Changing Treatment Paradigm in Diabetes
OCTOBER 02, 2017
MD Magazine Staff
Peter L. Salgo, MD: We’re talking about interesting stuff that we never really were able to get at before.
Christian T. Ruff, MD, MPH: I think that’s what’s fascinating and, in my opinion, I actually think that there probably was never very good data that we ever needed to do these trials to begin with. But, I am thankful that we did.
Peter L. Salgo, MD: Be very specific, which drugs? The cardiovascular risk?
Christian T. Ruff, MD, MPH: Well, I think that there was this signal for the thiazolidinediones (TZDs) that turned out not to be true. And certainly, it’s taken a huge amount of machinery by the FDA, and billions and billions of dollars to do cardiovascular outcome safety trials. I’m not sure that needed to be done, but it ended up being a great for these patients, because we now are talking about drugs that may be beneficial. We would have never had that data had the FDA not required it.
Karol E. Watson, MD, PhD, FACC: I agree with you. But think about if the FDA doesn’t approve statins just because they lower LDL [low-density lipoprotein]. Why are we approving other classes on surrogate markers?
Christian T. Ruff, MD, MPH: No, it’s a valid point.
Peter L. Salgo, MD: Well, we do have these little worrisome things in the IRIS study. You mentioned weight gain, heart failure, bladder cancer.
Karol E. Watson, MD, PhD, FACC: Yes, and fractures.
Peter L. Salgo, MD: And fractures.
Christian T. Ruff, MD, MPH: And I think the big thing is the edema and heart failure. We know that diabetics, up to 50%, could, at some point, develop heart failure. And so, there’s a big chunk of the diabetic population where TZDs are never going to be an appropriate therapy.
Karol E. Watson, MD, PhD, FACC: This is off topic, but I do think that’s going to be a really big thing in the future. There seems to be some kind of microvascular myocardial dysfunctions. They have really stiff hearts—really prone to heart failure.
Peter L. Salgo, MD: Who’s the appropriate population for a TZD, and what populations should you avoid the use of TZDs in?
Rosemarie Lajara, MD, FACE: I think we already alluded to the ones that we would have avoided—your individuals with congestive heart failure.
Karol E. Watson, MD, PhD, FACC: Most of our patients.
Christian T. Ruff, MD, MPH: Yes, most of our patients.
Stephen A. Brunton, MD, FAAFP: I think the thing is, it is generic and it’s effective. So, I think as part of the oral armamentarium, they can have an important role.
Christian T. Ruff, MD, MPH: Yes, I do think, also, that for elderly patients who are already at risk for fractures, this probably is a drug I would think more carefully about if I could use another agent.
Peter L. Salgo, MD: I don’t want to leave this topic without talking about DPP-4 [dipeptidyl peptidase 4] inhibitors, and cardiovascular safety. Christian, can you lead us down that particular road?
Christian T. Ruff, MD, MPH: Yes. There are 3 DPP-4 inhibitors. They’ve all been studied in large cardiovascular trials. We have saxagliptin, alogliptin, and sitagliptin. In the drugs, unlike with the GLP-1 [glucagon-like peptide 1] receptor agonists and the SGLT2 [sodium-glucose co-transporter-2] inhibitors, there doesn’t appear to be a cardiovascular benefit. For the most part, these drugs are also very safe from a cardiovascular signal. There was 1 trial, the SAVOR-TIMI 53 study, with one of the drugs that seemed to show there was an increased risk of heart failure.
Now, this was in patients who were at-risk for developing heart failure—they either had heart failure at baseline or they had elevated markers or bad kidney function. For the other 2 drugs, one of them looked like there was no signal. And there was a retrospective study for alogliptin that said that there may have been signal in patients who were in heart failure when the study was enrolled. So, I do think the drugs are pretty clean (from a cardiovascular perspective). There is some data that revealed that one of the drugs is associated with heart failure, although not heart failure related deaths. But, for the most part, I think there was a pretty clean cardiovascular signal.
Karol E. Watson, MD, PhD, FACC: There are boxed warnings on 2 of the drugs, though.
Rosemarie Lajara, MD, FACE: Correct.
Christian T. Ruff, MD, MPH: Right, but I do think the data for alogliptin is a post hoc analysis of only patients who showed up with heart failure.
Peter L. Salgo, MD: Are the DPP-4 inhibitors going to slowly be relegated?
Christian T. Ruff, MD, MPH: Nothing from a safety perspective, but I think for the fact that you have other cardiovascular drugs that have an overwhelming...
Karol E. Watson, MD, PhD, FACC: I think there’s a new bar.
Rosemarie Lajara, MD, FACE: Right.
Peter L. Salgo, MD: Well then, there’s a new sheriff in town, right?
