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Table of Contents
CONFERENCE HIGHLIGHTS
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 143-147

Conference highlights: The 81st Annual (Virtual) conference of the American diabetes association: June 25–29, 2021


Imperial College London Diabetes Centre, Al Ain, United Arab Emirates

Date of Submission16-Jul-2021
Date of Acceptance16-Jul-2021
Date of Web Publication26-Aug-2021

Correspondence Address:
Dr. Mohamed Suliman
Imperial College London Diabetes Centre, Al Ain
United Arab Emirates
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdep.jdep_31_21

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  Abstract 


The American Diabetes Association (ADA) annual conference is the most notable annual event in diabetes. Like many conferences in 2020 and 2021, it was held virtually due to the COVID-19 pandemic. In this highlights summary, we selected the sections that we felt are particularly relevant to practicing clinicians. The results of several long-awaited studies were released. These include the GRADE study, SURPASS, and STEP studies. The first ADA-European Association for the Study of Diabetes consensus on the management of type 1 diabetes was also aired during the conference. Besides, the AMPLITUDE-O study with new data on the cardiovascular and renal effects of Efpeglenatide was published. The role of Teplizumab for the prevention of type 1 diabetes and Volagidemab in patients with type 1 diabetes were discussed. Furthermore, the PROMISE study on the safety and accuracy of next-generation 180 days implantable continuous glucose monitoring systems was published. New news included advancing the role of glucagon in treating and preventing severe hypoglycemia. Furthermore, the Effects on heart failure with preserved ejection fraction from a pooled analysis of SOLOIST and SCORED studies were presented. Finally, data on Dapagliflozin in COVID-19 (DARE-19) and the STRENGTH versus REDUCE-IT studies were compared and contrasted. We hope to present a concise summary of the conference highlights for those who missed the live event.

Keywords: American Diabetes Association, diabetes, education, glucagon, research, trials


How to cite this article:
Suliman M, Mohammed NH. Conference highlights: The 81st Annual (Virtual) conference of the American diabetes association: June 25–29, 2021. J Diabetes Endocr Pract 2021;4:143-7

How to cite this URL:
Suliman M, Mohammed NH. Conference highlights: The 81st Annual (Virtual) conference of the American diabetes association: June 25–29, 2021. J Diabetes Endocr Pract [serial online] 2021 [cited 2021 Dec 7];4:143-7. Available from: https://www.jdeponline.com/text.asp?2021/4/3/143/324793




  Introduction Top


The American Diabetes Association (ADA) annual conference is the most important annual event in diabetes. It originally was planned to be held in Washington, USA. However, due to the COVID-19 pandemic, it was held virtually like many conferences in 2020 and 2021. In this highlights summary, we chose the sections that we felt were of importance to practicing clinicians. The second virtual ADA conference saw many essential diabetes studies and developments presented, which can impact clinical practice.


  Conference Highlights Top


GRADE study

This long-awaited study was the first comparative effectiveness study of 4 anti-hyperglycemic drugs added to metformin. A total of 5047 patients were recruited between June 2013 and April 2017. People of white ethnicity constituted 66%, while blacks constituted 20%. The mean age at baseline was 57 years, body mass index (BMI) 34, diabetes duration 4.2 years, and HbA1c was 7.5%.[1] The patients were randomized to the glucagon like peptide-1 receptor agonists (GLP1-RA), liraglutide, the basal insulin analog glargine, the sulphonylurea glimepiride, and the DPP4 inhibitor sitagliptin were followed up for a mean of 5 years (range: 4–7.8 years). Importantly, SGLT2 inhibitors were not used because Food and Drug Administration (FDA) only approved them in 2013 after the study started. Furthermore, pioglitazone was not used because of the concerns about the safety of thiazolidinediones at the time of planning the study. All patients were on metformin at a mean dose of 2000 mg/day. The results presented at the ADA meeting were considered preliminary as only 90% of outcomes have been adjudicated.

