The first virtual American Diabetes Association (ADA) Scientific Sessions were held from June 12-16, 2020. The ongoing coronavirus pandemic has not stopped the scientific and health care community from gathering online to share exciting new findings and engage in discussions about diabetes. This year’s virtual sessions gave us the opportunity to listen to many more lectures than we would normally be able to do due to conflicts with concurrent sessions.
Day one was packed with a multitude of sessions. In one streamed presentation—organized under the heading Integrated Physiology/Obesity—strategies for achieving diabetes remission using obesity treatment were reviewed. Presenters noted that in patients with prediabetes, a weight loss of 7-10% is recommended to prevent progression to diabetes, while a 5% weight loss is recommended to achieve clinical benefits in patients with diabetes1 . Lifestyle interventions were also discussed, specifically those measures outlined in the Action for Health in Diabetes (LOOK AHEAD) trial. This study was designed to look at the effect of lifestyle intervention on cardiovascular outcomes in patients with diabetes. Although the primary outcome of reduced cardiovascular events was not met, the study demonstrated diabetes remission in 11.5% of patients in the first year and 7.3% at year four2. Different dietary regimes were also compared. The Mediterranean diet was found to be well tolerated although it was less effective in achieving diabetes remission than the low-calorie and low-carbohydrate diet. The Diabetes Remission Clinical Trial (DIRECT) study which I have written about previously (Diabetes Remission: Is it Possible?) was also highlighted; in this trial a very low calorie diet (800 kcal/day) was used in the initial phase of the weight management program and 46% of the intervention group achieved diabetes remission3. The disparity between the limited use of pharmacologic treatment for obesity versus other measures was brought to our attention by Dr. Ania Jastreboff who noted that only 2% of adults with obesity receive pharmacotherapy4. She also discussed pharmacotherapeutic options that are currently available, as well as newer treatment options on the horizon, including tirzepatide, a dual GIP and GLP-1 receptor agonist still in clinical trials. Tirzepatide showed an average glycated haemoglobin (HbA1c) reduction of 1.7-2.0% and average weight loss of 11.5 to 12.5 lbs (5.2 to 5.7 kg) in a 12-week study5. Metabolic surgery is recommended to treat patients with type 2 diabetes with body mass index (BMI) > 40 kg/m2 and in adults with BMI of 35-39.9 kg/m2 who do not achieve durable weight loss and improvement in their underlying comorbidities with non-surgical methods6. Bariatric surgery leads to greater and more sustained weight loss, with diabetes remission rates of 30-80%7 and can also reduce the risk of cardiovascular events and development of congestive heart failure8.
Improving TIR with Automated Insulin Delivery
A symposium on the next generation of automated insulin delivery (AID) systems for patients with type 1 diabetes included results from four new clinical trials (findings not yet published). Two systems were tested: the Minimed 780G Advanced Hybrid Closed Loop (AHCL) and Insulet’s Omnipod Automated Glucose Control System. The Minimed 780G AHCL system was found to improve overall time in range (TIR) from baseline with a reduction of average HbA1c in adults from 7.5% to 7.0%. Entering the study, the participants (n=159) had an overall 54% TIR; with a target of 100 mg/dL, they achieved an overall increase to 73% TIR. With a target of 120 mg/dL, that percentage of TIR increased to 79%. There was also a reduction in hypoglycemia exposure throughout the day and night9. This was followed by a presentation of the Fuzzy Logic Automated Insulin Regulation (FLAIR) Study which compared the 670G to the 780G (AHCL) systems in adolescents and young adults (age range 14-29 years). Differences observed between the two systems included the 780G having lower glucose target set points (100 mg/dL or 120 mg/dL) while the 670G was set at 120 mg/dL. The 780G was able to perform additional automated bolus correction on top of the “auto basal” correction which both systems share. TIR was higher with the 780G (67%) compared to the 670G (63%) from a baseline of 53%. The percentage of those achieving >70% TIR went up from a baseline of 12% to 22% on the 670G and 32% on the 780G. FLAIR was also the first study to report combined metrics of TIR >70% and time below 54 mg/dL of less than 1%, with the 780G achieving higher percentages (30% vs 21%). The third study compared the AHCL with a predictive low glucose monitoring therapy (PLGM), and further confirmed improvements in TIR (70.4% vs 57.9%) from a baseline of 59% without increased risk of hypoglycemia for the AHCL. In addition, having a lower set point of 100 mg/dL was associated with a better overall TIR (72.6%) than that seen with a set point of 120 mg/dL (65.0%). The final presentation was on Insulet’s Omnipod Horizon, the first AID system that can be controlled with a smartphone. The Omnipod is a patch pump designed for three days of wear; the pre-pivotal study showed an increase of TIR from 65.6% in adults to 73.8%, while in children TIR increased from 51% to 70.1% from standard therapy. An interesting feature of this study was that it was conducted during the winter holidays, a challenging season during which TIR typically dropped by an average of 3%. These short-term studies suggest that the advances being made in insulin pump technology are resulting in more convenient and “smarter” devices that can improve glycemic control. We hope that more long-term studies will be available soon.
