EASD 2020 (European Association for the Study of Diabetes)

September 21-25, 2020; Virtual; Day #2 – Draft

Executive Highlights

  • In tech, Insulet SVP and Medical Director Dr. Trang Ly announced that the pivotal trial for the Omnipod 5 hybrid closed loop system has completed. Dr. Ly also maintained the 2Q20 plans to read out results from the pivotal trial at ATTD 2021 in February and launch the system in the US in the “first half of 2021.” In the morning, University of Antwerp’s Dr. Anass El Malahi presented exciting data strengthening the argument for Time in Range as a primary metric for assessing glucose control. Using data from Belgium’s RESCUE trial (n=515 adult type 1 insulin pump users), Dr. El Malahi demonstrated a strong correlation between Time in Range and several microvascular complications, particularly retinopathy. Elsewhere, we have coverage from Roche and Sanofi-sponsored symposia and two interesting posters on MiniMed 670G.

  • In therapy, it was a big day on the type 1 front – we caught up with the INNODIA program, comprised of 31 academic centers, 6 pharmaceutical partners, 2 patient organizations, and 1 small to medium enterprise devoted to improving type 1 diabetes drug development in Europe. Three INNODIA trials are set to begin this fall: MELD-ATG for anti-thymocyte globulin (ATG); (ii) IMPACT for IMY-0098; and (iii) VeR-A-T1D for verapamil SR, while a fourth – CFZ533 for iscalimab – has already commenced. We also heard re-hashes of several exciting mid-stage type 1 programs, including positive phase 2 data from Novo Nordisk’s combination anti-IL-21/liraglutide, J&J’s golimumab, and vTv Therapeutics’ glucokinase activator TTP399.

  • In big picture, the illustrious Prof. Roy Taylor shared intriguing pancreas morphology photos from participants who experienced “diabetes remission” from the landmark DiRECT trial. These results are the first to demonstrate that the abnormal pancreas can return to normal morphology during type 2 remission. We were also treated to a Q&A session with EASD leadership, in which President Stefano Del Prato shared EASD’s exciting plans for its future virtual platform and how the organization plans to “keep the congress alive for the rest of the year.”

  • Also see below for more on The diaTribe Foundation’s Seventh Annual Solvable Problems in Diabetes Forum, featuring Profs. Partha Kar, Melanie Davies, Kamlesh Khunti, Pratik Choudhary, and our very own Kelly Close.

The world keeps spinning and EASD continues on. We rolled on into day #2, the first official day of conference sessions. See our top highlights from day #2 below and see our day #1 report for the biggest highlights from pre-conference symposia!

Table of Contents 

Diabetes Technology Highlights

1. Retrospective Sub-Study of Belgium RESCUE Trial Shows Association Between Time in Range and Microvascular Complications, Especially Retinopathy

University of Antwerp’s Dr. Anass El Malahi presented powerful data strengthening the argument for Time in Range as a primary metric for assessing glucose control. Using data from Belgium’s RESCUE trial (n=515 adult type 1 insulin pump users), Dr. El Malahi demonstrated a strong correlation between Time in Range and several microvascular complications, particularly retinopathy. The sub-study from Dr. El Malahi builds on a growing evidence base validating Time in Range – see a 2018 Diabetes Care paper from Drs. Roy Beck and Rich Bergenstal showing a link between lower Time in Range and higher rates of microvascular complications and a 2019 DT&T paper linking Time in Range with carotid intima-media thickness, a CVD risk biomarker. As CGM has become more common, Time in Range has become a very popular metric for both patients and providers to assess glycemic control and to manage diabetes. However, some have been less open to trusting Time in Range as a primary metric due to a number of things, including the absence of a long-term outcomes “DCCT-like” trial for Time in Range validating the link between Time in Range with complications.

  • Notably, higher Time in Range was significantly associated with fewer microvascular complications in this trial. For example, half of participants with a Time in Range <40% had at least one microvascular complication, i.e., peripheral or autonomic neuropathy, retinopathy, or nephropathy. In contrast, just 27% of those with a Time in Range >70% had at least one microvascular complication. We will be back on p values.

  • Retinopathy was very strongly correlated with lower Time in Range, with the average retinopathy rate in the Time in Range > 70% group of 22% far lower than the rate of retinopathy of Time in Range <40% group – fully 50% of those with Time in Range less than 40% had retinopathy.

  • Notably, just 8% of those with Time in Range over 70% had nephropathy, and 10%-13% had nephropathy between 40% and 69% Time in Range – the big change came between 40% Time in Range, where 30% of those with Time in range under 40% had nephropathy.

  • Notably, the link between microvascular complications and Time in Range existed independent of diabetes duration. The 22% retinopathy rate seen in the Time in Range >70% group is considerably higher than the 5% retinopathy rate reported by the DCCT group with estimated Time in Range >70%. We will be asking experts their views on this.


  • The correlation between macrovascular complications and Time in Range was less clear. About one in five participants in the Time in Range <40% group had presence of at least one macrovascular complication, while just 3% of participants in the Time in Range >70% group had at least one macrovascular complication. However, the rates of macrovascular complications were low once Time in Range crossed 40% - nephropathy, above, is similar to this as well and some would term nephropathy itself as closer to a “macrovascular” benefit rather than a microvascular one.


  • Higher Time in Range was also linked to fewer diabetes-related hospitalizations. Mean Time in Range for participants who had no hypo- or DKA-related hospitalizations in the last twelve months was 64%, compared to 59% for participants who had been hospitalized in the last twelve months (p=0.02).

  • Interestingly, the data from the RESCUE study also showed that while A1c was significantly improved after initiating CGM, Time in Range remained very similar. The mean A1c in the group improved just four months after initiating CGM from 7.6% to 7.2%. After 24 months, mean A1c had was reduced by 0.3% compared to baseline. In contrast, mean Time in Range at baseline 63% and remained in the low 60% range through every time period. This was somewhat surprising and we look forward to getting more expert commentary on this.

  • As a reminder, the RESCUE data set includes outcomes from national reimbursement of CGM in Belgium for type 1s on insulin pump therapy. The registry includes data from September 2014 to January 2017. The first data from the registry were presented at EASD 2017, demonstrating a 75% reduction in hypoglycemia/DKA-related hospitalizations in the first 12 months following CGM initiation.

2. Insulet Omnipod 5 Hybrid Closed Loop Pivotal Trial Complete, Set to Read Out at ATTD 2021 in February; Reaffirmed Commitment to FreeStyle Libre 2 Integration

Insulet closed things out on EASD Day #2, with SVP and Medical Director Dr. Trang Ly hosting an hour-long symposium. The biggest news from the symposium came towards the end, with Dr. Ly sharing that the pivotal trial for Insulet’s Omnipod 5 hybrid closed loop system has now completed. Dr. Ly also maintained the 2Q20 plans to read out results from the pivotal trial at ATTD 2021 in February and launch the system in the US in the “first half of 2021” – it’s incredible that this timeline is holding, given COVID-19 uncertainty. The three-month trial initially began at the end of December 2019, temporarily paused in March due to a “software anomaly,” and resumed again in June. During today’s presentation, Dr. Ly mentioned that a “majority” of pivotal participants have already moved on to the extension phase of the trial. A few months ago at ADA, Stanford’s Dr. Bruce Buckingham shared results from the pre-pivotal trial (n=18 adults and 18 children), focusing in on strong system usability results. He also stressed high time in closed loop (97%) – we are not surprised by this. During the symposium, Dr. Ly made similar comments, noting that the Insulet design team spent a lot of time thinking about “alarms, usability, simplicity, and ease-of-use.”