The primary metabolic outcome (i.e. time to drug failure) was the time taken to reach HbA1c ≥7% on the maximum tolerated dose of each drug. In comparison, the secondary metabolic outcome was the time to HbA1c ≥7.5% on maximum tolerated dose before adding glargine, and the tertiary metabolic outcome was the time to HbA1c ≥7.5% on maximum tolerated dose after adding glargine.

The time to reach the primary outcome was 2.4 years for liraglutide, 2.4 years for glargine, 2.2 years for glimepiride, and only 1.8 years for sitagliptin. Liraglutide reached the primary outcome 21 days longer than glargine, 72 days longer than glimepiride, and 185 days longer than sitagliptin. Similar findings were seen for the secondary and tertiary outcomes. No difference was seen between the four drugs in albuminuria, estimated glomerular filtration rate (eGFR), or neuropathy regarding the microvascular complications. However, for the macrovascular outcomes, the endpoint of all combined cardiovascular (CV) outcomes was superior with liraglutide compared with the other three drugs (P = 0.048). However, the difference in the other CV outcomes of major adverse cardiac events (MACE), hospitalized heart failure (HHF), or mortality was not statistically different between the four drugs, although there was a trend for better outcomes with liraglutide than the other three drugs.

All four drugs were well-tolerated with adverse events, including severe hypoglycemia that occurred in 1.4% of those treated with glimepiride, while there were more GI side effects with liraglutide. Other planned analyses from the GRADE data include prediction of response by phenotype, studies on pharmacogenomics, continuous glucose monitoring (CGM) results analysis performed in 1700 patients, and quite importantly, analysis of data on cost-effectiveness and quality of life. In conclusion, this study showed that the GLP-1RA, liraglutide performed best among the four drugs followed by glargine, while sitagliptin had the worst outcomes. Possible implications for this study on type 2 diabetes guidelines could be that the DPP4 inhibitors may have to be relegated and not given equal place to other drugs because of their poor metabolic outcomes in this study, their failure to show benefits in cardiovascular outcome trials (CVOTs) in addition to their high cost.

The SURPASS studies

In 2019, the results of a phase 2 study of the GLP-1/GIP co-agonist Tirzepatide (TZP) in patients with type 2 diabetes showed that this drug resulted in very impressive reductions in HbA1c and weight.[2] Following this, a series of phase 3 studies to test the efficacy and safety of Terazapatide were conducted. During this ADA meeting, results of 4 of these studies (SURPASS 1, 2, 3, and 5) were presented. In all four studies, three doses of TZP: 5, 10, and 15 mg were tested against comparators.[3] In all four studies, the primary endpoint changed from baseline HbA1c. For the four presented studies, the mean age at baseline was between 54 and 60 years, BMI 32–34, and HbA1c was between 7.9% and 8.3%.

All four studies showed that TZP resulted in superior reductions in both HbA1c and weight compared to comparators, as shown in [Table 1]. Adverse events included GI side effects similar to those with other GLP agonists with no new risks identified.
Table 1: Summary of the steps studies

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Other ongoing studies of TZP include tripeptide CVOT versus dulaglutide, which plans to recruit 12,500 patients and is expected to report in 2024, the SURMOUNT-1 study in obesity excluding type 2 diabetes (2400 patients) and SYNERGY-NASH study in patients with NASH. So, in conclusion, this new GLP-1/GIP co-agonist has demonstrated robust HbA1c and weight lowering efficacy in patients with type 2 diabetes, more than the currently available GLP-1 agonists with a similar safety profile.

