwal emphasized that UACR should be included with eGFR as the primary metric for measuring chronic kidney disease – although many know this, some are still skeptical since eGFR is often discussed and UACR has often been unknown to people with diabetes themselves, in particular. dQ&A has more information on this front – for more information there, write to rwood@d-qa.com and/or info@d-qa.com.  It is very useful that Mr. Power used the UACR as the measure of chronic kidney disease, and points to the ability of the UACR metric to detect the early stages of CKD. These data make a strong case for prevention and the massive effect a simple screening program can have on patient outcomes and healthcare costs.

African-Caribbean individuals with type 1 are 1.43x more likely to develop retinopathy in London study (n=1,876); Findings from Scotland show that disparities in type 2 prevalence have widened in past 14 years

In an afternoon session, Dr. Anastasios Mangelis (King’s College London) and Mr. Jack Wang (5th-year medical school at University of Edinburgh) shared their short oral presentations on the topic of disparities and diversity in diabetes. First, Dr. Mangelis explained that patients with type 1 diabetes in East London who are of African-Caribbean descent are at significantly greater risk for developing sight-threatening diabetic retinopathy than their non-African-Caribbean counterparts. His study drew from clinical and digital retinal imaging data from 1,876 people (50% male, 72.3% Caucasian, 17.4% African-Caribbean, and 10.3% other) with type 1 diabetes, as documented by the primary care records of those who attended diabetes eye screening in Southeast London. The median duration of follow up was six years, and patients did not have retinopathy at baseline.

  • Of patients who developed sight-threatening diabetic retinopathy after six years, 24% were African-Caribbean; in contrast, people of African-Caribbean descent made up only 16% of those who did not progress to sight-threatening diabetic retinopathy. Based on Dr. Mangelis’s analysis, at 14 years of follow up, patients in the African-Caribbean group with type 1 diabetes had a 60% chance of developing sight-threatening diabetic retinopathy, compared to only a 40% chance for patients of non-African-Caribbean ethnicities. Indeed, Dr. Mangelis calculated that African-Caribbean individuals in the sample were 1.43 times more likely to develop sight-threatening diabetic retinopathy than their other-race counterparts (p<0.05). Given this data, we are curious what factors, either social, environmental, structural, or epigenetic may account for these disparities. We also find this study particularly striking given its focus on development of complications as they relate to type 1 diabetes - much of the data on Black populations and health disparities focuses on type 2.

*Note that the graph above shows survival probability, meaning the percentages (40% and 60% for African-Caribbean and Other groups at 14 year follow up) refer to the likelihood that they will not develop sight-threatening diabetic retinopathy

  • Mr. Wang presented on the prevalence of type 2 diabetes in Scotland, which he explained varies by age, sex, and socio-economic deprivation.  Indeed, his group used a February 2021 extract of the Scottish electronic population-based register of diagnosed diabetes and mid-year population estimates for 2019 to estimate diabetes prevalence for patients between the ages of 35 and 84 (n= 255, 764). Overall prevalence in this age group increased to 8.3% in 2021, compared to 7.3% in 2007, which was the last time a similar analysis was conducted. Mr. Wang then generated data on age-standardized prevalence of type 2 diabetes by sex and quintiles based by socioeconomic status, which was scored according to the Scottish Index of Multiple Deprivation. Sex-specific relative risks for age-standardized diabetes prevalence for the lowest and highest quartiles were estimated. Ultimately, the review found that diabetes prevalence remains higher in men than women, in older than younger people, and in those who experiencing higher levels of social deprivation. The results also indicated that age standardized prevalence was higher for men than for women for all social deprivation quintiles and was inversely associated with socio-economic status. Indeed, from 2007 to 2021, the relative risks for age-standardized diabetes prevalence for Q1 compared to Q5 have increased from 2 to 2.5 for women, and from 1.6 to 1.9 for men.

 

Data from Swedish National Registry (n=36, 303) shows that prior CVD, prior HF, and CKD increase risk for all-cause mortality for patients with type 1 (HR = 1.91, 1.92, and 1.47, respectively)

In an afternoon session, Dr. Lovisa Lyngfelt (Institute of Medicine, Göteborg, Sweden) presented real-world evidence on the relationship between cardiovascular disease (CVD), heart failure (HF), chronic kidney disease (CKD) and the risk of mortality for patients with type 1 diabetes in the Swedish national diabetes registry (n=36, 303). In Dr. Lyngfelt’s study, cumulative mortality was described using Kaplan-Meier curves and was evaluated for association to previous CVD, prior HF, and CKD. Data from January 2015 to December 2017 were analyzed, and a total of 1127 patients died during this period, with an observed crude total mortality rate of 0.92 deaths per person-year. Notably, this study defined type 1 diabetes as use of insulin under the age of 30, which may not be entirely accurate given the increasing rate of childhood and youth onset type 2 diabetes.

  • Dr. Lyngfelt and her colleagues found that for patients with type 1 diabetes, a previous history of CVD, HF, and CKD were all associated with an increased risk in death (see the table below). Indeed, 18% of patients with a prior diagnosis of CVD died, whereas only 1.7% of those without CVD died during the two year period. 31% of those with prior heart failure died, compared to 2.4% of those who did not have previous HF. Moreover, Dr. Lyngfelt reported that mortality increased with progression of CKD, from moderate (eGFR= 60-90) to high (eGFR= 30-59) to very high (eGFR<30). As CKD became more severe, mortality rates increased from 6% to 13% to 23%, respectively. This is compared to a baseline mortality rate of 2% among those with no CKD (eGFR>90).

Risk Factor

Hazard Ratio (95% CI) for All-Cause Mortality

Prior CVD

1.91 (1.66-2.20)

Prior HF

1.92 (1.66-2.23)

Impaired Kidney Function: moderate, high, and very high CKD stages, respectively

1.47 (1.19-1.80); 2.78 (2.11-3.66); 3.80 (2.80- 5.16)

  • Importantly, a combination of these three risk factors caused a 10-fold increase in all-cause mortality. This is shown in the chart below, which shows cumulative mortality for people with T1D and varying degrees of CKD, with and without previous CVD and HF. Moving left to right in the top row, the graph shows the increase in cumulative mortality at each stage of CKD. The upper and lower levels of the chart compare the relative risks with no prior CVD vs prior CVD, and show that prior CVD increases risk for mortality at all stages of CKD. Finally, comparing the blue to the orange line reveals that patients with previous record of HF (orange) have higher risk of mortality at every stage compared to those who have no record of HF (blue). The bottommost, righthand graph describes the associated risk for a combination of all three risk factors, which results in a 57% mortality rate. While shockingly high, Dr. Lyngfelt is careful to note that this is the rate for patients who died within the two-year study period, which totaled 1,127 people out of the 36,303-person cohort and thus describes a somewhat biased cohort.

Swedish real-world study reveals that established CVD in type 2 diabetes is associated with excess mortality, hospital spending, and days absent from work

During a session on the epidemiology of diabetes complications, Ms. Sofie Persson (Lund University, Sweden) presented an abstract on the burden of established CVD in type 2 diabetes at the societal and economic level. The retrospective analysis examined Swedish national population register data from 455,000 people with type 2 diabetes and 2,126,000 matched controls from 2007 to 2016. When adjusted for age, sex, and educational level, participants with type 2 diabetes and established CVD (n=136,000) had a four-fold increased risk of death compared to their type 2 counterparts without established CVD. Beyond the excess mortality risk, established CVD was also linked to greater hospital-based care costs for diabetes complications. The mean annual hospital spending for diabetes complications amounted to €2,758 ($3,180 USD) per person. A whopping 89% of hospital spending was attributed to those with established CVD, driven primarily by acute MI, angina pectoris, and stroke. Ms. Persson noted that end-stage renal disease and eye disease also contributed substantially, which suggests that established CVD is associated with an increased burden from other complications. On average, people with type 2 diabetes cumulatively had 146 days absent from work, of which nearly half (47%) were attributed to established CVD. The total annual cost of work absences due to established CVD amounted to €9,337 per person ($10,766 USD). The excess mortality, outsized hospitalspending, and lost productivity among people with type 2 diabetes and established CVD clearly poses an enormous burden to both individuals and society. The high costs identified in this real-world study suggest that early initiation of cardioprotective treatment is a crucial step to reduce hospital spending and days absent from work for those with type 2 diabetes. While there is ample evidence showing that SGLT-2s confer strong cardioprotection and renal protection, use of these and other guideline-directed therapies remains concerningly low. Since uptake of these agents remains a challenge, we’d press for more research into translation of guidelines into practice.

  • During the ten-year study period, 30% of participants with diabetes were observed with established CVD, which was defined as any registration of the any of the following five conditions: coronary artery disease, stroke, amputation, peripheral vascular disease, or non-fatal cardiac arrest. No demographic information was shared, but Dr. Persson explained that the cohort was on the younger side to include those participating in the labor market. While the numbers presented in this analysis are quite staggering, Ms. Persson speculated that studies of older cohorts might yield even greater hospital spending estimates. Given that nine out of every ten Euros spent on diabetes complications are linked to CVD, there is a clear need for earlier prevention, diagnosis, and treatment of cardiovascular-specific complications in patients with type 2.