  • In the final slide of her presentation, Dr. Ly re-affirmed Insulet’s plans to integrate Omnipod 5 with Abbott’s FreeStyle Libre 2, sharing, “We haven’t announced any dates yet, but it’s happening.” The integration between Omnipod 5 (then known as Horizon) and FreeStyle Libre 2 was announced back in February, becoming the first AID system with finalized partnerships with two CGM manufacturers. The planned integration between FreeStyle Libre 2 and Omnipod 5 became unclear in June, when FreeStyle Libre 2 was cleared by the FDA as an iCGM, but came with a surprising “warning/limitation” against use with “automated insulin dosing (AID) systems, including closed loop and insulin suspend systems.” During our conversations with Abbott, the company seemed confident that the “warning/limitation” would eventually be removed and today’s re-commitment from the Insulet side seems to suggest both parties have confidence in ultimately getting an FDA-cleared Omnipod 5 + FreeStyle Libre 2 system to market. However, given the two companies are still in their very early stages of integration, Omnipod 5 will certainly come to market first with Dexcom G6 integration, the system set-up used in the pivotal trial. 

  • As a reminder, Omnipod 5, will be Insulet’s first-generation hybrid closed loop system. The system will launch with Dexcom G6 integration and importantly, smartphone control. We’ve previously expected Insulet to initially launch smartphone control on Samsung Galaxy phones with support for other phones coming later – for those not using smartphone, Omnipod 5 can also be controlled by a dedicated device (similar to the Omnipod Dash PDM). Insulet’s talking points on Omnipod 5 have remained remarkably consistent for a long time, focusing on system usability and having multiple glucose set points. Dr. Ly offered some interesting perspective on the variable set points (targets can be set to 110, 120, 130, 140, or 150 mg/dl), noting that new to AID users could “ease” into the therapy by beginning with higher set points and working their way down.

  • Dr. Ly also briefly commented on yesterday’s announcement for broader international Omnipod Dash rollout. The system is now available in eight countries: the US, UK, Netherlands, Italy, Sweden, Finland, Norway, and Denmark. In the “coming weeks,” the system will be rolled out to France, Belgium, Germany, Austria, Switzerland, and Israel.

3. Roche’s integrated Personal Diabetes Management Strategy Drives A1c 1.3% Reduction (Baseline Not Shared) and Generates 15% Cost Savings; Roche’s AI-Powered Glucolytics App Currently in Beta Testing

Headlined by Roche’s integrated Personal Diabetes Management (iPDM) strategy, Roche chose to emphasize personalization and digital health during its industry symposium. Real-world data from 32 practices and 19,475 patients over four years indicated Roche’s iPDM strategy was associated with mean A1c reductions of 1.3% (baseline not shared) and resulted in a total of 2,808 avoided deaths and complications. That’s quite a remarkable number, as 2,808 deaths and complications would represent over 14% of the study group. The data also indicated huge cost savings of $24.6 million over 10 years associated with Roche’s iPDM – the equivalent of 15% of the participating practices’ health budgets. On a shorter, twelve month time scale, the results demonstrated average A1c reductions of 0.5% (baseline 8.5%) as well as an 8% reduction in hypoglycemic events – the latter is particularly meaningful. iPDM use was also associated with a 20% improvement in adherence to medication regimens. Additionally, both patients and providers experienced improved satisfaction with care while using the iPDM strategy and patients treated according to Roche’s iPDM strategy gained o.5 life years and 0.3 quality adjusted life years. According to Mr. Joerg Hoelzing (Roche Diabetes Care) the RocheDiabetes Care Platform is one of the key components of Roche's iPDM strategy. It connects healthcare professionals seamlessly to people with diabetes integrating the complete host of Roche's diabetes products (e.g., Accu-Chek BGMs, insulin pumps, mySugr, etc.) with patient medical records, and third party products such as insulin pens or CGM.

  • The RocheDiabetes Care Platform also supports a new “Remote Patient Monitoring solution” giving providers access to patient data “outside of conventional care settings.” Using data analytics algorithms to find patterns in patient data, providers and care teams will receive alerts about patient “irregularities” allowing them to respond quickly and adjust treatments as necessary. Additionally, providers will be able to personalize individual remote monitoring programs to meet patient needs. Providers are also able to communicate directly with patients through Roche’s platform, allowing patients to ask questions and request additional support. Roche envisions its Remote Patient Monitoring solution as a “bridge between the doctor’s office and people with diabetes going about their everyday lives.”

  • Notably, Roche introduced its new Glucolytics app, currently in beta testing, as a pillar of its iPDM strategy. Glucolytics integrates continous glucose readings, activity data, HCP and medical records and uses AI and machine learning to predict “nighttime hypos and after-meal glucose” while also “revealing hidden glucose patterns.” Glucolytics is able to predict nighttime hypoglycemia events with 86% accuracy and has accurate post-meal glucose predictions (see image below).  The Glucolytics algorithm is built off a four-step process answering: (i) what happened; (ii) why did it happen; (iii) what might happen in the future; and (iv) how can the patient/provider adapt behaviors and treatments to avoid future glycemic events. These AI-generated recommendations and predictions are already available as a beta version integrating CGM data.

  • Mr. Hoelzing also highlighted Roche’s Accu-Chek SugarView app designed specifically for people with diabetes in low- and middle-income countries. The Accu-Chek SugarView app allows patients to take a photo of their Accu-Chek Active test strip that is then contextualized according to ADA glucose range standards to help patients understand the factors impacting their glucose values. Despite a lack of access to medical care in many low- and middle-income countries, smartphones have become increasingly prevalent meaning app-based glucose insights have the potential to fill gaps in care and improve glycemic outcomes. The AccuCheck SugarView app was CE-Marked in December 2019 and as of 3Q19, was already available in Nigeria, the Philippines, Mexico, India, Pakistan, Vietnam, and Indonesia.

  • Soon the RocheDiabetes Care Platform will also support the RocheDiabetes InsulinStart service, providing personalized support for patients transitioning to insulin from oral medications. Healthcare professionals are able to enroll tyoe 2 patients in the RocheDiabetes InsulinStart program through a web-based service that sends patients follow-up text messages with reminders to check glucose levels. By responding to these messages, patients participate in a feedback system that will also aid in insulin dosing calculations. The RocheDiabetes InsulinStart service is compatible with 99% of long-acting insulins on the market giving patients the freedom to use the insulin best suited to their needs while still receiving the support they need to transition to insulin therapy. Given the well-documented reluctance from both patients and providers to initiate insulin therapy, it’s encouraging to see efforts to use technology to make the transition easier.

  • With its open ecosystem, Roche is hoping to increase patient choice and allow both patients and providers to mix and match devices and software to meet individual needs. Additionally, Roche is marketing its iPDM platform as a means to combat therapeutic inertia through a parallel approach of centralizing patient data in an open ecosystem to make it accessible to providers, and utilizing analytic and predictive algorithms to recognize patterns in patient data to support therapeutic decisions. However, during Q&A, Mr. Hoelzing did recognize it is challenging to convince manufacturers with proprietary, closed systems to join an open ecosystem like Roche’s iPDM. That said, Mr. Hoelzing said Roche already has “80 devices” connected to its iPDM platform and is seeing an increased willingness to share data among other industry leaders.

4. Two Posters on MiniMed 670G: Nine-Month, Sustained Positive Outcomes for Youth Transitioning Straight from MDI; >30% Rise in Percentage of Type 1s Achieving A1c and Time in Range Targets After Six Months

Tuesday afternoon’s poster sessions included two posters with promising findings on the sustained glycemic improvements associated with MiniMed 670G use. While there is much excitement around MiniMed 780G and its potential to further improve glycemic control (see the Medtronic symposium on 780G from Day #1), it is still great to see the improvements which patients can achieve with MiniMed 670G, which had a quarter of a million users as of May. In particular, these two studies are especially promising in that they suggest that MiniMed 670G can help people with diabetes achieve sustainable glycemic improvements and are effective tools for improving glycemic outcomes in children and adolescents with diabetes.