Insights on Adverse Cardiac Outcomes, Culinary Medicine, and CGM
On day two of the virtual sessions we heard updates on the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. The DAPA-HF prospectively evaluated the efficacy and safety of dapaglifozin in patients with chronic heart failure and reduced ejection fraction with or without diabetes. Data published late last year reported a 26% reduction in the treatment arm in combined risk of cardiovascular death, hospitalization for heart failure or an urgent visit for worsening heart failure requiring intravenous therapy (P<0.001)10. The inclusion of a population without diabetes gave researchers the opportunity to explore incident diabetes occurrence. Among the 2,605 trial participants without diabetes at baseline, 6% developed diabetes and 95.5% of those individuals had prediabetes at baseline (HbA1c 5.7%-6.4%). Over a median follow-up of 18.2 months, there was a 32% reduction in incidence of new onset diabetes in the treatment arm compared to the placebo group (P=0.019). Further analysis found that all-cause mortality was higher in this group of patients. DAPA-HF was the first sodium-glucose co-transporter 2 (SGLT-2) inhibitor trial that showed a potential benefit of the drug in diabetes prevention.
Another topic I found interesting was the role of culinary medicine in diabetes prevention and management. Diet is a key contributor to obesity, which in turn is a risk factor for type 2 diabetes. Dr. Linda Shiue shared that 50% of premature deaths in the general population were due to lifestyle factors and only 10% of Americans met recommended dietary guidelines. However, a survey conducted among internal medicine residents reported that the majority felt inadequately trained to advise patients about food and eating behaviors11. The introduction of culinary medicine curriculum at different levels of medical education at Stanford University as well as the Training Kitchen Collaborative formed by the Culinary Institute of America and Harvard T.H. Chan School of Public Health, are among the programs created to bridge this gap.
After a session in which the value of continuous glucose monitoring (CGM) in patients with type 2 diabetes was debated, I came away in favor of the use of this technology, although cost is still a factor to consider. Dr. Athena Philis-Tsimikas discussed several studies that evaluated intermittent use of CGM in patients with type 2 diabetes on basal insulin, oral and non-insulin agents and those with early diabetes or prediabetes, which led to improvement in clinical and behavioral outcomes. Taking the opposing view, Dr. Elbert Huang took us through a cost analysis of the use of CGM in patients with type 1 and type 2 diabetes and emphasized the greater cost efficacy and savings achieved with other options in diabetes care. These included the use of angiotensin converting enzyme inhibitors to treat hypertension and prevent end stage kidney disease, as well as multi-intervention risk factor control.
New Perspectives on Improving Beta Cell Function and Diabetes Subtypes
On day three, new insights from the Restoring Insulin Secretion (RISE) Study were presented. The purpose of the study was to identify treatment approaches that could preserve or improve beta cell function in adults and youths (10-19 years old) with dysglycemia. In the adult arm, four interventions were studied: 1) 12 months of metformin alone; 2) 3 months of insulin glargine followed by 9 months of metformin; 3) 12 months of liraglutide combined with metformin; or 4) 12 months of placebo. There was also a surgical intervention arm (laparoscopic banding) in the adult group. The pediatric arm of the study examined the use of metformin alone and insulin followed by metformin. Young people were found to have higher insulin resistance, higher insulin secretion and reduced insulin clearance. In those with impaired glucose tolerance (IGT), beta cells were more responsive to glucose than in the adult group with IGT. The mechanism behind this phenomenon was further explored looking at alpha cell function. However instead of finding hyperglucagonemia leading to raised levels of insulin, lower levels were reported in youths than in adults. In examining the effect of differing interventions on glucagon levels, only liraglutide and gastric banding were associated with reductions that were attributed to lowering of BMI.
In another session, Dr. Emma Ahlqvist expounded on heterogeneity in diabetes with a discussion of the five subtypes of the disease (severe autoimmune diabetes, severe insulin resistant diabetes, severe insulin deficient diabetes, moderate age related diabetes, moderate obesity related diabetes) based on clinical parameters. She also discussed how the subtypes differ in terms of response to treatment as well as development of complications. The next speaker, Dr. John Dennis, expanded on this topic and addressed the delivery of precision medicine in the treatment of patients with type 2 diabetes. At the University of Exeter, investigators have developed a novel research framework whereby they applied discoveries from routine clinical data (based on United Kingdom electronic primary health care records) and replicated the analysis in clinical trial data. He shared their findings looking at differential response to sulphonylurea and thiazolidinedione; age and BMI were identified as positive predictors, with female sex and higher BMI having greater response to thiazolidinedione, while male sex and lower BMI resulted in a more favorable response to sulphonylureas. This finding was replicated in data analysis of the A Diabetes Outcome Progression Trial (ADOPT). Going a step further, the Exeter team applied clinical variables from the subtypes of cluster (HbA1c, age, sex, BMI) into treatment model selection. Using data from the Rosiglitazone Evaluated for Cardiovascular Outcomes of Glycemia in Diabetes (RECORD) trial, they found that when patients were randomized into treatment groups concordant with their prediction model, HbA1c response was better. Heterogeneity in diabetes is also seen in patients with gestational diabetes mellitus. Based on findings from the Genetics of Glucose Regulation in Gestation and Growth (Gen3G) study, patients could be subtyped to the following categories: insulin-resistant, insulin-deficient or mixed gestational diabetes. Further trials on dietary modification and different pharmacotherapy options among the subtypes are currently being conducted12.
