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Implications of Using SGLT2 Inhibitors With HFpEF and HFrEF


Steven Nissen, MD, and Nihar Desai, MD, MPH, provide an overview of the implications of the studies using SGLT2 inhibitors in patients with HFpEF & HFrEF.


Steven Nissen, MD: We do need replication. We have the DAPA-HF trial. I’m really glad we have EMPEROR, which is the ongoing trial that I hope we report relatively soon with empagliflozin. If we get replication—this impact is clear across several drugs in the class—that will be very exciting to see. Who knew? Who knew that when we studied these newer drugs for diabetes, we’d actually discover cardiovascular benefits we never anticipated?

I hammer home the point. That’s the whole point of doing outcome trials. You find out things you didn’t expect; you find benefits and risks. I would make 1 more broad comment. Everyone thought that the DPP4 inhibitors would have benefits. Here is a class of drugs that are very expensive and cost as much as the SGLT2 inhibitors, but have absolutely no benefits whatsoever. There’s nothing other than lowering blood sugar, yet they’re much more widely used than the SGLT2 inhibitors. It’s something that bothers me a lot, and it suggests that we’re not doing a good job of talking to our colleagues about evidence-based medicine.

Neil Minkoff, MD: I want to come back to that. Because you brought it up, could you say a few words about any differences you would expect between EMPEROR-HF and DAPA-HF?

Steven Nissen, MD: First, so far we haven’t seen any real differences across the class. The drugs work by the same mechanism. They have about the same blood sugar–lowering effect. The trial design will result in some differences in outcomes. What’s the mix of patients that you study? How advanced is their disease? How many of them are secondary versus primary prevention? By and large, what we’re likely to see is a class effect, but we do need to see it in multiple drugs. We have seen differences in some other classes. For example, with the GLP1 agonists, lixisenatide didn’t provide any benefits, whereas liraglutide did. We have to really do this. Historically, in medicine, we’ve always required that you show something in a couple of drugs in the class before we say it’s a class effect.

Neil Minkoff, MD: Just to make sure we’re capturing it, I’ll bring it back to you, Nihar. What are the differentiations or implications of preserved versus reduced ejection fraction [EF].

Nihar Desai, MD, MPH: Yes, that’s a big point. I agree with Steve that what we saw in DAPA-HF is hopefully what we’ll see in the other trials that are being done. The EMPEROR program with empagliflozin has 1 study underneath it. It’s actually a number of studies. There’s the EMPEROR-Reduced, which has the systolic heart failure patients, and then EMPEROR-Preserved, which has the preserved ejection fraction patients. The EMPEROR-Reduced trial looks very similar to DAPA-HF, at least based on everything we’ve heard about it. If EMPEROR-Preserved reports out the way we all hope it will—to Steve’s point, if these drugs do have the kinds of effects that we all want on heart failure, those extend not just to reduced-EF patients but to the preserved EF patients—that will be a very important stride forward for the field and for our patients. Again, that will be the first real therapy that can improve outcomes and care in those patients. About half the patients with heart failure are actually preserved ejection fraction, yet we have very little by way of dedicated therapies for them. We’re all eagerly awaiting that. Steve’s point about the need for replication, and making sure the trials are done well and reported out in a timely way, is critical for that. If we get the same kind of data that we’ve seen thus far for reduced EF on the preserved EF, that will be an important step forward.

Steven Nissen, MD: I’d like to make another comment if I could, Neil, about the pharmacoeconomic implications here. Let’s face it: These drugs are not free. They’re costly. You want to see that you’re affecting outcomes that have economic costs. That’s why I’m so excited about the SGLT2 inhibitors. They lower blood sugar, and they do so effectively. But they have all of these ancillary benefits—reducing death, reducing hospitalization for heart failure. We’re going to have to ask more of the diabetes drugs that we use. You can give a drug, a sulfonylurea, that’s so inexpensive it’s practically free. But we don’t see any benefit other than lowering blood sugar, and that may not be the most cost-effective approach. If we have drugs that lower blood sugar equally well but keep you out of the hospital, keep you from developing heart failure, and keep you from dying, then we have to ask the payers to value that and make it a little easier for us to prescribe these drugs.

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