  • Following up six-month data presented at ATTD 2020, Dr. Goran Petrovski (Sidra Medicine) shared nine-month data on youth (n=30, ages 7-18) transitioning directly to MiniMed 670G from MDI after a 10-day initiation. Through month six: participants’ mean A1c fell from 8.2% to 6.9% and their mean Time in Range increased from 46% to 73% (+6.5 hours/day!). The data from months seven to nine show that participants sustained these positive results, achieving an A1c of 6.8% and a Time in Range of 74%. Similarly, the reductions in time above and below range that were achieved after three months were also sustained after nine months. Also impressive, time in auto mode was 87% in month one, which was sustained through month nine when time in auto mode was 89%. The data from Dr. Petrovski is not only very important because it represents a traditionally poorly-controlled group (adolescents), but also because it demonstrates the ability to “accelerate” patients straight from MDI to MiniMed 670G.

  • Dr. Pilar Beato-Vibora (University Hospital of Badajoz) presented six-month clinical outcomes for children (n=22) and adults (n=36) with type 1 started on MiniMed 670G after being on predictive low glucose suspend (60%), CSII + BGM (19%), MDI + BGM (12%), or MDI + CGM (9%). Overall, participants’ mean A1c was reduced by 0.4% at three months (baseline 7.4%), a drop that was sustained at the six-month endpoint and quite significant from a low baseline A1c. Mean Time in Range increased significantly from 63% to 73% after three months on MiniMed 670G (+2.4 hours/day), remaining even at 72% at six months. Likewise, time above 180 mg/dl and time above 250 mg/dl improved significantly, dropping from 35% to 26% (-2.2 hours/day) and from 9% to 5% respectively at month six. The cohort experienced zero hospitalizations due to DKA or hypoglycemia during the trial. Particularly noteworthy, after six months, the percentage of participants achieving target A1c of <7% rose 30% to 61%, and percentage of participants achieving the target Time in Range of >70% rose a whopping 36% to 57%. This improvement was already seen after three months (53% meet A1c target and 60% meet Time in Range target) and was sustained through six months. Participants spent 86% and 88% of time in auto mode at three and six months respectively, and experienced 0.6 exits per day.

5. Sanofi-Sponsored Symposium: Dr. Rich Bergenstal Advocates for CGM in Drug Trials, Dr. Pratik Choudhary on Using Time in Range in the Clinic

In a powerful sign of the growing importance of CGM and diabetes technology in pharmaceutical therapies, Sanofi dedicated the final hour of its symposium to discussing CGM, Time in Range, and “integrated care.” The busy Dr. Richard Bergenstal (International Diabetes Center) gave a popular presentation, giving an overview of CGM, but also calling for more use of CGM in clinical trials for drugs. After discussing the limitations of A1c, Dr. Bergenstal noted that CGM-derived metrics (e.g., Time in Range) could be much more powerful at understanding and evaluating various therapies and intervention strategies, rather than relying exclusively on topline A1c results. Dr. Bergenstal then provided two examples of clinical trials assessing Time in Range. Firstly, the inRange study (ClinicalTrials.gov page), currently recruiting, will evaluate CGM outcomes for ~340 type 1s randomized to either Toujeo (insulin glargine) or Toujeo (insulin degludec) basal insulins. The second, the OneCARE study, which took place in Spain and will be presented as a poster at EASD 2020, also compared insulins glargine and degludec using both CGM-derived metrics and patient-reported outcomes.

  • Leicester Diabetes Research Center’s Dr. Pratik Choudhary nicely made the case for using Time in Range in clinical practice, saying, “[Time in Range] works because it incorporates both mean glucose and variability into the same number.” Additionally, the metric “makes more sense” to patients – a sentiment we’ve heard from both providers and people with diabetes over the last few years. Notably, Dr. Choudhary also shared data gathered from his center, showing that the proportion of fingerstick results in range correlated well with A1c and in a similar way to CGM-derived Time in Range. In other words, BGM-derived proprtion in range metrics could be used in a similar way to CGM-derived Time in Range, further establishing the importance of building in connectivity and well-designed reports for the majority of people with diabetes still on BGM.

Diabetes Therapy Highlights

1. Update on INNODIA: Standardizing Phase 2 Trials for Type 1 Drug Development using a Master Protocol

 

INNODIA – an “INNOvative approach towards understanding and arresting type 1 DIAbetes” – is comprised of 31 academic centers, 6 pharmaceutical partners, 2 patient organizations, and 1 small to medium enterprise (SME) devoted to improving type 1 diabetes drug development. The objective of INNODIA is fivefold: (i) established a clinical infrastructure throughout Europe to identify, enroll, collect bio-samples, and phenotype newly diagnosed individuals with type 1 diabetes and their relatives; (ii) create a collaborative research network; (iii) facilitate R&D for novel type 1 treatments; (iv) bring results together into a large research database; and (v) standardize clinical trial designs for studies in newly diagnosed type 1. In this presentation, Dr. David Dunger (University of Cambridge) expanded on this last objective, defining the structure of INNODIA’s Master Protocol (MP) or study “backbone” and providing an overview of the 4 trials currently taking place under the INNODIA umbrella. Dr. Nicolas Bovy (Imcyse Specific Active Immunotherapeutics) later expanded on the details and foundational research behind one of these trials, IMPACT.

  • INNODIA’s natural history study backbone necessitates that investigators identify and enroll newly diagnosed type 1 diabetes patients around 6 weeks from diagnosis and follow them over the course of two years. At baseline and 4 pre-specified timepoints – 3-, 6-, 12-, and 24-months – researchers  collect various bio-samples (e.g. blood or urine) and gather a variety of prescribed measurements. These measurements run the gamut from A1c and autoantibodies to ‘multi-omic’ sample analyses (e.g. lipidomics, transcriptomics, and genomics) for the purpose of identifying novel immune biomarkers of type 1 and assessing efficacy of experimental treatments. Unique to the INNODIA, participants are also instructed to regularly collect and send dried blood spot (DBS) samples following self-administered mixed meal tolerance tests (MMTTs) – these samples can subsequently be assessed for C-peptide level at a centralized  INNODIA laboratory. All sample collection, storage, processing, and analysis is rigorously standardized between trials at 6 central hubs across Europe, and data is continuously uploaded to a central database.

  • The INNODIA backbone has been adapted to establish a MP in order to facilitate clinical trial designs whilst maintaining the strict rigor and standardization of sample collection. There are currently four scheduled INNODIA related  trials: (i) MELD-ATG evaluating the efficacy of anti-thymocyte globulin (ATG); (ii) IMPACT investigating the antigen-specific immunotherapy IMY-0098; (iii) VeR-A-T1D (funded by JDRF), looking at the hypertension drug verapamil SR; and (iv) CFZ533 (sponsored by Novartis) evaluating the monoclonal antibody iscalimab in newly diagnosed type 1 diabetes patients. With the exception of CFZ533, which was initiated in November 2019, all trials are expected to begin this fall, complete by 2022, and readout before or during 2023. Of note, INNODIA was prompted to move forward with the MP in February 2020, when they received Positive Scientific Advice from EMA.

  • In a separate talk, Dr. Nicolas Bovy (Imcyse Specific Active Immunotherapeutics) presented the initial phase 1b results of IMCY-0098 in type 1 diabetes – the immunotherapy being explored in INNODIA’s upcoming phase 1b/2a IMPACT study. IMCY-0098 is a novel molecule that induces cytolytic CD4+ T-cells to kill immune cells (T-cells and antigen-presenting cells) in the pancreas and/or draining lymph node; the drug has been engineered to only attack those cells which are autoreactive towards insulin-producing cells. IMCY-0098 was studied initially in the phase 1b EXALT trial investigating the drug in newly diagnosed type 1 diabetes, both in a primary 24-week study and in a 1-year follow-up study. IMCY-0098 was injected subcutaneously at baseline, 2-, 4-, and 6-weeks in the main study (n=41), with follow-up at 24-weeks. IMCY-0098 met its primary safety endpoint, being well-tolerated by study participants without increases in adverse events or disease exacerbation. In addition, IMCY-0098 treatment increased the number of cytolytic CD4+ T cells as measured by the marker granzyme, with significant increases found in those with type DR4+ human leukocyte antigen (HLA) complexes. At the highest dose tested, IMCY-0098 also significantly reduced the number of CD8+ pathogenic T-cells implicated in beta cell destruction in this cohort. Finally, this highest dose also appeared to have a protective effect of C-peptide preservation in DR4+ participants, although only up to 24 weeks.

