Top Studies, Highlights From ADA 2021

This transcript has been edited for clarity.

Akshay B. Jain, MD: Hi. My name is Dr Akshay Jain, and with me is Dr Harpreet Bajaj. Together, we're the columnists of Medscape's Sugar Beat. We are very excited to discuss highlights of the American Diabetes Association 81st Scientific Sessions, especially the clinically relevant points.

The Incretins

Let me start off with the glucagon-like peptide 1 (GLP-1) studies. The SUSTAIN FORTE study, for which Dr Bajaj was one of the coauthors, was a head-to-head comparison of the glycemic-lowering effect of semaglutide 2.0 mg/wk vs 1.0 mg/wk on the background of metformin plus or minus sulfonylurea therapy.

[Among patients with] a baseline A1c of 8.8%, semaglutide 2.0 mg/wk reduced the A1c by 2.2% vs 1.9% with the lower dose of semaglutide. The weight reduction was about 0.93 kg more with the higher dose. In my opinion, the A1c difference, although statistically significant, may not be too clinically relevant from strictly the glycemic control point of view, although the weight reduction was quite significant.

If the 2-mg dose ever comes out on the market, depending on the cost difference between the two doses, it may be worthwhile to consider a different agent to achieve further glycemic control based on the target for our patients.

The other incretin molecule at ADA this year was the glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 combination, tirzepatide — a first-in-class molecule. The SURPASS bouquet of studies looked at tirzepatide efficacy with the 5-mg, 10-mg, and 15-mg doses. SURPASS-1 looked at efficacy as monotherapy among patients with a baseline A1c of 7.9%. The A1c reduction was between 1.8% and 2.0%, and nearly 90% of patients were able to achieve the A1c goal of < 7%.

SURPASS-2 was a head-to-head comparison with semaglutide 1.0 mg/wk with background metformin. Tirzepatide, at every single dose, led to statistically significant A1c and weight reduction compared with semaglutide.

Finally, in SURPASS-3, a head-to-head comparison against insulin degludec, and SURPASS-5, a comparison in addition to baseline insulin glargine, tirzepatide led to a significant A1c reduction at all doses.

Overall, the SURPASS studies seem to indicate that tirzepatide might be the most potent noninsulin agent for A1c reduction, with the most weight loss seen among all agents currently approved for diabetes treatment. Rates of gastrointestinal side effects, such as nausea, were similar to those seen with other GLP-1 therapies historically.

There was also the GRADE study. Harpreet, what do you think about the GRADE study?

Harpreet S. Bajaj, MD, MPH: The GRADE study is another win, if it pans out in the final analysis. The caveat with the analysis — at least on the cardiovascular endpoints — [is that it] was a preliminary analysis where not all the cardiovascular endpoints have been adjudicated yet.

This is a National Institutes of Health (NIH)–funded, large study with a 5-year duration of follow-up, comparing glargine insulin vs liraglutide vs glimepiride vs sitagliptin — four different classes of agents — with the primary outcome of glycemic achievement. Interestingly, the cardiovascular endpoint was a broad cardiovascular endpoint, not just the typical major adverse cardiovascular events (MACEs). With about 90% of outcomes adjudicated, liraglutide was better for the broad cardiovascular endpoint vs the other three agents.

The relevance is that this is a different population from than in LEADER, for example, because this is a newly or recently diagnosed patient population, with a second agent added after metformin. Even though the cardiovascular outcome is a secondary outcome, if the final analysis shows statistical significance, I think this will have repercussions on guidelines as well as standard of care. One other caveat I must mention is that there is no sodium-glucose cotransporter 2 (SGLT2) inhibitor arm in this trial, so we cannot say anything about that.

Continuing with the GLP-1 receptor agonists, there's a lot of hype about obesity and GLP-1s. What's new there, Akshay?

In Obesity Treatment

Jain: There were so much metabolic data released at ADA this year, especially the STEP constellation of studies looking at the anti-obesity effect of semaglutide 2.4 mg/wk, which our viewers will realize has been approved recently by the US Food and Drug Administration (FDA) for the management of obesity.

Overall, the efficacy with this therapy has been quite impressive, with weight loss of about 15% when used in conjunction with diet and lifestyle modification. Impressively, one third of patients lost more than 20% of body weight.

In particular, the STEP 1 study showed that when used in patients with prediabetes, semaglutide 2.4 mg/wk had a much higher likelihood of preventing progression to diabetes. The STEP 4 study once again emphasized that anti-obesity treatment needs to be continued long-term, because discontinuation can often lead to a rebound increase in weight. More important, I think there needs to be even more awareness about the management of obesity and its consideration as a chronic disease.

Newer Insulins

ADA also had many studies on newer insulins. Harpreet, what's your take on the weekly insulins?

Bajaj: Briefly, two new once-weekly basal insulins are in clinical development. One is called BIF, or basal insulin Fc. Another is called icodec. Further data from the phase 2 studies were presented for both of these insulins. The phase 3 studies are about to start or are ongoing.

There was a large amount of data on continuous glucose monitoring (CGM) analysis for these two insulins. The bottom line seems to be that once-weekly insulins, at least based on the phase 2 data, appear to have similar glycemic benefits as the daily basal insulin we are used to using, with similar hypoglycemia events as well as CGM metrics. This should be an interesting space to follow in the future.

I'd like to thank the viewers for watching our highlights from the ADA Scientific Sessions. As always, the Sugar Beat team continues to bring clinical perspective to what's new and happening in the field of diabetes and metabolic disorders.

Thank you, Akshay. And thank you, viewers.

Harpreet S. Bajaj, MD, MPH, is a community endocrinologist in Brampton, Ontario, Canada, and vice chair of the Diabetes Canada Guidelines. His clinical and research interests are the prevention and management of diabetes and its related complications. He is the founder of STOP Diabetes Foundation and volunteers with numerous community public health organizations to raise awareness of diabetes prevention and treatment.

Akshay B. Jain, MD, is a clinical endocrinologist who has practiced in three countries, focusing on mitigating the complications of diabetes and obesity. He is fluent in six languages and has spoken at more than 500 programs internationally.

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