COMMENTARY

SGLT2 Inhibitors Beyond Diabetes: A Team Effort in CVD and Renal Disease

Matthew J. Budoff, MD; Jay H. Shubrook, DO

Disclosures

July 16, 2020

Editorial Collaboration

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This transcript has been edited for clarity. The discussion was recorded on June 2, 2020, before VERTIS-CV was presented at the American Diabetes Association annual meeting.

Matthew J. Budoff, MD: Thank you, everyone, for joining us today. I am Matthew Budoff, a preventive cardiologist at the UCLA School of Medicine. My primary practice is at Harbor-UCLA in Torrance, California.

Jay H. Shubrook, DO: And I'm Jay Shubrook, a professor in primary care at Touro University California in Vallejo, California. My practice focuses largely on diabetes in the primary care and specialty settings.

Today we will be talking about sodium-glucose cotransporter 2 (SGLT2) inhibitors. This exciting new class of medications has many effects, and we're going to talk about where they fit in cardiology versus primary care practice today. Matt, where do SGLT2 inhibitors fit in cardiology?

Budoff: We have two separate but important roles for SGLT2 inhibitors now. The first indication was for risk reduction for cardiovascular events in patients with established cardiovascular disease — what we would call "secondary prevention" — and that was supported by cardiovascular death reduction as a primary benefit. More recently, the new indication is to use these agents in patients with congestive heart failure, either to prevent hospitalizations or to actively treat people with established congestive heart failure. So the two roles for SGLT2 inhibitors in cardiology are the prevention role and the heart failure role.

Shubrook: This is important because in primary care, I think of this as a diabetes medication — something that's going to lower glucose — but now I may see my patient after discharge from the hospital, or even after their first posthospital visit, coming from a cardiologist, already taking an SGLT2 inhibitor.

Budoff: We're being asked to consider prescribing SGLT2 inhibitors more and more. The American College of Cardiology has come out with a statement encouraging their use; the American Heart Association has come out with guidelines for use; and, more recently, the American Diabetes Association and the American Association of Clinical Endocrinologists/American College of Endocrinology guidelines also encouraged use of SGLT2 inhibitors for cardiovascular indications.

Shubrook: Something similar is happening with the SGLT2 inhibitors and kidney disease as well.

If I'm in the primary care setting, and I'm thinking about using an SGLT2 inhibitor, I may consider using it for someone who already has cardiovascular risk factors or someone who may have had an event. How do I best interface with cardiology, if I want to start one of these agents?

Budoff: Obviously, collaboration is going to be key when we think about how we're going to use these agents, because they frequently cross over from the diabetes space into primary care and into cardiology. From a cardiology standpoint, I imagine most cardiologists would be very happy if the primary care physician or the endocrinologist initiates therapy, because we see this broad-based benefit. It's remarkable that across multiple different trials, we see a very similar benefit for cardiovascular disease prevention, and specifically for heart failure reduction or prevention. I believe that cardiologists would prefer not to be the primary person prescribing these drugs because they are diabetes drugs. I think it's going to take a while for most cardiologists to get comfortable using a drug that is a hypoglycemic.

Shubrook: Let me take that a step further. Let's say I have a patient who I think has reasonably good glucose control, but maybe has had a cardiovascular event or even more acutely has been treated for heart failure. We could be using an SGLT2 inhibitor purely for its cardiovascular effects, even for someone who may not need the glucose benefit, correct?

Budoff: Absolutely. And the recent DAPA-HF heart failure trial, which enrolled people without diabetes, showed that it didn't lower blood sugar in that population, but it did lower heart failure and cardiovascular death rates. So we need to really think about this.

I would also encourage people, at least from a cardiology perspective, to consider substituting this drug when the A1c control is good, when you're happy with the diabetes control, but they're on a sulfonylurea or even a dipeptidyl peptidase-4 (DPP-4) inhibitor. Consider using an SGLT2 inhibitor instead, because this drug has cardiovascular outcome benefits and those other drugs are either neutral or maybe even harmful.

Shubrook: That matches the guidelines' recommendations. If someone has a compelling indication — cardiovascular disease, nephropathy, or heart failure — there are agents that have independent benefit, and we should be making those switches. For me, the challenge would come with patients on other cardiac medications.