    • The upcoming IMPACT study – which is set to begin recruiting in October 2020 – will seek to identify and/or verify the optimal dose, administration schedule, clinical efficacy, and safety of IMCY-0098. It will also attempt to identify an immune profile associated with the greatest treatment efficacy. The study will enroll 84 patients in two steps: step 1 will involve newly diagnosed type 1 participants ages 18 to 45, and step 2 will enroll newly diagnosed individuals ages 12 to 45.

2. Dr. Vivian Fonseca Touts Real-World Benefits of Early GLP-1/Basal Insulin Combination Therapy in Patients with Type 2

In a moderated poster, the brilliant Dr. Vivian Fonseca (Tulane University School of Medicine) presented real-world results supporting the simultaneous initiation of basal insulin and a GLP-1, over a sequential regimen. While current ADA/EASD guidelines state that patients who have not met their A1c goals on either therapy alone can consider adding the other injectable as a treatment intensification, there is little evidence on whether or not the timing of intensification impacts clinical outcomes. Using retrospective data on patients with type 2 and A1c ≥9% on OADs (n=6,339) from the Optum Humedica EMR database, Dr. Fonseca and his collaborators discovered that patients who initiated the therapies “simultaneously” (≤30 days apart) achieved the strongest glycemic outcomes at six and 12 months for all four primary endpoints: proportion of individuals achieving (i) an A1c <7%; (ii) an A1c <8%; (iii) ≥1% reduction in A1c from baseline; and (iv) ≥2%reduction in A1c, followed by individuals who started the therapies within 31-90 days of each other; Baseline A1cs for these two cohorts were 10.9% (±1.54%) and 10.7% (±1.51%), respectively.

  • In terms of clinical implications, these findings suggest that first treating patients with either a basal insulin or GLP-1 and waiting to assess treatment efficacy before adding the other may not be the most effective strategy. These data harken back to results from VERIFY, presented at EASD 2019, which found that the early combination of metformin and Novartis’ DPP-4 inhibitor Galvus (vildagliptin) doubled the time to initial treatment failure vs. monotherapy and sequential intensification. As Dr. Dan Drucker convincingly put it, “Diabetes is a serious disease! Think more like an oncologist (early combination therapy) rather than a traditional treat to failure approach. Well-tolerated drug combinations with established safety profiles should be used earlier.” Although his words were in regard to Galvus and metformin, we think they certainly apply in this case as well.

3. Lilly’s Ultra-Rapid Insulin Lyumjev Shows Superior PPG and Lower Hypoglycemia than Humalog in Type 1 Pump Users

New phase 3 data for Lilly’s recently approved Lyumjev (ultra-rapid acting insulin lispro) shows superior PPG control and lower hypoglycemia compared to Humalog (insulin lispro) when administered by pump in people with type 1 diabetes. The 16-week study enrolled 432 people with type 1 diabetes using insulin pumps (mean age 46 years, mean A1c 7.6%, mean diabetes duration 26 years), randomizing them 1:1 to Lyumjev or Humalog. On the primary outcome of A1c change, Lyumjev showed non-inferiority to Humalog (-0.7% vs. -1.0%, p=0.565). Furthermore, in standardized mixed meal tolerance tests, Lyumjev showed significantly greater reductions in 1-hour (difference: -24 mg/dl, p<0.05) and 2-hour post-prandial glucose than Humalog (difference: -28 mg/dl, p<0.05). Notably, participants wore blinded CGM prior to randomization and at weeks 8 and 16 of the study and time-in-range (TIR) was measured as a secondary endpoint. According to this CGM data, there was no difference in TIR between Lyumjev- and Humalog-treated participants (57.9% vs. 57.5%), but those on Lyumjev showed significantly less time spent in severe hypoglycemia (22 vs. 29 minutes/day, p=0.006) and moderate (63 vs. 77 minutes/day, p=0.006) hypoglycemia. As for adverse events, Lyumjev-treated participants had a higher rate of infusion-site related adverse events (60.5% vs. 44.7%) but the rate and incidence of severe hypoglycemia and DKA did not differ between the groups. Overall, this data adds further support for the strong clinical profile of Lyumjev, particularly in the context of pump therapy. Lyumjev’s indication in the EU, Japan, and Brazil is for both MDI and pump therapy, but it is only approved in the US for use with MDI. We certainly hope this latest phase 3 trial puts to rest any concerns over the use of this therapy with pumps.

4. Arecor’s Ultra-Rapid Insulin AT247 Shows Faster Onset/Offset and Superior Glucose-Lowering to NovoLog and Fiasp in Phase 1 Study

Dr. Eva Svehlikova (Medical University of Graz) presented encouraging phase 1 PK/PD results for Arecor’s ultra-rapid insulin candidate AT247 in people with type 1 diabetes. The trial enrolled 19 men with type 1 diabetes (mean age 35 years, mean A1c 7.1%, mean diabetes duration 20 years), each of whom received a single subcutaneous dose (0.3 units/kg) of either AT247, insulin aspart (Novo Nordisk’s NovoLog), or fast-acting insulin aspart (Novo Nordisk’s Fiasp) in a cross-over manner during a euglycemic clamp procedure. Overall, AT247 had a significantly faster onset of glucose-lowering action with a treatment difference of -23 and -9 minutes as compared with NovoLog and Fiasp respectively. Furthermore, the glucose-lowering effect in the first hour after dosing, measured in terms of area under the curve of the glucose infusion rate (AUCGIR0-6omin), was significantly greater for AT247 than NovoLog or Fiasp (212 vs. 49 vs. 91 mg/kg, respectively). Finally, a measure of the offset of insulin exposure (Time to late 50% Cmax insulin) was significantly faster for AT247 with a treatment difference of -22.5 and -20 minutes as compared with  NovoLog and  Fiasp respectively. Overall, these results point to a very promising clinical profile for AT247, and we look forward to seeing how the candidate performs in larger, longer-term studies. In the initial announcement of these results, Arecor CEO Sarah Howell indicated that the company is eyeing AT247 for use in future artificial pancreas systems, in addition to use for traditional MDI insulin therapy. We agree that the full potential of next-gen ultra-rapid insulins may be best unlocked in AP systems – currently, ultra rapid-acting insulins such as Fiasp have struggled to make a large impact on the market.

5. Anti-IL-21 + Liraglutide Combination “Arrests Progression of Beta Cell Destruction” in Recently Diagnosed Type 1s

Professor Chantal Mathieu reviewed Novo Nordisk’s phase 2 trial of anti-IL-21 + liraglutide in adults with recently diagnosed type 1 diabetes. Full results from this 80-week study (n=304) were first presented at ADA 2020. Professor Mathieu highlighted the key efficacy and safety findings – namely, that this combination approach protects beta cells and improves glucose control while reducing total daily insulin requirements. Together, anti-IL-21 and liraglutide (Novo Nordisk’s once-daily GLP-1 agonist Victoza) led to a 48% improvement in post-meal C-peptide secretion vs. placebo (p<0.01) and to a 33% improvement vs. liraglutide alone (p=0.02). Mean A1c dropped 0.4% and total daily insulin dose was 32% lower in the combination arm vs. the placebo arm, though neither finding was statistically significant. Fittingly, given the improved glucose control and reduced insulin load, there were numerically fewer hypoglycemia episodes in the combination group vs. the placebo group (34% fewer). Although this result did not meet statistical significance either, Professor Mathieu emphasized the low absolute number of events (~4 per group) and suggested that the trend toward reduced hypoglycemia is extremely promising. The beneficial effects on C-peptide and A1c disappeared once therapy was stopped at 54 weeks (see the second image below); the implication, according to Professor Mathieu, is that continuous treatment will be necessary to really arrest the process of beta cell destruction in type 1 diabetes. On safety, she underscored that anti-IL-21 was “very, very well-tolerated.” Liraglutide did cause more GI side-effects than placebo, as expected, but these symptoms were somewhat attenuated in the combination arm.

