At Issue: The implications of SELECT on CVD prevention in high-risk patients with obesity
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Key takeaways:
- In the SELECT trial, semaglutide reduced risk for CV events vs. placebo in people with obesity and CVD.
- Discussion centers on what extent newer weight-loss drugs should be prescribed by cardiologists.
The SELECT trial, which showed semaglutide, a GLP-1 receptor agonist also approved for diabetes, reduced CV events in people with overweight/obesity and CVD but no diabetes, was one of the most important developments in cardiology in 2023.
The results — a 20% reduction in CV death, MI and stroke in patients assigned semaglutide 2.4 mg (Wegovy, Novo Nordisk) compared with those assigned placebo at nearly 40 months — represent the first time a pharmacologic intervention for overweight or obesity has been shown to reduce CV complications. The findings were presented at the American Heart Association Scientific Sessions and simultaneously published in The New England Journal of Medicine.
The trial, conducted in a population of 17,604 adults with preexisting heart disease, which included prior MI, stroke or symptomatic peripheral artery disease, and overweight or obesity but no diabetes, raised the specter of whether the newer weight-loss drugs should be considered CV drugs routinely prescribed by cardiologists.
Healio spoke with several leading cardiologists about the implications for CVD prevention.
Deepak L. Bhatt, MD, MPH
The SELECT trial got a lot of attention, deservedly so. At the AHA Scientific Sessions and in The New England Journal of Medicine, we got a lot of information. From a bottom-line perspective, I would categorize this trial as a home run. It was clearly very positive, showing that the GLP-1 agonist semaglutide vs. placebo reduced CV events by 20%. By that, I mean hard CV events — the composite of CV death, MI and stroke. And, this was a population of patients without diabetes; they were at high risk for diabetes, but they did not actually have diabetes. They were overweight or obese with CVD — a high-risk population in whom there was a significant benefit.
This extends our knowledge of semaglutide and shows benefits not just in those with diabetes, but even in those without diabetes that have overweight or obesity plus CVD. This is really important.
Beyond the reduction in the primary endpoint, which was significant, there was also a lower rate of all-cause mortality. This might be the source of some debate out there among academic circles, because strictly speaking, this endpoint was in a statistical hierarchy. There were things above it on the list that weren’t statistically significant, so you can’t really claim formal statistical significance. Having said that, I believe that mortality was reduced; the P value was less than .05. MI was significantly reduced. Heart failure was reduced. Nephropathy was reduced. So, it makes sense that mortality should be reduced. It’s really just a matter of enough events and long enough follow-up. There was a trend toward reduction in CV death. It all seems consistent: a real finding, and a critically important finding.
While this was a secondary prevention trial, it opens the door on weight loss as a primary prevention strategy aided by pharmacotherapy. We have had a problem in the past with drugs for obesity having all sorts of nasty side effects. While semaglutide can have side effects too, this is going to open up the door to a whole series of drugs that are useful not just for diabetes, but for weight loss, and additionally have CV benefit.
Bhatt is director of the Mount Sinai Fuster Heart Hospital, the Dr. Valentin Fuster Professor of Cardiovascular Medicine at Ic ah n School of Medicine at Mount Sinai and a member of the Healio | Cardiology Today Editorial Board.
Sean Heffron, MD
Source: NYU Langone Health
Certainly, the most important clinical indication is that semaglutide 2.4 mg reduced the overall major adverse CV events in people without diabetes. This is a huge swath of our CV and coronary artery disease population with overweight or obesity. Semaglutide is another tool in the toolbox for cardiologists.
Semaglutide 2.4 mg already has an indication for weight management in people with overweight or obesity. I don’t know that these results will expand the patient population eligible for this therapy, but it may give another indication, which may strengthen the likelihood of a clinician using it for a patient.
As a cardiologist, I don’t treat obesity or overweight if the patient doesn’t have diabetes, but I certainly treat CVD. I think a lot of people have already embraced this medication. This trial brings semaglutide more clearly into the CV space, and this will hopefully result in a greater number of patients receiving a drug that will improve CV outcomes.