Systematic review finds substantial heterogeneity in associations between weight loss and CVD among people with diabetes; Dr. Jean Strelitz calls for longer-term, intentional studies to assess impact of intentional weight loss on CVD and mortality risk

Dr. Jean Strelitz (University of Cambridge, UK) presented the results of a systematic review of observational studies and trials assessing the impact of weight loss on CVD events and mortality in people with type 2 diabetes (SO 264). The review aimed to assess the association between weight loss and CVD events and mortality to better understand the impact of intervention-driven weight loss on CVD events and mortality. Based on an initial search of 13,227 titles, the systemic review included 14 observational studies and three trials of behavioral interventions targeting weight loss. Studies assessing pharmaceutical interventions or bariatric surgery were excluded. Overall, the systematic review’s findings were unconclusive, signaling the need for further investigation to assess the long-term impact of weight loss of CVD and mortality in people with diabetes, as well as the need to understand how much weight loss should be achieved to see cardiovascular and mortality risk benefits.

  • The meta-analysis of the three trials assessing behavioral interventions that targeted weight loss found that the intentional weight loss was not associated with a significant change in CVD events. Of the three trials, only one saw a small significant reduction in CVD events with intervention-driven weight loss, while the other two saw a large range of associations with wide confidence intervals. Dr. Strelitz argued that the short duration of the studies (five to ten years of follow-up) may not be sufficient to detect associations with CVD events, which may see benefits at fifteen to twenty years (a similar argument was made in the evidence report for the consensus statement on diabetes screening and behavioral interventions in August).

  • The results of observational studies were highly variable. Some saw increased mortality and CVD with weight loss, some saw decreased CVD events and mortality with weight loss, and others saw no significant change. Dr. Strelitz suggested that the results likely differed due to differences study duration, baseline CVD risk, and the inclusion or exclusion of unintentional weight loss. This makes it challenging to draw conclusions about the benefits and risks of weight loss on CVD events and mortality. That said, weight gain was consistently associated with higher risk of CVD events and all-cause mortality, suggesting that at the bare minimum, weight gain should be avoided to prevent further increasing the risk of CVD and mortality.

Young-onset diabetes (<40 years old at T2D diagnosis) increases odds of retinopathy by 89% relative to those diagnosed at ages 60+ even when adjusted for diabetes duration, sex, age, A1c, blood pressure, and cholesterol

In an intriguing oral session, Dr. Katrina Tibballs (University of Oslo, Norway) presented data from the ROSA 4 Study, which estimated the prevalence of young-onset diabetes (YOD) in Norway and studied the relationship between age at diagnosis, duration of type 2 diabetes, and rates of macro- and microvascular complications (OP 47). For this study, young-onset diabetes (different from youth-onset diabetes) was defined as a type 2 diabetes diagnosis between the ages of 18 and 40 years. While we know that individuals with youth-onset type 2 diabetes face rapid accumulation of diabetes-related complications after diagnosis, this study is unique in that it elucidates outcomes for those diagnosed earlier than average, but still in their adult life. Dr. Tibballs and her team drew on a cross-sectional primary care dataset from emergency medical records in Norway in 2015, which pooled data from 10,242 Norwegian individuals with type 2 diabetes. The primary outcome of the study was retinopathy. In the sample, 10.2% (n=980) of the total study participants were <40 years old when diagnosed with type 2 diabetes. Among those diagnosed before age 40 (those with young-onset diabetes), the average age of onset was 33 years old. Overall, the study found a strong association between the age at diagnosis of type 2 diabetes and retinopathy. The study also found that retinopathy prevalence is higher in YOD despite more intensive glucose-lowering treatment and that excess retinopathy in YOD is mediated by higher A1c and longer diabetes duration.

  • The risk of developing retinopathy was nearly four times higher in the YOD group compared to those diagnosed at 60 years of age or more (OR=3.87). Although the prevalence of retinopathy is duration-dependent with those having diabetes for longer at higher risk for developing retinopathy, the rate of retinopathy development was much faster in YOD group, with the prevalence of retinopathy much higher in those with YOD five years after diagnosis than in those who have had diabetes for five years but were diagnosed at age 41+ (see below). Notably, Dr. Tibballs explained that men with YOD are at higher risk of retinopathy than women: men have a relative prevalence of 40% after 13-14 years of diabetes compared to ~22% for women during this same time period (and men are consistently higher across all diabetes durations). After adjustment for diabetes duration, sex, highest education level, A1c, systolic blood pressure, and LDL cholesterol, retinopathy still shows a strong association with age of diagnosis of type 2 diabetes (OR=1.89 for YOD vs. those diagnosed at ages 60+).

  • Those with YOD also had a higher A1c despite a higher proportion being treated with insulin and glucose-lowering medications. The average A1c for the YOD population was 7.6%, compared to 7.3% for those diagnosed with T2D between 40-49 years of age, and 6.9% for those diagnosed 50 years and above. This is true even though 35% of those with YOD take insulin and 75% are on other glucose-lowering agents. Notably, in the YOD group, A1c showed a greater increase with age and diabetes duration. Among those with YOD, the relationship between A1c and diabetes duration was stronger in men relative to women, though for both groups, A1c increased as diabetes duration increased.

REVEAL-CKD analysis finds 49% undiagnosed CKD among US patients with type 2 diabetes, higher prevalence of undiagnosed CKD among women and older patients (n=76,494)

Dr. Eric Wittbrodt (AstraZeneca) presented an analysis of the REVEAL-CKD observational study assessing the prevalence of undiagnosed CKD. The present analysis examined data from over 76,000 US commercially insured patients who fulfilled the KDIGO criteria of having received two consecutive eGFR values indicating stage 3 CKD (eGFR ≥30 mL/min/1.732 and <60 mL/min/1.732). Overall prevalence of undiagnosed CKD was 49%, consistent with findings from a 2019 Janssen observation study. Dr. Wittbrodt highlighted that the prevalence of undiagnosed CKD was higher in women than in men and increased with age. Approximately 57% of CKD stage 3 cases in women with type 2 diabetes were diagnosed, compared to approximately 42% of cases in men with type 2. The overall proportion of undiagnosed CKD in patients ≥65 years was 51%, nearly double the proportion in patients <45 years in TriNetX (28%) and dramatically higher than that in LCED (37%). Dr. Wittbrodt noted that rates of undiagnosed CKD were lower in patients with comorbid conditions, which we’d presume stems from the fact that these patients are likely to have more frequent interactions with the healthcare system and therefore more opportunities for CKD screening. Dr. Wittbrodt concluded that the results from this large, retrospective analysis suggest a need for more proactive diagnosis and monitoring of patients at earlier stages.

  • REVEAL-CKD examined data from the TriNetX and LCED databases, where patients had a mean age of 70 years and approximately 50% were female. Criteria for undiagnosed CKD included having two stage 3 eGFR values (between three months and two years of each other) without receiving a corresponding diagnostic code at any time before and up to six months after the second eGFR measurement. Given that the rates of undiagnosed CKD were consistent across both the TriNetX and LCED cohorts, as well as the 2019 Janssen study, we’d advocate for more patient and provider education on the importance of eGFR and UACR testing. In particular, we’d imagine that targeted screening for women and older patients is likely to be helpful in improving diagnosis rates. As Dr. Wittbrodt noted in the Q&A, frequency of eGFR screening is quite variable and can be affected by a patient’s access to care, insurance coverage, health literacy, and more. Ultimately, we’re glad to see more attention to the high rates of CKD underdiagnosis through the REVEAL-CKD trial and we look forward to future translational studies to examine potential solutions.

European Diabetes Forum symposium: emphasis on actionable data from health registries; call for formation of EU Diabetes Registry; WHO global 2030 diabetes targets

In the European Diabetes Forum’s (EUDF) symposium, speakers approached the topic of acting on health-related data from different vantage points that collectively revealed it will take more than just data registries to improve diabetes-related outcomes. Dr. David R. Matthews (University of Oxford, UK) chaired the two-hour session, kicking off with an introduction in which he argued that key healthcare and industry stakeholders must rework diabetes care delivery to optimize diagnosis, treatment, and management. Specifically, he explained that there is a great necessity for an integrated, honest, and global view of diabetes and its implications, and this unmet need can be met through registries, but only if: (i) we organize all stakeholders; (ii) we align on realistic priorities and urgencies; (iii) we agree on a unified vision; and (iv) we achieve impactful policy-level changes . Dr. Matthews shared that “data & registries” is one of EUDF’s three strategic forums, along with “self-care, technology digitization” and “integrated care.” By offering specific policy recommendations on the use of health data and registries, Dr. Matthews explained that EUDF hopes to “unlock the full potential of health data” and improve long-term outcomes in diabetes. We certainly agree that measuring and comparing diabetes outcomes at the population level while identifying variation and its causes will reveal where outcomes are unoptimized or under-optimized and help providers deliver targeted interventions to improve population level care.