  • We’re excited by the potential for GLP-1 agonist combination therapy in type 1 diabetes, especially since Novo Nordisk terminated its development program for standalone liraglutide in type 1 back in 2015. The company has received Orphan Drug designation for anti-IL-21/liraglutide co-administration, and is currently in talks with FDA about the design of a phase 3 trial. There is some speculation that Novo Nordisk’s second-generation GLP-1 agonist semaglutide (Ozempic) will be substituted for the first-gen liraglutide in future studies. Our ears are peeled for updates.

  • We always appreciate EASD’s focus on type 1 intervention and prevention. In an afternoon session on novel agents in type 1, Dr. Teresa Quattrin also re-presented results from the phase 2 T1GER study for J&J’s golimumab in type 1 intervention. In addition, though not an interventional therapy, we also heard a data from the phase 1b/2 Simplici-T1 trial for vTv Therapeutics’ once-daily, liver-selective glucokinase activator TTP399, confirming the drug’s efficacy on A1c and TIR and relatively clean safety profile.

6. From Dietary Changes to the Role of Bile in Metformin’s Mechanism of Action: Highlights from a Glucose-Lowering Therapies and Liver Symposium

In the symposium entitled, “Glucose-Lowering Therapies and the Liver,” we were especially struck by two presentations from Mr. Daniel Sansome (Adelaide Medical School) and Dr. Hanna Kahleova (Director of Clinical Research, Physicians Committee for Responsible Medicine). Despite sharing the same broad category, the two presentations covered widely different topics:

  • Daniel Sansome examined the effects of endogenous and exogenous bile acid on metformin’s ability to lower glucose levels. Mr. Sansome’s study (n=13) found that intestinal bile acids did not play a vital role in metformin’s ability to lower glucose and stimulate GLP-1. In a double-blinded, randomized, cross-over study, the researchers enrolled participants with type 2 diabetes, well-controlled by diet and lifestyle only. For each participant, a silicone catheter was inserted via the nostril, placing a balloon and aspiration channel in the duodenum and an infusion channel in the jejunum. Participants underwent four infusions: (i) bile exclusion and placebo; (ii) bile exclusion and metformin (1g); (iii) bile inclusion and metformin (1g); and (iv) bile inclusion, metformin (1g), and the exogenous bile acid taurocholic acid (TCA). Bile exclusion was achieved via balloon inflation, and metformin or TCA was infused into the jejunum. Metformin significantly decreased plasma glucose when the balloon was inflated, and bile was excluded. Infusing exogenous TCA bile acid and metformin had no effects on the levels of plasma glucose. In future studies, Mr. Sansome hopes to evaluate the chronic use of metformin and the effects of bile acid, in addition to examining the effect of metformin on glucose absorption in the intestines.

  • Dr. Hanna Kahleova presented a study on the effects of a 16-week vegan diet on body weight, visceral fat, intramyocellular lipids, and liver fat. The study randomly assigned overweight or obese participants (BMI 28-40 kg/m2) without diabetes to start a vegan diet or remain on their current diet (n=244). In contrast to the control group, participants on a vegan diet lost a significant amount of weight (-6.4 kg), two-thirds of which stemmed from a loss of visceral fat (-224 cm3). While there was no significant change in intramyocellular lipids, levels trended downward in the vegan diet group and trended upward in the control group. The group on a vegan diet also exhibited a significant 34% decrease in hepatocellular lipids. Conversely, those who maintained their previous diets displayed non-significant, slight increases in liver fat percentage. Notably, Dr. Kahleova found that the thermic effect of food increased by 14% in the vegan group, signifying that a vegan diet increased post-prandial metabolism. Dr. Kahleova postulated that such changes may serve as the underlying mechanism precipitating weight loss on a vegan diet.

Big Picture Highlights

1. Swedish National Diabetes Register Shows 36% Increased Risk of Vascular Dementia with Type 2 Diabetes; Dementia Risk Increases with Poorer Glycemic Control

A very closely-watched oral presentation highlighted new findings from the Swedish National Diabetes Register, detailing the connection between type 2 diabetes, A1c, and dementia. The registry-based study involved over 2 million people, followed for a median of 6.8 years. Compared to people without diabetes, those with type 2 diabetes had a 36% increased risk of vascular dementia (HR 1.36, 95% CI 1.03-1.39) and an 8% increased risk of non-vascular dementia (HR 1.08, 95% CI 1.04-1.12), and, quite surprisingly, an 8% lower risk of Alzheimer’s disease dementia (HR 0.92, 95% CI 0.87-0.98). The study further showed that, indeed, dementia increase worsens with poor glycemic control. Compared to people with type 2 diabetes and an A1c <52 mmol/mol (i.e. 6.9%), those with an A1c >87 mmol/mol (i.e. 10.1%) had a higher risk of all forms of dementia: vascular (HR 1.93, 95% CI 1.53-2.42), non-vascular (HR 1.67, 95% CI 1.45-1.91), and Alzheimer’s disease (HR 1.34, 95% CI 1.03-1.75). As a reminder, the loss of memory and cognitive function that characterizes dementia can have many possible etiologies. Vascular dementia is caused by a reduced blood supply to the brain (due to stroke, diseased blood vessels, etc.), while non-vascular dementia is due to a wide range of other causes (including Parkinson’s disease, fronto-temporal lobe damage, etc.). By contrast, Alzheimer’s disease dementia is a genetically influenced condition, associated with a distinct neuropathology – namely the accumulation of amyloid-beta plaques and tau tangles in specific areas of the brain. The association between type 2 diabetes and increased risk of dementia in general has long been appreciated, but the relationship between diabetes and individual dementia subtypes is less clear-cut. In particular, the especially high risk of vascular dementia in people with type 2 diabetes suggests that the mechanism of the diabetes/dementia association could involve blood vessel damage in the brain, essentially placing dementia among the ranks of the other macro- and micro-vascular complications of long-term hyperglycemia.

  • With this association between diabetes and dementia, it remains an open (and very exciting) question whether glucose-lowering therapies can in turn reduce dementia risk. Enthusiasm is particularly strong for the potential of GLP-1 agonists in this area, and Novo Nordisk has shown keen interest in the potential of liraglutide and semaglutide for Alzheimer’s disease. Additionally, vTv is currently investigating its oral small molecule azeliragon in a phase 2/3 trial of patients with both mild Alzheimer’s and type 2 diabetes. The study seeks to confirm post-hoc findings from the phase 3 STEADFAST trial (October 2018), which demonstrated a statistically significant (p=0.01) improvement on the Alzheimer's Disease Assessment Scale-Cog (ADAS-COG) in people with diabetes treated with azeliragon (n=33) compared to the placebo group (n=22) after 12 months. Patients treated with azeliragon demonstrated improved cognition and function, reduced brain atrophy, and decreases in inflammatory biomarkers. Given these new findings from the Swedish National Diabetes Register, we would like to see additional studies in people with vascular dementia, where at least on a preliminary basis, the diabetes/dementia relationship appears much stronger than it is for Alzheimer’s disease. 

  • For more from the Swedish Diabetes Registry, we recommend “Swedish National Diabetes Register: 84% of Adult Type 1s, 94% of Pediatrics Now Using CGM (Mostly FreeStyle Libre); Massive Population-Level Outcomes Improvements from 1996 to 2018” from our Day #1 Highlights report.

