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Dr Javed Butler on SGLT2 Inhibitors' Role in Preventing HF


When results from the EMPA-REG OUTCOME trial came out, nobody was expecting empagliflozin to have a particularly robust benefit on heart failure and several questions were raised as a result, said Javed Butler, MD, MPH, MBA, chairman for the Department of Medicine at the University of Mississippi.

When results from the EMPA-REG OUTCOME trial came out, nobody was expecting empagliflozin to have a particularly robust benefit on heart failure and several questions were raised as a result, said Javed Butler, MD, MPH, MBA, chairman for the Department of Medicine at the University of Mississippi.


The American Journal of Managed Care® (AJMC®): Can you introduce yourself and tell us about your work?

Dr. Butler: I'm professor and chairman of the Department of Medicine at University of Mississippi, and I'm a cardiologist by training. My clinical career focused on heart failure and my research career focused on heart failure clinical trials.

AJMC®: What are the most important things we have learned about SGLT-2 inhibitors since the EMPA-REG OUTCOME trial and what data points are you most looking forward to seeing in EMPEROR Reduced?

Dr. Butler: When the EMPA-REG trial came out, heart failure was not a primary endpoint, it was a secondary endpoint. Nobody was expecting that degree of robust benefit for heart failure that we saw. So several questions came up at that time. The first question was, is it just a fluke, like, maybe we just got lucky. Can you replicate it? And then the second question that came up is that the EMPA-REG trial had a combination of both people who had known heart failure at baseline, about 10 to 15% of the population, and about 80 to 85% of the population did not have heart failure at baseline. So the question is, is the heart failure data related to prevention of heart failure or is it related to treatment of heart failure?

Subsequently, over the next few years, we got multiple cardiovascular outcomes trials that came out with dapagliflozin, with canagliflozin, with ertugliflozin. And while the other results may vary a little bit, what we saw consistently was the heart failure benefit across all the trials and about the same, about 30%, relative risk reduction. Basically, we answered one question that is, that's not a fluke. It's replicated over and over again. But then it turns out that if you look at the data of people who had baseline heart failure, and who did not have baseline heart failure, those groups of patients benefited. In other words, you have also now proven that in patients with diabetes, you are preventing heart failure. The question is, if you are going to stick your neck out and say that we are actually treating heart failure, then we really need some more dedicated trials. And that's why we started doing the DAPA-HF Deliver, EMPEROR Reduce, EMPEROR Preserve, more focused heart failure trials, not preventing heart failure in patients with diabetes, but treatment of heart failure itself.

Now, one last point. It also turned out that once we understood the mechanism of action of these drugs a little bit better, we started questioning, well, maybe these drugs will benefit people who don't even have diabetes. They do so many things in the body that may have nothing to do with diabetes. So the way the heart failure trials were being designed were to look at patients with or without diabetes. While the drugs were first discovered as treatment for diabetes, the first trial that showed results, DAPA-HF with dapagliflozin, that drug showed that the benefit was almost the same in patients with or without diabetes, so they are more cardiovascular drugs. What we are looking for in EMPEROR is basically to replicate the results of DAPA-HF so that we are more comfortable that this is a result which is replicated, especially in patients who don't have diabetes, and that we can make it as a standard of care in heart failure with reduced ejection fraction (HFrEF).

AJMC®: How can cardiologists work alongside doctors in different specialties to determine which patients will benefit most from this multidimensionally beneficial drug?

Dr. Butler: This issue sort of comes up. I mean, there's dapagliflozin, an endocrinologist's drug, a primary care's drug, a cardiologist's, a nephrologist's drug. I honestly think, this is like the patient's drug, right? So it doesn't matter where the patient's touch point is, I think we all have to take on the responsibility that the patient does not not get disease modifying therapy, especially considering that many of these comorbidities tend to overlap. It's a multi-organ system benefit in a lot of overlapping patients. What I can say to my cardiologist friends, is that people will get used to a new class of drugs pretty easy. I mean, we have done that in cardiology over and over again that new classes of drugs are introduced. But at least if there is reluctancy, that I don't have self-efficacy to use this drug and I'm uncomfortable, then remember to prescribe it and work with your endocrinologist or primary care physicians who are more comfortable. I think the first order of business is that somebody gives it and you create a partnership. But the second order is that we need to sort of create some pathways and education for cardiologists so that they feel comfortable using it themselves.

AJMC®: How do the costs of SGLT-2 inhibitors compare with other treatment options for HFrEF (ACE inhibitors, beta-blockers)?

Dr. Butler: I won't know the answer precisely. I would assume that the answer depends a lot on regional variation and insurance coverage and all that kind of stuff. But obviously, SGLT-2 inhibitors are not generic and neither is receptor blocker valsartan/sacubitril or various other drugs. Some of the beta blockers, some of the mineralocorticoid receptor antagonists and ACE inhibitors and ARBs, they are generic. There will certainly be a cost difference, and those drugs will be cheaper. But what exactly is the cost of this? I don't know. It really depends on the region.

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