  • Dr. Robert Heine, PhD (Chair, EUDF Strategic Forum Data & Registries) called for a pan-European diabetes registry while cautioning that stakeholders must “buy-in” for it to deliver better health outcomes. Dr. Heine explained that the European diabetes registry could be an important step in improving European diabetes care for several reasons: (i) it could standardize indicators for continuous benchmarking because at present the heterogeneity of EU health registers does not allow for cross-border data interoperability; (ii) it could improve and harmonize diabetes care throughout Europe, understanding that registries help organize and govern health data at local, regional, and national levels; (iii) it could monitor and support EU policies on diabetes; and perhaps most interestingly (iv) it would respect the law – as it stands, an existing EU Parliament Resolution calls on the Commission to “coordinate, register, monitor, and manage comprehensive epidemiological data on diabetes, and economic data on the direct and indirect costs of diabetes prevention and management.” Dr. Heine argued that a European Diabetes Registry is a concerted effort that will fulfill this resolution.
    • In support of the EU Diabetes Registry, Dr. Heine invoked Hong Kong’s Diabetes Register, and shared data showing that its introduction coincided with improved microvascular and macrovascular outcomes. Referencing Wu et al.’s 2020 study (n=390,071 men, n=380,007 women) titled “Trends in diabetes-related complications in Hong Kong, 2001–2016: a retrospective cohort study” from Cardiovascular Diabetology, Dr. Heine showed that the event-rates of complications between 2001-2016 decreased substantially after the Registry was created in 1995.
    • Dr. Heine ended with a rousing call to action. With no frills, he left a list of action items: (i) develop the right procedures and governance models for registries; (ii) engage stakeholders in diabetes; (iii) automatically collect data; and (iv) link diabetes registries to other registries and make them future proof.

  • Dr. Andrzej Rys (European Commission) gave a useful summary of the European health data space, explaining that interoperability can enable primary applications of data in healthcare, and secondary applications in its re-use. He summarized the learnings from his talk in a useful table, which we’ve repurposed below.

 

Use of data for healthcare (primary)

Re-use of data (secondary)

 

Sharing of health data for healthcare

Single market for digital health products and services

Access to health data for research, innovation, public health policy making,

AI

Problems

-Limited control of patients over their health data

-Limited interoperability between HCPs

-Uneven national legislative frameworks

-Uneven quality framework

-Uneven procedures for prescriptions, reimbursement, liability

-Low re-use of health data

-Cumbersome cross-border access to health data

-Fragmented digital infrastructures

-Limited provision of data for training of AI

-Difficulties for regulators to evaluate AI algorithms

-Uncertainty on AI liability in health

Areas of Work

-Control of patients over their data

-Interoperability

-Role of e-health agencies

-Reinforced EU governance (eHealth Network)

-Reinforced MyHealth@EU

-Eliminate barriers to free movement

-Labelling

-Interoperability

-Reimbursement

-Liability

-Governance and rules for access to health data

-Data FAIRification

-Digital infrastructure (EHDS2)

-Support for development and rollout of AI

-Data for AI

-Support for regulators

  • Representing the Non-Communicable Disease (NCD) arm of the World Health Organization, Dr. Bente Mikkelsen (Director, NCD, WHO) advocated for global health targets that ensure all people with diabetes have equitable access to care. Dr. Mikkselsen explained that there are several factors motivating the WHO’s focus on diabetes, including: (i) the alarming rise in number of people with diabetes; (ii) insufficient preventative measures; (iii) lack of diagnosis and treatment; (iv) lack of access to therapies and technologies; and (v) lack of access to PCPs. The propensity to tackle the diabetes epidemic was so strong, that at the 74th World Health Assembly, there was an explicit ask for the Director-General of the WHO to “develop pathways of how to achieve the targets for the prevention and control of diabetes” while providing “support for strengthening diabetes monitoring and surveillance.”
    • Dr. Mikkelsen presented five global coverage targets, listed in the report, to be achieved by 2030: (i) 80% of people with diabetes are diagnosed; (ii) 80% of people with diagnosed diabetes have good control of glycemia; (iii) 80% of people with diagnosed diabetes have good control of blood pressure; (iv) 60% of people with diabetes receive statins; and (v) 100% of people with type 1 diabetes have access to insulin and SMBG. While these targets are certainly ambitious, Dr. Mikkelsen explained that they are necessary to fulfill the vision of the WHO’s Global Diabetes Compact. She concluded by listing seven action areas and key milestones (pictured below) for the WHO as they proceed in completing this goal.

Two RCTs show 40% reduction in “diabetes relapse” with intensive, 12-week interventions of insulin glargine, metformin, and a DPP-4 or GLP-1 in combination with lifestyle changes

In a session on interactions of the digestive system and glucose metabolism, we were struck by two abstracts on non-surgical approaches to achieve remission of type 2 diabetes. Dr. Hertzel Gerstein (McMaster University, Hamilton, Canada) gave an energetic presentation on the results of the REMIT-sita study of a 12-week intervention with insulin glargine, metformin/sitagliptin, and lifestyle changes (n=102). Participants in the intensive treatment group showed a 38% risk reduction in relapse compared to the control group over one-year of follow-up, though this relapse occurred without normalization of glucose tolerance. Based on our understanding of the study, “relapse” was used to describe a patient’s risk of not achieving type 2 diabetes remission meaning a risk reduction in relapse was indicative of a higher chance of achieving remission for patients in the intensive treatment group. Dr. Natalia McInnes (McMaster) presented the results of the REMIT-iGlarLixi trial analyzing 12-week treatment with fixed-ratio insulin glargine/lixisenatide, metformin, and lifestyle approaches (n=160). This study found a 43% risk reduction in relapse in the intervention vs. control group at 24 and 36 weeks, but not at 48 and 64 weeks. Taken together, these findings suggest that brief treatment with insulin glargine, metformin, and a DPP-4 or GLP-1, in combination with targeted lifestyle modifications, can lead to remission of type 2 diabetes, at least in the short-term. To date, relatively few studies have investigated non-surgical approaches to remission, though the field appears to be gaining traction. Recently, we’ve seen compelling evidence for reversion to normoglycemia for those with prediabetes with semaglutide, as well as with Virta’s low-carb, continuous remote care intervention. While the remission documented in REMIT-sita and REMIT-iGlarLixi appears to align with the latest consensus report’s definition of remission in type 2 diabetes, it is unclear whether this remission lasts beyond one year. Likewise, the failure to achieve normalization of glucose tolerance in REMIT-sita raises questions about the extent to which glycemic control was restored. Given that metabolic surgery is quite invasive and costly, we are happy to see investigation into simpler and more cost-effective approaches. We were excited to hear Dr. Gerstein boldly assert that “remission is the future of type 2 diabetes” and we look forward to more comprehensive studies in this field.

  • Both studies used a similar methodological approach and employed the same definition of remission. Adults newly diagnosed with type 2 diabetes were randomized to either intensive treatment with combination pharmacotherapy and frequent lifestyle intervention or standard of care. After randomization, participants with A1c <7.3% at 12 weeks were asked to stop diabetes medications and were followed for one year with A1c measured at 24, 36, 48, and 64 weeks. The REMIT-sita study also included fasting plasma glucose tests at 16 weeks and oral glucose tolerance tests at 24 weeks. Both studies examined the primary endpoint of time to diabetes relapse, defined as meeting one of the following criteria: (i) re-initiation of diabetes medications; (ii) A1c ≥6.5%; or (iii) ≥50% of capillary glucose levels ≥10 mmol/l over one week. These criteria appear to align with those laid out in the latest consensus report on the definition of remission in type 2 diabetes, which defines remission as achieving an A1c <6.5% for at least three months without the use of glucose lowering drugs.
    • Baseline characteristics were similar in REMIT-sita and REMIT-iGlarLixi, with good baseline glycemic control (average A1c 6.6% and 6.8%, respectively), an average age of 56 years, and an average diabetes duration of two years. The REMIT-sita cohort was somewhat diverse, with approximately 45% of participants identifying as white (n=102). REMIT-iGlarLixi was relatively male-skewed, with 30% and 40% of female patients in the intervention and control groups, respectively (n=160). While both RCTs were fairly small, we are encouraged by the preliminary results and hope to see larger, more diverse trials of non-surgical remission for type 2 patients in the future.

  • Speculating on the impact of diabetes duration and intervention duration, Dr. Gerstein stated his belief that a brief intervention of just three to six months is necessary for remission. Excitingly, Dr. McInnes added that such an intervention may be sufficient even in patients who have had diabetes for many years. She pointed to a similar RCT of 12-week intensive treatment with metformin, insulin glargine, and dapagliflozin that found that people who had up to eight years of diabetes duration were able to respond to the intervention. That a relatively simple, short-term intervention is sufficient to achieve remission of type 2 diabetes is quite exciting, though we’d certainly like to see longer-term trials in a broader population to validate these findings. 

Twelve-month RCT (n=216) shows high frequency (10 kHz) spinal cord stimulation is safe and effective in treating painful diabetic neuropathy; 86% participants in treatment arm report >50% pain reduction at six months

Dr. Erika Peterson (University of Arkansas) presented findings from a 12-month, multicenter RCT comparing high-frequency spinal cord stimulation (SCS) to conventional medical management (CMM) in patients with painful diabetic neuropathy (n=216). As a reminder, Dr. Peterson presented three-month results from this same study at EASD 2020, where SCS was shown to be a safe and effective treatment regimen that improves quality of life for individuals with painful diabetic neuropathy. Six-month data from this study are also already published in JAMA Neurology, with a paper on the 12-month results forthcoming. This RCT investigated the differential impact of SCS on perceived pain, neurological foot function, dysesthesia severity, and quality of life outcomes in patients with diabetes (95% type 2s, mean age 61, 63% male, 80% White). Patients were randomized to either CMM (n=103) or CMM with 10 kHz SCS (n=113), with an optional crossover at six months. SCS is conducted via a small device implanted near the lower spine through a minimally invasive, non-pharmacological, reversible process. Notably, it is not a novel pain treatment: SCS has been proven safe and effective and has been used as a treatment for chronic pain for 50 years. More recently, high frequency (10 kHz) SCS has been shown to be effective and superior to low frequency SCS for back and leg pain based on two-year RCT data (Kapural et al. 2016), and preliminary prospective data suggests that it is effective in reducing pain related to painful diabetic neuropathy (Galan et al. 2020).