2. Dr. Antonio Ceriello on the Relationship Between COVID-19, Diabetes, and Cardiovascular Disease

In a very timely talk, Dr. Antonio Ceriello (IRCCS MultiMedica) fleshed out the connections between COVID-19 and cardiovascular risk management in people with diabetes. His talk focused on lessons learned based on (i) controlling hyperglycemia; (ii) anti-diabetes drugs; (iii) ACEs and ARBs; (iv) corticosteroids; (v) hydroxychloroquine; and (vi) thrombosis. Diabetes is one of the most important contributors to COVID-19 hospitalization and outcomes, and the CORONADO study showed that the presence of hyperglycemia at hospital admission is a stronger indicator of disease prognosis than previous trends of glycemic control. This was further corroborated by evidence from the Pisa COVID-19 study, which showed that hyperglycemia at admission was associated with severity of prognosis in patients without diabetes as well. Moving to glycemic variability, a study by Wen-Cheng Chao et al. found that hyperglycemic variability in the first day of ICU admission was associated with increased 30-day mortality in patients with sepsis. While studies of anti-diabetes drugs on COVID-19 outcomes have not yet been performed (a study of SGLT-2 inhibitor dapagliflozin is underway), a review of potential therapies states that GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors could be promising given their abilities to reduce inflammation. The potential of ACEs/ARBs is a little more unclear; while some studies have concluded that taking ACEs/ARBS increases risk for COVID-19, others have found no association. Corticosteroids, like dexamethasone, have reduced 28-day mortality in patients with COVID-19 on some form of respiratory support – but Dr. Ceriello cautions that one must weigh the pros and cons the high glycemia steroids can promote. The use of hydroxychloroquine (HQ) has also been heavily debated and sensationalized by media, even after the retraction of papers showing its benefit based on methodological issues. Dr. Ceriello emphasized HQ’s negative side effects, like heart damage and increased hypoglycemia, which are especially harmful for people with diabetes.

  • These trends and mixed results can be explained by lack of communication between different medical specialists. Dr. Ceriello candidly stated that communication has failed. With this, scientific hypotheses were falsely equated to evidence without substantial proof. Much of this perception was driven by media and “fake news” – as Dr. Ceriello put it, human behavior prevailed over scientific consistency, which led to confusion in treatment options for COVID-19. He concluded that the main learning from this is that effective communication, collaboration, and trust are needed between HCPs, patients, professional bodies, healthcare organizations, governments, the media, and the general public to reach successful treatments in the COVID-19 pandemic.

Select Q&A

Q: Can SGLT-2s be initiated in COVID-19 for those newly diagnosed with type 2 diabetes?

A: There is no evidence that you can’t, but there is a trial underway, so we’ll have an evidence base soon. Depending on the severity of COVID-19, you do need to pay attention to possible side effects.

Q: What about DPP-4s?

A: There was hope, but I think there are papers coming out that show DPP-4s don’t make a difference in outcomes. (Editor’s note – while DPP-4 inhibitors have not been associated with better macrovascular outcomes, they have been associated with better diabetes management over a significantly longer time, in VERIFY.)

Q: Is there any difference in prognosis between controlled and uncontrolled patients with diabetes when they get COVID-19?

A: There is strong evidence that diabetes is exposing people to worse prognoses but based on the level of hyperglycemia when they are admitted to the hospital. Having diabetes alone is not enough to have bad prognosis if they are well-treated (editor’s note – we believe what this speaker may have meant is “There is strong evidence that [having] diabetes is associated with worse prognoses based on the level of hyperglycemia when they are admitted to the hospital. Having diabetes alone is not enough to have bad prognosis if their diabetes is well-managed.”)  

3. Two-Year Weight Loss Induced Remission of Type 2 Diabetes Restores Normal Pancreas Morphology.

The illustrious Prof. Roy Taylor (Newcastle University) spoke today about his discovery that the shrunken, irregular pancreas seen in type 2 diabetes normalizes in volume and shape over two years of “diabetes remission.” Prof Taylor spoke to readers of Closer Look in an interview interview last April and we were very keen to hear his talk today. DiRECT trial participants (n=64) using an intensive weight loss program were followed over a 24-month period and compared to controls without diabetes. As opposed to “non-responders”, “responders” were participants who met pre-specified A1c goals (<6.5%) and fasting blood glucose levels (<7 mmol/L). At baseline, non-responders and responders had a significantly smaller pancreas volume when compared to non-diabetic controls. Over the 24-month study, responders showed greater beta cell function and change in pancreas volume than non-responders (p = 0.003). Notably, Dr. Taylor found that responders increased pancreas volume approached the pancreas volume of controls without diabetes. Dr. Taylor explained that these improvements followed a return of near-normal beta cell insulin secretion and decreased intrapancreatic fat content.

  • In addition to volume changes, the irregular shape of responders’ pancreases also returned to normal. Fractal dimension was used to measure changes in border irregularity, whereas magnetic resonance offered a visualization of smoothed borders - the drastic changes in pancreas borders are visibly shocking.

  • Very significantly, this the first study to demonstrate that the abnormal pancreas can return to normal morphology during type 2 remission. Dr. Taylor postulated that these same changes in pancreas volume and borders, in reverse order, may indicate the onset of type 2 diabetes, but further studies on this point are needed.

4. Q&A with EASD Leadership on Plans to Create the “Netflix” of Diabetes, How COVID-19 is Democratizing Scientific Conferences, and Hot Topics at EASD 2020

We caught up with EASD President Prof. Stefano Del Prato and SVP Prof. Chantal Mathieu at an EASD press Q&A session to hear their thoughts on EASD’s first fully virtual conference and big picture hopes for the organization. To open, Prof. Del Prato noted that a record 20,000 participants have now signed up for this year’s meeting, with the highest participation from Brazil. Notably, considering the substantial cost of travel that would have been required to fly from Brazil to Vienna, Prof. Del Prato suggested that this statistic was indicative of the “democratization” of information engendered by a virtual conference. Prof. Del Prato also elaborated that while the core of EASD 2020 is the five-day conference, leadership hopes to “keep the congress alive for the rest of the year.” Rather than creating “a bigger repository of information, symposia, presentations, and so on,” EASD will create a specialized virtual platform, utilizing data on which topics were most popular during the live sessions. For a specific topic like GLP-1s, the platform could potentially curate presentations from ‘bench-to-bedside,’ in order for participants to not only learn new clinical data but see where it originated. In summary, Prof. Del Prato stated, “I think one of the great values of the virtual program is the flexibility. I like to think of what we do as a sort of “diabetes Netflix platform.” So, you can go for something you are interested in, and then move to another one or getting attracted in. The amount of information embedded in EASD is incredible. I think it is our duty and task to leverage on that because there is a lot of knowledge. There is a method of transferring that knowledge to as many people as possible.” – Inspiring words indeed! We cannot wait to explore EASD’s ‘Netflix of diabetes’ the second that it is available.

  • When asked about the science or sessions they are most looking forward to, Prof. Mathieu explained that her “coup de coeur” is with (i) GLP-1s in obesity; (ii) SGLT-2 inhibitors in renal disease; and (iii) intervention and prevention of type 1 diabetes. Novo Nordisk’s GLP-1 Saxenda (liraglutide 3.0 mg) is currently leading the front on the former point, and positive data from DAPA-CKD is fueling the second. While type 1 efforts are still, as Prof. Mathieu put it, “making little steps,” research on combination therapies like golimumab, teplizumab, and combination anti-IL-21 and liraglutide continues.

  • Prof. Del Prato took a slightly different approach, stating that he was most looking forward to further alignment between different practice guidelines. While there is still some tension between the ESC 2019 guidelines, which prioritized GLP-1/SGLT-2 inhibitors as first-line therapies, and ADA/EASD, Prof. Del Prato was very optimistic about a more connected future. He stated, “I think this can all really be evolved into a more coordinated and shared path to introducing the right treatments at the right time. Soon, we will have many of the guidelines coming together – the message will become stronger and stronger. There will be more common ground to work. So, I think on top of all the science that is going to be supported, I think of this as a need and potential opportunity.

Early on Tuesday, we heard from Dr. Fahd Al-Mulla (CSO at Dasman Diabetes Institute, Kuwait), Dr. Nick Wareham (University of Cambridge), and Dr. Ernesto Maddaloni (Campus Bio-Medico University, Italy) on novel biomarkers in type 2 diabetes. Dr. Al-Mulla and Dr. Maddaloni focused their talks on the power of specific biomarkers as indicators for type 2 diabetes. While Dr. Al-Mulla delved into scientific specifics on ANGPTL8 as a biomarker for type 2 diabetes and obesity, Dr. Maddaloni’s presentation centered on wrist circumference as an indicator for type 2 diabetes and cardiovascular disease, focusing instead on the big-picture correlations and the accessibility and affordability of the tool. In this very strong talk, Dr. Wareham discussed evidence for several biomarkers, and focused meaningfully on how the field is making sense of and using biomarkers in diabetes and obesity predictions.