Debating the Role of Diabetes Therapy in Cardiovascular Protection
The virtual debate on day four between two cardiologists on the use of SGLT-2 inhibitors or GLP-1 receptor agonists for primary prevention of cardiovascular disease surely kept many glued to the screen as we first listened to Dr. Mikhail Kosiborod present information in support of the use of these agents. He believes that there is no physiologic reason that preventive therapies would only work for secondary prevention. This perspective was rebutted by Dr. Darren McGuire, who argued that prevention does not equal treatment. Using antibiotics as an example, he stated that a medication that treats a disease is not useful for prevention. Dr. Kosiborod shared evidence from a meta-analysis on SGLT-2 inhibitors and their impact on reduction in hospitalization from heart failure and chronic kidney disease progression and noted that GLP-1 receptor agonist use reduced major adverse cardiovascular events (MACE) in groups with and without established atherosclerotic cardiovascular disease (ASCVD). He further proposed that the vast majority of patients with diabetes without established cardiovascular disease would benefit from preventive use of the drugs. Dr. McGuire weighed in on the poor cost efficacy of using GLP-1 receptor agonists in primary prevention, basing his arguments on data from the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial. He calculated that in order to prevent a single MACE in the primary prevention group, 333 patients would require treatment with a GLP-1 receptor agonist at a cost of $3.4 million annually. Dr. McGuire also pointed out that the definition of cardiovascular disease in the debate would be ASCVD as defined by regulatory bodies and in randomized control trial outcomes. Taking this into account, meta-analysis on both class of drugs on ASCVD outcomes did not show benefit in the multiple risk factor group.
Updates on Once-Weekly Insulin and the VERTIS-CV trial
Results from a phase 2 study on the once-weekly basal insulin Icodec by Novo Nordisk were discussed in another symposium, with Icodec showing similar reduction in HbA1c to that achieved with Glargine U100 in a 26-week study. The reduction in mean 9-point self-blood glucose monitoring profile was similar, with Icodec resulting in a slightly greater improvement (7.9 mg/dL). Changes in body weight were comparable and rates of hypoglycemia were low with both types of insulin. Once weekly treatment with basal insulin would indeed be an attractive option to overcome some barriers to insulin initiation, however dose titration and adjustment may be a challenge.
On the final day of the sessions, the results of the eValuation of ERTugliflozin EffIcacy and Safety CardioVascular Outcomes Trial (VERTIS-CV) were revealed. Ertugliflozin is the fourth SGLT-2 inhibitor to be assessed for efficacy on cardiovascular outcomes. A total of 8,246 patients with type 2 diabetes and ASCVD were enrolled with a mean duration follow-up of 3.5 years. Rates of discontinuation were low and final vital status was available in more than 99% of patients. Metabolic outcomes were similar to those seen with other SGLT-2 inhibitors, with HbA1c reduction of 0.5% at 18 weeks and mean weight reduction of 2.4kg for ertugliflozin 5mg and 2.8kg for a 15mg dose. In terms of primary outcomes looking at MACE, ertugliflozin showed similar event rates compared to placebo and only showed significant superiority in the secondary outcome of hospitalization for heart failure, with a 30% relative reduction. Although there was a trend in reduction of renal composite outcomes, it did not reach statistical significance. With the high selectivity towards SGLT- 2 (up to 2000 times) and similar population of patients with established ASCVD, it is surprising that ertugliflozin did not demonstrate cardiovascular benefits like those seen with empagliflozin. The panel discussed this and suggested that there could be other receptors or proteins engaged by the drug with potential effects on cardiac myocyte as demonstrated in animal models. There was, however, clear homogeneity between the VERTIS-CV and other SGLT-2 inhibitor cardiovascular outcome trials in terms of benefit of reduced rate of hospitalization due to heart failure.
I really enjoyed the virtual scientific sessions this year and having the recordings readily accessible gives me the opportunity to review points that I might have missed during a live session or that require some time to digest. The topics I have described are just a fraction of the many additional interesting sessions available. I share the sentiments of most speakers who were disappointed that the sessions could not be held live and in person. Nevertheless, I must congratulate the American Diabetes Association effort in ensuring that “the science never stops.”
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Pei Lin Chan, MBBS (IMU), MRCP (UK)
Read previous columns from Dr. Chan.
Any editorial comments about this article can be sent to: Jane.Savio@worldwidediabetes.org