PracticeUpdate Diabetes Best of 2018

ADA 2018 21

SGLT2 Inhibitors in theManagement of Type 2 Diabetes Interview with John (Jack) L. Leahy MD by Jason Sloane MD

proven cardiovascular benefit really. And that all changed in 2015 with the famous EMPA-REG trial, which is a trial using empagliflozin, and then there’s a subsequent trial using canagliflozin called the CANVAS trials. What they have clearly shown is a reduction in car- diovascular risks, our standard famous MACE cardiovascular risks, but also to a huge surprise, a big reduction in heart failure risks in these patients, something that’s never really existed with our drugs before, with renal protection…dramatic renal protection in people with modest renal dysfunction, maybe even people with- out renal dysfunction; that’s open to some debate right now. So the cardiovascular outcome results with the SGLT2 inhibitors are really amazing, and it looks like it’s a class effect. There’s a lot of studies out there now that’s looking at real-world data, even with some of the drugs that don’t have finished cardi- ovascular outcome trials yet, and it really looks as if this reduction in cardiovascular death, and also protection against heart failure seems to be a class effect and it wouldn’t surprise me if renal pro- tection is the same thing, so life has changed because of these drugs. Dr. Sloane: That’s great news for practitioners and patients alike. Last but not least, I was wondering if you had any sequence where you would add or think to add an SGLT2 inhibitor in your treatment of type 2 diabetes after metformin? Dr. Leahy : This is the really important question, and in fact, it’s not just a question from us. The American Diabetes Association dealt with this issue, like many of the national diabetes societies around the world, because of the trial data with empagliflozin we talked about, and also the CANVAS trial. In 2018, for the first time, the treatment guidelines of the American Diabetes Association say that after metformin, if your patient has a history of cardiovascular disease, then they should now be started on a drug with known cardiovascular protection, and the drugs they mostly highlight are either SGLT2 inhibitors or a few of the GLP-1 drugs. And so the sequence is really evolving, that these drugs need to be used ear- lier in the course than maybe they ordinarily would, especially in people with proven cardiovascular disease. And my prediction is sometime in the near future we’ll be talking about that with peo- ple with renal disease. We’ll be doing the same thing. www.practiceupdate.com/c/70070

Dr. Leahy is Director of Endocrinology at the University of Vermont Medical Center and a Professor at Larner College of Medicine at UVM in Burlington, Vermont. Dr. Sloane: How do SGLT2 inhibitors work to control blood sugar in patients with type 2 diabetes, briefly if you would? Dr. Leahy: SGLT2 inhibitors are the newest drugs we have. They’ve been around for a couple of years, and the easiest way to think about them, in terms of mechanism of action is they promote glyco- suria. They inhibit one of the main biological processes that when we filter glucose into the beginning…through the glomerulus into the beginning of the filtrate, it gets sucked back into the blood so that…usually, we’re not supposed to excrete any glucose, so our agents overcome that. They don’t hurt kidneys they certainly block that…they simply block that process, and so one of the major effects is you’re peeing out glucose. You also happen to pee out salt and water, so that’s good for blood pressure. Those are the direct effects, but there’s also indirect effects. They’re insulin sensitizers in part because of the weight reduction, you lower insulin levels because of that, so that’s actually a good thing in terms of some of the downstream effects. Glucagon levels go up a little bit, all these indirect effects, but the bottom line is the weight reduction, the blood pressure reduction and the glucose reduction are all an effect of the loss of glucose initially through the urine. Dr. Sloane: In terms of possible side effects of these medications, are there large side effects that you look out for or test for in your practice? Dr. Leahy: Some of the side effects are obvious, which is if you’re going to have urine which is enriched in glucose, then there will be a higher rate of vaginal yeast infections, and that’s real, I would guess, in my practice. Maybe I’mmaking up a number, but we’ll say maybe 20% of women will have a problem with a yeast infection, often women who have had yeast infections before, so I usually ask for that. Men who are not circumcised run a small risk of hav- ing a yeast infection of balanitis. It’s not all that common, but it certainly can occur, and urinary tract infections. I think, when those drugs first came to us, we were really con- cerned about urinary tract infections, but in fact, I would say yeast infections are really probably much more of a common issue than actually urinary tract infections, so those are the common things we would think about. There’s a few others. Volume depletion-related problems can occur because they’re kind of acting like diuretics in some respects, so especially in older folks who are pretty well treated with blood pressure and maybe have labile blood pres- sure, there is a small risk of hypotensive events. There is this rare, but very talked about side effect, something called euglycemic diabetic ketoacidosis. It’s not something that comes up very often, but the fact is, it’s real. People can present with clear metabolic acidosis and anion metabolic acidosis, ketones present, blood sugars are not that high because we’re taking a drug where peo- ple are excreting glucose, but as a general statement, these are pretty safe drugs with a pretty low rate of side effects generally. Dr. Sloane: In terms of recent evidence of SGLT2 inhibitors improving cardiovascular outcomes, what do you think have been the most sig- nificant trial outcomes? Dr. Leahy: This is huge. If we go back 3 years ago, there was no diabetes drug that we could talk about, whether it was having any

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VOL. 2 • NO. 4 • 2018