American Diabetes Association 80th Scientific Sessions

June 12-16, 2020; Virtual; Day #3 Highlights

Executive Highlights

  • ADA Day #3 is in the books – and boy was it a busy day! See our top highlights across diabetes technology and therapy below.

  • Diabetes therapy:

    • Promising phase 2 results for Novo Nordisk’s once-weekly insulin “icodec” showed comparable glycemic efficacy and safety to Lantus. In presenting these data, Dr. Julio Rosenstock was very bullish on the candidate’s future impact, stating that if results hold up in phase 3, he believes that the weekly basal insulin has the potential be transformational for type 2 diabetes.”

    • A poster by Dr. Rich Bergenstal added to the growing arsenal of evidence linking time-in-range to hard outcomes. Drawing on the DEVOTE trial of Novo Nordisk’s Tresiba, Dr. Bergenstal showed that time-in-range was associated with a lower rate of first MACE. Specifically, there was a 22% risk reduction for MACE among the cohort of type 2 patients with 50%-70% time in range vs. those with ≤50% time in range. The benefit was amplified for patients with ≥70% time in range, who faced a 33% lower risk of MACE compared to their counterparts with ≤50%.

    • Despite safety concerns, development challenges, and regulatory hurdles, Profs. Chantal Mathieu and Tina Vilsbøll shared a positive outlook on SGLTs and GLP-1s as adjunct therapies for type 1 diabetes. Both speakers underscored that each therapy can provide safe benefits to a specific niche within the type 1 population, and they described these ideal patient candidates – we appreciated this session especially considering the many setbacks that SGLTs in type 1 have faced over the past year+.

    • We also have much, much more below that you’ll want to read – to start, we heard important commentary on Invokana’s renal indication in an SGLT-2/Kidney focused session, learned more about the potential link between CV risk/mortality and hypoglycemia in a new CAROLINA CVOT analysis, enjoyed a riveting debate on ADA vs. ESC guidelines regarding metformin as a first-line therapy, and saw new data for Zealand’s dasiglucagon, Lilly’s ultra-rapid acting insulin, and Hua Medicine’s glucokinase activator dorzagliatin.

  • Diabetes technology:

    • We saw several presentations today around new AID systems and AID in new populations. Stanford’s Dr. Laya Ekhlaspour read out very positive results from a small (n=12) study of Tandem’s Control-IQ in young children (ages 2-5 years). Compared to run-in, every glycemic outcome was improved with Control-IQ at home, including Time in Range (+1.8 hours/day), time >180 mg/dl (-1 hour/day), and time <70 mg/dl (3.7% vs. 1.5%). Two presentations on Beta Bionics’ iLet bionic pancreas confirmed a 2020 start for the insulin-only pivotal (enrollment “nearly completed”), while we saw the first data Lilly has shared on its AID system in a small, inpatient feasibility study.

    • There rounded up five notable posters related to Medtronic’s 7-day Extended Wear Infusion Set (EWIS). The posters did an excellent job outlining some of Medtronic’s work and considerations to develop the new set, while another poster showed 7-day survival rate of ~81%, higher than the published survival rate of Medtronic’s 3-day infusion set at 3 days (77%). The device is CE-Marked as of ATTD 2020 and currently in US pivotal trial.

    • On the CGM side, an Abbott poster showed significant A1c reductions in basal-only and non-insulin-using type 2s one year after using FreeStyle Libre. The retrospective analysis found FreeStyle Libre decreased A1c by 0.9% in non-insulin type 2s (baseline: 8.5%) and 0.6% in basal-only type 2s (baseline: 8.5%) after six months, with the benefits sustained out at 12-months. We were also thrilled to hear Dr. Shivani Agarwal share some takeaways from implementing inpatient CGM during the COVID-19 pandemic at the Albert Einstein Medical Center.

    • See below for data on Glooko’s MIDS basal titration system, moving stories from OHSU’s Novel Interventions in Children’s Healthcare program, and more.

Table of Contents 

Diabetes Therapy Highlights

1. Full Phase 2 Results for Novo Nordisk’s Once-Weekly Insulin Icodec Show Comparable Glucose-Lowering Efficacy and Safety to Insulin Glargine

Dr. Julio Rosenstock presented highly-anticipated phase 2 results for Novo Nordisk’s once-weekly basal insulin candidate, insulin icodec, demonstrating comparable glucose-lowering efficacy and safety to insulin glargine. Novo Nordisk also simultaneously released a statement at the end of the presentation – see here. From a baseline of 8.1%, icodec delivered an A1c reduction of 1.33% compared to 1.15% for the comparator of insulin glargine after 26 weeks. Although a nominally larger A1c reduction was associated with icodec treatment, this difference was not significant, as the 95% confidence interval barely crossed zero (95% CI for treatment difference: -0.38% to 0.02%). On hypoglycemia (both level 2 and 3 combined), rates for icodec were numerically higher than the glargine group, but this difference was not significant (60.55/per 100 pt. years vs. 52.36; p=0.85). Rates of level 1 hypoglycemia were also higher for the icodec group when compared to glargine (see table below). However, these trends were not significant, and Dr. Rosenstock assured viewers that rates of hypoglycemia in both groups were generally low and demonstrated strong safety. Importantly, duration of hypoglycemic events when they did occur were similar between the two groups – there had previously been some concern that because of the longer duration of action of the weekly icodec, that this may lead to longer hypoglycemia events; however, this was not found to be true. These hypoglycemia results may be interpreted as somewhat disappointing, as some had hoped that icodec may actually deliver a benefit on this outcome. However, it’s entirely possible that a large sample size – as is expected to be collected in phase 3 – may further flesh out this potential benefit. We’ll be looking closely for this in phase 3, along with hoping to see CGM data collected as well – speaking of, the phase 3 trial is expected to start later this year and will be designed to identify not only clinical but also convenience-related benefits.

Table 1 – Summary of Key Results

 

A1c

Proportion reaching A1c ≤7%

Proportion reaching A1c ≤6.5

Proportion w/ Level 1 Hypo

Proportion w/ Level 2 Hypo

Proportion w/ Level 3 Hypo

Icodec

-1.33%

72%

49%

54%

16%

1%

Glargine

-1.15%

68%

39%

38%

10%

0%

Table 2 – Summary of Key Results

 

Nocturnal Level 1 Hypo

Nocturnal Level 2 or 3 Hypo

Weekly Insulin Dose

FPG mean change from baseline

9-point SMBG profile mean change

Icodec

10%

2%

*229 U/week

-58 mg/dL

*-7.9 mg/dL vs. glargine

Glargine

11%

4%

284 U/week

-54 mg/dL

--

  • Dr. Rosenstock asserted that if these results are replicated in phase 3, he “personally believes that the weekly basal insulin has the potential be transformational” in type 2 therapy. He noted that the benefits of a weekly basal insulin that delivers similar glycemic efficacy and safety to the current once-daily standard of care would be immense. Fewer injections for the weekly insulin may increase adherence and compliance, along with reducing barriers to initiation insulin therapy that currently contribute to therapeutic inertia. Novo Nordisk’s CSO Dr. Mads Thomsen has voiced similar optimism on this front, pointing out that he sees insulin naïve patients with type 2 as the main target for therapy, as they may benefit from insulin therapy earlier in disease progression but are currently hindered by frequent finger pricking and injections (as well as titration changes) that come with daily insulin therapy.

  • Baseline characteristics: For the 247 participants, mean age was 59.6 years, average type 2 diabetes duration was 9.7 years, A1c was 8.1%, BMI was 31.3 kg/m2, and fasting plasma glucose levels were 181 mg/dL. All participants were insulin-naïve, and the only other diabetes meds they were on were metformin and potentially a DPP-4.

  • As background, icodec was developed to achieve a half-life of ~196 hours by engineering the insulin molecule to have a strong yet reversible binding to albumin. Albumin-binding is a common technique used in drug development to prolong duration of action of peptide/protein drugs. This binding of albumin allows for a circulating depot of icodec to exist, which is able to act very similarly to a human insulin molecule but be much more slowly cleared (and therefore allow for once-weekly dosing). Previous in vitro studies have established this similarity to human insulin’s action, confirming “specific and full agonism of the human insulin receptor” and the same dose-dependent mode of action as human insulin.

  • Novo Nordisk is also investigating icodec as a combo therapy with once-weekly semaglutide (deemed “icosema”). The once-weekly combo completed a phase 1 trial in December 2019 that compared it vs. icodec and semaglutide individually. According to a 4Q19 update from Novo Nordisk, next steps for the candidate are currently being discussed. We’re very excited about this candidate, especially given the incredible efficacy seen in clinical trials of daily basal/GLP-1 combos (Novo Nordisk’s own Xultophy and Sanofi’s Soliqua).

  • Elsewhere in the long-acting insulin landscape, Lilly also has two separate once-weekly candidates. These candidates are currently in phase 1 and phase 2. Rezolute was also studying a once-weekly candidate, but mixed phase 1 results led the company to discontinue its development.

  • Novo Nordisk’s ambitions within the insulin space go far beyond the once-weekly icodec, as the company also multiple other candidates in development. Phase 1 candidate FSI965 is expected to be a next-gen once-daily insulin that is best-in-class in terms of glucose-lowering and specifically geared toward positively impacting micro and macrovascular complications. Even more excitingly, Novo Nordisk also has a glucose-sensitive insulin candidate that is expected to move into phase 1 sometime this year – we presume this candidate is part of the company’s Ziylo acquisition in 2018.

Interview with Dr. Todd Hobbs
  • In a separate interview with Close Concerns, Dr. Todd Hobbs (Vice President and Chief Medical Officer, Novo Nordisk) expressed his optimism about the role for icodec in motivating initiation of and adherence to insulin regimens. He emphasized that the nature of icodec treatment – a simple weekly injection – may make physicians and patients “more amenable” to therapy. Given that icodec has shown to be as effective as glargine in this trial, he hopes icodec would lead fewer patients to delay insulin treatment. While work outside of therapy needs to be done to increase the number of patients meeting A1c targets, he hopes that icodec would make a “dent” in this problem by expanding the repertoire of therapy options available to patients. 

  • While the benefits of combination therapy with icodec and injectable semaglutide (“icosema”) have yet to be determined, Dr. Hobbs expressed optimism it would yield better outcomes than icodec alone. According to Dr. Hobbs, the therapy design – a single injection combination therapy – benefits patients specifically by reducing the frequency of dosing. Combining icodec with Rybelsus (a once-daily oral semaglutide) would potentially create more treatment burden for patients, for example. He also capitalized on the choice of semaglutide as the GLP-1 receptor agonist to be used in combination with icodec: compared to Victoza (liraglutide), semaglutide has been shown to facilitate more robust changes in weight loss and glucose control.

  • On incorporating diabetes technologies into existing treatment strategies, Dr. Hobbs agreed that continuous glucose monitoring (CGM) data should be used to influence therapy decisions. Dr. Hobbs exclaimed that “the standard of care for type 1 patients should be CGM” and that he was “fully supportive” of expanding the technology to patients with type 2. He also expressed hope that their therapy products would increase patient time-in-range, an endpoint that he believes, as someone with type 1 diabetes himself, “makes a lot of sense” to have in clinical trials. He admitted that expanding CGM accessibility and education remains a significant obstacle.