Let's say I have a patient with heart failure, and I want to start him on an SGLT2 inhibitor. I'm often worried about what to do with the angiotensin-converting enzyme (ACE) inhibitor or the angiotensin receptor blocker (ARB). And what am I going to do with the diuretic? Often, I send a letter to the cardiologist or nephrologist first and say, This is what I'm thinking. Do you have any advice there? I'd love to hear your thoughts about that.

Budoff: I'm very comfortable prescribing an SGLT2 inhibitor with the ACE or the ARB, assuming the patient's blood pressure is okay. The diuretic poses a bit more of an acute issue, especially in patients who are euvolemic. If the patient's blood pressure is reasonable and volume status is normal, and they're already taking furosemide or hydrochlorothiazide, they might become volume-depleted when we add an SGLT2 inhibitor. We have to remember that this drug is an osmotic diuretic; this causes you to lose glucose, and also causes you to lose salt. I often will reduce or stop the dose of a diuretic when I initiate an SGLT2 inhibitor. Then, if the patient begins to gain a little volume and develop some edema, I can always add a low dose of furosemide or hydrochlorothiazide.

Shubrook: I love that approach. I think patients actually see it as a victory, to have one medicine that can do two things. It may help lower the glucose and lower the blood pressure. But if it takes the place of a diuretic or reduces the need for a diuretic, that often is a victory for our patients.

Budoff: Absolutely. We have to remember that these drugs tend to lower the blood pressure slightly. From a hypertension standpoint and a volume standpoint, the SGLT2 inhibitors may be an excellent substitute for these other drugs. Plus, we don't get potassium wasting with the SGLT2 inhibitors as we do with the diuretics. So in the long run, it's probably a safer alternative as well.

Shubrook: In the primary care setting, we certainly are nervous about using SGLT2 inhibitors if someone has a history of diabetic ketoacidosis or Fournier gangrene. From a cardiologist's viewpoint, is there anyone you would not prescribe an SGLT2 inhibitor?

Budoff: Excellent question. The only person I might be cautious about is one with prior amputation. We saw a higher risk for amputation with two of the four agents, although the Europeans say it may be a class effect. The concept of giving someone with poor peripheral circulation an agent that decreases their volume, either diuretics or SGLT2 inhibitors, is worrisome. If you are going to use an SGLT2 inhibitor in those settings, I'd be very cautious and keep a close eye on them.

Shubrook: But it sounds as if, for everybody else, you're pretty much on board, and as long as we're working together and watching volume status, it is a good match for both of us.

Budoff: Yes. We're going to see more and more pressure for cardiologists to start these agents as with the nephrologist, because the guidelines are going to change. On the basis of the CREDENCE trial, I'm confident that the renal guidelines are going to become more aggressive in recommending these drugs. From a cardiology standpoint, we're already starting to see some of the guidelines and FDA indications become more open about these having direct cardiac applications. I believe we're going to need a team effort here and have everyone on board when we initiate these therapies. I often think of them as the next iteration of ACE inhibitors.

ACE inhibitors are widely used in primary care and widely used in endocrinology; cardiology loves them, nephrology loves them. We all use them for slightly different reasons. But we all initiate that therapy. And I believe in the long run, SGLT2 inhibitors will be similar.

Shubrook: That's an excellent summary. We both know that as powerful as renin-angiotensin system (RAS) agents are, they're still underutilized. This is really a call for people to consider SGLT2 inhibitors for their patients who have diabetes and/or a compelling indication of atherosclerotic cardiovascular disease, heart failure, or nephropathy. And it sounds like this is a place where primary care can take the lead and work collaboratively with nephrologists, cardiologists, and heart failure teams to do the best for their patients.

Budoff: Absolutely. And to my cardiology colleagues, do not be afraid of hypoglycemia. By themselves, these agents are safe. If a patient is already on a sulfonylurea or insulin, then we have to think about that because those drugs can still cause hypoglycemia. But the hypoglycemic risk of these SGLT2 agents, especially when they're used with things like metformin or even a glycoprotein 1 (GLP-1) receptor agonist, is low. So don't let that be a total hindrance to getting these drugs on board. And of course, the specialist needs to work with the primary care doctor and endocrinologist when this is appropriate.

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