Cardiovascular
Semaglutide cuts cardiovascular risk by 20% in people with heart disease, obesity: SELECT
Nov
November 11, 2023
4 min read
Key takeaways:
- This is the first trial to show a reduction in hard cardiovascular outcomes for an obesity treatment.
- Serious adverse events were less common with semaglutide 2.4 mg vs. placebo.
PHILADELPHIA — In the SELECT trial, treatment with weekly injectable semaglutide 2.4 mg was superior to placebo for reducing cardiovascular risk in adults with preexisting heart disease and overweight or obesity but without diabetes.
“Semaglutide 2.4 mg is the first weight-management therapy … proven in a rigorous randomized controlled trial to reduce the risk of cardiovascular events, which establishes overweight and obesity as a modifiable risk factor for CVD and, as a treatment, will be applied much more broadly to the expanding population of patients with overweight or obesity and CVD,” A. Michael Lincoff, MD, vice chairman for research at the Robert and Suzanne Tomsich Department of Cardiovascular Medicine and an interventional cardiologist in the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at the Cleveland Clinic, said during a press conference at the American Heart Association Scientific Sessions.
Source: Shutterstock
Semaglutide 1 mg injection was the first GLP-1 receptor agonist approved by the FDA for treatment of type 2 diabetes (Ozempic, Novo Nordisk). In 2021, semaglutide 2.4 mg (Wegovy, Novo Nordisk) received approval for chronic weight management in adults with obesity and at least one weight-related comorbidity.
Ania M. Jastreboff
“The SELECT trial is a turning point: Treatment with semaglutide 2.4 mg demonstrates clear secondary cardiovascular benefit in people with obesity without diabetes. … The trial builds on existing literature demonstrating safety and cardiovascular benefit in people with diabetes and now expands it to people with obesity,” Ania M. Jastreboff, MD, PhD, associate professor of medicine and pediatrics (endocrinology) at Yale University School of Medicine, director of the Yale Obesity Research Center and co-director of the Yale Center for Weight Management, said during a discussion of the results, which were simultaneously published in The New England Journal of Medicine.
Reduction in hard cardiovascular outcomes
No lifestyle or pharmacologic intervention for overweight or obesity has been shown to reduce CV complications, Lincoff said at the press conference. Thus, the SELECT trial was designed to evaluate whether once-weekly semaglutide 2.4 mg would reduce the incidence of major adverse CV events specifically in a population of 17,604 adults with preexisting heart disease, which included prior heart attack, stroke or symptomatic peripheral arterial disease, and overweight or obesity but no diabetes.
Over nearly 40 months of follow-up, a primary CV endpoint event — which included death from CV causes, nonfatal heart attack or nonfatal stroke — occurred in 6.5% of patients assigned semaglutide 2.4 mg compared with 8% assigned placebo (HR = 0.8; 95% CI, 0.72-0.9; P < .001 for superiority).
A. Michael Lincoff
“Notably, the difference in rates between the two treatment groups began to emerge very early … within the first months,” Lincoff said.
Consistent trends were observed for each component of the composite primary outcome in addition to death from any cause, according to the results. The researchers also reported reductions in coronary revascularization and kidney function deterioration among those assigned semaglutide 2.4 mg.
Mean change in body weight after 104 weeks was –9.4% in the semaglutide 2.4 mg group and –0.9% in the placebo group. Waist circumference also decreased, by 7.6 cm and 1 cm, respectively.
While no patient had diabetes at baseline, the researchers observed a reduction in progression to diabetes and prediabetes with semaglutide 2.4 mg. The percentage of patients who progressed to diabetes during follow-up was 3.5% in the semaglutide 2.4 mg group and 12% in the placebo group (HR = 0.27; 95% CI, 0.24-0.31). Similarly, progression to prediabetes was 21.3% and 50.4%, respectively (HR = 0.33; 95% CI, 0.3-0.36).
Serious adverse events were less frequent with semaglutide 2.4 mg (33.4% vs. 36.4%; P < .001), including reduced rates of cardiac disorders and infectious events, Lincoff said. Adverse events leading to discontinuation of the study drug occurred in 16.6% of the semaglutide 2.4 mg group and 8.2% of the placebo group (P < .001), driven almost entirely by differences in gastrointestinal side effects, he said. There was no increase in adverse events of special interest, including acute pancreatitis and gallbladder-related events, cancers or psychiatric disorders.