2. Superior Time-in-Range (≥70%) Associated with 33% CV Risk Reduction in DEVOTE, Further Validating TIR as Surrogate Endpoint

A poster by Dr. Rich Bergenstal added to the growing arsenal of evidence linking time-in-range to hard outcomes. Drawing on the DEVOTE trial of Novo Nordisk’s Tresiba (insulin degludec), Dr. Bergenstal showed that time-in-range (TIR) was associated with a lower rate of first MACE (non-fatal MI, non-fatal stroke, or CV death). Specifically, there was a 22% risk reduction for MACE among the cohort of type 2 patients with 50%-70% TIR vs. those with ≤50% TIR (HR=0.78, 95% CI: 0.55-1.09). The benefit was amplified for patients with ≥70% TIR, who faced a 33% lower risk of MACE compared to their counterparts with ≤50% TIR (HR=0.67, 95% CI: 0.53-0.85). We should note that 1.00 is well outside this latter confidence interval, and although the 22% risk reduction did not reach statistical significance, there was a significant overall association between increased TIR and decreased MACE rate (p<0.01). The analysis was conducted on a subset of DEVOTE participants (n=360) for whom the researchers had complete 8-point glucose profiles, which were used to derive time-in-range; 65% of this subgroup had ≥70% TIR. We can’t help but imagine the power of using CGM in a major CVOT like DEVOTE, and how that could move the field forward by leaps and bounds in validating TIR as a surrogate endpoint for long-term health outcomes. While some may say, “Of course we understand the limitations to adding CGM in a clinical trial that is already long, expensive, and intensive for patients …” we imagine that the problems are not length, cost, or degree of intensive-ness, but more just design and the fact that CGM may impact the outcome. But, we would love to ensure CGM will be used in future trials and we’d love to see a roundtable on this topic, to hash out issues around design, length of time CGM is used, cost, and other factors. And, of course we and many others wonder what impact could be gleaned from even a two-week CGM period within the context of a larger study.

  • Previous post-hoc analyses of DEVOTE have similarly focused on outcomes beyond A1c and their correlation with CV morbidity/mortality. This is fitting, given that Tresiba’s PK/PD profile leads to reduced hypoglycemia (40% risk reduction vs. Sanofi’s Lantus [insulin glargine], p<0.001 for superiority). An analysis called “DEVOTE 2” found that high day-to-day glycemic variability was associated with a 58% rise in risk for all-cause death (p=0.004). Another called “DEVOTE 3” underscored the relationship between severe hypoglycemia and all-cause death (HR=2.51, 95% CI: 1.79-3.50); in the 15 days immediately following a severe hypo episode, mortality risk was more than 4-fold (HR=4.20, 95% CI: 1.35-13.09).

  • Taken all together, these analyses, including the latest by Dr. Bergenstal, offer a robust package of results emphasizing the importance of studying outcomes beyond A1c for their long-term health consequences. It should be enough, we think, that TIR affects quality of life for people with diabetes – there is certainly agreement on this point among thought leaders. That said, a clear link to hard outcomes like heart attacks, strokes, and death will help sway the broader diabetes community (including regulators, worldwide PCPs, etc.) to adopt outcomes beyond A1c, and will augment our scientific understanding of this disease.

3. GLP-1 Agonists & SGLT Inhibitors for Type 1 – Not All Hope is Lost, According to Profs. Chantal Mathieu and Tina Vilsbøll

Despite safety concerns, development challenges, and regulatory hurdles, Profs. Chantal Mathieu and Tina Vilsbøll shared a positive outlook on SGLTs and GLP-1s as adjunct therapies for type 1 diabetes. To be clear, their focus was not on global regulatory approvals or widespread adoption of these agents in type 1. Rather, they underscored that each therapy can provide safe benefits to a specific niche within the type 1 population, and they described these ideal patient candidates. This is, of course, in hindsight, how it always should have been discussed – hindsight is 20/20 from a Close Concerns/diaTribe perspective. It has certainly been a rough year-plus for SGLTs as adjuncts in the US, with FDA denying approval to Lexicon’s Zynquista (sotagliflozin), AZ’s Farxiga (dapagliflozin), and Lilly/BI’s Jardiance (empagliflozin). AZ and Lilly/BI have since removed dapa and empa from their type 1 diabetes pipelines; Lexicon continues to be bullish on sotagliflozin, but we aren’t expecting FDA approval anytime soon. The story looks a little different outside the US, as EMA has approved dapagliflozin and sotagliflozin for type 1s with certain restrictions (BMI ≥27 kg/m2, only the lower dose authorized), and indeed, Dr. Mathieu emphasized these limitations during her talk. Overall, though, we sense a shift away from the notion that SGLTs and GLP-1s should be broadly available for all who have or treat type 1 diabetes, toward the idea that endocrinologists and diabetes specialists should consider these treatments for their most engaged patients. We pause a little bit about how engaged is sometimes “coded” but we have so much belief in these pioneers working on this from the EU and look forward to learning more. While it is undoubtedly disappointing that there are not approvals in the US, given the major unmet needs in type 1 diabetes and the fact that the most vulnerable patients may not yet be defined as those most engaged, we feel there is a way, particularly if limitations of A1c itself are addressed. We hold hope that SGLTs can be more widely available for people with type 1 in the US someday, as knowledge advances around mitigating DKA risk. For now, we value discussions like this one that illuminate where HCPs should start in incorporating adjunct therapies for their type 1 diabetes patients.

Dr. Mathieu displayed subgroup analyses from DEPICT and inTandem showing that elevated DKA risk nearly disappears when low doses are given to patients with overweight/obesity (BMI ≥27 kg/m2). Low dose in this case means 5 mg dapagliflozin daily or 200 mg sotagliflozin daily. Dr. Mathieu also highlighted the lack of a DKA signal for 2.5 mg empagliflozin in EASE, with the caveat that this was a single trial. She summarized the key benefits to SGLT inhibitors as an add-on to insulin – increased time-in-range, meaningful weight loss, etc. – stating, “SGLTs remain promising for type 1, I do believe that.” Then, she turned to the topics of patient selection and risk management.

  • “We handpick the patients who get an SGLT inhibitor.” Dr. Mathieu shared real-world data from her own practice in Belgium, showing that ~4% of ~1,500 individuals with type 1 diabetes received an SGLT prescription. She prescribes an adjunct only to adult patients whom she trusts to be diligent about ketone monitoring and to contact their care team when worried about possible DKA. In addition, the patient must have A1c below 9%-10%, a BMI above 27 kg/m2, and sufficient insulin on board (≥20 units/day). Of the 71 type 1s who were prescribed an SGLT inhibitor, 12 dropped off, citing fear of recurrent genital infections/DKA, insufficient A1c or weight benefit, pregnancy planning, or high cost. Mean duration of therapy was 16.7 months (about 1.33 years), and in that time, A1c dropped from an average of 8.2% to 7.9%, while body weight declined from a baseline 200 lbs to 193 lbs. Matching the findings from randomized controlled trials, 4% of people (3 individuals) experienced DKA.

  • On DKA risk mitigation, Dr. Mathieu’s key message was “education, education, education.” She showed the cards she gives to her patients alongside an SGLT prescription; the cards contain directions on proper measurement of ketones, as well as contact info for the care team. She reviewed the STICH protocol and the STOP DKA protocol, which highlight stopping the treatment, testing ketones, taking insulin, hydrating, and eating carbs. Dr. Mathieu argued that educating clinicians is just as important as educating patients. Moreover, she reminded viewers that participants in DEPICT, inTandem, and EASE received fairly intensive education around DKA and were given all the testing supplies they needed. Providing sufficient support will be much more challenging in the real world, without the infrastructure of an RCT program, which brought Dr. Mathieu back to her message of explicitly prioritizing education.

  • According to Dr. Mathieu, an uptick in hypoglycemia following introduction of an SGLT inhibitor is a signal that insulin dose wasn’t adjusted properly. She claimed that hypoglycemia risk is an avoidable problem when it comes to adjunct type 1 therapy. The solution is down-titrating daily insulin. Basal/bolus doses fell ~10% in the DEPICT trials, and there was no significant increase in hypoglycemia in Dr. Mathieu’s real-world patient pool.

Dr. Vilsbøll emphasized that despite mixed results on adjunct GLP-1 therapy, the weight loss efficacy of this drug class should not be overlooked, especially given the rising prevalence of overweight/obesity within the T1D population. Of all the study results she summarized (including, but not limited to, ADJUNCT ONE, Lira Pump, and MAG1C), the weight loss benefit of a GLP-1 agonist was consistent. Dr. Vilsbøll anchored her remarks around a case study of a 23 year-old woman with type 1 diabetes who is struggling with body weight, mild retinopathy, and elevated cholesterol, and she announced that she plans to initiate low-dose semaglutide (Novo Nordisk’s Ozempic) for this patient. She framed weight loss as the key upside to GLP-1 use, positioning type 1s with overweight/obesity as the ideal patient population for this particular adjunct treatment. Indeed, all participants in Lira Pump had overweight/obesity (in addition to being on CSII), and liraglutide (Novo Nordisk’s Victoza) improved A1c without causing additional hypoglycemia. The increased symptomatic hypoglycemia in ADJUNCT ONE raised concerns (although severe hypo was balanced across arms), and was one reason Novo Nordisk terminated the development program for liraglutide in type 1 diabetes. That said, Dr. Vilsbøll presented a subgroup analysis showing that this risk was driven entirely by patients who were C-peptide negative, the implication being that earlier intervention with an add-on GLP-1 agonist could yield benefits without excess symptomatic hypo.

  • Dr. Vilsbøll presented data from two relatively new clinical trials, which investigated short-acting exenatide (AZ’s Byetta) and albiglutide (GSK’s now-discontinued Tanzeum) as add-ons to insulin in type 1. In line with previous RCTs, MAG1C found a transient benefit on A1c (p=0.36) and a significant benefit on body weight (p<0.0001) with exenatide. Dr. Vilsbøll noted that “the conclusions were not that magical” and that Byetta doesn’t likely have a future as an adjunct type 1 treatment, not least because injection burden was tremendous in this study (3 exenatide + 4 or more insulin injections per day). Pozzilli et al. recently published a paper in JCEM. They were interested in whether newly-diagnosed type 1s could benefit from immediate introduction of an adjunct GLP-1, but one year of albiglutide therapy had no appreciable effect on preserving beta cell function.

4. SGLT-2s and the Kidney: Dr. Tuttle Highlights Invokana’s Broad Renal Indication and Class-Wide AKI Risk Reduction

In a review of CREDENCE, UW’s Dr. Katherine Tuttle asserted that the magnitude of benefit for SGLT-2 inhibitors in CKD is highly favorable and particularly impressive on top of standard-of-care management. Dr. Tuttle pointed to the primary composite outcome NNT of 22 over 2.5 years and emphasized that all NNTs (for ESKD, HHF, the composite of CV death + MI + stroke, and the renal composite of ESKD + doubling of serum creatinine + renal death) were all below 50. Indeed, as the body of evidence supporting SGLT-2 inhibitors and their accompanying label indications have continued to grow, SGLT-2s have blossomed into a truly remarkable drug class: oral agents capable of lowering A1c and weight, reducing heart failure events, slowing the progression of renal disease, and in some cases reducing MACE events. Dr. Tuttle especially highlighted that CREDENCE garnered J&J’s Invokana (canagliflozin) an indication that includes CV death, which is more likely to kill people with CKD than ESRD. This inclusion was attributed to the strength of risk reduction on the primary composite endpoint (HR=0.70, 95% CI: 0.59-0.82), which was compelling despite the close miss of superiority on CV death alone (HR=0.78, 95% CI: 0.61-1.00). Invokana’s full renal indication includes risk reduction for ESKD, doubling of serum creatinine, CV death, and hospitalization for heart failure in people with type 2 diabetes and diabetic nephropathy with albuminuria. There is no indication for reduction of renal death because, as Dr. Tuttle noted, very few renal deaths occurred and the risk estimate was therefore unreliable.