  • The cohort receiving 10 kHz SCS had significantly higher pain relief at six and 12 months compared to baseline and compared to the conventional care arm. In the intervention arm, 86% of participants experienced a >50% pain reduction after six months of SCS, and this result was maintained through the 12-month mark. In contrast, 0% of the control arm reported an >50% reduction in pain at six months. However, for patients in the control arm who chose to receive the intervention in a 12-month follow-up, 84% reported an ≥50% pain reduction after initiation of the to 10 kHz SCS therapy. Likewise, the intervention arm saw a significant reduction in their visual analog scale pain score from 7.2 at baseline to 2.4 at month one and 1.7 at month three. Meanwhile, the conventional care arm saw no significant change in their visual analog pain score (7.6 at baseline vs. 7.4 at 6 months) until crossover to 10 kHz SCS, at which point these patients immediately experienced a significant decline in visual analog pain scale scores and maintained this decrease through the 12-month endpoint.
  • 68% of participants in the high frequency SCS group had improved neurological functioning compared to baseline at 12 months. Comparatively, 0% of patients in the conventional medical management arm had better neurological functioning after six months, which improved to 62% at 12-months after crossover.
  • Participants reported a significant reduction in dysesthesias at six months. Through patient-reported surveys, the investigators created summative anatomic heat maps showing the extent to which patients experienced numbness (n=54), tingling (n=32), burning (n=27), or coldness (n=21). These maps, shown below, reflect a significant decrease in the severity of these dysesthesias in those treated with 10 kHz SCS at six months.

  • In all quality-of-life metrics, the high frequency SCS group saw improvements relative to baseline and relative to the control group, which saw no significant change in any metric compared to baseline until crossover at six months. Importantly, these improvements in quality-of-life were accompanied with no change in glycemic control, as A1c did not change through the conclusion of the study in either cohort. Furthermore, among patients with permanent SCS device implants (n=154), no stimulation induced neurological deficits occured, and infection was the most frequently occurring study-related adverse event – affecting a total of 8 patients (or 5.2% of those with implants). This result is consistent with the literature values, which point to a 2.5%-10% range of infection rates for SCS procedures (Eldabe et al. 2016).

12-month prospective observational study (n=256) finds 0.42% incidence of diabetic foot ulcers in Catalonian primary care clinics

On behalf of the GEDAPS Diabetic Foot Study Group, Dr. Judit Llussà Arboix (Primary Health Care Center Sant Roc, Badalona, Spain) presented data from an observational prospective study assessing the incidence of diabetic foot ulcers in primary care centers. Notably, Dr. Arboix shared that this study is, to her knowledge, the first study of its kind tracking foot-related complications in primary care settings. Dr. Arboix stressed that diabetes related lower extremity complications are the leading cause of amputation in developing countries, with “one lower limb lost because of diabetes every 30 seconds” globally. Given that 80% of diabetes related amputations are preceded by ulceration, Dr. Arboix stressed the importance of primary care to provide: (i) early diagnosis of ulcers through careful evaluation; (ii) personalized treatment to prevent ulcer progression; and (iii) referral to specialists who can “save legs, and lives.” Dr. Arboix then introduced the GEDAPS group’s observational field study (n=256), which was published in Primary Care Diabetes and was conducted across 36 primary care centers (25 urban and 11 rural) in Catalonia, Spain. The aim of the study was to assess the incidence of diabetic foot ulcers in people with type 2 diabetes and to clarify any characteristics of the patients who had ulcers. For reference, Catalonia’s population of just over 500,000 has a 9.4% prevalence of type 2 diabetes. Participants >18 years old and with type 2 diabetes were enrolled if they had a new active foot ulcer during a clinic visit.

  • During the 12-month recruitment period, the incidence of new diabetic foot ulcers was 0.42%. Most ulcers were on the toes and were superficial. Of those who presented with a new ulcer, the most common associated risk factors were hypertension (81%), hyperlipidemia (69%), and obesity (43%), and the most common complications were peripheral arterial disease (65%), peripheral neuropathy (65%), and kidney disease (58%). Just over 50% of those diagnosed with ulcers were insulin-treated, and 41% were on oral medications. While the overall incidence of diabetic foot ulcers was 0.42%, it was lower in urban centers compared to rural centers (0.35% and 0.7%, respectively). The investigators also monitored the prognosis and outcomes from participants during a 12-month follow-up period, the results of which are forthcoming.

DIATEMP RCT (n=304) finds lower associated costs with thermometric foot-monitoring (€6,067) compared to usual care (€7,376) in preventing diabetic foot ulcer recurrence, at expense of QoL

Dr. Jaap van Netten, PhD (Academic Medical Center, Amsterdam) shared data from the DIATEMP trial showing that at-home foot monitoring is cost-effective in preventing diabetic foot ulcer (DFU) recurrence but reduces quality of life. As an introduction to his presentation, Dr. van Netten explained that most prior research studies on the cost-effectiveness of DFUs did not collect data to inform the analysis but instead used Markov models that were based on existing information, which might introduce high degrees of bias. Of the three studies Dr. van Netten could find that did collect original data as a part of their protocols, none of them used a “societal perspective,” considering the benefits at the population-level. Dr. van Netten explained that the lack of adequate research on this project is largely what motivated the DIATEMP trial, a multicenter, 18-month RCT (n=304) studying the cost-effectiveness and cost-utility of at-home foot skin temperature monitoring for the prevention of DFUs from a societal perspective. Participants were randomized to either receive usual care (with podiatric treatment, education, and therapeutic footwear) or “enhanced care” (i.e., usual care plus measuring skin temperatures at six to eight plantar sites per foot each day). The primary outcomes in this study were cost-effectiveness (“the proportion of participants with ulcer recurrence”) and cost-utility (“quality-adjusted life years (QALY) during the 18-month study”).

  • During the 18-month study, total foot care costs in the enhanced care group were lower than those in the usual care group (€6,067 vs. €7,376, respectively); however, this difference was not significant (p=0.450). Furthermore, enhanced care was more effective than usual care as measured by incidence of ulcer recurrence, which were 36% and 47%, respectively. During a separate conversation with Dr. van Netten, we learned that this estimate was gathered from the most conservative imputation strategy to avoid over-interpreting the findings. Currently, Dr. van Netten and his group are working on a journal publication that will publish the results of all data imputation strategies and have additional commentary on both the statistical and economic significance of the findings. We’ll be watching to see if alternative imputation strategies see significance in the total foot care costs.
  • While trending toward cheaper, enhanced therapy was accompanied with a trend toward lower quality of life. Participants in the enhanced care group, on average, had 1.09 quality-adjusted life years vs. 1.12 in the usual care group (p=0.35). Dr. van Netten attributed this difference to the daily burden of recurrent temperature monitoring and concluded that HCPs should carefully consider the unique circumstances of their patients before recommending that they monitor their feet for DFUs.

Treatment Algorithm and Guideline Highlights

ADA/EASD 2021 Consensus Report on the Management of Type 1 Diabetes in Adults published in Diabetes Care and Diabetologia; updates since draft presented at ADA 2021

A truly impressive collection of KOLs from across the US and Europe gathered this morning to unveil the ADA/EASD’s Consensus Report on the Management of Type 1 Diabetes in Adults published simultaneously in Diabetes Care and Diabetologia, while over 1,000 attendees tuned in virtually. Today’s presentation built upon a similar session at ADA 2021 in which a draft of the Consensus Report was made available for public comment until July 8th. According to panel co-chair Dr. Richard Holt (University of Southampton), “public comments from a range of healthcare professionals on both sides of the Atlantic were received, responding as an individual or on behalf of groups or professionals working in clinical care, academic and pharmaceutical industry…we read all of these comments carefully and modified the report accordingly.” Additionally, Dr. Holt shared that the majority of comments received “related to clarifying the wording of certain sections, and no major changes were needed” to the initial draft of the Consensus Statement. Below is a summary of the Consensus Statement sections as presented by the international consensus panelists as well as a discussion of key knowledge gaps that remain in the treatment of type 1 diabetes. In summarizing the goals of the report, Dr. Anne Peters (USC), co-chair of the report committee, expressed that that a central goal of the consensus report is to provide essential information on type 1 diabetes care to primary care physicians, given that about half of people with type 1 diabetes in the US are solely treated in that setting.