The STEP studies of semaglutide 2.4 mg in obesity

Semaglutide 1 mg weekly has been in use for a few years and has proved one of the potent GLP1-RAs in HbA1c and weight reduction. A higher dose of Semaglutide of 2.4 mg weekly has been tested in a series of phase 3 studies to assess its efficacy as a treatment for obesity.[4],[5] All 4 STEP studies ran for 68 weeks, mean age 46–55 years, BMI 36–38. The STEP 1 study tested Semaglutide 2.4 mg QW versus placebo in patients with obesity, STEP 2: Semaglutide 2.4 mg QW versus Semaglutide 1 mg QW versus placebo in patients with type 2 diabetes, STEP 3: Semaglutide 2.4 mg QW versus placebo in patients with obesity who received low-calorie diet + intensive behavioural therapy and STEP 4: Semaglutide 2.4 mg QW versus placebo in patients with obesity after 20 weeks treatment with Semaglutide 2.4 mg QW. [Table 2] shows the results of these studies in terms of HbA1c and weight reduction. Adverse events included GI side effects similar to other GLP-1RAs with no other risks. In conclusion, Semaglutide 2.4 mg weekly was shown to be effective and safe for obesity treatment, and following the results of the STEP program, this drug has been approved by the FDA for obesity treatment on June 4, 2021.
Table 2: The characteristics and evidence of these new options

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Cardiovascular and renal effects of efpeglenatide (AMPLITUDE-O)

This study tested the CV and renal effects of the exendin-4 based GLP-1RA, efpeglenatide, in patients with type 2 diabetes.[6] A total of 4076 patients were randomized to efpeglenatide 4 or 6 mg or placebo. The mean age was 65 years, 87% were Whites, the mean diabetes duration was 15 years, HbA1c 8.9%, BMI 33, and 15% were on SGLT2 inhibitors. Prior CV disease was present in 90% of patients, while 32% had baseline eGFR <60.

Efpeglenatide reduced the primary outcome of 3-point MACE by 27% (heart rates [HR]: 0.73, 95% confidence interval [CI]: 0.58–0.92, P = 0.0069 for superiority). The effect on CV mortality or total mortality did not reach statistical significance. The combined secondary outcome of renal events was reduced by 33% (HR: 0.67, 95% CI: 0.57–0.79, P < 0.0001). The renal benefit was mainly driven by reduced albuminuria, while eGFR deterioration did not reach statistical significance. The benefit on MACE was similar in the group on SGLT2 inhibitors (15%) and those not on these drugs. Hence, in conclusion, another GLP-1RA proved to have CV benefits, this time, it is an exendin 4-based molecule, and the beneficial effects of SGLT2i and GLP-RAs on CV risk appear to be additive.

Consensus report of the American Diabetes Association and European Association for the Study of Diabetes on the management of type 1 diabetes

After the significant impact that the consensus report from the ADA and European Association for the Study of Diabetes (EASD) had on managing patients with type 2 diabetes, the first draft of a consensus report on the management of type 1 diabetes was presented at the ADA. Consultation on this draft ended on July 8, and the final version of the report will be presented at the EASD conference in September 2021. There are 16 sections in this report covering broad areas such as diagnosis, schedule of care, education, monitoring, insulin therapy, hypoglycemia, psychosocial care, DKA, islet transplantation, adjunctive therapy, and special populations. It recognizes that the diagnosis of type 1 diabetes can be challenging, and an algorithm for diagnosis is provided. Age, BMI, C-peptide, and antibodies were all felt to help make the diagnosis, but no single clinical feature confirms type 1 diabetes in isolation.

Teplizumab for the prevention of type 1 diabetes

In a study published in 2019, teplizumab was shown to delay progression to type 1 diabetes in high-risk patients.[7] An extension to that study was presented in which teplizumab was shown to result in a 32.5 months delay in the median time to diagnosis of type 1 diabetes (HR: 0.46, P = 0.01). Teplizumab is the first drug to demonstrate preservation of beta-cell function, leading to delay in onset of and potentially prevention of clinical type 1 diabetes. The FDA advisory committee voted in favor of teplizumab use, and it is expected to be approved for this indication.

