COMMENTARY

Peters on Tirzepatide: 'Impressive, but We Need to Know More'

Anne L. Peters, MD

June 18, 2021

This transcript has been edited for clarity.

Hi. Today I'm going to discuss dual incretin therapy. This is an exciting new therapy in the treatment of type 2 diabetes (T2D), and we have topline results from some of the clinical trials that have been performed. We're going to learn a lot more at the upcoming ADA meetings, where the full trial results will be reported.

First, a little background. We've had GLP-1 receptor agonists around for a while now, and we all know how they work. We're pretty familiar with them. When it comes to GIP [glucose-dependent insulinotropic popypeptide], it seemed to me that at least in trials where they just looked at GIP alone, there wasn't a great benefit. But it turns out that when you combine the two, when you make an agent that is synergistic and is both GIP and a GLP-1 receptor agonist — called a twin incretin — you have incredible benefits; there is much greater A1c reduction and weight loss than we see with GLP-1 receptor antagonism alone.

This new medication is called tirzepatide and it's a novel GIP/GLP-1 receptor agonist; it's based on the native GIP sequence that has then been modified.

The initial phase 2 trials showed significant A1c and weight loss benefits. It's a once-weekly injection. It did have gastrointestinal (GI) side effects — at that point, fairly similar to those that we see with GLP-1 receptor agonists.

The SURPASS Trials

The studies that have been done are called the SURPASS clinical trials. This is a huge clinical trial program because this is a new class of drugs. They've enrolled more than 13,000 participants with T2D around the globe. I believe that there are 10 clinical trials — five of the pivotal trials, and also cardiovascular outcome studies.

They compare a variety of doses — 1 mg, 5 mg, 10 mg, and 15 mg — with placebo or an active comparator. They're looking at everything. For instance, SURPASS-1 compares tirzepatide with placebo, SURPASS-2 compares it with 1 mg of semaglutide. They compare it with insulin degludec, glargine, an SGLT2 inhibitor, metformin. This is a very comprehensive approach to looking at this agent to see what it does compared with agents we're used to using.

The primary endpoint for all of these trials is the change in A1c from baseline. But there are many secondary endpoints, including change in body weight and seeing how many people achieve specific targets, as well as the impact on rates of hypoglycemia.

Dr Julio Rosenstock has taught me most of what I know about these agents, and he is going to be one of the presenters at ADA. He stated that all four trials that have been announced, and which will be discussed, met their primary and secondary endpoints; tirzepatide showed substantially greater reductions in A1c and body weight compared with placebo and all active comparators. So this has great potential to advance our ability to treat people with T2D.

On the other hand, I think we need to know a little bit more. I always want to make sure that any new agent is safe for my patients. I do know that these agents probably have more GI side effects than we see with the higher doses of the existing GLP-1 receptor agonists. They seem to have a higher dropout rate in the clinical trials because of the GI side effects compared with the more traditional agents, so we need to get a sense of how these drugs behave in terms of side effects.

But if you look at the data that we've seen thus far, they're pretty darn impressive in terms of A1c reduction and weight loss. Hopefully, they'll be another tool that we have to treat our patients with T2D. Thank you.

Anne L. Peters, MD, is a professor of medicine at the University of Southern California (USC) Keck School of Medicine and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts, and three books, on diabetes, and has been an investigator for more than 40 research studies. She has spoken internationally at over 400 programs and serves on many committees of several professional organizations.

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