  • Goals of the report. Dr. Richard Holt began this much-anticipated symposium by acknowledging that existing guidance for type 1 diabetes management exists within broad, non-specific guidelines. The consensus committee began work in January 2020 to create a report specifically for T1D comparable to the highly influential 2018 ADA/EASD consensus report on T2D management. Dr. Holt also specified the broad management strategies involved in supporting people with T1D: effectively delivering insulin to maintain glucose levels as close to the target range to prevent the development and progression of diabetes complications; minimizing episodes of hypoglycemia and preventing episodes of diabetic ketoacidosis while treating these appropriately should they occur; effectively managing cardiovascular risk factors; and minimizing the psychosocial burden of living with type 1 diabetes while promoting psychosocial wellbeing. As clarified in the Q&A period, the committee elected to not include in this report detailed management of cardiovascular and microvascular risk factors since they felt those topics were well-covered in other guidelines. We were glad to hear Dr. Holt highlight the importance of setting individualized glycemic for patients and considering Time in Range, time below range, time above range, and glycemic variability measures, in addition to the standard measures of A1C/GMI, pre-prandial glucose, and post-prandial glucose. Dr. Holt also emphasized that any reduction in A1c from high baseline has significant clinical implications even if specific targets and goals are not reached and that diabetes management extends far beyond glycemic management – a sentiment we heard earlier at EASD 2021 from Dr. Rich Bergenstal (International Diabetes Center).
  • Diagnosis. Dr. Hans de Vries (University of Amsterdam) tackled the diagnosis of type 1 diabetes in adults. Given that ~40% of people who have their type 1 diabetes diagnosed over the age of 30 years old are first misdiagnosed, there is significant need for more stringent diagnosis protocols. Key measures have now been organized into a handy diagnostic algorithm, which focuses on presence of autoantibodies, age, and C-peptide as points of clarification. Notably, diagnosis was a popular topic during the live Q&A post-presentation, in which Dr. de Vries clarified that the consensus report advocates for moving away from C-peptide testing at diagnosis as levels can often still be high among people with type 1 diabetes at this time. Instead, Dr. de Vries explained that the consensus guidelines advocate for C-peptide testing three years after diagnosis if there is still any doubt whether the patient has type 1 or type 2 diabetes. Back at ADA 2021, Dr. Ruth Weinstock (co-author on this section), also clarified that there is not yet evidence for all adults suspected of having diabetes to receive autoantibody screening, as the vast majority of people >35 years old have type 2 diabetes; HCPs should instead look for “any level of suspicion” that it may, in fact, be type 1 diabetes, then prescribe an autoantibody screening.

  • Schedule of care. Dr. Ruth Weinstock (SUNY Upstate Medical University) spoke about the schedule of care for new onset type 1 diabetes and general principles for type 1 diabetes management. Dr. Weinstock recommended that management of new onset type 1 include self-management education, glucose monitoring initiation (CGM preferred), insulin therapy initiation (MDI therapy preferred), and preparation for hyperglycemia and hypoglycemia. Generally, each visit should consist of an assessment of glycemic targets, self-management support, recommendation to use CGM if not using it, a change in insulin therapy as appropriate. The physical examination should include height, weight (every visit), BMI, blood pressure and pulse, skin examination at injection sites, cardiovascular examination, examination of the feet. Laboratory tests should include A1C (every 3-12 months), creatinine (annual), urine albumin:creatinine ratio (annual), lipid panel, ALT and AST, serum potassium (if taking ACEI/ARB/diuretic), and a TSH/vitaminB12/celiac screen. That said. Dr. Weinstock also emphasized that these timeline could be updated to be more frequent in patients at higher risk for developing comorbidities. Additionally, Dr. Weinstock homed in on the importance of patient-centered care and shared decision-making to support patients in making realistic and attainable diabetes management goals.

  • Diabetes self-management education and additional behavioral considerations. Ms. Amy Hess-Fischl (Kovler Diabetes Center) reviewed these two chapters within the new consensus report, leveraging her experience as both a Certified Diabetes Education & Care Specialist and Nutrition Specialist. Starting with the latter, Ms. Hess-Fischl emphasized that DSMES “should not be confined to one particular moment but offered on a continuous basis and tailored to the ever-evolving individual’s educational needs.” As outlined in the DSMES consensus statement, HCPs should recommend people with type 1 diabetes DSMES at four critical times: diagnosis, annually and/or when not meeting glycemic targets, when complications occur, and when life or care transitions occur. Notably, Ms. Hess-Fischl explained that these four timepoints, while similar to recommended DSMES intervention for type 2 diabetes, are tailored to type 1. Specifically, DMSES support during transitions for patients with type 1 could apply to life transitions such as age-related responsibilities in adolescents or the initiation or intensification of new technologies and therapies. In terms of behavioral considerations, Ms. Hess-Fischl paid special attention to the goals of nutrition therapy for type 1 diabetes; HCPs should first focus on ensuring that patients can match insulin doses with meal composition, then can explore specialized topics like low carbohydrate eating patterns and the effects of high fat and/or high protein diets.
  • Monitoring. For monitoring glucose, Dr. Irl Hirsch (University of Washington) strongly recommended the use of CGM, either real-time or intermittently scanned (i.e., FreeStyle Libre), with blood glucose monitoring (BGM) as a back-up option. He suggested most people can benefit from CGM with appropriate education, though CGM can increase psychological distress and cause alarm fatigue for some users. Still, Dr. Hirsch noted that CGM is the standard of care and should be offered to all people with type 1 diabetes. In terms of metrics, Dr. Hirsch noted that while there is a strong correlation between A1c and average glucose levels over 3 months, A1c is insufficient by itself since it does not provide information on glycemic variability and hypoglycemia. To mitigate this, Dr. Hirsch advocated in favor of increased education and adoption of CGM derived metrics such as GMI, Time in Range, and glycemic variability in clinical practice to supplement A1c and other laboratory measured metrics.
  • Insulin therapy. Dr. Sue Kirkman (UNC Diabetes Center) reviewed the latest on insulins in rapid fire. Big picture, ideal insulin replacement is best achieved with either multiple daily injections or pump therapy, and insulin analogues are the “treatment of choice” for type 1 diabetes. While the new report acknowledges that newer basal analogues may cause less hypoglycemia than “traditional” insulins, the true advantages of ultra-rapid analogues (like Novo Nordisk’s Fiasp and Lilly’s Lyumjev) apart from slightly earlier time of onset and peak action and reduced post-prandial hyperglycemia are less clear, given that reduction of A1c and hypoglycemia risk is consistent with older analogues. As a very tech-savvy edition, the report notes that insulin replacement is greatly enhanced by CGM and automation and points out that “the greatest benefits” are seen with hybrid closed loop technology.

  • Hypoglycemia. Dr. Eric Renard (Montpellier University) began by citing the SAGE study that demonstrated frequent occurrences of hypoglycemia in adults with T1D; about half of the studied population experienced a serious hypoglycemic event in the last three months. One contributing factor is impaired awareness of hypoglycemia, which affects about 25% of people and results in a 6-fold increase of severe hypoglycemia. To mitigate impaired awareness of hypoglycemia, Dr. Renard emphasized proactive detection during consultations through various educational trainings and revision of the target glucose range. As for treatment of hypoglycemia, Dr. Renard recommended 15g oral simple carbohydrate every 15 minutes until glucose is above 70 mg/dL with an additional 20g long-acting carbohydrate if distant from mealtime. However, if neuroglycopenic symptoms are present, subcutaneous/intramuscular/nasal glucagon or intravenous glucose should be administered.   

  • Psychosocial care. We were thrilled to see a chapter of the report dedicated to the all-important topic of psychosocial care, reviewed by Dr. Frank Snoek (Amsterdam UMC). In the ADA press release released after the first iterations of the guidelines were presented, report committee co-chair Dr. Richard Holt stated, “One of the strengths of this report is that we have paid particular attention to the psychological and social aspects of diabetes and the needs for us to incorporate psychosocial care and support within the holistic management of type 1 diabetes.” Indeed, much of Dr. Snoek’s presentation reviewed the undeniable psychological demand, impact on quality of life for people with diabetes and their loved ones, and social/financial hardships associated with type 1 diabetes. While the chapter did not give explicit recommendations as when psychosocial needs should be evaluated, the authors stated that “psychological health and social barriers to self-management should be evaluated periodically and discussed with the person with T1DM.” Furthermore, HCPs should ensure that referral pathways to higher levels of psychosocial support (peer support/informal coaching, then psychological therapy, then psychiatric treatment for severe mental illness) are prearranged. 
  • Diabetic ketoacidosis. Given its position as an extremely important complication of type 1 diabetes, DKA was broken out as a distinct category in the consensus report, today presented by Dr. Kirsten Nørgaard (Steno Diabetes Center). Importantly, the prevalence and incidence of DKA in adults is less well-studied than compared to children, and further research in this area is needed. The report outlines a variety of non-modifiable risk factors for recurrent DKA (low socio-economic status, young adult age, female sex, and ethnicity), as well as modifiable ones (previous DKA episode, high A1c, low self-management skills, psychiatric disorders, infections, somatic comorbidity, alcohol and drug abuse, less interaction with the healthcare team, and SGLT treatment), emphasizing that HCPs should look for these indicators. Several broad interventions have been shown to reduce DKA risk, including DSMES, behavioral health interventions, and in some cases, telemedicine. While treatment of DKA was deemed “out of scope,” Dr. Nørgaard stated that the available protocols all include the same general principles (fluid, insulin, and potassium) and that any one of them can be selected for use.
  • Pancreas and islet cell transplantation. Dr. Barbara Ludwig (University of Dresden) acknowledged that pancreas and islet cell transplantation, the only clinical beta cell replacement therapies currently available, have the potential to provide a functional cure for type 1 diabetes but require life-long immunosuppression. As a result, she emphasized the importance of a thorough risk/benefit assessment and trying more conservative treatments before undertaking these procedures. The majority of pancreatic transplantations are done simultaneously with kidney transplantations, but pancreas transplantations alone can be done, but mostly for young people with T1D, without comorbidities, who have frequent complications using insulin-based management. On the other hand, islet transplantations are less invasive, making them suitable for older people with coronary artery disease, and aim to establish normal glycemic levels (A1c <7%) with elimination of severe hypoglycemia. Notably, insulin independence is not a main therapeutic goal of islet transplantation. Dr. Ludwig concluded by encouraging clinicians to balance procedural risk and metabolic needs and let individual patient preference drive the line of action. 