  • Dr. Tuttle homed in on an additional renal benefit that has been associated with SGLT-2s: reduced risk of acute kidney injury. The hazard ratio for AKI with canagliflozin was 0.85 in CREDENCE (95% CI: 0.64-1.13), and the other SGLT-2 outcomes trials in diabetes – DECLARE, CANVAS, and EMPA-REG – also trended in favor of the SGLT-2, reaching statistical significance in DECLARE (HR=0.69, 95% CI: 0.55-0.87) and EMPA-REG (HR=0.76, 95% CI: 0.62-0.93). Combining data from all four trials indicates an overall 25% risk reduction (HR=0.75, 95% CI: 0.66-0.85). Dr. Tuttle indicated that this was particularly important within the population with CKD and emphasized that AKI events in CREDENCE were adjudicated and therefore very reliable. The importance of AKI incidence to people with CKD is readily apparent, but this finding is also very reassuring given ongoing concern that SGLT-2s cause AKI via intravascular volume contraction. While that risk is real, it should also be weighed against reduced risk overall.

  • Dr. Tuttle highlighted the recent early stop for Dapa-CKD. Very notably, Dapa-CKD enrolled people both with and without diabetes – giving hope for potential renal benefits with dapagliflozin in CKD outside of diabetes, just as Dapa-HF demonstrated efficacy of dapagliflozin for treating heart failure in those without diabetes. We appreciated Dr. Tuttle’s characterization of the early stops for both CREDENCE and Dapa-CKD: In nephrology, trials have been halted early by data monitoring committees – but never before for efficacy. This underscored both the challenging nature of treating renal disease and the new era of CKD management that SGLT-2 inhibitors are bringing. Here’s a quick summary of the three renal outcomes trials for SGLT-2 inhibitors:

Drug

Trial Name

Population

Completion Date/Latest Update

J&J’s Invokana (canagliflozin)

CREDENCE

n=4,401 with type 2 diabetes, Stage 2 or 3 CKD (eGFR ≥30 to <90 ml/min/1.73 m2), and macroalbuminuria (UACR >300 to ≤5,000 mg/g). Type 1 patients excluded.

 

Landmark full results released in April 2019; Novel renal indication approved by FDA in September 2019

AZ’s Farxiga (dapagliflozin)

Dapa-CKD

n=4,000 with CKD (eGFR ≥25 to <75 ml/min/1.73 m2), with or without diabetes. UACR ≥200 and ≤5000 mg/g. Type 1 patients excluded

Trial halted early due to efficacy, ahead of expected November 2020 completion; Fast Track designation received from FDA in August 2019

Lilly/BI’s Jardiance (empagliflozin)

EMPA-KIDNEY

n=5,000 with CKD (eGFR ≥20 to <45 mL/min/1.73m² or eGFR ≥45 to <90 mL/min/1.73m² with UACR ≥200 mg/g) with or without diabetes. Type 1 patients included.

Expected completion June 2022; Fast Track designation from FDA received in March 2020

5. Is There an Association Between Prior Hypoglycemia Events and CV Risk/Mortality? Dr. Julio Rosenstock Presents Mixed Evidence From CAROLINA CVOT

Dr. Julio Rosenstock presented a novel analysis of the CAROLINA trial finding that antecedent hypoglycemia events were associated with higher risks for all-cause mortality and non-CV mortality, but not with any other CV-related endpoint. Between the two arms of the trial (DPP-4 linagliptin and sulfonylurea glimepiride), hypoglycemia events were associated with a 49% greater risk of all-cause mortality (95% CI: 16% to 92%; p=0.002) and 116% increased risk of a non-CV death (95% CI: 57% to 197%; p<0.0001). Significant associations were not seen for other endpoints in the trial, including 3P-MACE, stroke, MI, hospitalization for heart failure, and CV death (see plot below).

  • As a reminder, CAROLINA found neutrality on CV outcomes between linagliptin and glimepiride, along with significant differences on hypoglycemia rates between the two therapies. In the trial, 38% of patients experienced any form of hypoglycemia in the glimepiride arm vs. 11% in the linagliptin arm, resulting in a hazard ratio of 0.23 (95% CI: 0.21-0.26, p<0.0001). Considering only moderate (≤70 mg/dL) and severe (requiring assistance) hypoglycemia, linagliptin conferred a sizable 82% risk reduction (HR=0.18, 95% CI: 0.15-0.21, p<0.0001), and on the serious and costly outcome of hospitalization due to hypoglycemia, a significant, 93% risk reduction (HR=0.07, 95% CI: 0.02-0.31, p=0.0004), despite only 29 events occurring (27 with glimepiride, 2 with linagliptin).

  • We note that the link between hypoglycemia and CV outcomes has been long-debated within the diabetes community. Traditionally, a direct causal relationship between severe hypoglycemia and MACE/mortality has been considered, and has been supported by evidence suggesting that severe hypoglycemia induces several potentially adverse effects in the vasculature and the heart. Conversely, at CODHy 2019, we heard Prof. Eberhard Standl argue that a bi-directional relationship between severe hypoglycemia and CV risk exists, with an emphasis on the possibility of a reverse causation between nonfatal MACE events and severe hypoglycemia. Dr. Standl pointed to analyses of the TECOS CVOT for sitagliptin and EXSCEL CVOT for exenatide as showing a robust association between severe hypoglycemia events and previous major CV events, with a near doubling in risk of a severe hypoglycemia event following a nonfatal CV or HF event. We’d be interested to see a similar analysis of CAROLINA – did CV events in the trial make it more likely that patients experienced severe hypoglycemia events, and was this risk modified whether patients were on linagliptin or glimepiride? 

6. ADA vs. ESC on Replacing Metformin as First-Line Therapy; Drs. Davies and Cosentino Face-Off

There is a small but important difference in the latest ESC vs. ADA guidelines on type 2 diabetes treatment, and this was the focus of a riveting debate between Dr. Francesco Cosentino and Prof. Melanie Davies. The experts agreed that drugs with proven cardioprotective benefit should be initiated earlier in type 2s with ASCVD. Where their opinions diverged was around whether metformin should be recommended as first-line therapy for this high-risk patient group. Dr. Cosentino defended the ESC’s 2019 guidelines, which deprioritize metformin and instead position GLP-1 agonists and SGLT-2 inhibitors as first-line for type 2s with ASCVD. He argued that these agents exert their CV benefits with or without background metformin, citing subgroup analyses of EMPA-REG OUTCOME and HARMONY. In EMPA-REG, empagliflozin (Lilly/BI’s SGLT-2 Jardiance) significantly reduced risk for three-point MACE irrespective of a patient’s concomitant metformin use (p=0.14 for the interaction). Similarly, in HARMONY, albiglutide (GSK’s now-discontinued Tanzeum) demonstrated consistent risk reduction for three-point MACE among patients taking metformin and those who weren’t (p=0.928 for the interaction). We should note that Prof. Davies countered here and emphasized that the majority of participants in diabetes CVOTS (upwards of 70%) were on background metformin. When they weren’t, there was typically a specific reason such as intolerance or low eGFR, which makes it challenging to interpret these subgroup analyses without adjusting for key differences in patient characteristics. Prof. Davies explained the rationale for keeping metformin in its first-line spot in the ADA/EASD 2019 consensus statement (and by extension, in the 2020 ADA Standards of Care). In most health economies, it would be unrealistic to deprioritize a generic drug with a longstanding reputation for safety and glucose-lowering efficacy, especially when the alternative is two drug classes that remain quite pricey. Prof. Davies asserted that guidelines must take cost-effectiveness into account, alongside clinical evidence. On that note, she underscored that there have been no head-to-head trials comparing metformin to GLP-1s or SGLT-2s in treatment-naïve patients. Dr. Cosentino countered by asking, is metformin still first-line based on evidence, or at this point, is it based on habit?

In our view, both speakers made compelling points. While we would love to see swift intervention with a cardioprotective diabetes drug in all type 2s at high CV risk, we’re aware that the ESC recommendations are somewhat controversial to some (read more KOL comments here – several suggest that ESC has gone beyond the available data). Ultimately, we think that the major points relate to evidence and it’s interesting to see that when RCT isn’t available, expert advice comes in. We feel that current Standards of Care are not being translated optimally for patients, particularly given the extremely disturbing and unsettling data from the Mayo Clinic given on ADA Day #1: (Medicare Beneficiaries are 55% and 69% Less Likely to be Prescribed GLP-1s and SGLT-2s Than People w/ Commercial Insurance, According to New Expert Analysis). Moreover, Prof. Davies argued that removing metformin as the first-line treatment option is unnecessary and could even be “distracting” from the overarching goal of getting more high-risk patients on a GLP-1 or SGLT-2 – many experts agree, given multiple adherence issues associated with metformin. What we need to focus on instead, she explained, is training physicians to recognize and proactively address CV risk in people with diabetes.

7. 52-Week PRONTO-T1D Data: URLi Beats Humalog on Postprandial BG and Late-Postprandial Hypoglycemia, Not A1c; Strong Safety Profile

52-week data from Lilly’s phase 3 PRONTO-T1D study of ultra-rapid lispro (URLi) in type 1 diabetes demonstrated maintenance of lower postprandial blood glucose with mealtime URLi (n=451) compared to mealtime insulin lispro (Humalog, n=442) out to one year. There was no difference in A1c at 52 weeks – i.e., URLi was non-inferior to Humalog on A1c lowering. Here are the key glycemic results:

There was no imbalance in treatment-emergent or serious adverse events, and there was no difference in severe hypoglycemia, nocturnal hypoglycemia, or documented symptomatic hypoglycemia (<54 mg/dl) over all 52 weeks. There was also no difference in postprandial hypoglycemia 0-4 hours post-meal, but URLi was associated with a 31% reduction in late postprandial hypoglycemia (RR=0.69, p=0.023). There were no differences in body weight changes, insulin doses, or ratio of bolus to total dose. There were more injection site reactions with URLi compared to Humalog, but these were only seen in 3.3% of participants and were mostly mild; none led to treatment discontinuation. There was no concern over insulin antibodies.

  • 26-week data from PRONTO-T1D and PRONTO-T2D were presented at ADA 2019: mealtime URLi demonstrated non-inferiority to Humalog on A1c reduction (postmeal URLi gave a significantly higher A1c) and also delivered superior postprandial glucose control on mixed-meal tolerance test. The study included three arms: mealtime URLi (n=451), mealtime Humalog (n=442), and postmeal URLi (n=329; open-label). All participants used MDI regimens and had a starting A1c of 7.0%-9.5%. Importantly, the postmeal URLi arm did not continue to 52 weeks. ~92% of participants completed the full study duration and treatment. Baseline characteristics were: mean age 44 years, 56% men, BMI 27 kg/m2, 19 years of T1D, 56% glargine/44% degludec, and 12% used personal CGM/FGM.

