Safety Concerns in New Class of Drugs for Diabetes

Peter Salgo, MD: Let’s go to some personal stories. You are clinicians. You’re using these drugs. Helena, what is your personal experience with the GLP-1s [glucagon-like peptide-1 receptor agonists], the DPP-4s [dipeptidyl-peptidase-4 inhibitors], the SGLT2 [sodium-glucose cotransporter 2] inhibitors? And are there any safety considerations we need to think about?

Helena W. Rodbard, MD: I really like the new developments because they really help us to provide better care for our patients. So [for] the GLP-1 receptor agonists, among other things, what I like and what my patients like, is the weight loss. So what are the considerations? There is always a but. It’s that they have to be increased gradually because they’re injectable currently—the orals are not available yet. But they have to be increased gradually because they can cause gastrointestinal [adverse] effects—nausea, vomiting, diarrhea, and so on. But that’s why we increase them gradually as tolerated, and sometimes we don’t even reach the maximal permitted dose. We just go to what we can do. But the weight loss is not insignificant. And in fact, 1 of the GLP-1 receptor agonists is currently being tested for basically only a much higher dose. So semaglutide is being currently tested to verify, to ascertain cardiovascular benefits—but in people who don’t have diabetes, people [who] have risk for diabetes because they’re obese and many of them have cardiovascular disease. So that’s my take on GLP-1 receptor agonist.

DPP-4 inhibitors, I like them as well, and primary care physicians like them very much. Why? Because they’re easy; they’re simple. It’s a pill a day, very, very easy to take. They’ve been around for a long time, as Om said. The first 1, sitagliptin became available in October 2006, so it has been a long experience. There is a cardiovascular outcomes trial that’s called TECOS, showing the safety of it. And basically there are no side effects. It has efficacy—not wonderful efficacy in the long run, but in the short term, it’s not a bad drug at all. Those are the DPP-4 inhibitors. The SGLT2 inhibitors are a very interesting class of drugs. We just heard about the mechanism of action. But now very interestingly, we’re finding out about heart failure prevention, and we are also finding out about the renal, as the CREDENCE study has shown, just published this week in the New England Journal of Medicine, so that is very, very exciting. We have a lot to offer to our patients, and it is a pill. In fact, it’s indicated [only] for people with type 2 diabetes. Off-label, many of us, particularly endocrinologists, are using it for people with type 1 diabetes as well.

Peter Salgo, MD: Just to stop you there. Personal communication from Helena, et al. This is something that you’ve just experienced.

Helena W. Rodbard, MD: In my experience. Me and some other people. And in fact, there are clinical trials ongoing in people with type 1 diabetes, and I’ve had the opportunity to participate actually in 3 of such trials, using SGLT2 inhibitors in people with type 1 diabetes, as well as a new class of SGLT2/SGLT1. It’s a combination.

Peter Salgo, MD: We’re going to get to that too. But you seem to like these new drugs.

Helena W. Rodbard, MD: I love them.

Peter Salgo, MD: They should great.

Helena W. Rodbard, MD: I love them.

Peter Salgo, MD: You love them?

Om P. Ganda, MD: I think I agree with what was just said by Helena, that these are very exciting drugs. Every drug has some pros and cons, and every drug has some [adverse] effects. But relatively speaking, the incidence of adverse effects with these drugs is really very, very small compared [with] what we see in the past. And most importantly, they don’t cause hypoglycemia. You can combine them with metformin and not have any hypoglycemia. In some cases down the line, if you need insulin—which many people with type 2 diabetes need, for right or wrong reasons, lifestyle included—…you have to watch and see whether the insulin dose has to be reduced a little bit once you put these drugs on board. And we have specific indications now, 2019 ADA guidelines [American Diabetes Association Standards of Care] recommend that if you have somebody with cardiovascular disease, you can pick and choose any of these 2 classes of drugs, in particular, SGLT2 inhibitors and GLP-1 receptor analogs. Both have very good qualities, but again, when it comes to history of heart failure, I would choose [an] SGLT2 inhibitor over the GLP-1 receptor analog.

Peter Salgo, MD: Do you have an agent that’s preferred on the basis of age?

Helena W. Rodbard, MD: Well, I would look for agents that don’t cause hypoglycemia, because that’s a major concern. I certainly try to avoid the use of sulfonylureas in general. But I certainly would not use sulfonylureas in [the] elderly [patient] population, people [who] live by themselves, people [who] may be more vulnerable. It’s 1 class of drugs that I try to shy away from. Among the new ones, I probably would prefer the class of DPP-4 inhibitors, the incretins, and GLP-1 receptor agonists. One potential issue with SGLT2 inhibitors is that they can cause orthostatic hypotension. So they deplete volume, and people may be a little bit more vulnerable to basically passing out. But it doesn’t happen often. It’s part of what we indicate to people when we start them on drug—we make sure that they drink plenty of fluids.

Peter Salgo, MD: You were talking about the weight issues and how some of these drugs are more beneficial because they can promote weight loss. What about for patients who are not over their target weight to begin with? Does that make a difference?

Helena W. Rodbard, MD: Very few people are not over their target, especially people with type 2 diabetes. But yes, it does make a difference. Those people would be typically the ones that I would feel would be good candidates for DPP-4 inhibitors because those are weight neutral.