GLP-1 Agonists for the Treatment of Type 2 Diabetes - Episode 7
Vanita Aroda, MD: With other classes of agents, you see pretty comparable clinical effects, but that’s not the case with GLP-1 [glucagon-like peptide-1] receptor agonists. All of them are very different in terms of delivery, the pharmacokinetics, pharmacodynamics, size, structure, and the effects on glucose and weight. And this is sometimes interesting to go over with patients because when you show them the different array of types of delivery and types of injections that are available, you start seeing what the patient preferences are.
For example, some of them, like liraglutide, lixisenatide, and semaglutide, come in multidose pens that are clicked, and then you can dial up to the dose and inject. And these are with fine needles. With exenatide once-weekly, and then also with albiglutide, you have a device, an autoinjector, and you have to shake and mix the diluent with the substance. And so patients need to get comfortable with that.
With dulaglutide the needle is hidden so that the patients don’t see the needle. It’s kind of retracted, so some patients prefer that. There are lots of differences between the different agents, not only in their clinical effect and in their basic structure and basic mechanism but also in the delivery choices.
John B. Buse, MD, PhD: We’ve done probably 30 to 50 trials with essentially all these GLP-1 receptor agonists, and we have a very large clinic where we’ve treated thousands of patients with GLP-1 receptor agonists. I think, in general, patients are extremely pleased with the class because of their properties to not only lower blood sugar as good or better than any other drug that they’ve tried before but also to promote clinically meaningful weight loss.
Now there are 5%, or maybe even 10%, of patients who don’t tolerate the drug very well in the beginning; and a few percent, 2% or 3% of patients, who just have a terrible time with it and stop. For the most part, it may be appropriate to go up slowly on the dose and give it time and encourage patients to really be careful about eating small meals. I think what the drug is really doing is promoting satiety, or this sense of being full. And a little bit like at Thanksgiving dinner: If you push it with how much you eat and get that sense of satiety, it doesn’t feel very good. So by counseling about small meals, going up with the dose slowly, and giving it time, the vast majority of people can continue with the drug.
Other than nausea, and, in some patients, loose stools or diarrhea, there are not a lot in the way of adverse effects. The exenatide once-weekly has these skin nodules. There is labeling around pancreatitis. The large trials have suggested that there isn’t really an increased risk of pancreatitis compared with the general population of type 2 diabetes, but we don’t use it in patients with a prior history of pancreatitis.
There’s labeling in the long-acting agents about increased risk of thyroid C cell, hyperplasia, and cancer in rodents. So clearly a problem for mice and rats. There’s no evidence for increased risk of medullary thyroid cancer in humans, but we recommend not using this class of drugs in people with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia. Otherwise, I think the drug is well tolerated. The class and the benefits are great. In general, the longer-acting agents have less nausea than the shorter-acting agents. And if someone doesn’t tolerate 1 agent in the class among the long-acting agents, they may tolerate 1 of the others—exenatide once-weekly is probably the best tolerated of the lot.
John Anderson, MD: I have experience using all of these. In 2005, exenatide twice-a-day came out. We used a lot of it. We had to really talk about nausea, and obviously GI [gastrointestinal adverse] effects are the No 1 type of adverse effects that you have to talk patients through. But I’ve used all these agents. I’ve used the once-a-days; I’ve used the once-a-week options. Those of us in primary care make some decisions based upon benefits of each agent. We also make a lot of our decisions based upon what the patient can afford and what’s available on their formulary. So that’s why I think all providers need to kind of be facile with all these agents in the class.
Transcript edited for clarity.