  • URLi (future trade name Lyumjev) has been submitted for approval in the US, EU, and Japan. The candidate received a positive CHMP opinion in the EU in February 2020 for both type 1 and type 2 diabetes, and US submission occurred in 3Q19. We have no reason to expect regulatory hurdles for URLi’s approval, but Lilly has also been particularly quiet about the candidate – which has only increased our curiosity about their clinical and commercial strategy. (We have an inkling that closed-loop systems are a significant part of that strategy, based on Lilly’s significant investment in URLi pump studies – that was confirmed today at ADA.) There is an obvious comparison between URLi and Novo Nordisk’s Fiasp (faster-acting aspart), in terms of both their place within each company’s diabetes portfolio and the clinical data for the candidate compared to its predecessor. We’ll be interested to see whether/how Lilly’s approach differs, and while we’re pleased that both of these companies continue to invest in insulin and expanding options available to patients, we’d also like to see greater investment in alternative classes for patients without access yet (type 1 outside the EU, type 2s in countries without strong reimbursement), especially given that improving prandial insulin is slow (the results do not yet approach next-gen basal results) and more emerging evidence that insulin increases inflammation and that all on insulin should strive to take the optimal amount. Many need more insulin, which we’d also like to see become a bigger focus – and more can also benefit from combination therapy that is safer and more tolerable.  

8. Dr. Tadej Battelino Finds No Relationship Between Dasiglucagon Concentration and Elevated Nausea/Vomiting in Adolescents Using Rescue Treatment Compared to Children

Dr. Tadej Battelino (University Children’s Hospital, Slovenia) dove into full results from the phase 3 pediatric study of Zealand’s HypoPal dasiglucagon rescue pen, which demonstrated significantly improved median time to blood glucose recovery (first increase of ≥20 mg/dL) compared to placebo (p<0.001). Zealand previously announced topline results for the trial in September 2019, and since then, submitted HypoPal to FDA in March 2020. Most enlighteningly, Dr. Battelino elaborated on what may be driving elevated rates of nausea and vomiting adverse events in participants ages 12-17 years old (“adolescents”) using dasiglucagon compared to their younger counterparts ages 6-11 years old (“children”). Interestingly, no relationship was found between exposure to dasiglucagon and nausea and vomiting based on maximum concentration of dasiglucagon in the blood (Cmax), area under the curve (AUC300), or participant BMI. As such, Dr. Battelino suggested that the increased nausea and vomiting in adolescents on dasiglucagon was likely due to small sample size. To note, Lilly’s nasal glucagon Baqsimi seems to induce less nausea in users; however, it has higher rates of head/facial discomfort, and Xeris’ GVOKE glucagon injection has similar elevations in nausea and vomiting. Of course, some patients will be on board with these mild adverse events in exchange for a much easier-to-use hypoglycemia rescue option – we suspect some could also receive more optimal training that would result in less nausea overall or earlier decisions during “trials” that the therapy is not for them.

  • The study randomized n=41 children (aged 6-17 years old) to (i) dasiglucagon 0.6 mg (n=20); Novo Nordisk’s first-generation GlucaGen 1.0 mg (n=10); and placebo (n=11). Participants had a median A1c of 7.6% (5.3-11.2), diabetes duration of six years, and BMI of 20 kg/m2, though only 44% of study participants were female. Following induced hypoglycemia, median time to glucose recovery was 10 minutes (95% CI: 8 – 12 min) in the dasiglucagon arm, compared to 30 minutes (95% CI: 20 – n/a min) in the placebo arm (p<0.001). Time to recovery was non-inferior to that shown by GlucaGen, which also displayed a 10-minute recovery time. Dasiglucagon similarly met all secondary endpoints including, plasma glucose recovery within 10, 15, 20, and 30-minute timeframes, as well as plasma glucose change from baseline for the same windows.

  • Last we heard from Zealand during its 1Q20 update, the launch of HypoPal is still expected in “early 2021.” If approved (and we expect it will be – as a sidenote, the FDA has stated there will be no Ad Comm, not that that is evidence on approval prospects), HypoPal will be the third “next-generation” hypoglycemia treatment to hit the US market. For reference, Baqsimi delivered $6 million and $16 million in its first and second quarters on the market, while the GVOKE pre-filled syringe pulled in $1.6 million and $1.7 million in 4Q19 and 1Q20, respectively.

9. Full Results from 24-Week Phase 3 SEED Study Indicate Improved Beta Cell Function with Glucokinase Activator Dorzagliatin (HMS5552), Though Effect on Weight and Long-Term Benefit Unknown

CEO and CSO of Hua Medicine Dr. Li Chen (Hua Medicine, China) detailed full results from the double-blind portion of the phase 3 SEED study investigating oral glucokinase activator (GKA) dorzagliatin (HMS5552) in patients with type 2 diabetes. As announced in positive topline results in November 2019, dorzagliatin met its primary endpoint in the trial, demonstrating a 1.1% reduction in A1c (from baseline of ~8.4%) at 24 weeks compared to an 0.5% reduction on placebo (p<0.0001). Dorzagliatin also showed a solid safety profile, with very low hypoglycemia incidence (0.3%) and no serious adverse events. In terms of secondary endpoints, reduction in two-hour postprandial glucose was observed with dorzagliatin vs. placebo (-2.83 vs. -0.50 mmol/L, p<0.001). We were also interested to see Dr. Chen hone in on significant beta-cell function improvement, as measured by HOMA 2-β, over placebo (+3.28%, p<0.05) (though we’re not entirely sure how clinically relevant this difference is). Looking to the future, we’ll be curious to see more long-term maintenance data regarding A1c improvement, particularly A1cs that are not associated with hypoglycemia.

  • SEED was a multi-center (40 study sites in China), randomized, double-blind, placebo-controlled trial. Of the 975 individuals screened, n=461 participants completed the four-week placebo run-in and were randomized to either a 24-week treatment period of (i) dorzagliatin 75 mg, twice daily (BID); or (ii) placebo BID. Mean age was ~53 years old, with a 65/35 split between male and female participants. Baseline A1c was ~8.4% and BMI ~25 kg/m2. Participants underwent diet and exercise interventions for at least three months before the trial but were otherwise diabetes therapy naïve.

  • Looking ahead, Dr. Chen confirmed that all participants have completed the 28-week open-label treatment period as well – we’ll be sure to keep our eyes peeled for this data. In terms of combination oral therapies, Hua Medicine has also demonstrated successful combination effects with SGLT-2 inhibitor empagliflozin and DDP-4 inhibitor sitagliptin, and we look forward to hearing more as these pairings advance into later stages of clinical trial.

  • At an intriguing session earlier at ADA 2020 on the progression of type 2 diabetes, University of Washington’s Dr. Steven Kahn expressed concern over the long-term success of type 2 therapies that work primarily on beta cells. Although glucokinase activators also have dual action in the liver, we wonder if the candidate will be able to deliver sustained control without more specifically addressing insulin resistance. We have yet to see any data on dorzagliatin’s effects on weight or BMI. However, we do note that the oral format is a very attractive point for “next-gen” type 2 therapies. 

  • Hua Medicine is currently the only company pursuing a GKA in type 2 diabetes. Previously, phase 2b results from the AGATA trial for vTv Therapeutics’ TTP399 in type 2 garnered significant praise from Dr. John Buse at EASD 2018, however the company has since prioritized the compound in type 1 diabetes (see results from part 2 of Simplici-T1 at ADA 2020). Similarly, industry-wide hope for the GKA class has been mixed. Recent GKA discontinuations include Lilly/Yabao’s phase 2 LY2608204 and Ligand’s preclinical candidate (no longer in the pipeline). Key opinion leaders, like Newcastle University’s Dr. Philip Home, have even suggested that GKAs are unlikely to yield significant clinical benefits in type 2, though an A1c drop of -1.1% would certainly qualify as being clinically meaningful. That being said, the type 2 drug landscape has become increasingly competitive in recent years, backed by impressive CV and renal benefit, and we imagine it will be a long road ahead for a GKA to gain the same momentum as serious competition from the incretin front.

10. Additional Data from DiRECT Implicates Lipogenesis as Potential Driver of Diabetes Relapse

Newcastle’s Ms. Alison Barnes (Senior Research Associate and Dietitian) presented additional findings from the DiRECT trial during an early-morning symposium on lifestyle interventions for type 2 diabetes remissions. Findings show that de novo lipogenesis, and the subsequent increase of palmitic acid, may cause beta cell dysfunction and diabetes development after initial remission (i.e. “relapse”). Ms. Alison Barnes began her presentation with a refresher on the DiRECT trial, which found that a very low-calorie diet (450-800 cal/day) conferred type 2 diabetes remission in 36% of enrollees at the two-year mark. Ms. Barnes emphasized the link between weight loss and 24-month remission given that 64% of participants who lost at least 10 kg were in diabetes remission. With this, remission in DiRECT depended on beta cell capacity to recover once excess fat was lost, showing significant differences in insulin response between responders and non-responders at 12 and 24 months. When looking at differences between responders and relapsers, plasma V-LDL levels remained stable in responders but increased in the 12-24 month period in relapsers. Furthermore, responders lost 2% more pancreatic fat than relapsers throughout the two-year study (p=0.002). The inverse relationship between palmitic acid synthesis and beta cell function between responders and relapsers (i.e. responders show lower levels of palmitic acid and higher beta cell function, and vice-versa for relapsers) supports fatty acid synthesis’ role in type 2 diabetes onset. During Q&A, the session moderator asked about how this data can inform how clinicians identify potential responders to very low-calorie diets, to which Ms. Barnes stressed the benefit coming from these diets isn’t only limited to diabetes status. While there is not enough data to classify responders or non-responders with certainty, low-calorie diets still hold promise for patients in regard to weight loss, reduce medication-use, and delaying initiation of more medications. Rather than deciding who should be on these diets based on the potential for remission, Ms. Barnes believes that clinicians should have honest conversations with patients about their expectations and only continue with this diet for patients who are still motivated to try knowing that they are not guaranteed diabetes remission.

  • For more detail and context on the DiRECT program, see our recent interview with lead investigator Dr. Roy Taylor.

11. Dr. Green Decries Poor Guideline Adoption and Stresses Importance of Outpatient Preventive Care to Minimize Covid-19 Impact

Duke’s Dr. Jennifer Green discussed the translation of new cardiorenal evidence to clinical practice, pointing to poor adherence to new treatment guidelines in the management of diabetes. After praising the swift incorporation of new data into professional society guidelines, Dr. Green pointed to this analysis (which we heard about at AHA 2019) showing that <3% of patients with CVD and diabetes insured by Anthem are on a high intensity statin, an ACEi/ARB, and a GLP-1 agonist or SGLT-2 inhibitor. Perhaps even more concerning, Dr. Green said, is that 37% were taking none of the three and 41% were only taking one, despite very clear indications in favor of all three. This state of affairs led Dr. Green to pose the question, “Are we lost in translation” of evidence-based care guidelines? The answer seems to be a resounding yes, leading Dr. Green to argue that we “can’t toss this around between specialties” in an apparent indictment of the barriers both endocrinologists and cardiologists commonly cite against making guideline-recommended treatment changes. That list of barriers is long, and Dr. Green rattled off therapeutic inertia, lack of knowledge, risk-benefit concerns, care coordination issues, medication cost, lack of acceptance, and lack of time for patient discussion and training. During Q&A, moderator Dr. David Cherney described two obstacles he commonly hears providers name: Cardiologists and nephrologists are reluctant to interfere with glucose management, and endocrinologists are apprehensive about making diuretic and anti-hypertensive adjustments. Dr. Green argued that these are easily surmountable issues. For example, when starting an SGLT-2, check a patient’s volume status and reduce diuretics as you add the SGLT-2 if it makes sense – “you can always add it back.” Further, Dr. Green said, there are opportunities to actually swap out drugs to make for safer and even cheaper treatment regimens that are more in line with current guidelines. Diabetologists must cease deferring to cardiologists for CV protection, and cardiologists must become comfortable prescribing “diabetes” drugs. To this end, Dr. Green highlighted the Lilly/BI sponsored COORDINATE-Diabetes study, run by Duke across 46 US cardiology clinics, which aims to enhance uptake and implementation of cardioprotective diabetes agents in cardiology practices.  To be sure, many healthcare systems are poorly set up for collaboration between different specialty clinics – and patients may see providers in difference systems altogether. We’re glad to see new diabetes drugs driving efforts to better align providers, and we’re excited about the impact this could have on patient care and outcomes.

