GLP-1 Receptor Antagonist Therapy in Type 2 Diabetes

Julio Rosenstock, MD: There are combination therapies that have just been approved by the FDA, recently. One is the combination of insulin glargine and lixisenatide, which is a GLP-1 (glucagon-like-peptide 1); or degludec, which is a basal insulin, and liraglutide. They were approved, specifically, with a little bit of a difference in how you titrate. Degludec with liraglutide is a once-a-week option. The other is twice-a-week, but it doesn’t matter. A patient can do it once-a-day—1 unit every week, or 2 units every week—as long as they do it systematically. And the other thing, which never made sense to me, is that we have given the GLP-1s on a fixed dose. Boom, this dose and so on. But this is a peptide. This is a hormone. We use that, titrating slowly and gradually, so that you will use as you need and as you tolerate, like you would do with other peptides.

Carol Wysham, MD: They’re doing that with liraglutide for years.

Peter Salgo, MD: Lixisenatide?

Julio Rosenstock, MD: Only 3 dosages.

Carol Wysham, MD: No. You get 10.

Peter Salgo, MD: Let’s discuss lixisenatide. The FDA was working on the approval, and there was a GetGoal clinical program. What was that all about?

Carol Wysham, MD: The GetGoal program was the combination of lixisenatide and glargine insulin. Lixisenatide is a GLP-1 receptor agonist. It’s what we call a “short-acting GLP-1 receptor agonist,” which means that you take it within an hour of a meal, it works, it peaks around the time of the peak of the meal absorption, and then lasts for about 6 to 8 hours. Its advantage is that it has a profound effect on delaying the release of the nutrients into the intestine, so that the insulin secretion (which in type 2 diabetes is delayed and slow), has a better chance of matching. This short-acting agonist, whether it’s exenatide or it’s lixisenatide, just flattens out the postprandial curve better than rapid acting insulin. It is a good medication for particularly addressing those people that have big postprandial spikes.

Peter Salgo, MD: Does that make it a different drug from the other GLP-1 receptor antagonists?

Julio Rosenstock, MD: There’s a difference, because this is short-acting. There are 2 short-acting options— exenatide and lixisenatide. Exenatide is given twice-a-day, and lixisenatide is given once-a-day. Liraglutide is a much longer-acting option, and then you have dulaglutide, once weekly. The ones that are long acting have some tachyphylaxis in terms of the effect on the gastric emptying. They don’t have much of a gastric effect. They have a little bit of postprandial effect, and predominantly have an effect on the fasting and that the blood sugar comes down in the fasting. They have a carryover effect throughout the day. Lixisenatide is short acting, so you give it before breakfast and boom, they flatten the postprandial at breakfast. It has some carryover effect after lunch. Why after lunch? Maybe because, as Carol said, there is no nutrient exposure to the beta cell and there is no insulin secretion. The beta cell probably gets recharged and acts after lunch, and so on. So, it’s very specific in the postprandial effect.

Transcript edited for clarity.