Heffron is a c ardiologist in the Center for the Prevention of Cardiovascular Disease at NYU Langone Heart and as sistant p rofessor of m edicine , Leon H. Charney Division of Cardiology , NYU Grossman School of Medicine .
Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC
The SELECT trial is a game-changer for cardiology. Obesity is a serious, chronic life-threatening disease that substantially increases CV risk, but it previously has not gotten the same level of attention as other chronic diseases. Chronic weight management is not just “cosmetic”; it is life-saving. In the SELECT trial, among high-risk patients with established CVD with overweight and obesity, weekly subcutaneous semaglutide 2.4 mg significantly reduced major adverse CV events by 20% over 40 months. This is a significant reduction — as great, if not greater, a magnitude of reduction that we see with other prevention therapies such as lipid-lowering therapy.
Although these were secondary endpoints, we also saw that semaglutide 2.4 mg reduced the HF composite outcome by 18% and all-cause mortality by 19%; a mortality benefit, the hardest of endpoints to meet. This was not a dedicated weight-loss study, and the weight reduction of 9% with semaglutide 2.4 mg in SELECT was significant but lower than what was seen in the prior STEP trials. Nevertheless, semaglutide 2.4 mg conferred significant improvement in cardiometabolic measures such as BP, C-reactive protein and lipids, and as might be expected, there was a significant reduction in the progression to incident diabetes or prediabetes. The therapy was safe without significant increase in serious adverse events, although GI symptoms were more common with semaglutide, as seen in prior trials. This is something that often can be mitigated with slow titration of these therapies and making adjustments in diet.
Despite the established benefits of statin therapy, CVD events still occur in statin-treated patients; we call this “residual risk.” It is time for cardiologists and other health care professionals to start implementing chronic weight management strategies to address residual cardiometabolic risk in patients with overweight/obesity. GLP-1 receptor agonists are now firmly established as CV prevention medications, not only for persons with type 2 diabetes, but also for patients with CVD without diabetes with elevated weight. It is in the wheelhouse of cardiologists to implement therapies proven to be effective for CV prevention. Just like treatment of BP and lipids, treatment of obesity is firmly established as an important component for CV risk reduction in high-risk patients.
Michos is associate professor of medicine and director of Women’s Cardiovascular Health at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and a member of the Healio | Cardiology Today Editorial Board.
Eugene Yang, MD, FACC
The results are very positive and potentially a major game-changer. SELECT was a secondary prevention trial that included patients we commonly see in practice. When we look at the benefit — a 20% relative risk reduction in death from CV causes, nonfatal MI or nonfatal stroke with semaglutide 2.4 mg — compared with results of other secondary prevention trials with nonstatin therapies, the SELECT findings were more robust. The number needed to treat was in the 60s to prevent one major event.
What was not discussed, and hopefully will be unpacked later, is cost. These drugs are very expensive. How do we decide which treatment is best for which patient? It makes it difficult to understand exactly which patients we should put on these therapies in the context of health economics, as the pool of people eligible for these therapies is growing. The question remains: How are we going to equitably distribute the treatment and who are the people we should be targeting for therapy? That’s something we need to think about more carefully. Secondary and post hoc analyses to be conducted will help drive the conversation of who are the right people to target.
Yang is professor of medicine at the University of Washington School of Medicine and the chair of the American College of Cardiology Prevention Council.
Reference:
For more information:
Deepak L. Bhatt, MD, MPH, can be reached at deepak.bhatt@mountsinai.org; X (Twitter): @dlbhattmd.
Sean Heffron, MD, can be reached at sean.heffron@nyulangone.org; X (Twitter): @heffron_sean.
Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC, can be reached at edonnell@jhmi.edu; X (Twitter): @erinmichos.
Eugene Yang, MD, FACC, can be reached on X (Twitter) at @accmediacenter.
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