  • Dr. Green argued that outpatient preventive care is critical to ameliorating the negative impact of Covid-19 on people with diabetes, CKD, and CVD, while cautioning that there’s no data yet to show improved outpatient care delivery improves outcomes against Covid-19. In order to “maximize health at home,” providers should focus on continuing to deliver routine and acute care, adhering to guideline-based risk reduction, and addressing disparities in care – which have almost certainly been magnified by the pandemic. Dr. Green made a point to outline the multiple ways that Covid-19 is and will be detrimental to people with diabetes. People with diabetes hospitalized due to infection (i) have longer stays, (ii) are more likely to need ICU care, ventilation, and renal replacement therapy, and (iii) have higher risk of mortality, per Dr. Green, and the pandemic has reduced inpatient and outpatient encounters for coronary heart disease, diabetes care, stroke, and heart failure by >50% each.

12. CVD Interest Group Session Shines Spotlight on Greater Risk of HF in Women with Diabetes

In a professional interest group discussion on diabetes and cardiovascular disease, University of Virginia’s Dr. William Horton presented concerning data on the excess cardiovascular risk in women with diabetes. While in the general population women have fewer CV events than men of the same age, CV risk is actually the same between men and women with diabetes. The situation is even more dire for heart failure: Women with type 2 diabetes have 9% greater excess risk of HF than men, and this rises an incredible 47% for women with type 1 diabetes. Furthermore, rates of HFpEF, the form of HF with that is less-responsive to current therapies and more tightly linked to adiposity, obesity, and diabetes, are higher in women vs. men with diabetes. Why does diabetes interact differently with cardiovascular disease on the basis of sex? According to Dr. Horton, one possible reason could be greater severity of diabetes among women. According to a recent report from the Diabetes Collaborative Registry, only 18.6% of women with diabetes meet all four major ADA treatment targets (A1c <7%, LDL <100 mg/dl, blood pressure <140/90 mm Hg, and non-smoking status) vs. 23.6% of men (OR 1.31; 95% CI: 1.26-1.36; p<0.001). Furthermore, women tend to develop type 2 diabetes at a higher BMI than men do and spend approximately two additional years in the prediabetes stage, implying greater exposure to hyperglycemia before diabetes diagnosis. Another non-mutually-exclusive hypothesis for the excess CV risk among women with diabetes is persistent under-diagnosis and under-treatment of both CV disease and diabetes in women, related to the long history of underrepresentation of women in clinical trials and the corresponding lack of data on how signs and symptoms of these diseases may manifest differently in women vs. men. We couldn’t agree more with Dr. Horton’s call for more trials to understand gender differences in CV disease, particularly HF, and the mechanisms underlying this. We hope this also provides an impetus for more personalized screening methods for CV disease in women with diabetes and greater enrollment of women (and other under-represented groups) in CVOTs.

  • Given sex-differences in CV risk, there is also reason to think that there may be sex-differences in the CV benefits of pharmacotherapies. To this end, Dr. Horton highlighted a recent claims-based study comparing the risk of non-fatal CV events in women vs. men with diabetes (n=167,254) with DPP-4 inhibitor, GLP-1 agonist, and SGLT-2 inhibitor therapies relative to SFUs. Very interestingly, over SFUs, GLP-1 agonists were associated with a 43% risk reduction for non-fatal CV events in women vs. only an 18% risk reduction in men (HR 0.57 vs. 0.82, p=0.002). A similar trend appeared for SGLT-2 inhibitors, though it did not reach statistical significance (HR 0.58 vs. 0.69, p=0.27). It remains unclear whether these results imply that SFUs are particularly dangerous for women with diabetes (we would believe this, since women are at higher risk of obesity) or whether GLP-1 agonists and SGLT-2 inhibitors are particularly beneficial (easier to take therapies are positive for everyone, but possibly particularly women, given the higher number of responsibilities many women have). Nonetheless, we look forward to much more research on this topic. `

13. Discussion on Diabetes Self-Management Education and Support (DSMES): Leaders Call to “Raise the Roof” on Number of DSMES Users, New Guidance from the 2020 Consensus Statement

We tuned into a bustling session on the 2020 DSMES consensus statement for adults with type 2 diabetes, just published in Diabetes Care, led by the always inspiring Dr. Margaret Powers (HealthPartners), Ms. Joan Bardsley (Medstar), and Dr. Clipper Young (Touro University, CA) as well as longtime patient leader Ms. Anna Norton, CEO of Diabetes Sisters. We loved watching the “chat box” light up with lively discussion from Diabetes Care and Education Specialists from around the world, who all agree that DSMES is underutilized and that streamlining referral and reimbursement to these services will be critical to improving access moving forward. According to data presented by Dr. Powers, only 5% of Medicare beneficiaries with newly diagnosed diabetes receive DSMES services (even though it is in fact covered), and only 7% of individuals on private health insurance use DSMES within 12 months of diagnosis.

  • Dr. Powers emphasized the importance of having open, encouraging conversations with patients when introducing them to DSMES services. In particular, she recommends beginning appointments with questions to identify patients’ strengths and needs. Even though HCPs may be hesitant to “go down a rabbit hole” by questioning patients at the beginning of an appointment, Dr. Powers emphasized that these “rabbit holes” are often the most important topics to discuss. Asking patients, “How can we best help you?” often opens up surprising conversations that can be highly informative to later care. Furthermore, HCPs should express that DSMES is not simply “telling patients what to do”; it is a fluid, collaborative, and patient-centered process that utilizes personalized goal setting and behavior change support.

  • The new guidelines highlight four critical times to provide and modify DSMES: (i) at diagnosis; (ii) annually and/or when not meeting treatment targets; (iii) when complicating factors develop (i.e. develop renal disease, planning pregnancy, changes in basic living needs, especially during COVID-19); and (iv) when transitions in life and care occur (i.e. going into a nursing home, discharge from inpatient to outpatient, starting CGM, insurance changes). As with much of diabetes care, education is not a “one and done” process. Goals need to be continually reassessed and developed based on the needs of the patient.  

  • Ms. Bardsley made the insightful comment that referral to DSMES services does not only have to be done when a patient is doing “poorly.” Honing-in on the “support” aspect of the DSMES, she noted that Specialists should also support patients to ensure that any beneficial behaviors continue into the future. We were reminded of The diaTribe Foundation alumni Adam Brown’s emphasis on the importance of “bright spots,” or points in diabetes self-management that are working and could be done more often. 

  • One key area where recommendation of DSMES services could be increased is at the transition from in-patient to out-patient care. One Specialist in the “chat box” mentioned that often patients who are diagnosed with diabetes in the hospital receive survival skills education but are not then referred to DSMES. As most in-patient care is already at capacity, automatization of a PCP appointment and DSMES referral from the PCP at hospital discharge could streamline efforts for all parties involved.

  • Many session attendees seemed interested in the ins and outs of reimbursement for DSMES. One Specialist mentioned providers are often not aware of the ADA guidelines for DSMES diagnostic criteria (for commercial insurance patients) or Medicare diagnostic criteria (for Medicare beneficiaries).

    • Dr. Powers also took the time to clarify that all providers (MD, DO, NP, PA) can make referrals to DSMES, though Medicare only allows referral from the provider “primarily responsible” for diabetes care.

  • Overall, we are very impressed by the comprehensive and collaborative nature of the new consensus document and hope to see payers and providers continue to support Diabetes Care and Education Specialists in this important endeavor. A hearty congratulations to the ADCES (f0rmerly known as AADE), ADA, Academy of Nutrition and Dietetics, American Academy of Family Physicians, American Academy of PAs, American Association of Nurse Practitioners, and the American Pharmacists Association. Now, we’d like to see lots of focus on, given this incredible content, how the marketing and translation for multiple groups can be optimized even further.

14. Phase 2 Trial of CXCR1/2 Inhibitor Ladarixin for New-Onset T1D Meets Key Secondary and Subgroup Endpoints

In an oral presentation, Dr. Paolo Pozzilli (University of Rome, Italy) reviewed encouraging data from a phase 2 trial of CXCR1/2 inhibitor ladarixin to restore beta cell function in new-onset type 1 diabetes. The trial enrolled people newly diagnosed with type 1 diabetes, within 100 days of beginning insulin therapy (mean age 26 years, mean BMI 22.5 kg/m2, mean A1c 7.5%). Participants were randomized 2:1 to ladarixin or placebo and received three separate four-week treatment cycles (14 days on the drug, 14 days off the drug) and were then followed for up to one year. Unfortunately, there was no statistically significant difference between ladarixin and placebo for the primary endpoint of mixed-meal tolerance test (MMTT)-stimulated AUC of C-peptide (p=0.330 at week 13 and p=0.404 at week 26). However, in subgroup analyses ladarixin was superior on this endpoint for the subgroup of participants with below-median fasting C-peptide levels at baseline (i.e. participants with lower diabetes severity; p=0.041). Furthermore, after 26 weeks ladarixin showed superiority over placebo for the composite secondary endpoint of HbA1c <7% and daily insulin requirements <0.50 units per kg in the whole study population (76.6% vs. 45.8%, p=0.0095). Adverse reactions included dyspepsia (16% of the ladarixin group) and headache (16% of both the ladarixin and placebo groups), and no concerns were raised regarding the overall safety profile of the therapy. Dr. Pozzilli emphasized that although the trial did not meet the primary endpoint, secondary and subgroup analyses show promise for the agent (perhaps in a more specific patient population) and warrant further, larger studies.