PROMISE study: Safety and accuracy of next-generation 180-days implantable continuous glucose monitoring system

In this multi-center study, the accuracy and safety of the subcutaneous implantable (Eversense) CGM system were tested, including the evaluation of the next generation chemically modified model (adding sacrificial boronic acid (SBA) to reduce oxidation of the glucose binding indicator and slowing sensor degradation). One hundred and eighty-one participants were subjected to induced hypoglycemia and hyperglycemia in a clinic setting to assess glucose levels in the range of 40–400 mg/dl between day 1 and 180. The mean age was 48 years, and baseline HbA1C was 7.6%.[8]

Regarding accuracy, the system showed an overall mean absolute relative difference (MARD) of 9.1%, which was stable across different glucose ranges. The SBA modified (next generation) sensor showed a better overall MARD of 8.5% compared to 9.1%, notably improved in the hypoglycemia range of 40–60 mg/dl with a MARD of 7.5%, compared to 9.4%. Moreover, the modified sensor's 180 days survival was 90% compared to 65%. Concerning safety, no serious events related to device insertion or removal, and there were only 2 (1.1%) mild skin infections. The study confirmed the accuracy and safety of this long-term implantable CGM system and the value of the SBA-modified version in significantly improving the accuracy and longevity of the sensor.

Volagidemab in patients with type 1 diabetes

Patients with type 1 diabetes have dysfunctional α-cells with a paradoxical increase in glucagon following carbohydrates ingestion, contributing to the postprandial hyperglycemia by increasing hepatic glucose output. Volagidemab is a human monoclonal glucagon receptor antagonist given subcutaneously once weekly, which in phase I trial increased time in range (TIR) by 15% and reduced insulin dose by 26% in patients who have type 1 diabetes. Two-phase II randomized, blinded, placebo-controlled trials evaluated the efficacy and safety of this molecule in 153 patients with type 1 diabetes who had a mean baseline HbA1c of 7.5%.[9] The group receiving volagidemab had a placebo-subtracted HbA1c reduction of –0.5%, which was even higher in the group with a baseline HbA1C >7.5% with a reduction of –1.02%. The proportion of patients achieving HbA1c of <7% was 59% compared to 28% in the placebo group, and TIR was increased by 6%–7% while the total insulin dose was reduced by 15%. The time below range remained stable with no increased risk of hypoglycemia. Minor adverse events were noticed, including a transient rise in alanine transaminase and a 3–4 mmHg rise in systolic blood pressure. This promising adjunctive therapy for type 1 diabetes is now entering phase III trials.

Advancing the role of glucagon in treating and preventing severe hypoglycemia

Hypoglycemia has an enormous impact on patients' quality of life with type 1 diabetes and is a major obstacle to achieving targets, especially with the resultant fear following an attack of life-threatening severe hypoglycemia. Glucagon has been the mainstay of treating severe hypoglycemia for over 60 years. However, there are major challenges with its use due to the need for reconstitution and the multiple complex steps for administration, especially during the stress of a severe attack.

Recently, three new options have become available to advance the role of glucagon. These are the nasal glucagon, approved in 2019,(xx), liquid-stable, ready to inject human glucagon, approved in 2019, and liquid-stable, ready to inject glucagon analog (Dasiglucagon) 2021. [Table 2] shows the characteristics and evidence of these new options.[10],[11] These three options represent significant progress in providing successful and simplified therapy for severe hypoglycemic attacks.

Several studies were presented examining the role of micro-doses of glucagon in handling impending hypoglycemia and preventing exercise-induced hypoglycemia. Compared to the use of oral carbohydrates, this approach appears to be equally effective while minimizing the risk of rebound hyperglycemia traditionally observed in these settings; larger studies are currently in progress.

