Mechanisms of Action of GLP-1 Agonists in T2D

APRIL 29, 2019
MD Magazine Staff

Vanita Aroda, MD: Through the wealth of studies that we’ve had, we see a benefit of GLP-1 [glucagon-like peptide-1] receptor agonists compared with other classes of agents. And we see this directly in the head-to-head comparative studies. For example, compared with insulin, we see comparable or even greater glucose-lowering efficacy, without weight gain, without hypoglycemia. Very consistently among the GLP-1 receptor agonists compared with DPP-4 [dipeptidyl-peptidase-4] inhibitors, we see greater glucose-lowering with greater weight loss. Similarly compared with the other classes—for example, sulfonylureas, etc—we see a very consistent benefit in terms of getting patients to goal—the percentage of patients achieving glycemic targets without hypoglycemia and with some weight loss.

John Anderson, MD: GLP-1 receptor agonists really exert 4 main effects. First, they stimulate the beta cells of the pancreas to produce insulin in a glucose-dependent fashion. That means when the glucose goes up, insulin is secreted. When the glucose goes down, just like normally, it shuts off. This is very unlike a sulfonylurea where when you give it, it just goes and goes and goes until it runs out.

The other part of this is that when you give a GLP-1 receptor agonist, you’re also suppressing glucagon. And remember that I mentioned that the hyperglucagonemia, that failure to suppress glucagon after a meal, causes the liver to dump more glucose into the blood stream. So it’s responsible for these huge postprandial swings in some of these patients. The other thing that a GLP-1 receptor agonist can do is slow gastric emptying. And I don’t really mean slow it, I mean restore it back to a more normal level of function because most of these patients empty too quickly. They had this huge carbohydrate glycemic surge after meals. We’re actually restoring their gastric emptying to normal. And the other thing the GLP-1 receptor agonists will do is cause a feedback mechanism to the central nervous system to actually suppress appetite.

So that’s why I consider these agents to be the most physiologic agents for the treatment of type 2 diabetes [T2D]. They hit so many different core defects. That’s why they’re so efficacious. That’s why they have these wonderful non-glycemic benefits of reduction of weight, with some reduction of triglycerides and lipids—all of the things we want in our patients.

John B. Buse, MD, PhD: The GLP-1 receptor agonists are, again, injectable therapies. GLP-1 is a naturally occurring peptide produced in the intestinal tract in response to meals. And in nature, GLP-1 stimulates insulin production by the beta cells. It reduces the postprandial rise in glucagon after meals, and both of those result in glucose lowering. But also, it slows gastric emptying. It’s part of the ileal brake. So the idea is that as the GLP-1 comes out, it sort of retains the food a bit more in the stomach so that digestion occurs more slowly, allowing the insulin to catch up. And in the brain it promotes satiety.

As a pharmacologic therapy we have analogs of human GLP-1, and then we have derivatives of a Gila monster salivary protein, exenatide, which has been developed into a drug, and lixisenatide is an analog of exenatide. Pharmacologically, the long-acting ones are different than the physiologic story I told you about, in that the gastric emptying effect tends to wear off after about 24 to 48 hours. The short-acting ones do have this effect on gastric emptying. And because we’re using the drugs at exposure levels about 10 times higher than the natural state, there’s a robust enhancement of insulin secretion. It actually sort of normalizes insulin secretion in the setting of at least early type 2 diabetes, and has a very robust effect on satiety. So people have this sense of not needing to eat more early in the meal. Sometimes they feel that as feeling full like after a Thanksgiving meal. Sometimes that’s not entirely pleasant. Some people perceive it as nausea. But in general, those adverse effects go away over a period of days to weeks in most patients.

So if we were to go down a list of the GLP-1 receptor agonists, the first one that was released is exenatide. It’s derived from the salivary protein of the Gila monster, and it’s administered as an injection twice a day. Subsequently, it was developed into a once-a-week formulation called exenatide once-weekly. That is also an injection. They’ve taken the same exenatide protein and have mixed it in some beads that are slowly absorbed. It’s the most slowly absorbed of the GLP-1 receptor agonists, and probably, as a result of that, it has the best GI [gastrointestinal] tolerability. But it does have an additional issue probably in part related to the beads of forming some skin nodules and sometimes some skin irritation. So there is less nausea, but a new problem with skin irritation.

The next agent that was released into the market was liraglutide. It’s a once-a-day injection but provides for 24-hour coverage. So it actually lowers fasting glucose. Exenatide in the twice-a-day formulation is so short-acting that it doesn’t do as well for fasting glucose. So the ones that have 24-hour coverage like liraglutide, and the once-weekly formulations do lower fasting glucose and, therefore, are generally associated with better A1C [glycated hemoglobin] reductions.
 
And then there’s [so called] son of liraglutide called semaglutide. So it’s the same kind of molecule that’s been tweaked to make it a bit more potent, and perhaps it has extra penetration in the brain. It’s unclear exactly why it has the benefits that it has. But semaglutide is arguably the most powerful agent that we have. It’s once-weekly and is associated with more weight loss and greater A1C reductions than the rest.

Dulaglutide is a fusion peptide where they’ve fused a GLP-1 analog with a big protein. As a result of that fusion, it doesn’t penetrate the brain quite as well. Therefore, it is not quite as good in terms of weight reduction as liraglutide and semaglutide, but it’s pretty close. It’s actually quite good. And it has the advantage of having this really nice pen where you don’t see the needle. It’s the one that I often call the magic wand.

And lastly there’s lixisenatide, which is an analog of exenatide. Frankly, it has a half-life of about 3 hours. And even though it’s marketed as once a day, it really doesn’t cover the day very well. Therefore, it’s not as good in A1C reduction or weight reduction. It’s really used as a combination with insulin glargine as a once-a-day injection, which is quite nice. There’s also liraglutide mixed with insulin degludec as a co-formulated product as well, and those co-formulated products are extremely powerful glucose-lowering agents because they combine the power of insulin with the activity of a GLP-1 receptor agonist.

Transcript edited for clarity.

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