Using SGLT2 Inhibitors for Quadruple Therapy in the Management of HFrEF

James Januzzi, MD: We have one more class of the so-called 4 pillars, which I'm going to ask Dr Butler about. And then we have a rapid-fire about new therapies on the horizon. Javed, about SGLT2 [sodium-glucose cotransporter-2] inhibitors. This is the newest class, and you've done some remarkable work on the EMPEROR studies, there's the DAPA-HF study in reduced ejection fraction, and many other studies now looking at the impact of this therapy in HFrEF [heart failure with reduced ejection fraction]. When do you suggest adding an SGLT2 inhibitor and is this just for patients with diabetes or are there other patients who benefit from them?

Javed Butler, MD: The pharmacodynamic profile, the mechanism of action, the effects on the heart, the vasculature kidney, and the systemic effects clearly demonstrate that SGLT2 inhibitors are cardiovascular risk-modifying agents that have glycemic control properties as an antioxidant glycemic agent and good drugs for diabetes. But SGLT2 inhibitors go far beyond, and we have data and HFrEF in chronic kidney disease and HFrEF that diabetes doesn't matter—all of these patients benefit from these therapies. In terms of when to use these therapies, if you were to go to the drawing board and say, “I want to design an ideal drug for heart failure,” what would that be? Well, you want 1 pill once a day, no dose titration, improve clinical benefit, improve quality of life benefit, well-tolerated early benefit within weeks of giving the therapy, and all the other common reasons for which some of these therapies are not tolerated and heart failure, cardiac or hypotension or dizziness or potassium-created heart rate issue. None of those are issues. You get a checkmark for all of this with an SGLT2 inhibitor. I would say that you can pretty much start at any point you want. Now, of course you have to be careful about the contraindications. This is not a drug for a patient with type 1 diabetes with history of allergies, people on dialysis. But short of that diabetes or no diabetes, whether you're hospitalized, whether you're an outpatient, if you have HFrEF, whatever your baseline therapy, this therapy can be initiated and will improve outcome.

James Januzzi, MD: That's a great answer. These really are a truly revolutionary treatment that we fit in so easily in many of our patients. Javed, let me ask you a question about SGLT2 inhibitors. There are challenges that we know about with the drug. It may increase the risk for pelvic infections, yeast infections, particularly in people with diabetes, maybe increase urinary tract infection, but not urosepsis really. Because of the fact that the drug increases glucose output in the urine. One challenge that I have seen some clinicians struggle with is the fact that SGLT2 inhibitors, through their effect to reduce interglomerular pressure, will sometimes acutely increase the serum creatinine. Can you speak to that? And what does that really mean?

Javed Butler, MD: Two quick things. First of all, there is genital mycotic infection business, and we should give our patients simple advice to keep the area clean, dry and maintain genital hygiene. And now that we've gotten smarter, how would we use these drugs? If you look at earlier trials with SGLT2 inhibitors, the rate of these young mycotic infection used to be like 8%, 9%. And in the latest trial with SGLT2 inhibitors, it's down to 2.2%. Again, more than placebo, but the absolute rate has gone down. In other words, if you were to take some simple precautions, you can substantially reduce the risk of these adverse effects. Now, in terms of the creatinine issue or the GFR [glomerular filtration rate] reduction issue, remember that ACE [angiotensin-converting enzyme] inhibitors are renal protective drugs, but when we give patients ACE inhibitors, you have that bump in creatinine, which is because of intraglomerular hemodynamic changes. It's because of the ether and dilatation, and SGLT2 work on the other end causes [afferent] constriction. Exactly the same story. There is no renal damage. Both ACE inhibitors and SGLT2 inhibitors preserve renal function in the long run. And if you stop an ACE inhibitor or an SGLT2 inhibitor that initial drop in GFR or rising creatine comes back. Although not consistent across all studies, but some data would suggest that the initial drop in EGFR [estimated glomerular filtration rate] is associated with more preservation of renal function because it's a marker that you already were hyperfiltrating and the pressures were high. And therefore, you give this therapy and you have more of a drop than otherwise. I would not worry about this unless, and until it's extreme. If somebody has 15%, 20%, 25% reduction, I would worry about it, but if it's extreme and you're worried that somebody was dehydrated and on top of that, you're adding 2 more therapies. But 99% of the time, it's not an issue.

James Januzzi, MD: That's a great answer. The take-home for the viewers is you expect to see some change in serum creatinine, but in the long run, that translates to protection. Thus, don't overreact and stop the drug without thinking very carefully.

This transcript has been edited for clarity.