  • Adjunctive therapy. Dr. Jeremy Pettus (UCSD) presented on adjunctive therapies, acknowledging eloquently that there continues to be unmet need for adjunctive therapies that better address blood sugar, weight, and CV outcomes for people with type 1 diabetes. Using a handy chart, Dr. Pettus reviewed the four most prominent adjunctive therapies: metformin, pramlintide, GLP-1s, and SGLT-2 inhibitors. Of note, pramlintide is only approved for type 1 diabetes in the US, and SGLT-2 inhibitors are only approved in the EU. Dr. Pettus emphasized that despite it being the most widely used adjunctive, multiple clinical studies have shown that metformin has a minimal effect on blood sugar in type 1, and if no change on glucose or weight is seen after a trial period, patients should be taken off metformin. Pramlintide was highlighted as being the poster child for adjunctive therapies and being impactful more so for its exemplification of how drugs can be approved rather than its efficacy/use. Commentary on GLP-1s focused on the weight loss and cardiovascular plus renal benefits that Dr. Pettus expressed may benefit some patients, but at this time GLP-1 use in patients with type 1 diabetes is strictly off-label meaning providers must do a structed risk-benefit assessment before prescribing the medication to their patients. Similarly, SGLT-2s use in type 1s, which has been approved in a low dose for patients with a BMI ≥27 kg/m2 in the EU can be beneficial for patients at high risk for cardiovascular or renal disease, but must be considered carefully due to the increased risk of DKA.

  • Special populations. Dr. Tomasz Klupa (Jagiellonian University) discussed the management of T1D in pregnant women (as well as pre-conception and post-partum), older people, patients with advanced complications, and in-patients. Since diabetes in pregnancy has increased risks for hypoglycemia and DKA, Dr. Klupa recommended that women of child-bearing age with T1D seek guidance before trying to conceive to improve glycemic management, obtain folic acid, screen for diabetes complications, and avoid potentially teratogenic medication. He stressed that diabetes in pregnancy is best managed by a multidisciplinary team. For older paper and those with advanced complications, the key is individualization. Glycemic targets should be based on functional status and life expectancy rather than chronological age, and Dr. Klupa emphasized that technology should not be dismissed just because of a patient’s older age. For those with advanced complications, Dr. Klupa reminded clinicians that rapid improvement may be associated with transient worsening of retinopathy or acute painful neuropathy. Unfortunately, there is a lack of randomized controlled trials for in-patient T1D management, so Dr. Klupa referred to the T2D guidelines.  
  • Emergent and future perspectives. Dr. Jay Skyler (University of Miami) kept his commentary on future perspectives short and sweet, focusing on two main categories of innovation (i) beta cell replacements; and (ii) immunotherapies. Starting with the latter, Dr. Skyler outlined xenotransplantation (i.e., pig islets) and stem cell-based beta replacements as the two potential sources of new cells. On immunotherapies, Dr. Skyler shared that the most promising results in recent onset type 1 diabetes currently come from anti-CD3 monoclonal antibody teplizumab, low-dose anti-thymocyte globulin (ATG), and anti-TNF-alpha golimumab. In addition, teplizumab has shown efficacy in preventing the clinical onset of type 1 diabetes, and Dr. Skyler hopes that teplizumab “will hopefully soon be approved for that indication.”
  • Key knowledge gaps. Whereas Dr. Richard Holt (University of Southampton) presented on this topic during the unveiling of the ADA/EASD consensus guidelines at ADA 2021, Dr. Anne Peters (USC) stepped in at EASD, highlighting the major areas of development where many unanswered questions remain. Dr. Peters began by acknowledging her colleagues from the ADA, EASD, and other organizations who helped finalize the type 1 consensus guidelines during the review period. Dr. Peters then listed many areas in the treatment of type 1 diabetes that she believes have gaps of knowledge. Starting with technology, Dr. Peters doubled down on her sentiments from CEU 2021 where she stressed the importance of personalizing technology to the patient. Specifically, Dr. Peters emphasized that AID systems need to be simple enough and effective enough for all to use and questioned whether using bihormonal systems with glucagon and insulin might improve outcomes. On the burdens of technology, Dr. Peters explained that an evolving area will be diabetes technology that is not “stuck” outside the body, noting the limitations of infusion sets and sensor failures. On insulins, Dr. Peters asked how we might make insulin work more physiologically (rapidly on and off) in a way that can better self-adjust to a patient’s needs. Lastly, Dr. Peters emphasized that providers must better address health disparities and psychosocial issues for people with type 1 diabetes.

Full results from head-to-head GRADE Study (n=5,047, five-year duration); new final CV outcomes and quality of life data, analysis by baseline characteristics

In a midafternoon session, we were treated with full results from the NIDDK-funded GRADE study, the largest and longest study to compare the effectiveness of the four most common medications to treat type 2 diabetes. Preliminary but largely comprehensive results were presented at ADA 2021, and today, we learned that the results are set for submission to publications within a month. Broadly, results showed that GLP-1 liraglutide and insulin glargine were the most effective medicines in keeping A1c <7.0% (time to A1c ≥7% was the study’s primary outcome), while sulfonylurea glimepiride had an intermediate effect, and DPP-4 sitagliptin had the lowest effect. On the secondary outcome (time to A1c ≥7.5%), glargine was found to be most effective, followed by liraglutide, then glimepiride and sitagliptin. Primary and secondary outcome results did not change in today’s full readout. At ADA 2021, preliminary CV results (~10% of CV had not been adjudicated yet) indicated that liraglutide had a relative benefit over all three other drugs on “any CVD” (three-point MACE, hHF, unstable angina, TIA or revascularization). While largely similar, today’s full CV results indicated that liraglutide demonstrated a significant risk reduction on “any CVD” compared only to sitagliptin (32% reduced risk; p=0.036) and glimepiride (29% reduced risk; p=0.048), not glargine (p=0.087). As a reminder, the GRADE population had low CVD risk, unlike previous trials with GLP-1s conducted in populations with established ASCVD or high CV risk. Summarizing the CV results, Dr. John Buse (University of North Carolina) concluded that GRADE “does not provide strong evidence of a CV benefit for liraglutide in a lower risk population for CVD than previously studied” and called for more studies on the CV benefits of GLP-1s in low CVD risk populations. We also caught new data on participants’ quality of life throughout the study and new analyses of the primary outcome by various baseline characteristics. As shared at ADA and reiterated today, GRADE’s results set the stage for future analyses to enhance personalized medicine for type 2 diabetes. Cost-effectiveness and genomic analyses are in the works along with a substudy of patients using CGMs. Notably, photography/screenshots were not permitted during the session, hence our lack of visual representations.

  • Background on GRADE. As a reminder, GRADE enrolled 5,047 patients with type 2 diabetes who were randomized to basal insulin glargine, DPP-4 sitagliptin, sulfonylurea glimepiride, or GLP-1 liraglutide. The medications were given at no-cost to participants through industry donations. SGLT-2s, which are now commonplace, had only recently been approved and were not widely used in the US at the time of GRADE initiation; therefore, SGLT-2s were not included in the trial. Study participants had a mean age of 57 years, and 37% were women (large proportion of men was due to participant recruitment in 11 Veterans Affairs Medical Centers). Notably, about 20% of participants were Black, 4% were Asian, and 3% were Native American/Alaskan Native. 18% of participants were Hispanic/Latino. At baseline, mean A1c was 7.5%, mean BMI was 34.3 kg/m2, mean blood pressure was 128/77 mmHg, mean eGFR was 95 mL/min/1.73m2, and mean duration of diabetes was 4.2 years.
  • Cardiovascular outcomes with analysis by history of stroke or MI. Dr. John Buse (University of North Carolina) presented CV outcomes. After an average five years of follow-up, there was a significant difference in “any CVD” between the four therapies. Liraglutide demonstrated a significant risk reduction on “any CVD” compared only to sitagliptin (32% reduced risk; p=0.036) and glimepiride (29% reduced risk; p=0.048), but not compared to not glargine (p=0.087). In absolute terms, 6.6% of patients on liraglutide developed any CVD, while rates for glargine, glimepiride, and sitagliptin were 8.9%, 9.2%, and 9.5%, respectively. As a reminder, “any CVD” consisted of MACE, hHF, unstable angina, TIA or revascularization. While participants who had a prior history of stroke or myocardial infarction (MI) had more CVD events, there was no significant heterogeneity of the “any CVD” outcome based on prior history of MI or stroke (p=0.25). Between the four treatments, there was no significant difference in MACE (myocardial infarction, stroke, or CV death), hHF, CV death, or all-cause mortality, though liraglutide exhibited numerically fewer events for all outcomes.
    • Baseline cardiovascular characteristics. At baseline, about two-third of participants had a history of hypertension (67%) and were on blood pressure medications (69%). One in seven (14%) were smokers, and only 6.5% of participants had a history of heart attack or stroke. About a third (34%) had LDL cholesterol ≥ 100 mg/dL, and 66% were on lipid-lowering medications. 
  • Quality of life data. Dr. Margaret Tiktin (Louis Stokes Cleveland Veterans Affairs Medical Center) shared safety and quality of life results. Safety results did not change from the ADA 2021 presentation. Quality of life was assessed using the SF-36 form, which was collected from patients once-a-year for four years. After one year, quality of life scores peaked in all groups with patients on liraglutide having substantially higher scores (better quality of life) than patients in the other three treatment groups. After four years, quality of life scores returned to baseline in all treatment groups without significant differences. Liraglutide was significantly better than the other treatments for “general health perception” (p=0.023) and for the physical component score (p=0.004).
  • Heterogeneity in primary outcome by baseline characteristics. Dr. Naji Younes (George Washington University) presented highlights from ongoing analyses between baseline characteristics and the primary metabolic outcome (time to A1c ≥ 7%). He noted that additional analyses are ongoing with other outcomes. There were significant differences between treatment groups by baseline A1c (p=0.016) and by fasting plasma glucose (FPG) (p=0.007). This heterogeneity was attributable to sitagliptin, which performed worse (shorter time to A1c ≥ 7%) than other medications as baseline levels of A1c or FPG increased. Interestingly, participants in the oldest age group (≥60 years) had the lowest cumulative incidence of the primary outcome and there was a negative correlation between age and cumulative incidence of the primary outcome. More importantly, though, the effect of age on the primary outcome did not differ between treatment groups. Similarly, there was no significant heterogeneity between treatment groups by sex, race, or ethnicity. Lead GRADE investigator Dr. David Nathan (Harvard Medical School) emphasized during discussion that a key takeaway from GRADE is that each therapy worked similarly across various demographic groups, reminding attendees that patients received medications and care at essentially no cost. He suggested that any differences in outcomes observed between demographic groups on each of these therapies is largely attributable to accessibility to diabetes care and therapy.