15. Completer Analysis Affirms Safety of MannKind’s Afrezza on Lung Function Over Two Years

MannKind CMO Dr. David Kendall presented two-year data supporting the safety of inhaled insulin Afrezza (Technosphere Insulin) to pulmonary function, in people with type 1 and type 2 diabetes (n=963). Prior research has demonstrated that pulmonary function changes (specifically, FEV1 changes) with Afrezza are small, non-progressive, and reversible with therapy cessation. Dr. Kendall presented a post-hoc completer analysis of that same data, including people with type 1 or 2 diabetes and normal baseline lung function (FEV1 ≥70% of expected) who completed ≥five FEV1 measurements, including baseline and month 24. Of 377 subjects on Afrezza, 88% had no FEV1 tests with significant decline (defined as a ≥15% drop in FEV1 from baseline) over two years of TI use and 5 total tests, compared to 93% of the 586 subjects receiving usual diabetes care. Among those who did have FEV1 tests showing significant decline, 7% (TI) and 6% (usual care) had 1 test, 3% and 2% had 2 tests, and ≤1% in both groups had 3-5 tests showing significant decline. While ~12% of participants on Afrezza had a ≥15% decline in FEV1 at some point, only 2.1% experienced a persistent decline – that is, the decline occurred at ≥3 time points. All others experienced transient decline, meaning the drop occurred at ≤2 time points. This compares to 0.7% of participants on usual care experiencing persistent decline in FEV1. In other words, 98% of those on Afrezza and 99% on usual care did not have persistent, significant decline in FEV1 over two years of use. There were no associations with age, gender, race, or insulin dose, and mean percent change in FEV1 was similar between those who did (28% of participants) and did not experience coughing. Despite consistent positive findings on Afrezza’s pulmonary function impact, our sense is that many patients and providers remain confused about the product’s potential effect on their lungs or that they think there will be problems with reimbursement. Of note, and in light of COVID-19, MannKind reported that they would be sending new patients a device to measure FEV1 to help improve persistence.

16. Dr. Ele Ferrannini Reviews Decades of Research on Insulin Resistance in Banting Award Lecture

On the 99th anniversary of Banting and Best’s discovery of insulin, this year’s prestigious Banting Medal for Scientific Achievement was awarded to University of Pisa’s Dr. Ele Ferrannini for a prolific scientific career elucidating the kinetics of insulin and glucose in the human body. Dr. Ferrannini’s lecture followed his own personal journey in diabetes research. Stemming from a fascination with insulin resistance, Dr. Ferrannini’s early career focused on comparing insulin sensitivity between people with normo-glucose tolerance, impaired glucose tolerance, and type 2 diabetes and defining the many sites in which insulin resistance occurs (adipose tissue, skeletal muscle, liver, myocardium, smooth muscle/endothelium, and the list goes on). Later, Dr. Ferrannini turned his attention to the study of beta cell function – particularly the ways in which it is altered in diabetes and prediabetes, and how it can be improved by treatment. Current areas of interest include the partial restoration of beta-cell function after bariatric surgery and whether parameters of the beta cell can predict who will transition from normo-glucose tolerance to diabetes. Dr. Ferrannini closed with inspiring words: “The journey in diabetes does not end until we deconstruct the links between metabolism and complications, until we unify the pathophysiology of type 1 and type 2 diabetes, until we curb obesity, until we fully implement new pharmacology to treat diabetes, until we better learn how to prevent diabetes, and until life returns to normal again.” We were very moved by this, and by Dr. Ferrannini’s dedication of the award to all healthcare professionals who have died fighting the coronavirus epidemic. Our congratulations on this very well-deserved award.

Diabetes Technology Highlights

1. Abbott Poster Shows FreeStyle Libre Decreases A1c by 0.9% in Non-Insulin Type 2s (n=497) and 0.6% in Basal-Only Type 2s (n=277) After Six Months; Reductions Sustained at 12 Months

A very exciting Abbott-sponsored poster (84-LB) presented by Dr. Eden Miller (Diabetes Nation) showed significant A1c reductions in basal-only and non-insulin-using type 2s one year after using FreeStyle Libre. The retrospective analysis looked at LibreView data from November 2017 – September 2019, A1c data from Quest Diagnostics, and medical and pharmacy claims data from Decision Resources Group. Compared to A1cs values recorded within 0-180 days before starting FreeStyle Libre, 6-month A1c values were reduced by a remarkable 0.9% (baseline: 8.5%) in non-insulin type 2s (n=497; p<0.0001). Similarly, basal-only type 2s (n=277) saw their A1cs drop from 8.5% to 7.9% (p<0.0001) after six months. Looking out to 12 months, non-insulin type 2s saw a 0.7% A1c reduction, from 8.6% to 7.9% (n=120; p<0.0001) and basal-only type 2s saw a 0.5% A1c reduction, from 8.4% to 7.9% (n=87; p=0.001). Unfortunately, data on demographics and comorbidities were not assessed. Similarly, data on non-insulin medications (e.g., SGLT-2s, GLP-1s) was not available and it’s certainly possible that some of the participants analyzed may have been initiated on a new medication and FreeStyle Libre at the same time. Still, the results provide convincing evidence that FreeStyle Libre has considerable value beyond intensive insulin users. As stated by Dr. Miller in Abbott’s press announcement of the abstract, “These data highlight how use of Abbott's continuous glucose monitor could be game-changing for people beyond intensive insulin users, translating to broader use of the technology to benefit all those living with diabetes, no matter where they are in the spectrum of care.”

  • Looking ahead, many (especially payers) will be especially interested in cost savings analyses for CGM in these populations. This was a particularly hot topic at ADA yesterday, where we saw Dr. Rich Bergenstal present data showing a 60% reduction in acute diabetes events and 33% reduction in all-cause hospitalizations for ~2,500 adults with type 2 diabetes after starting on FreeStyle Libre – this study included adults on intensive and non-intensive insulin therapy. We also saw an observational study from France linking FreeStyle Libre to a 47% reduction in DKA rates in type 2s on intensive insulin therapy. Lastly, Dr. Irl Hirsch looked at previous studies and some of his own calculations to estimate the US healthcare system could save $4.6 billion in DKA-hospitalization cost savings alone by using CGM.

2. Tandem’s Control-IQ in Young Children (2-5 Years; n=12) Increases TIR by 1.8 Hours/Day, Time <70 mg/dl Reduces From 3.7% to 1.5% (-32 min/day)

Stanford’s Dr. Laya Ekhlaspour read out very positive results from a small (n=12) study of Tandem’s Control-IQ in young children (ages 2-5 years). The study involved 2-7 days of run-in, 48-hours of Control-IQ in a supervised hotel setting, followed by 3-days of home use. During run-in, participants used a study pump at home in open-loop; during the hotel phase, the children participated in 30 minutes of activity per day, but there were no restrictions on meals or snacks and boluses were delivered per parents’ routines. Compared to run-in, every glycemic outcome was improved with Control-IQ at home. The study’s primary outcome measured the percentage of subjects meeting less than 6% time <70 mg/dl and less than 40% time >180 mg/dl goals. At baseline, one-third of participants met both goals, compared to two-thirds during the hotel phase (p=0.01) and 75% in the Control-IQ at home phase (p=0.002).

  • Time in Range was improved by 1.8 hours/day with Control-IQ at home vs. open-loop at home (62% vs. 68%). Most notably, Control-IQ at home delivered large reductions in hypoglycemia, reducing time <70 mg/dl by 32 min/day (3.7% vs. 1.5%; p=0.004) and time <54 mg/dl by 7 min/day (0.6% vs. 0.1%; p=0.004). Time in hyperglycemia (>180 mg/dl) was decreased by 1 hour/day (34% vs. 30%), though this difference was not statistically significant (p=0.075).

  • As we saw with Control-IQ’s adult and older children pivotals (read outs at ADA 2019 and ATTD 2020, respectively), Control-IQ delivered the biggest improvements overnight (11 PM – 7 AM). Time in Range overnight was 59% at baseline, compared to 79% during the hotel phase and 76% during the at home phase. Time >180 mg/dl was reduced from 39% at baseline to 24% during at home and time <70mg/dl was reduced from 2.1% to 0%.

  • Tandem’s Control-IQ is currently approved for ages 14+, but comes with a specific black box warning against use in patients under 6 years old. Mean total daily dose in this study was 15U/day and a special modification from Tandem was required to carry out the study for patients this young. Pediatric indication (6+ years) has already been submitted to the FDA, but larger and longer studies will certainly be needed in this very young population.

3. Five Medtronic Posters on Extended-Wear Infusion Set: 7-Day Survival Rate of 81%; Can Reduce Annual Insulin Waste by 5-10 Vials Compared to 2/3-Day Sets

We rounded up five posters on Medtronic’s Extended Wear Infusion Set (EWIS), which was CE-Marked as of ATTD 2020 and is currently in pivotal trial in the US. At ATTD, Dr. Ohad Cohen (Medtronic) shared that EWIS included a new “H-Cap Connector” to improve site performance, improved tubing to improve insulin preservative retention & stability, and an improved adhesive patch for better adherence. Three of the posters below do an excellent job outlining some of Medtronic’s work and considerations around those three improvements. A final poster also calculates ~$1,500-$3,000 in annual cost savings from reduced insulin waste with a 7-day infusion set.

  • A small (n=21 participants) study showed 7-day survival rates of ~81% for Medtronic’s EWIS (994-P). The 21 participants wore four infusion sets (82 total insertions) until set failure or seven days. There were no safety signals, including DKA, severe hypo- or hyperglycemia, device-related severe adverse events, and death. Survival of the extended-wear set at 7-days (80.5%) was actually higher than the published survival rate of Medtronic’s 3-day infusion set at 3 days (77%). When this data was first presented at ATTD 2020, Dr. Cohen also noted that survival rate increased to 85% if insertion failures were removed. Reasons for failure were site reaction/blood (7% of all wears), insertion failure (5%), unexplained hyperglycemia (3%), and adhesive failure (3%). Notably, the total daily dose did not increase over the seven days, indicating insulin delivery efficiency was not significantly changed over the entire period.

  • A modified version of Medtronic’s 3-day infusion set showed 7-day survival rates of ~73%-75% (997-P). The study, presented by Dr. Bruce Buckingham (Stanford), modified the cap of the MiniMed Quick-set connector to create a chamber which contained either foam or foam with 80 units of heparin (anticoagulant). Twenty participants were randomized into foam or foam + heparin groups to start. The participants wore their modified infusion sets for a week (or until failure) before crossing over. The study lasted four weeks (four insertions) with crossover after each week. The rate of 7-day survival was not significantly affected by the addition of heparin, as both modified versions had 7-day survival rates of ~73%-75%. The connector foam, without heparin, is part of Medtronic’s EWIS, in addition to other improvements.

  • Medtronic tested seven different adhesives across three studies – the best performing variant achieved an 8-day survival rate of 100% (986-P). The studies enrolled 75 adults testing 2 adhesive variants each, totaling 150 adhesive placements. “Non-functional” Medtronic pumps were used to simulate conditions. Eight-day survival rates for the first four variants (adhesives used with current infusion sets) ranged from 63% to 89%; eight-day survival rates for three new adhesive variants ranged from 75% to 100%. Across variants, there were no significant differences around overall appearance, skin irritation, or device awareness; however, the newer adhesives trended slightly more difficult to remove and clean off. The highest-performing adhesive (100% 8-day survival rate) was chosen in Medtronic’s EWIS.

  • In-vitro and porcine tests showed infusion set wear-time and inflammatory response were significantly impacted by loss of preservatives in the insulin (1012-P). One test demonstrated pumping insulin through an infusion set lowered the preservative content, though this did not significantly impact insulin chemical stability. However, lower preservative content insulin created more aggregates when the insulin was shaken. With increased aggregates in the insulin solution, the inflammatory response was greatly increased in an in-vitro cell culture and greatly decreased survival time of an infusion set in a porcine model.

