The Advantages of Insulin, GLP-1 Combinations

Dennis P. Scanlon, PhD: Let’s turn for a moment and talk about the new insulin GLP-1 (glucagon-like peptide-1) combinations—the combination therapies. Mary Ann, maybe I’ll start with you. What’s the clinical rationale for combining these therapies?

Mary Ann Hodorowicz, RDN, MBA, CDE: It’s like a marriage made in heaven. I use that analogy. You’re getting the best of multiple worlds. And just for the sake of people watching this video, the GLP-1s have 3 main mechanisms of action: They increase glucose dependent insulin secretion (which is wonderful), decrease glucagon secretion (so the liver is not generating liver glucose), and decrease gastric emptying (to give better postprandial, post-meal blood sugar control). So, you combine those 3 mechanisms of action from the GLP-1 with the insulin’s ability to lower pre- and prandial blood glucose. It’s like a 4-way marriage made in heaven—these 3 functions of GLP and then the insulin.

Dennis P. Scanlon, PhD: Dr. Bloomgarden, you’re a science guy, and you know a little bit about the studies that some of these therapies were based on. Can you talk to us about the dual trials—the LixiLan trials?

Zachary Bloomgarden, MD: Another way of looking at it, extending on the physiologic points that you made, is simply to say that we have known, for a long time, that after basal insulin, you often go to basal bolus (in one way or another), where you give insulin before meals (the rapid-acting, or somewhat rapid-acting), and you give basal insulin. But there’s an entirely different way of achieving this, which is basal insulin plus a GLP-1 receptor activator. And that essentially gives you a better version of basal bolus insulin. You enhance endogenous insulin secretory capacity, you decrease this paradoxical and inappropriate high glucagon, and you delay gastric emptying. In not all, but many cases, you achieve good control with less weight gain and less hypoglycemia. Looked at another way, there are a number of studies, which have been done and are still being done, comparing basal insulin with GLP-1 receptor activators. By and large, the GLP-1 receptor activators come out better for people who are not severely hyperglycemic to start with. But, in almost all the studies, a substantial proportion of the patients in either group don’t get to goal.

So, the next step has been to say, “Okay, let’s explore these combinations of treatments.” And where they’ve been looked at previously—insulin glargine plus liraglutide; insulin glargine plus exenatide; now, studies with insulin glargine plus a long-acting form of exenatide called lixisenatide; or another approach with that, insulin degludec that I mentioned earlier, plus liraglutide—it’s all sort of the same thing. And whether it’s in 1 syringe or 2, it gives you a wonderful way of having basal bolus insulin. And another actually not unimportant benefit is that you may wind up giving less of the GLP-1 receptor agonist and have less gastrointestinal side effects, which are really the Achilles heel of the GLP-1 drugs. Even in the clinical trials where you have patients who are so motivated to stay on the drugs, about 10% drop out over the course of, let’s say, a year.

Mary Ann Hodorowicz, RDN, MBA, CDE: Because of the gastrointestinal side effects.

Zachary Bloomgarden, MD: Because of the side effects—because of diarrhea and nausea. And if you give just a little bit less because it’s mixed with insulin, you can make it more tolerable. So, these are great treatment approaches.