Prof. Christopher Wanner compares CKD management guidelines across KDIGO, ADA/EASD, and ESC, highlighting the importance of annual eGFR and UACR screening; Prof. Hiddo Heerspink emphasizes strong cardiovascular and renal risk reduction with SGLT-2s and finerenone

In a session on current guidelines for kidney disease, Prof. Christopher Wanner (University Clinic Wurzburg, Germany) compared the EASD/ADA, KDIGO, and ESC guidelines. Above all, Prof. Wanner stressed the importance of annual screening for eGFR and UACR, which is recommended by all three guidelines. Although this recommendation is clear and consistent across the three major organizations, he noted that implementation varies at the national and local level. In particular, Prof. Wanner identified cardiology outpatient clinics as an area for improvement, stating that albuminuria testing is “absolutely missing” in this setting. Prof. Wanner then discussed five components of CKD management across the guidelines: (i) comprehensive care; (ii) glycemic monitoring and targets; (iii) lifestyle interventions; (iv) antihyperglycemic therapies; and (v) approaches to management. While he described a general harmonization of the guidelines, Prof. Wanner highlighted key differences in recommended glucose-lowering agents – more on this below. Looking ahead, he expressed anticipation for the inclusion of MRA finerenone in the latest version of these living guidelines, which are updated every October.

  • While the three guidelines generally agree on comprehensive care, approaches to management, and lifestyle interventions, Prof. Wanner described some divergence in their recommendations for glucose control and antihyperglycemic therapies. On glucose lowering medications, he explained that KDIGO guidelines continue to recommend metformin as first-line treatment, with an recommendation for the addition of SGLT-2s into treatment regimens. While we’d agree with Prof. Wanner that metformin is cheap and well-studied in a variety of global populations, we’d certainly press for more prominent positioning of SGLT-2s, given the wealth of evidence for their cardio and renal-protective benefits in addition to their glucose-lowering effects. Indeed, the 2021 ADA and ESC guidelines include a class 1A recommendation for SGLT-2s – the highest level of recommendation based on strong evidence from recent large-scale RCTs. We are glad to see that SGLT-2s are being incorporated in the latest ADA and ESC guidelines, and we’d hope that the next KDIGO guidelines reflect this consensus.
    • On glycemic monitoring and targets, Prof. Wanner noted that the ADA and EASD guidelines call for a target of A1c below 7%, whereas KDIGO recommends an individualized target from 6.5 to 8%, based on a patient’s graded risk. We are happy to see KDIGO advocating a more individualized approach to CKD management, particularly among older and more frail patients.

  • In terms of lifestyle management, current guidelines call for a cumulative duration of 150 minutes of physical activity per week and reduction of salt intake to 2 grams of sodium per day. Prof. Wanner noted that both are weaker recommendations, as they lack strong evidence gathered via large-scale RCTs. Given that a healthy diet and exercise are important in overall diabetes management and offer a non-invasive and more cost-friendly approach, we look forward to further, more comprehensive studies investigating the extent to which lifestyle modifications contribute to CKD risk reduction and management.
  • Later in the session, Prof. Hiddo Heerspink (University Medical Center Groningen, Netherlands) discussed the use of SGLT-2s and MRA finerenone in type 2 diabetes and CKD. He emphasized that SGLT-2s can be initiated at eGFRs >25 mL/min/1.73m2 (>30 mL/min/1.73m2 for canagliflozin) and continued even when the eGFR falls below these lower threshold levels. In fact, Prof. Heerspink noted that some patients have even continued dapagliflozin on dialysis. Turning to finerenone, he highlighted the highly significant 23% risk reduction for the composite kidney outcome alongside a 14% reduction in MACE in the FIDELITY pooled analysis. Prof. Heerspink emphasized that the eGFR trajectories of finerenone mirror those of SGLT-2s, slowing progression of kidney function decline during prolonged treatment. Overall, he concluded that both agents provide strong renal and cardiovascular risk reduction for patients with type 2 diabetes and CKD and called upon HCPs to implement these agents in clinical practice. Looking ahead, Prof. Heerspink mentioned that the FIND-CKD trial has recently begun and will investigate whether finerenone confers renal protection in non-diabetic CKD.

Dr. Ildiko Lingvay calls for weight-centric management of type 2 diabetes independent of baseline A1c; focus on weight loss of 15% or more

In this session, Dr. Ildiko Lingvay (UT Southwestern) highlighted a new approach to diabetes management: one that moves away from the gluco-centric approach and towards weight loss management. In particular, the discussion focused on new recommendations proposed by Dr. Lingvay and her team, which highlight weight loss as the principal goal of treatment in most patients with type 2 diabetes. She argued there are three main subgroups of type 2 diabetes – diabetes with CVD, adiposity-related diabetes, and isolated hyperglycemia – and patients should be treated in accordance with the primary driver of their disease. Dr. Lingvay noted that while historically glycemic control was the only goal of diabetes management, the scope has shifted to include cardiorenal protection as a primary goal in patients with high-risk or established cardiovascular disease. The proposed approach to treating adiposity-related diabetes mimics that seen in patients with CVD: prioritizing medications that reduce risk for the up-stream cause of diabetes, in this case, obesity, rather than hyperglycemia, the down-stream result. For the first time, given the medications on the market, achieving 15% weight loss is actually feasible. Dr. Lingvay noted it will take a village to implement this paradigm shift, signaling efforts from patients, providers, and payers, but argued this approach is “the future” and that the work must be done to make it a reality. 

  • Dr. Lingvay outlined three main subgroups of type 2 diabetes – diabetes with CVD, adiposity-related diabetes, and isolated hyperglycemia – which should be used to direct treatment. Notably, Dr. Lingvay argued that the primary driver of adiposity-related diabetes is insulin resistance, which is the typical mechanism associated with the development of type 2 diabetes, and suggested that the prevalence could range from 40-70% of the type 2 diabetes population depending on the population. She noted that diabetes with CVD, which should be treated using a cardio-centric approach, occurs in 20-40% of the population, and that 10-20% of patients have isolated hyperglycemia, attributed to beta-cell dysfunction, which be treated with a gluco-centric approach. Though this stratification doesn’t fit the exact definition of precision medicine, which has been a major theme of this year’s conference, it certainly is moving in that direction by treating patients based on their underlying pathophysiology.

  • Dr. Lingvay advocated for patients with adiposity-related diabetes to be treated for weight loss, independently of baseline A1c. In the proposed algorithm, patients in this subgroup are started on anti-obesity pharmacotherapy and initiate lifestyle modifications with the goal of losing 15% of body weight. If weight loss goals are not met, the algorithm recommends switching or adding additional anti-obesity agents, and if goals still are not met, the guidelines recommend bariatric surgery. Moreover, the guideline-directed therapy also recommends that additional weight-sparing glucose-lowering agents such as metformin, SGLT-2s, and GLP-1s can be added to therapy if A1c is still above target following first-line treatment.

  • Implementing a weight-centric approach to diabetes will be a multi-stakeholder effort. Dr. Lingvay noted that there is much work to be done to making this vision a reality, starting by making sure providers who treat patients with diabetes are knowledgeable about obesity. They need to educate their staff and peers about the condition, while creating supportive environments to promote patients’ weight loss journeys. Guidelines also need to be updated and unified to include the most recent data to prevent conflicting recommendations for the treatment of obesity. Moreover, Dr. Lingvay noted that payers must be a part of the conversation, arguing they should be updating their health economics models to project the potential utility of 15% weight loss among their members.

