Q&A: Javed Butler, MD, MPH, MBA, discusses the current heart failure medication landscape
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Key takeaways:
- SGLT2 inhibitors and GLP-1 receptor agonists continue to demonstrate benefit for patients with heart failure.
- Such successes also produce challenges such as polypharmacy and adherence.
Few areas in cardiology are as active as development and implementation of medical therapies for heart failure, and few people are as familiar with that landscape as Javed Butler, MD, MPH, MBA, FACC, FAHA, FESC.
At the American College of Cardiology Scientific Session, Butler, president of the Baylor Scott and White Research Institute, senior vice president and Maxwell A. and Gayle H. Clampitt Endowed Chair for research for Baylor Scott and White Health, distinguished professor of medicine at the University of Mississippi and a member of the Healio | Cardiology Today Editorial Board, presented the results of EMPACT-MI, one of the meeting’s most anticipated late-breaking clinical trials. He and colleagues found that administering the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) soon after an acute MI did not significantly lower risk for the primary endpoint of HF hospitalization or death from any cause compared with placebo among patients with increased risk for HF, but it did reduce risk for certain HF-related outcomes in that population. The findings were also published in The New England Journal of Medicine.
Healio spoke with Butler about how the mechanism of action of SGLT2 inhibitors may have contributed to the results of EMPACT-MI, other recent and future trials that have the potential to impact the medical therapy landscape for patients with HF and the challenges that are produced by having so many new medical therapies for the HF patient population.
Healio: Did the results of EMPACT-MI surprise you?
Butler: The trial disappointed in that there was no mortality benefit. But a substantial HF benefit that we have seen with SGLT2 inhibitors in other disease states was also replicated. In that sense, SGLT2 inhibitors being cardioprotective from a HF perspective was not a surprise and is a welcome addition to the post-MI population.
Healio: Why do you think we saw a lack of mortality benefit?
Butler: SGLT2 inhibitors primarily work in the cardio-kidney-metabolic axis with the prevention of myopathy development as opposed to atherosclerosis. Even if you look at patients with ischemic cardiomyopathy and type 2 diabetes in the EMPA-REG OUTCOME study, those patients had their ischemic events more remotely than those in EMPACT-MI. Their primary issue was remodeling, or myopathy, and all those patients benefited from an SGLT2 inhibitor. Acute mortality related to MI is more related to things like cardiogenic shock, recurrent MI, stent thrombosis, septal ruptures, etc. All those things that occur in the earlier phase of MI are not things that we can expect to be modified by an SGLT2 inhibitor.
The second reason is that being a pragmatic trial, we had all-cause mortality as part of the primary endpoint as opposed to cardiovascular mortality. Considering the portion of 20% to 25% non-cardiovascular mortality and the early post-MI cardiovascular mortality, which may not be modifiable with SGLT2 inhibitors, the total mortality burden in this trial showed no mortality signal. Finally, the post-HF development follow-up on average was less than 1 year, and there were not enough mortality events to impact the overall mortality results.
Healio: What do you think the cardiology community will take away from these findings?
Butler: That will depend on how the guideline communities take the results. If you have a powerful benefit in a secondary analysis, but you don’t achieve your primary endpoint, that always leads to a lot of debate. Which way the guidelines committee will lean, I don’t know. I can only give my opinion that the heart failure results, the ability to prevent heart failure post-MI, show a significant benefit. And improvement of HF outcomes is not a surprise finding: It has been shown consistently in diabetes, chronic kidney disease and HF, and now in post-MI patients. I hope people will consider early use of SGLT2 inhibitors in those patients post-MI whom they deem to be at a high risk for HF.
Healio: Were there any other presentations or sessions at ACC that stood out to you?
Butler: There were a couple of other things in the heart failure arena that were impressive. One was the REDUCE-AMI trial showing that in patients with MI who underwent early revascularization and had preserved ejection fraction, a beta-blocker over a period of 3 years showed no benefit. We will need to review those data carefully. That will change practice, but that will also lead to a lot of discussion in the community. There was another paper presented, STEP-HFpEF DM, which showed patients with the obesity phenotype of HFpEF and diabetes benefiting in terms of symptoms, exercise capacity and quality of life from semaglutide 2.4 mg (Wegovy, Novo Nordisk), similar to STEP-HFpEF last year, which included similar patients without diabetes. Beyond SGLT2 inhibitors, at least with the obesity phenotype of HFpEF, maybe GLP-1 receptor agonists are making their way into the therapeutic armamentarium as well.
Healio: It was interesting that in STEP-HFpEF DM, about one-third of participants were already on SGLT2 inhibitors, and yet they still saw additional benefit with semaglutide. Was that expected?
Butler: Absolutely. We have seen this when there are non-overlapping mechanisms of action. For example, if you give an ACE inhibitor on top of an angiotensin receptor blocker, you don’t get much benefit because these are overlapping mechanisms of action. But if you have two drugs that work in distinct mechanisms of action, the second one will work regardless of what the baseline therapy is. There are enough distinctions between SGLT2 inhibitors and GLP-1 receptor agonists that there is good reason to believe that they would work regardless of whether someone was taking one or the other at baseline. Also, in part, the mechanism of action of improving HFpEF outcomes with semaglutide is through weight reduction, whereas the weight reduction component with SGLT2 inhibitors is modest. So at least to me, it was not a surprise that a GLP-1 receptor agonist helped patients with the obesity phenotype of HFpEF who were already on an SGLT2 inhibitor.
Healio: What other studies are coming out soon that could make an impact?
Butler: The biggest in the HF world is the FINEARTS-HF study of finerenone (Kerendia, Bayer) in patients with HFpEF. Hopefully, we will see that later this year. Also anticipated is the heart failure substudy of the SELECT trial, which was the CV outcomes trial for semaglutide 2.4 mg in patients with obesity and atherosclerotic CVD, where we will see the amount of benefit in that population. Hopefully that paper will be out soon. And then there is the FLOW trial of semaglutide in patients with chronic kidney disease and type 2 diabetes, a population that is at higher risk for CVD and HF, that will be coming out soon.
Healio: What sort of challenges are cardiologists and their patients facing these days that need to be addressed?
Butler: The biggest thing is that we are thinking about all of these cardiovascular, kidney, metabolic and diabetes-related diseases not as separately as we initially thought. They are interlinked with common pathophysiologic mechanisms. So, the good news is, a lot of the medications have benefit across multiple organ systems and address multiple diseases simultaneously for prevention and treatment. That’s great. The problem is that these successes have led to polypharmacy, which raises several issues. One is that adherence is a challenge, which has led to work on the polypill, long-acting drugs and other ways to improve adherence. Another challenge is financial. How do we give all the effective therapies to patients to give them the best chance? The last is education. There are so much enriched clinical trial data in so many disease states that for primary care physicians and general practitioners not involved in any specific specialty, it may be challenging to follow it all. So how at a system level do you optimize population management so that all patients get appropriate care?
References:
- Butler J, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2314051.
- Kosiborod MN, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2313917.
- Yndigegn T, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2401479.
For more information:
Javed Butler, MD, MPH, MBA, FACC, FAHA, FESC, can be reached at butlzih@gmail.com; X (Twitter): @javedbutler1.
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