  • Dr. Wareham emphasized the importance of differentiating between correlational (e.g. nutritional biomarkers) versus causal (e.g. measures of glycemia, branch-chain amino acids, plasma proteins) biomarkers for diabetes and obesity risk.  In the thousands of studies exploring biomarkers for type 2 diabetes, few explore causality, and per Dr. Wareham, several indicators with strong association are unlikely to be causal while those with weak or moderate associations may actual reflect causal mechanisms. Dr. Wareham also argued that using biomarkers to predict diabetes requires a balancing act between reach and prediction accuracy: while adding a questionnaire, clinical measures, biomarkers, and genetics to already-available information might improve prediction accuracy, they limit the number of people such a tool might reach. To Dr. Wareham, comparing the value of predictive models for type 2 diabetes is like comparing axes and spades: it depends on the purpose. The public health or clinical rationale determines which tools should be used and whether prediction accuracy or reach should be prioritized. In Q&A, Dr. Wareham doubled down on this sentiment: “In my mind, the deficiency in predicting diabetes is not in getting new biomarkers, but rather in implementing what we already know.”

  • Dr. Fahd Al-Mulla’s talk focused on ANGPTL8, a lipid-related biomarker for type 2 diabetes and obesity. Even when adjusted for: (i) age, gender, and ethnicity, (ii) BMO and waist/hip ratio, or (iii) A1c, HOMA-IR, HOMA-ß, BMI, and waist/hip ratio, a higher amount of ANGPTL8 in plasma is highly correlated with developing type 2 diabetes (odd ratios 10.94, 10.09, and 7.37 respectively, p<0.0001). When induced at normal levels, ANGPTL8 drives distribution of fatty acids in white adipose tissues. However, with high levels of ANGPTL8, fatty acids are deposited in skeletal muscle and the liver as well, leading to obesity, diabetes, NASH/NAFLD. Based on Dr. Al-Mulla’s research, it also appears that mutated ANGPTL8 might be correlated with higher ANGPTL8 activity because it is less effective than wildtype ANGPTL8 in feedback inhibition. Thus, having mutant ANGPTL8 might put individuals at higher risk for diabetes, although Dr. Al-Mulla does not have evidence showing that causation yet.

  • Focusing on a more accessible and affordable indicator, Dr. Ernesto Maddaloni discussed the value of wrist circumference as a clinical marker of insulin resistance and cardiovascular disease. In a 2011 cross-sectional study of overweight and obese adolescents and children (n=477, average age 10 years), Dr. Capizzi and colleagues found that bone tissue area – but not adipose tissue area – was significantly associated with insulin resistance and is more strongly associated with adiponectin-leptin ratio (measure of adipose dysfunction) than are adipose tissue distribution and total fat (not to mention far easier to measure). Given the strength of bone tissue area as an indicator, wrist circumference a powerful measure because it is an easy-to-detect, affordable measure of skeletal frame size that is not severely confounded by body fat variation. Notably, a later study found a similarly significant correlation between wrist circumference and cardiovascular disease in children with obesity. Among adults, a ~nine-year prospective study (n=6,393) found a strong correlation between wrist circumference and diabetes in both genders. In fact, a one-standard-deviation increase in wrist circumference was associated with a 17% increase in diabetes incidence in males (p=0.012) and a 31% increase in diabetes incidence among females (p<0.0001).

6. Stefano Del Prato Delivers Presidential Address for the 56th Annual Meeting.

In front of a scenic, virtual background, Dr. Stefano Del Prato delivered the 56th Annual Meeting Presidential Address, touching on COVID-19, virtual meetings, and future directions for the EASD. With a somber and human tone, Dr. Del Prato began with a moment of silence to commemorate his EASD colleagues lost due to COVID-19. From there, he spoke on the growing role of telemedicine and posed the question, “will this experience change the delivery of diabetes care?”. From the 2000+ papers on diabetes and COVID-19 that have been published thus far, it certainly seems so. Whereas switching to a virtual platform may be challenging for some organizations, Dr. Del Prato was nothing less than positive and optimistic about the EASD’s new way of gathering. As background, the EASD has used some degree of virtual supplementation in past years, on which Del Prato boasted some impressive numbers. For example, in Barcelona last year, the Congress drew 15,000 in-person attendees. An additional 15,000 people interacted with the website during the 2019 Congress, and over the past 10 months, the website remained open, seeing another 70,000 consistent accesses: “we realized that we have the opportunity to reach out to the entire world, thanks to the flexibility of the virtual platform.”

  • While in-person interaction and networking seem to be the greatest loss of virtual meetings, Dr. Del Prato and the EASD have a solution: the 3D Virtual EASD 3D plaza. “Let me invite you to stroll around the EASD plaza, where you can meet with your peers, mingle, visit the EASD, EFSD, many other booths, and visit the Association Village,” said Dr. Del Prato. This 3D experience is truly unlike anything we’ve seen yet at virtual meetings.

  • The presidential address also included a detailed description of EASD’s E Learning Platform, which has been expanding rapidly since it’s inception in 2018. Dr. Del Prato explained that the 56th Annual Meeting content will be revitalized for 365 days on the virtual meeting platform and the EASD plans to translate the E-Learning sites into other languages, including French, Spanish, Arabic, and Mandarin. Our team is impressed by the EASD’s comprehensive effort to reach such an international audience.

  • Looking ahead, Dr. Del Prato noted that the ADA and EASD draft consensus on managing hyperglycemia in type 1 will be presented next year at ADA 2021. Dr. Del Prato emphasized his excitement about the ongoing partnership between the two organizations, who released a joint consensus report on managing hyperglycemia in type 2 in 2018.

7. EASD’s 52nd Claude Bernard Lecture: Dr. Takashi Kadowaki’s Journey through Unraveling the Pathophysiology of Type 2 Diabetes

EASD Day #2 kicked off with a fascinating lecture by Dr. Takashi Kadowaki (Toranomon Hospital & The University of Tokyo), the 52nd awardee of the Claude Bernard Medal and Lecture. As introduced by conference president Prof. Stefano Del Prato (University of Pisa, Italy), the Claude Bernard prize is “EASD's highest award in recognition of an individual's innovative leadership and lifetime achievements in diabetes research.” In his lecture entitled “What is type 2 diabetes? A long journey to seek the truth,” Dr. Kadowaki took the audience through four distinct stages in his research journey: (i) the nature and role of insulin resistance versus insulin secretory defects; (ii) the link between IRS-1/IRS-2 proteins, obesity-related insulin resistance, and type 2 diabetes; (iii) adiponectin and the “AdipoR” receptor in obesity-related insulin resistance and diabetes; and (iv) the genes controlling susceptibility to type 2 diabetes in Japanese and East Asian individuals. Dr. Kadowaki presented decades worth of groundbreaking, critically important research while demonstrating a tremendous sense of humility and optimism for the future of diabetes research. Ending on an encouraging note, Dr. Kadowaki remarked, “While I look forward to continuing my research journey, I wish the younger generation of researchers to take up the challenge to gain further insights into this disease.”