  • Assuming insulin costs of $300/vial ($3/U), Medtronic estimated annual savings of ~$1,500 to $3,000 per user with a 7-day infusion set vs. 3-day (1167-P). The estimate used a total daily dose of insulin of 35U/day, translating to 5-10 vials per year of reduced insulin waste. Savings would be lower for those using >35U/day as the pump reservoir wouldn’t hold enough volume for seven days of insulin. Medtronic is also taking a look at the environmental benefits from increasing reservoir volume and extending infusion set wear time.

4. Dexcom-Sponsored Symposium Sheds Light on Success, Failures, and Opportunities for Inpatient CGM Implementation During the COVID-19 Pandemic

During a Dexcom-sponsored symposium, Dr. Shivani Agarwal (Albert Einstein) presented takeaways from implementing inpatient CGM during the COVID-19 pandemic at the Albert Einstein Medical Center, a three-hospital system in the Bronx. The FDA first authorized use of CGM in the hospital setting in April in the early stages of the pandemic, giving both Abbott and Dexcom the greenlight. Dr. Agarwal characterized the overall experience as positive, sharing key insights for early implementation, logistics, training, challenges, lessons, and future opportunities. For context, Dr. Agarwal noted that some of these experiences were unique to her hospital and patient population and that naturally, other hospital systems attempting to bridge the implementation gap should consider their unique circumstances. Regardless of the conditions, Dr. Agarwal shared the key to success in any setting is obtaining buy-in and support all around from hospital staff.

  • Early Implementation: Identifying eligibility criteria for patients requiring CGM on top of maintaining a positive attitude were two critical components of success during implementation. At her hospital system, type 1 patients, individuals with documented hypoglycemia, those experiencing insulin drips and requiring one-hour fingerstick measurements were eligible. Exceptional circumstances per nurse request or where self-monitoring was not possible also existed. To reiterate, creating a positive environment to encourage hospital buy-in was key.

  • Logistics: Nurse practitioners were responsible for inserting sensors in the arm. Receivers were placed on the door of the patient room facing outwards, within 20 feet of the patient, and reused after sanitization.

  • Training: A dedicated training team was assembled to help hospital nurses and medical staff learn how to interpret CGM data and make treatment decisions. Paper instructions were placed on patient doors, and 1:1 conversation was regularly utilized between hospital staff and a care team. Alarm triggers were used when signal disconnects occurred, indicating the need for a point-of-care fingerstick test. The hospital validated CGM readings with the common “20/20” rule, where CGM readings must be within 20 mg/dl or 20% of the fingerstick value. Interestingly, not all data was documented into the hospital’s electronic medical records system. Dr. Agarwal noted that an ongoing point of clarification is determining how much CGM data is necessary to collect and store from patients.

  • Successes: To-date, Dr. Agarwal shared that CGM has been implemented on twenty patients within the hospital system. The reduced need or personal protective equipment and hospital staff contact led to massive hospital buy-in. CGM use also shifted how care teams within the inpatient ward operated and increased appeal for additional medical device usage in inpatient settings. Today, hospital physicians partner with inpatient nurses and care teams to provide educational lessons about technology used in the hospital setting, increasing overall enthusiasm for future pilots.

  • Future: Dr. Agarwal shared that additional information on integrating CGM into data records and identifying patient characteristics most amenable to CGM are critical. Additional randomized control trials to determine the safety, accuracy, and utility of CGMs in hospitals are needed, along with securing legal approval to use cellphones as receivers.

5. Users Randomized to Glooko’s MIDS Basal Titration System and Control Group (Paper-Based Titration Tool) Have Similar A1c Reductions at 16 Weeks

In a large prospective RCT, use of Glooko’s FDA-cleared Mobile Insulin Dosing System (MIDS) for basal insulin titration in type 2 diabetes resulted in similar A1c reductions as standard of care (paper titration + enhanced CDCES support) at 16 weeks. The study enrolled 242 adults with type 2 diabetes who were on (89%) or initiating (11%) basal insulin and were not on or planning to start short-acting insulin. Both groups used Tresiba pens (Degludec U-200) and the Degludec Step-Wise titration algorithm which is based on fasting SMBG readings and personalized treatment plans to adjust insulin doses in increments of two units. The difference was the algorithm was configured by a provider and baked into the patient-facing Glooko app (see a deeper dive on this in the bullets), or done manually by the patient on a worksheet, with the guidance of an educator. At week 16, median A1c had improved significantly in both groups (-1.3% in MIDS; -1.2% in control), but the between-group difference was not significant. Similarly, median daily insulin doses increased significantly from baseline in both MIDS (+8 units) and control (+10 units) groups, but there was no between-group difference. While there were unfortunately no CGM outcomes to share (even periodic blinded CGM wear would’ve gone a long way), SMBG outcomes were presented: notably, proportion of readings <70 mg/dl were similar between MIDS and control (0.9% vs. 1.6%), but the MIDS group had significantly higher percent of readings in 70-180 mg/dl (77% vs. 70%) and fewer percent of readings >250 mg/dl (5% vs. 9%). While the study was planned (and failed) to show superiority of MIDS on the primary outcome of A1c reduction, we consider this study to be a major victory for Glooko and the field of digital health. Scripps Health’s Dr. Athena Philis-Tsimikas, the presenter, does as well:We’ve always known that having the help of an educator starting someone on insulin can encourage and allow them to better manage their diabetes. It’s impressive that you could do this equally with a digital tool that didn’t have as much contact with patients and you still see effect on A1c.” Indeed, MIDS is far more scalable and user-friendly than paper-based titration–assuming a base level of technological literacy and access—and there was no sacrifice in quality of outcome. Furthermore, a clinic that uses MIDS will free up its educators to do other, higher-impact work. We are hopeful that this rigorous study will propel MIDS and the handful of other basal titration apps (many also FDA-cleared) to increased adoption.

  • Dr. Philis-Tsimikas provided a glimpse at the clinician and patient interfaces. The clinician interface—which is presumably built right into Glooko—allows the clinician  to enter insulin type and starting dose, titration period/end date, SMBG data sufficiency requirements, and to configure fasting target range and adjustment paradigms. On the other end, SMBG readings are synced remotely via the Glooko mobile app, which reminds the patient to take fasting blood glucose readings and inject insulin daily. Every three days, a “Dose Adjustment Check” will determine, based on the clinician-configured plan, whether a dosage change is needed. Both interfaces look simple and intuitive. Last we heard, MIDS was piloting at a small number of US clinics—we wonder if this has since expanded.

6. Beta Bionics Gen 4 iLet Insulin-Only Pivotal Enrollment “Nearly Completed”; Home-Use Study Shows +1.9 Hours/Day TIR, Time <54 mg/dl From 0.6% to 0.2% With Bi-Hormonal vs. Insulin-Only

Dr. Jordan Sherwood (Massachusetts General Hospital) provided a detailed breakdown of positive results from Beta Bionics’ first home-use trial using liquid-stable dasiglucagon. Results from the 14-day crossover study were first announced via press release about one year ago. Towards the end of his presentation, Dr. Sherwood also shared that the insulin-only pivotal trial for Beta Bionics’ Gen 4 iLet is “currently underway,” with enrollment “nearly completed.” Assuming the trial will commence soon, it will come at a ~three-month delay from previous expectations to start in 1Q20; the goal is for insulin-only iLet to launch in ~early/mid-2021.

  • The small, home-use study randomized 10 adults with type 1 diabetes with pump and CGM experience to insulin-only and bi-hormonal iLet configurations. After one week, participants crossed over to the other configuration. The bi-hormonal configuration drove 1.9 more hours/day in-range (71% vs. 79%; p=0.002), reduced time <54 mg/dl by 6 min/day (0.6% vs. 0.2%; p=0.15), and reduced mean glucose from 149 mg/dl to 139 mg/dl, compared to the insulin-only configuration. Though not mentioned today, time <70 mg/dl was 2.4% during the bi-hormonal period and 3.6% during the insulin-only period – a difference of ~17 minutes. Notably, participants initiated therapy by entering only their body weight into the device (and no other parameters).

  • New from today, Dr. Sherwood also provided a look at subject-level differences in the insulin-only vs. bi-hormonal configurations. As shown below, nine of the ten participants saw lower mean glucose with the bi-hormonal iLet; this difference was significant (p<0.05) for eight of the ten participants. Additionally, Dr. Sherwood noted that during the bi-hormonal phase, 9/10 of participants had mean glucose below 154 mg/dl, which would correspond to an A1c ~7%; half of participants had mean glucose <154 mg/dl during the insulin-only phase. Time <54 mg/dl was low in both arms, though 8/10 participants saw improvements with the bi-hormonal configuration. With insulin-only iLet, 6/10 participants reached the consensus target for <1% time <54 mg/dl, compared to 9/10 participants with bi-hormonal iLet.

7. Bi-hormonal Bionic Pancreas Optimal for Mean Glucose (136 mg/dl) and TIR (81%) at 100 mg/dl Set Point, with no Increase in Hypo (Compared with 115 and 130 mg/dl)

MGH’s Dr. Marwa Tuffaha presented Bionic Pancreas (Beta Bionics) data from 2015 showing that lower glucose targets reduce mean glucose and greater time-in-range without additional hypoglycemia. Since this study was conducted a few years ago, the Bionic Pancreas AID system consisted of an iPhone 4s running a control algorithm, a Dexcom G4, and two Tandem t:slim pumps (one with insulin and one with glucagon). While today’s gen 4 iLet is fully-integrated, the algorithm is the same, requiring only body mass to initialize and qualitative meal announcements. 20 participants with type 1 diabetes and wide demographic ranges (e.g., A1c 6.1%-9.3%, ages 21-78 years, BMI 20-42 kg/m2, and diabetes duration 5-54 years) were enrolled in a random-order, real-world crossover study evaluating the Bionic Pancreas at three set points (130 mg/dl, 115 mg/dl, and 100 mg/dl), plus usual care. As seen in the figure below, lower targets were associated with significantly lower mean sensor glucose (lowest: 136 mg/dl @ 100 mg/dl target) and higher mean time in 70-180 mg/dl (highest: 81% @ 100 mg/dl target). These stellar outcomes did not come at the cost of more time <60 mg/dl, which is explained by a significantly higher daily dose of glucagon—8.3 ug/kg were administered daily with the 100 mg/dl set point. Interestingly, there was no difference in total daily dose of insulin across set points, though we’d bet there was significantly more “prandial” insulin delivered with the lower set points, quickly bringing users back into range, as opposed to the highest set point where meals were likely handled more conservatively leaving the basal rate to chase highs for the rest of the day. User preference was very high across all three set points, though with significantly higher satisfaction for the 100 mg/dl set point. Note that the participants were not blinded to the system setting, so one might expect higher satisfaction ratings with the lowest set point. None of the patients in the study had DKA or severe hypoglycemia, there was no difference in hypoglycemia symptoms, interventions, or carbs administered per day, and glucagon-induced nausea was not an issue. The integrated Gen 4 iLet with Zealand Pharma’s dasiglucagon is expected to enter pivotal trials in the back half of this year (see FFL 2019) — enrollment is “nearly complete” (see above).