Effects on heart failure with preserved ejection fraction from the pooled analysis of SOLOIST and SCORED studies

SOLOIST and SCORED studies examined the effects of sotagliflozin, a combined SGLT 1 and 2 inhibitor, in patients with heart failure (HF) and chronic kidney disease (CKD), respectively.[12],[13] In the 1758 patients with heart failure with reduced ejection fraction (HFrEF), sotagliflozin reduced the primary endpoint of total CV death, HHF, and urgent HF visits by 22% (HR: 0.78, 95% CI: 0.63–0.96, P = 0.02). On the other hand, in the 739 patients with heart failure with preserved ejection fraction (HFpEF), sotagliflozin reduced the same primary endpoint by 37% (HR: 0.63, 95% CI: 0.45–0.89, P = 0.009). This was the first randomized data from a prespecified analysis of clinical trials to show a significant effect of therapy on HFpEF.

Dapagliflozin in COVID-19 (DARE-19)

Most patients hospitalized with COVID-19 had at least one comorbidity such as type 2 diabetes, hypertension, atherosclerotic cardiovascular disease (ASCVD), HF, or CKD. These patients with cardiometabolic risk were at extremely high risk of COVID-19 progression and death. There are theoretical reasons for a beneficial effect of an SGLT2 inhibitor on these patients, and 1,250 high-risk patients hospitalized with COVID-19 were randomized 1:1 to dapagliflozin or placebo. Their mean age was 61 years, 42% were females, and 50% had type 2 diabetes.[14]

The primary outcome of time to organ failure or death at 30 days was numerically lower with dapagliflozin but did not reach statistical significance (HR: 0.80, 95% CI: 0.58–1.10, P = 0.168). It was concluded that dapagliflozin in patients admitted with COVID-19 and cardiometabolic risk factors did not reduce organ failure or death. However, it was safe. The practical implication for this to practice is that SGLT2 inhibitors do not have to be stopped in patients admitted to hospital with COVID-19.

Strength versus Reduce-IT

The REDUCE-IT study published in 2020 tested the effect of Icosapentethyl (EPA) on CV risk. In this study, 8179 patients were randomized to (EPA) or placebo mineral oil. At baseline, the triglyceride level was 216 mg/dl, LDL-c was 75 mg/dl, 70% had previous ASCVD, 30% had diabetes, and the mean follow-up time was 4.9 years. The primary outcome of 5-point MACE was reduced in the EPA group by 25% (HR 0.75; P < 0.001) with an number needed to treat of 28.[15]

The STRENGTH study tested the effect of a different omega-3 preparation, omega-3 carboxylic acid, which combines EPA + DHA and more EPA on CV risk by randomizing 13,078 patients omega-3 CA or placebo, which in this case was corn oil. At baseline, the triglyceride level was 240 mg/dl, LDL-c was 75 mg/dl, 56% had a previous ASCVD, 70% had diabetes, and the mean follow-up time was 39 months.[16] In contrast to the REDUCE-IT, the STRENGTH study was stopped early for futility. The primary outcome of 5-point MACE was not reduced by omega-3 CA (HR 0.99; P = 0.84). The authors of the STRENGTH study suggested that the reason for benefit in REDUCE-IT was likely from mineral oil as a placebo. Evidence was shown that mineral oil was probably harmful as it increased LDL-c by 11% and hs-CRP by 32%. The results of the REDUCE-IT study appear to have been thrown into doubt by the STRENGTH study and the suggestion of harm from the use of mineral oil as a placebo. It was suggested that another study might need to test the effects of EPA on CVD using a neutral placebo.[17]


  Conclusion Top


For the second time around, the annual ADA conference is held virtually. However, the conference kept up the tradition of its predecessors. It saw many essential diabetes studies and developments, which can impact clinical practice in the short and long terms.

Authors contribution

Equal contribution to drafting, revision and approval of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Compliance with ethical principles

Formal ethical approval for conference highlights' type of study is not required.

Data availability

Not applicable.



