Role of SGLT2 Inhibitors in Treating PAD

Transcript: Deepak L. Bhatt, MD, MPH: Marc, before we leave medical therapy that already has data to talk about some of the newer data that have just come out, let me go back to talk a little about SGLT2 inhibitors. These have become evidence-based therapies for diabetes. Many guidelines are now moving them to second- or even first-line therapy given the great data in terms of cardiovascular outcomes. One controversy that came up in the context of PAD [peripheral artery disease], as you know, was in the CANVAS trial. There was a signal of increased amputation with canagliflozin. It really wasn’t a signal, but it was a statistically significant finding. It hasn’t been borne out in subsequent trials of canagliflozin, namely the CREDENCE trial, where there wasn’t any signal of excess amputation. It hasn’t been seen in the large outcome trials of empagliflozin.

In fact, you led and presented the dapagliflozin PAD analysis. Can you tell us what the current thinking is on SGLT2 inhibitors in PAD as a class and individually? Do any of them have a hazard in PAD? If the patient has PAD, do we need to worry about using them? If the patient has critical limb ischemia [CLI], do we have to worry about initiating therapy, or do we need to discontinue them? Could you address all those points where there’s a lot of uncertainty, confusion, and controversy?

Marc P. Bonaca, MD, MPH: I’ll certainly give my point of view because, as you point out, there’s a lot of data out there. I’ll say this has gotten a lot of attention in vascular circles because that finding of harm was a 2-fold risk. Without any understanding of the biological mechanisms, it got people’s attention. I’ll tell you my view. I’m thinking about the data, and these drugs have really important benefits for heart failure, kidney outcomes, and mortality. These are risks that PAD patients have very high rates of: kidney complications, for example. Those PAD patients with diabetes or heart failure have important gains and benefits from the therapies.

The only drug to show the risk was canagliflozin. It is unclear what was driving that risk. The absolute risks were highest in the patients with PAD, but the relevant risks were the same with or without PAD. In the other trials, didn’t see it. We didn’t see it in the DECLARE—TIMI 58 trial, and we didn’t see it in the empagliflozin trial. As you pointed out with CREDENCE—which was with the same drug, canagliflozin—in the renal subset, they didn’t see a risk. They managed the drug a bit differently. They didn’t bring in patients who were at high risk of amputation or in the setting where an amputation was likely. I think the most important finding from CREDENCE was that they used good foot hygiene, and there you see no risk.

My take-home message is that I don’t know if there’s a real risk there. I don’t think there’s definitely a class effect. Whether there’s a risk with canagliflozin, I don’t see convincing data. If you’re concerned about it, tell your patients with PAD to practice good foot hygiene. I think that is good for every patient with diabetes. If a patient came in with CLI, I probably wouldn’t initiate therapy at that time. If they were in the setting of peri-amputation, I might be cautious. I think once that issue is resolved, I wouldn’t deny a patient the therapy. I’d use caution in those very small subgroups of high-risk patients in the setting of CLI or amputation, but overall, I use the drugs in PAD. I don’t think there’s a class effect, and good foot hygiene is critical.

Deepak L. Bhatt, MD, MPH: I agree with all of that. In fact, there’s been recent guidance, in patients who are about to undergo surgery of any sort, to hold the SGLT2 inhibitors for a little bit. Mike, what are your thoughts about diabetes, PAD, and medications?

C. Michael Gibson, MS, MD: You 2 are the experts on that. I’m going to defer to the 2 of you.

Deepak L. Bhatt, MD, MPH: Do you think cardiologists should or shouldn’t play a role in managing these diabetes drugs, given that some of these drugs—SGLT2 inhibitors now—are clearly reducing heart failure? GLP-1 agonists do appear to be reducing atherosclerotic events. Is this something you think—beyond being involved with the trials, and in many cases leading the trials—cardiologists should actively be prescribing in patients, not just with PAD but also with cardiovascular disease more broadly?

C. Michael Gibson, MS, MD: Absolutely. These drugs are amazing. We have seen some data indicating mortality reductions. We’ve got to break down the silos and we all must become diabeto-cardiologists, or cardio-diabetologists. We have a common enemy, and we can’t continue to say this is an endocrine disease or this is a cardiology disease. It’s a syndrome that involves the heart, the periphery, and every vascular bed, and we all have to work together to combat this.

Deepak L. Bhatt, MD, MPH: That’s really a good way of thinking about it all.

Transcript Edited for Clarity