8. First Lilly AID Data Shows System is Safe in Small, Inpatient Feasibility Study—Negligible Hypoglycemia after Pizza/Pancakes, With or Without Premeal Bolus

Lilly’s Ms. Amy Bartee presented what we believe to be the first data Lilly has shared on its AID system (read about the system, which uses Dexcom CGM, a cool DEKA-developed pump, and the MPC algorithm from Class AP). This was a small (n=10) inpatient feasibility study that demonstrated safety in response to high carbohydrate meals with and without pre-meal boluses. Specifically, participants (mean age 52 years; mean A1c 7.1%; all pump users) were given four meal challenges over a 48-hour inpatient period: (1)  bolus with pizza (high-fat meal); (2) missed bolus with pizza; (3) bolus with pancakes (fast-acting carbohydrate meal); and (4) missed bolus with pancakes. As expected with the pizza challenge + bolus, there was a slow rise in glucose and extended postprandial period—the algorithm steadily increased basal insulin delivery to compensate, yielding <1% below 70 mg/dl and 66% time-in-range. In the pizza challenge + missed bolus, the algorithm responded with an immediate and incremental increases in basal delivery for the next four hours, delivering <1% below 70 mg/dl and 37% time-in-range. No correction boluses were given in either pizza challenge. In the pancake challenge + bolus, there was no hypoglycemia and 56% time-in-range. As expected, the pancake challenge + missed bolus was the most challenging for the algorithm, which rapidly ramped up basal insulin delivery but 60% of the next four hours were spent >250 mg/dl (no time <70 mg/dl). One patient required a correction bolus in this condition. Ultimately, the system was safe in every case, though the study emphasized the importance of bolusing for meals, particularly in the absence of automated corrections. Lilly has never shared specific timing for development of its AID system, though it has broadly said that Connected Care products will launch in stages over 2019-2021; we wouldn’t be surprised to see this timeline pushed back.

Percent time in ranges in four hours postprandial

 

Pizza with bolus

Pizza without bolus

Pancakes with bolus

Pancakes without bolus

% Time in 70-180 mg/dl

66%

37%

56%

18%

% time <70 mg/dl

0.8%

0.8%

0%

0%

% time >180 mg/dl

33%

63%

44%

82%

% time >250 mg/dl

11%

30%

11%

60%

 

9. Dr. de Bock Very Enthusiastic About 780G’s Impact on TIR in “Challenging” Adolescent Group

University of Otago’s Dr. Martin de Bock rehashed very positive MiniMed 780G CE registration trial (see Day #1 coverage), emphasizing that the greatest day-time time-in-range benefit was seen in the most challenging population: adolescents (ages 14-21). In fact, the whole population was skewed young, with a mean age of 23.5 years and 56% under 21. Said Dr. de Bock, “This is really exciting for us, especially as pediatric endocrinologists…Maybe we shouldn’t be so concerned about people who aren’t so adherent to their therapy – they are the most likely to see advanced time-in-range on [780G].” We would caution that the mean A1c in the study was 7.6% and all participants were already on a pump, so this population, though still adolescents, may not be the “most challenging of the challenging.” For reference, mean A1c in people ages 15-18 in the T1D Exchange Registry is 9.3%. Still, the signal is encouraging, and may due to the system’s improved user experience. There was only ~1 auto mode exit per week in this study, compared to ~1 per day as seen with the 670G. Similarly, the system significantly reduces alarms to 8 per day (vs. 13 per day with 640G). P-979 further elaborates ono improved satisfaction and sleep quality with 780G vs. 640G. Echoing his Friday comments, Dr. de Bock concluded: “If we had more time, we hypothesize we could’ve optimized settings…and seen overall Time in Range that was higher than reported here.”

10. Ultra-Rapid Insulins Safe and Effective in 670G & 780G, but Apparently Not More So Than Rapid-Acting Insulins; Possible Exception: 780G with Fiasp May Blunt PPG Relative to Novolog

We enjoyed back-to-back orals investigating the benefit of ultra-fast insulins in Medtronic’s (advanced) hybrid closed loop systems. In short, the benefit appears to be marginal, at best. However, it is does seem safe and feasible.

  • Atlanta Diabetes Associate’s Dr. Bruce Bode first showed in a double-blind crossover study (n=42) that there was no difference in glycemic outcomes with MiniMed 670G when participants used Lilly’s Ultra-Rapid Lispro (URLi) or Humalog. Time-in-range was 77% with Humalog and 78% with URLi, and time <70 mg/dl was ~2% in both cases. There was no difference in time-in-range between the two conditions during day or night, nor post-meal.  There were five cases of infusion site pain/reaction in the URLi condition vs. one in the Humalog condition, but overall, booth conditions were very safe and there were no discontinuations. We and a number of chat participants felt that perhaps the participants were already too well-managed on the 670G at baseline to see an impact of even faster-acting insulin. Mean baseline A1c was 7.1%, mean time-in-range was 78%, and participants were already spending ~90% in-range. Dr. Bode additionally proposed that a hybrid closed loop system that only modulates basal insulin “may not be optimized for the potential advantages of an insulin with differential effects seen primarily during bolus delivery.” Benefits may be realized, he reasoned, if it were used in a system that gives automated boluses, such as MiniMed’s AHCL (780G) system. The next oral looked at exactly that.

  • University of Melbourne’s Dr. Melissa Lee presented a similarly-designed crossover study (n=12) comparing the use of Novo Nordisk’s Fiasp and Novolog in the MiniMed 780G. Despite Dr. Bode’s hypothesis, this study found no overall benefit of Fiasp, with the potential exception of blunted postprandial spikes after breakfast. Though smaller, the study population was similar to above, with experienced pumpers with mean baseline A1c of 7.1%. In both conditions, time-in-range was ~80%, hypoglycemia was <0.5%, and mean glucose was <140 mg/dl, with no statistically significant differences but trends toward Fiasp benefit. There was no difference in CGM metrics postmeal when all meals were pooled, but when separated, incremental AUC over 2 hours was significantly lower with Fiasp only for breakfast. Breakfast-time may be unique for a whole host of reasons, said Dr. Lee: less insulin resistance in the morning, snacks/stress/exercise later in the day, or just simpler carbs at breakfast. While 780G was safe with both insulins, there were four individuals who experienced at least one mild infusion-site reaction using Fiasp vs. only one using Novolog. 

11. OHSU’s Novel Interventions in Children’s Healthcare Onboards Vulnerable Youth with Diabetes Technology While Addressing Social Determinants of Health

Dr. Kimberly Spiro (Oregon Health Sciences University) presented on the Novel Interventions in Children’s Healthcare (NICH), an innovative program at OHSU that attempts to provide access to diabetes technology supplies to underserved patients by addressing underlying social determinants. Participants, primarily children and teenagers, are paired with a trained interventionist, accessible 24/7, to solve issues that may prevent them from following medical instructions from endocrinologists and other clinical professionals. Participants receive 12 months of care on the program at no cost. The program has had major success in assisting diabetes challenged by a variety of social conditions including food insecurity, unreliable transportation, insecure housing, limited access to medical care, and Child Protective Services (CPS)/Department of Human Services (DHS) involvement. Overall, we’re excited to see interdisciplinary programs like these provide person-centered diabetes care and technology to break the intergenerational cycles of systemic inequities many in the healthcare system face. Dr. Spiro shared that in the US today, DKA serves as the number one cause of death for type 1 youth, with 65% of cases also impacting those under the age of 19. In our view, the vast majority of these deaths are preventable: just yesterday, we saw three presentations demonstrating that DKA-related hospitalizations could be greatly reduced (50%-80% reductions) by using CGM – we know this is true, and strongly believe that no patient should ever again be in the hospital for severe hypoglycemia or for DKA not associated with a diabetes diagnosis (and obviously, to reduce those dramatically is an important goal though unlikely it will get to 0% without a major increased focus on increased screening and prevention in type 1). Dr. Spiro presented several cases highlighting the sheer impact of the program. To-date, the program has helped 0ver 350 patients get access to diabetes technology which they otherwise would not have secured any assistance.

  • Case 1 – David (14 year-old, male, type 1): Prior to NICH, David had endured a variety of challenges with neglect. During his youth, he had moved around five different foster homes before moving in with an abusive aunt and uncle. At age ten, his aunt, serving as his primary contact, was diagnosed with cancer, and one year later, he was diagnosed with type 1. Shortly after, his uncle ceased all contact with his aunt, forcing David to skip school, run away from home, and miss appointments. During this time, David and his aunt’s relationship became tense. Simultaneously, his endocrinologist did not want to provide him with CGM or an insulin pump because of concern over impaired awareness of hypoglycemia. The reluctance to provide a CGM is perplexing to us. At that point, David had endured three episodes of DKA and had an A1c of 10.8%. After being referred to NICH, his interventionist addressed the potential pros and cons of CGM. David was able to open up about his concerns about being overwhelmed with data along with his concerns of his aunt being able to watch over him with remote monitoring capabilities. As a result, to ease David into technology, the interventionist onboarded him with Dario’s connected BGM system and Companion’s InPen, through which he shared data with both his aunt and interventionist. To better David’s relationship with his aunt, the interventionist used positive reinforcement behavior. For example, if David agreed on a treatment decision from the data such as taking insulin or choosing to exercise, he accumulated “points” with his aunt, which he could then use to spend time with friends. To give him a sense of personal control, his aunt started allowing him to be out with his friends as long as he checked the data and shared it with her. After using the Dario system, David agreed to begin using a Dexcom G5 CGM, during which he learned about his glucose patterns and how his behaviors affected to his diabetes management. Over time, he found the ideal alarm settings and through additional counseling to address prior trauma as recommended by his interventionist, his A1c dropped from 10.8% to 9% after the program. In a testament to the interdisciplinary effectiveness of NICH, David said the program has “opened up new resources” to him and helped “organize things in daily life.”

  • Case 2 – Samantha (13-year old, female, type 1): Prior to NICH, Samantha had endured trauma related to domestic violence. Her mother had two kids with two different partners and was briefly incarcerated, during which she lost access to her kids. After her mother’s jail time, without access to a sustainable job, Samantha faced homelessness, during which her A1c climbed all the way up to 14%! She was also unable to access any diabetes technology because of the Medicaid requirement of 4 document fingersticks/day for 90 days. However, after being referred to NICH, she worked for nine months with her interventionist and was eventually able to document 3-4 fingersticks per day. This enabled her to access the Dexcom G5 CGM, during which her interventionist taught her how to read glucose patterns. Before CGM, Samantha had refused to dose insulin before meals, but after seeing her patterns, she changed this habit. After three months on CGM, her A1c dropped from 14.1% to 10.2%, upon which she finished the program. While there is certainly more room for improvement, Dr. Spiro acknowledged that it was NICH which provided her with the problem-solving skills and confidence to use technology and create self-management practice in very difficult of circumstances.

  • Case 3 – (Matthew, 18 years old, type 1): Prior to NICH, Matthew had endured over 20 episodes of DKA. His parents endured significant mental health issues and were regularly on the run from DHS. After being diagnosed at age eight with type 1, Matthew left his house to live with his grandparents but was kicked out after having two episodes of DKA in the first three months of living with them. He eventually got a job and decided to independently live with a bicycle as his only mode of transportation but was on the verge of eviction throughout a period of insecure housing. During this time, Matthew would make anywhere from three to four emergency department visits per month. After being recommend a Dexcom G6 from an interventionist in NICH, Matthew’s hospitalization rate changed to only 1x/month while his A1c dropped from 14% to 9.4% upon completing the program.

 

--by Ursula Biba, Rhea Teng, Ann Carracher, Abigail Dove, Payal Marathe, Martin Kurian, Joseph Bell, Kira Wang, Ani Gururaj, Albert Cai, Brian Levine, and Kelly Close