Rosemarie Lajara, MD, FACE: The patient that will be the ideal candidate for a DPP-4 inhibitor will probably also be a candidate for a GLP-1, right? So, other than the injection part of this, you would gravitate towards the therapy that gets you the cardiovascular benefit.
Christian T. Ruff, MD, MPH: To Stephen’s point, maybe you’d use a TZD because of the efficacy on the glucose side. The DPP-4s don’t give you any benefit for the glycemia, right?
Stephen A. Brunton, MD, FAAFP: The issue is that they’re simpler to use. I think that’s why people use it. It still shocks me that a few percentage of people are using GLP-1 agonists, where you get much more bang for the buck, if you will, in terms of all of these benefits. But, it’s very easy to either add on therapy (to add a DPP-4), even though, as you mentioned, you don’t get the efficacy.
Karol E. Watson, MD, PhD, FACC: Yes, and then, injections are barriers to a lot of patients.
Stephen A. Brunton, MD, FAAFP: Not to patients. It’s actually more of a problem for us, as clinicians. If you tell patients, particularly, “You will lose weight,” they’ll inject themselves in the arm. I think we think it’s a barrier and, also, it’s an issue just because it takes a bit longer to explain how to use it. But, they’re safe. They’re effective. It’s shocking that they’re not using them more frequently.
Peter L. Salgo, MD: What is the typical reaction in your office? You say to a patient, “Look, there’s this great drug. We’ve got this new data. It’s 50% better in many ways, but you’re going to have to have an injection on a daily, or weekly, or monthly, or whatever basis.” What do they say?
Stephen A. Brunton, MD, FAAFP: Well, I think if you say, “But, you can have an injection,” I’m already putting a negative on it.
Peter L. Salgo, MD: All right, but how do you phrase it?
Stephen A. Brunton, MD, FAAFP: I say, “Frankly, it’s a tiny needle,” and I’ll inject myself in the office. I’ll try not to cry, and I will inject them in the office. But what I’ll do, is tell them to close their eye. I’ll ask them to tell me which arm they’re being injected in, and I’ll pinch one arm and I’ll inject in the other. The vast majority of my patients can’t even tell the difference. So, I think once they see that it’s not that big a deal, it’s much easier.
Christian T. Ruff, MD, MPH: The GLP-1s do have some gastrointestinal issues as well, right?
Rosemarie Lajara, MD, FACE: Right, but it subsides over time, for the vast majority, and it’s a little bit different depending on whether you’re using a short-acting versus a long-acting agent. But, again, all of these things are part of the education. More than anything, from a patient’s point of view, it’s more of the injection issue. You have to meet them where they are—their concept of what the injection can be. It may be your 6-mm needle, or it might be they’re thinking about this needle and that it’s going to cause insane pain.
Stephen A. Brunton, MD, FAAFP: An issue with the gastrointestinal effects, and frankly it may even help your lifestyle, is that I tell people, “Eat half of what you normally eat,” because a lot of the feeling of gastrointestinal distress is actually is a feeling of fullness, which is one of the benefits of the GLP-1s.
Karol E. Watson, MD, PhD, FACC: I have said that a million times. I think that’s part of the benefit of why they lose weight. You feel full.
Peter L. Salgo, MD: Tell me a little bit about the pragmatic use of these drugs— the storage, do they have to be refrigerated, do you pick them up once a week—in terms of patients dealing with this.
Stephen A. Brunton, MD, FAAFP: Liraglutide is available for 6 weeks without it being refrigerated. Exenatide is good for 4 weeks. The problem is, now we have once-monthly injections that make it so much easier. And with one of the agents, you can’t even see the needle. So basically, you inject the person. It’s so intuitive that it makes it much easier. And it really depends, frankly, on what’s covered, as well as kind of working to the patient’s lifestyle. But, really, I don’t see it as a barrier. Frankly, I see it as very easy. And particularly, as you mentioned, if you mention, “By the way, you may actually get your blood pressure decreased, and you may actually lose weight.” That’s it; it’s done. They say, “Let’s do it.”
Peter Salgo, MD: This is ridiculously good. What am I missing? Am I missing anything here? I don’t think so.
Karol E. Watson, MD, PhD, FACC: Well, remember that every medication has some potential adverse effect.
Peter Salgo, MD: Here it comes, I know.
Karol E. Watson, MD, PhD, FACC: I’m saying these look very clean, just like you said, but we can’t get cavalier.
Christian T. Ruff, MD, MPH: And, like all clinical trials, they are relative shorter in duration. I do think it’s important to say, when you roll these out broadly into the community and we look at people who have been using these drugs 10 years, or 15 years, there are sometimes signals that emerge that were unanticipated from the trials.
Stephen A. Brunton, MD, FAAFP: There’s a new agent, actually, that is even beyond, “the injection.” You have an implantable system that can last for 6 months, and it holds blood sugars very stable. That will be coming out in the future, and that overcomes a lot of the issues.
Transcript edited for clarity.