 
  References Top

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Wexler DJ, Krause-Steinrauf H, Crandall JP, Florez HJ, Hox SH, Kuhn A, et al. Baseline characteristics of randomized participants in the glycemia reduction approaches in diabetes: A comparative effectiveness study (GRADE). Diabetes Care 2019;42:2098-107.  Back to cited text no. 1
    
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Frías JP. Tirzepatide: A glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) dual agonist in development for the treatment of type 2 diabetes. Expert Rev Endocrinol Metab 2020;15:379-94.  Back to cited text no. 2
    
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Min T, Bain SC. The role of tirzepatide, dual GIP and GLP-1 receptor agonist, in the management of type 2 diabetes: The SURPASS clinical trials. Diabetes Ther 2021;12:143-57.  Back to cited text no. 3
    
4.
Wilding JP, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989.  Back to cited text no. 4
    
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Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: The STEP 4 randomized clinical trial. JAMA 2021;325:1414-25.  Back to cited text no. 5
    
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Gerstein HC, Sattar N, Rosenstock J, Ramasundarahettige C, Pratley R, Lopes RD, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med 2021;Jun 28. doi: 10.1056/NEJMoa2108269. Epub ahead of print.  Back to cited text no. 6
    
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Perdigoto AL, Preston-Hurlburt P, Clark P, Long SA, Linsley PS, Harris KM, et al. Treatment of type 1 diabetes with teplizumab: Clinical and immunological follow-up after 7 years from diagnosis. Diabetologia 2019;62:655-64.  Back to cited text no. 7
    
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Garg SK, Liljenquist DR, Bode BW, Christiansen MP, Bailey TS, Brazg RL, et al. Evaluation of the next generation 180-day long-term implantable eversense CGM system: PROMISE study. ADA 2021;Abstract 149-OR.  Back to cited text no. 8
    
9.
Pettus J, Boeder SC, Christiansen MP, Denham DS, Bailey TS, Akturk HK, et al. 236-OR: Volagidemab, a human glucagon receptor antagonist, improves glycemic control in subjects with type 1 diabetes (T1D): A 12-week, randomized, double-blind, placebo-controlled trial. Diabetes 2021;70 Suppl 1. [doi: 10.2337/db21-236-OR].  Back to cited text no. 9
    
10.
Seaquist ER, Dulude H, Zhang XM, Rabasa-Lhoret R, Tsoukas GM, Conway JR, et al. Prospective study evaluating the use of nasal glucagon for the treatment of moderate to severe hypoglycaemia in adults with type 1 diabetes in a real-world setting. Diabetes Obes Metab 2018;20:1316-20.  Back to cited text no. 10
    
11.
Pieber TR, Aronson R, Hövelmann U, Willard J, Plum-Mörschel L, Knudsen KM, et al. Dasiglucagon: A next-generation glucagon analog for rapid and effective treatment of severe hypoglycemia results of phase 3 randomized double-blind clinical trial. Diabetes Care. 2021 Apr 21;44(6):1361–7.  Back to cited text no. 11
    
12.
Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117-28.  Back to cited text no. 12
    
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Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021;384:129-39.  Back to cited text no. 13
    
14.
Kosiborod M, Berwanger O, Koch GG, Martinez F, Mukhtar O, Verma S, et al. Effects of dapagliflozin on prevention of major clinical events and recovery in patients with respiratory failure because of COVID-19: Design and rationale for the DARE-19 study. Diabetes Obes Metab 2021;23:886-96.  Back to cited text no. 14
    
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Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.  Back to cited text no. 15
    
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Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: The STRENGTH randomized clinical trial. JAMA 2020;324:2268-80.  Back to cited text no. 16
    
17.
Nissen SE, Lincoff AM, Wolski K, Ballantyne CM, Kastelein JJ, Ridker PM, et al. Association between achieved ω-3 fatty acid levels and major adverse cardiovascular outcomes in patients with high cardiovascular risk: A secondary analysis of the STRENGTH trial. JAMA Cardiol. 2021 May 16: e211157. doi: 10.1001/jamacardio.2021.1157. Epub ahead of print.  Back to cited text no. 17
    



 
 
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