  • Dr. Kadowaki’s research formed its foundations in 1984, when he made three critical observations about the pathophysiology of type 2 diabetes: patients with type 2 present with (i) early dysfunctions in glucose-induced insulin secretion; (ii) insulin resistance brought on by obesity; and (iii) a family history of the disease (i.e. a genetic basis). His interest in the genetics led him to investigate mutations in the gene encoding the insulin receptor tyrosine kinase, and particularly the downstream effects of the associated proteins IRS-1 and IRS-2; upon insulin binding to its receptor, IRS-1 and IRS-2 proteins become activated by the insulin receptor and go on to exert a variety of effects inside the cell. Using “knock-out” (KO) mouse models – mice which have either IRS-1 or IRS-2 effectively deleted from their genomes – Dr. Kadowaki came to two fundamental observations: while both IRS-1 and IRS-2 knock-out mice developed insulin resistance, only IRS-2 knockout mice developed diabetes. As a compensatory response to insulin resistance, beta cells in the IRS-1 knock-out mice underwent proliferation (“hyperplasia”) to maintain normoglycemia. Mice without the IRS-2 gene developed diabetes because they failed to exhibit this compensatory beta cell hyperplasia. In fact, IRS-1 knock-out mice only developed signs of type 2 diabetes when the gene encoding glucokinase (GK) was also removed from the genome – deleting GK impairs glucose-induced insulin secretion, so the compensatory hyperplasia was no longer able to compensate for the defective insulin response.

  • Dr. Kadowaki later went on to implicate IRS-2 in the pathophysiology of obesity-linked type 2 diabetes, playing a critical role in signaling pathways related to insulin resistance, hyperglycemia, and low-grade inflammation. In obese mouse models, Dr. Kadowaki initially identified that expression of IRS-2 – but not IRS-1 – was downregulated as a result of hyperinsulinemia. Knowing that obesity is characterized by a constant, baseline level of inflammation, Dr. Kadowaki sought to understand the relationship between IRS-2 under-expression and myeloid cells, the major actors in innate immunity. Using a myeloid-specific IRS-2 mouse KO model (i.e. mice with the IRS-2 gene deleted only from myeloid cells, not from any other body cells), Dr. Kadowaki reported a number of striking conclusions: without IRS-2 in myeloid cells, mice fed a high-fat (HF) diet developed insulin resistance of the liver and white adipose tissue (WAT) and experienced phenotypic changes in macrophages (a descendent of myeloid cells). These effects activated a series of signaling pathways which facilitate inflammation, increased gluconeogenesis from the liver (i.e. increased hepatic glucose output, contributing to hyperglycemia), and decreased glucose uptake by skeletal muscle. Further, although IRS-1 expression was unchanged in obesity, this protein appeared to play a role in increasing fat storage, NASH risk, and potentially cancer risk – all characteristics of obesity and obesity-induced type 2 diabetes.

  • Dr. Kadowaki also identified decreased adiponectin – a fat-specific hormone in WAT – as playing a crucial role in mediating obesity-induced type 2 diabetes, metabolic syndrome, and atherosclerosis (along with its receptors AdipoR1 and AdipoR2). In mouse models of diabetes and obesity, proper adiponectin signaling was associated with ameliorated insulin resistance, enhanced survival, and decreased risk of liver and colon cancer.  Through these observations, elucidation of the signaling pathways mediating adiponectin’s beneficial effects, and determination of the human AdipoR 3D structure, Dr. Kadowaki and colleagues developed a first in class adiponectin receptor agonist called AdipoRon. This small molecule acts on both AdipoR1 and AdipoR2 isoforms to improve insulin sensitivity, restore normal glucose and lipid metabolism, drive down inflammation, and promote endothelial function, among other beneficial metabolic and physiological effects. This agonist and others are currently being developed as treatments for type 2 diabetes and other obesity-related diseases. 

 

 

  • Using genome-wide association studies (GWAS), Dr. Kadowaki has conducted fundamental research into the genetic basis for type 2 diabetes susceptibility in Japanese and East Asian populations. Relative to Caucasian populations, individuals of Japanese or East Asian descent are more prone to developing type 2 diabetes at lower BMIs. In a recently published GWAS involving over 36,000 Japanese individuals with type 2 and over 155,000 controls, Dr. Kadowaki and colleagues identified 88 loci (fixed position on a chromosome) at which the nucleotide base differed significantly between groups (known as a single nucleotide polymorphism, or SNP). Compared to a similar GWAS conducted in Europeans, while some of the SNPs were similar between populations (both in genomic position and presumed functional activity), certain SNPs were unique to Japanese or European individuals. Interestingly, Japanese-specific SNPs were frequently found in genes or regulatory regions that have been implicated in the regulation of insulin secretion and beta cell gene expression. One SNP significantly associated with Japanese type 2 diabetes patients was found in the gene encoding the GLP-1 receptor; this SNP causes a single amino acid change in the receptor that subsequently increases GLP-1-induced insulin secretion. As European exhibited this change with far less frequency, Dr. Kadowaki suggested that Japanese and East Asian type 2 populations may be more responsive to GLP-1 receptor agonist and DPP-4 inhibitor drugs, which both target these incretin pathways (these effects have indeed been documented).

8. Non-Invasive Diagnostic Tools to Identify the Presence and Severity of At-Risk NASH: Dr. Vlad Ratziu Introduces NIS4

Dr. Vlad Ratziu (Sarbonne University, France) presented exciting new research correlating the presence of metabolic risk factors – most notably those associated with type 2 diabetes – with the presence and severity of NASH (n=2363). The study also proposed four blood-based biomarkers, collectively referred to as NIS4, to detect NASH and liver fibrosis. Currently, the only way to diagnose NASH is through a liver biopsy. These new, non-invasive techniques could increase NASH screening capacity and effectiveness, while also identifying individuals with milder forms of the disease.

  • Dr. Ratziu’s research showed that diabetes not only increases the risk of developing NASH, but also enhances risk of liver fibrosis in those who already have the condition. This study also brought to light other metabolic risk factors, including hypertension, dyslipidemia, and central obesity. Overall, the accumulation of risk factors correlated with increased prevalence of at-risk NASH: while the existence of one metabolic risk factor on its own was only associated with a 13% prevalence of having at-risk NASH, this figure rose to 68% in those with four metabolic risk factors.

  • The four non-invasive biomarkers used to assess NASH severity in this study, cumulatively called NIS4, were the microRNA miR-34a-5p, plasma protein alpha-2-macroglobulin (A2M), glycoprotein YKL-40, and A1c. While these factors are independent of each other, they are strongly associated – both clinically and biologically – with the development and progression of NASH when measured together. When the four biomarkers were collectively assessed in the NIS4 test, the presence of at-risk NASH was effectively ruled in or out for the sample group tested (n=469). Even more impressively, the diagnostic ability of NIS4 was robust irrespective of the presence and number of metabolic risk factors, including diabetes.

The diaTribe Foundation’s Seventh Annual Solvable Problems in Diabetes Forum

On EASD 2020 anticipation

  • To kick off the panel, the speakers discussed the talks they are most excited about at virtual EASD 2020. Professor Pratik Choudhary has broadly got his eye on the many sessions about therapies in type 1. For Partha Kar, “it’s anything Pratik is in.” We share his excitement for Dr. Choudhary’s research and are ourselves looking forward to his session on behavioral interventions on Thursday and checking out his poster “Determining the minimum duration of CGM monitoring to accurately estimate time below range.” Professor Kamlesh Khunti said he likes to look at the trials and compare that to what’s happening in the real world and comparing and contrasting the two. Professor. Davies intends to spend her time exploring a mixture of “type 1 work” and “new work coming out in obesity management” – she emphasized the degree to which she likes to focus on areas in which she is not directly working.  

  • The rest of the very interesting panel discussion included very interesting views from the group on the following – we’ll be back shortly with a much fuller discussion on: 

    • the interaction between diabetes and COVID-19;

    • diabetes technology in primary care;

    • Cities Changing Diabetes” and collaboration;

    • Diabetes risk reduction;

    • the study and uptake of new therapies with cardiovascular and kidney benefits; and

    • on the art of medicine and changing narratives surrounding diabetes.

--by Reshma Rajasingh, Leeza Petrov, Kamren Khan, June Dong, Sara Fragione, Elaine Young, Hanna Gutow, Katie Mahoney, Joseph Bell, Kira Wang, Abigail Dove, Payal Marathe, Ursula Biba, Albert Cai, Rhea Teng, and Kelly Close