Retrospective Norwegian study (n=275 general practitioners, GP) finds that GP adherence to screening guidelines reduces the 10-year risk of cardiovascular disease

Dr. Kjersti Nøkleby (University of Oslo) presented a study exploring the relationship between provider adherence to recommended standards of care and 10-year cardiovascular risk outcomes. The retrospective, cross-sectional analysis included 6,015 people with type 2 diabetes without CVD and their 275 general practitioners. Using data from electronic health records, general practitioners were put into quintiles based on the proportion of their patients receiving the six procedures of diabetes care: (i) A1c measurement; (ii) LDL-cholesterol measurement; (iii) blood pressure measurement; (iv) albuminuria screening; (v) recorded foot examination in past 15 months; and (vi) recorded eye examination in the past 30 months. The rates of recommended care varied widely across providers; some general practitioners delivered all six steps of care to just 8% of patients, while others had an impressive 96% of their patients following the guideline recommendations. The primary outcome of the study was estimated modifiable cardiovascular disease (CVD) risk, calculated based on a weighted, composite measure of risk factors that clinicians can control.  Secondary outcomes of the study included total CVD risk, modifiable risk with HDL-cholesterol, and the proportion of patients with poor glycemic control. The study found low general practitioner adherence to recommended diabetes screening procedures was associated with a higher risk of cardiovascular disease and a higher proportion of patients with A1c values >8.5%. This study offers pivotal feedback for general practitioners and cements an intuitive argument: increased testing measures lessen cardiovascular risks for patients.

  • The estimated 10-year risk of cardiovascular disease decreased with increasing screening performance of the general practitioner. After adjusting for confounding variables, patients treated by providers in the lowest quintile had a 75% greater risk of modifiable CV disease compared to patients with general practitioners in the highest quintile. Moreover, patients with general practitioners in the lowest quintile had 91% greater odds of having an A1c>8.5% than patients whose general practitioners were in the best performing quintile.
  • Provider demographics varied across the different quintiles; notably, providers in the lowest quintile of care were older and had more outdated organizational practices. Dr. Nøkleby has explored this question in depth in one of her earlier studies. She noted that “GPs in the poorest quintiles were older (>60 years) and did not use the modern structures in place to help organize their care… Few had routines for contacting the patients for yearly control, and those with larger lists (higher working load) tended to perform less procedures.” Time and unfamiliarity with modern guidelines and resources seem to have been the main obstacles in adhering to current diabetes process recommendations. With that said, new resources such as On@Pro, launched by Ascensia Diabetes Care, can help educate providers on the new guidelines. We don’t believe that these quintiles necessarily reflect the quality of the provider, but rather highlight the difficulty of covering all of ones’ bases for the many conditions a patient may be suffering from in one short visit. Increased education and streamlined diagnostics could perhaps increase the rates of adherence to the guidelines.

COVID-19 Highlights

Professor Naveed Sattar shows increased risk of severe COVID-19 for older type 1 patients; a call to action against the likely increase in obesity that will result from the pandemic

In this fast-paced session, Professor Naveed Sattar (University of Glasgow) reviewed several studies relating to diabetes and COVID-19, highlighting the increased risk severity and morbidity associated with the two conditions. Notably, Professor Sattar made the point that many of the risk factors that are associated with worse diabetes outcomes, including obesity, age, history of CKD or CVD, A1c, and socioeconomic status, are also associated with a more severe COVID-19 disease course. The risk of severe COVID-19 for patients with diabetes lies somewhere between 2 and 6-fold for patients with type 1 diabetes and somewhere between 1.5 to 5-fold for patients with type 2 diabetes when looking across several different analyses. Professor Sattar highlighted data from McGurnaghan et al. 2021, published in The Lancet Diabetes & Endocrinology in February, showing that the hazard ratios for total death or ICU hospitalization were 2.4 for T1D patients and 1.4 for T2D patients in Scotland. The analysis went on to show that prior diabetic ketoacidosis (DKA) and hypoglycemia events conferred significantly higher risk of severe COVID-19, with hazard ratios of 2.9 and 3.2 (p<0.0001 for both), respectively. The number of diabetes drugs prescribed, as well as the presence of microvascular and macrovascular complications also contributed to elevated risk. Professor Sattar also reviewed data from a 2020 study measuring the excess death related to COVID-19 in England. The study found that deaths increased over the corresponding prior 3-year weekly averages by 51% in people with type 1 diabetes, and 64% in people with type 2 diabetes. He noted that between 55-62% of the patients with diabetes who died also had underlying cardiovascular disease or chronic kidney disease. This data supports Professor Sattar’s common theme – totality of exposure to risk via complications leads to more severe disease.

  • Professor Sattar discussed compelling data showing that older patients (>40 years) with type 1 diabetes were at increased risk for severe COVID-19. Professor Sattar cited Barron et al. 2020 noting that the hazard ratio for the in-hospital COVID-19 mortality rate was 3.5 for patients with type 1 diabetes, compared to 2.03 for patients with type 2 diabetes. He noted that this is in stark contrast to younger patients with type 1 who had virtually no excess risk for COVID-19 mortality. Professor Sattar proposed that compounded exposure to hyperglycemia over the course of a lifetime for type 1 patients could be contributing to increased risk in older patients. Hyperglycemia over time causes vascular damage, which could worsen COVID-19 symptoms. However, Professor Sattar noted that at this point, it is too early to definitively say whether hyperglycemia per se is causing severe COVID or whether it is simply a marker associated with severity. Either way, these data aligns with recent findings from the US showing that age older than 40 years is a risk factor for patients with T1D and COVID-19.
  • Turning to the future, Professor Sattar worries that lifestyle changes due to COVID-19 will result in rising numbers of people obesity and diabetes. First and foremost, Professor Sattar expressed his dismay at the shortcomings of telehealth – calling it “suboptimal” care. He showed that across the board, there are meaningful drops in clinical care markers such as fewer blood pressure measurements, fewer A1c measurements, and fewer foot surveys being given. Professor Sattar noted in Q&A that telehealth may not be for everyone, and that he would prefer to see most patients face to face. Professor Sattar also argued that one of the largest consequences of the pandemic will be the increase in obesity and diabetes resulting from changing lifestyles. He argued people have become more sedentary, are engaging in less physical activity, and are doing more snacking as a result of the pandemic, which is causing weight gain across the globe. Professor Sattar argued that because obesity is associated with worse outcomes in COVID-19 and diabetes, this is the time for substantial obesity prevention and management efforts. He called on governments to intervene with initiatives to stem the rising tide of obesity.

Clinical considerations in addressing the disruptions to diabetes care post-COVID-19: Prof. Kamlesh Khunti advocates for the continuation of glucose-lowering medications in type 2s, shares two-stage risk assessment for returning to full care continuum

Prof. Kamlesh Khunti (Co-Director of Leicester Diabetes Centre, UK) discussed the challenges of caring for patients with diabetes who have recovered from COVID-19 in primary care settings and reinitiating the full continuum of diabetes care that was disrupted during lockdowns. Dr. Khunti began by acknowledging the wealth of data that suggests that people with diabetes are at higher risk for both poor outcomes and COVID-19 related death following a SARS-Cov-2 infection. On the challenges of re-starting the continuum of diabetes care that was disrupted during lockdowns, he emphasized that: (i) the use of glucose-lowering medications should not be discontinued following a SARS-CoV-2 infection (despite previous concerns); and (ii) primary care physicians must work to address the “backlog” of patients in a risk-stratified manner.

  • Dr. Khunti’s group conducted the largest study to date (n=2.8 million) on glucose-lowering therapies and the risk of COVID-19 mortality in people with type 2 diabetes. Using national data from England between February-August 2020, the researchers found a positive association between insulin therapy and DPP-4 inhibitors and risk of COVID-19-related death, though it found that metformin, SGLT-2 inhibitors, and sulfonylureas actually had a protective effect (see the table below). Dr. Khunti is careful to note that that though these results indicate associations between the prescription of some glucose-lowering drugs and COVID-19-related mortality, the findings are likely due to confounding factors, considering that different medications are used at different stages of type 2 diabetes disease progression. Given this, he advocated that this data does not support changing or stopping prescribing glucose-lowering drugs to people with type 2 diabetes in order to reduce COVID-19 mortality risk.

Medication

Adjusted HR for Taking Prescription vs No Prescription on COVID-19 Mortality Risk (95% CI)

Insulin

1.42 (1.35-1.49)

DPP-4 inhibitors

1.07 (1.01-1.13)

Metformin

0.77 (0.73-0.78)

SGLT-2 inhibitors

0.82 (0.74-0.91)

Sulfonylureas

0.94 (0.89-0.99)

  • Prof. Khunti emphasized the urgent need to “make up for lost time” and help patients with diabetes continue their care and shared a two-stage risk stratification process to prioritize patients who need to be seen sooner or seen in person vs. digitally. He referenced a helpful flowchart from Dr. Pam Brown (Lexington Medical Center) and Ms. Jane Diggle (Editor in Chief, Diabetes). The flowchart describes red, amber, and green levels of priority that are based on A1c, blood pressure, diabetes complications, CKD, cardiovascular problems, and BMI (see below). Prof. Khunti underscored the urgency of the situation by noting that even one year of poor glycemic control in people with type 2 diabetes can result in a 67% increase risk of myocardial infarction, 64% increase risk of heart failure, 51% increase of stroke, and 16% increase in the cumulative incidence in nephropathy. He also noted COVID-19 still poses a greater risk to people with diabetes compared to the general population, despite the growing availability of vaccines, citing a study that came out this past month showing that COVID-19 vaccines induce a weaker immunity response in people with poor glycemic control compared to those with normal glycemic control.