‘The most data, for now’
SELECT is “the largest and longest trial with the most data, for now, for this group of patients,” Lincoff said.
The trial was conducted at 804 sites in 41 countries. The mean age of participants was 61 years. Mean BMI was 33.3 kg/m2; 71.5% of patients met the BMI criterion for obesity. Most patients were well-treated with evidence-based therapies at baseline, including high use of lipid-lowering medications (90.1%), platelet aggregation inhibitors (86.2%) and beta-blockers (70.2%).
The researchers noted that the generalizability of the findings may be limited due to the lack of a globally representative patient population. Only 27% were women and 3.8% were Black. In addition, the results cannot be extrapolated to people with obesity who do not have a history of heart disease.
Additional analyses of the findings are planned, according to the researchers.
“Mechanisms of CV risk reduction with semaglutide remain speculative but may include those related to physiologic benefits from reduction of metabolically unhealthy body fat and/or actions of semaglutide other than weight loss,” Lincoff said during the presentation.
‘In the midst of a rapid transformation’
The global prevalence of obesity is expected to reach 1 billion by 2030.
“The lifetime risk of cardiovascular disease in people with obesity without diabetes is about 1 in 2 in women and 2 in 3 in men. Most people with cardiovascular disease do not have diabetes, yet that is where most of our evidence lies,” Jastreboff said at AHA 2023.
The landscape of obesity treatment has rapidly changed — and it continues to change at a rapid pace, Jastreboff said.
On Nov. 8, 2023, the FDA announced approval of the injectable GIP/GLP-1 dual incretin-based agonist tirzepatide (Zepbound, Eli Lilly) for chronic weight management among adults with obesity. Tirzepatide was previously approved for type 2 diabetes (Mounjaro, Eli Lilly) in 2022.
A number of anti-obesity medications are in phase 2 and phase 3 of development and many more in phase 1, according to Jastreboff.
Treatment of obesity is “in the midst of a rapid transformation,” Jastreboff said. “We are literally leaping forward from the past to the future at a watershed brought on by the recent introduction of highly effective anti-obesity medications.”
It is now time to think “beyond weight reduction, “ Jastreboff said. “This is really a call to action: Now is the time to treat obesity, improving health outcomes in people with cardiovascular disease.”
References:
Sources/Disclosures
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Lincoff AM, et al. LBS.01. Obesity – Novel therapeutics and implications for population health. Presented at: American Heart Association Scientific Sessions; Nov. 11-13, 2023; Philadelphia.
The SELECT trial was sponsored and funded by Novo Nordisk. Lincoff reports receiving research funding to Cleveland Clinic from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion and Novartis and consulting for Akebia, Alnylam, Ardelyx, BD, Brainstorm Cell, Cadrenal, Eli Lilly, Endologix, Fibrogen, GlaxoSmithKline, Intarcia, Medtronic, Neovasc, Novo Nordisk, Prevention Bio and ReCor. Jastreboff reports serving as a site principal investigator for the SELECT trial but was not involved in the manuscript or steering committee; Jastreboff also reports serving on scientific advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, Structure Therapeutics, Terms Pharmaceutical, WW and Zealand Pharmaceuticals and receiving research support from Eli Lilly, NIH/NIDDK, Novo Nordisk and Rhythm Pharmaceuticals.
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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.
Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC
Associate Professor of Medicine
Director of Women’s Cardiovascular Health
Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease
Disclosures: Michos reports serving on advisory boards for AstraZeneca, Bayer, Boehringer Ingelheim, Esperion, Novartis, Novo Nordisk and Pfizer.
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Eugene Yang, MD, FACC
I think 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.
Eugene Yang, MD, FACC
American College of Cardiology Prevention Council Chair
Professor of Medicine, University of Washington School of Medicine
Disclosures: Yang reports no relevant financial disclosures.
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Sean Heffron, MD
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 cardiovascular 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. I think 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.
Sean Heffron, MD
Cardiologist
Center for the Prevention of Cardiovascular Disease
NYU Langone Heart
Assistant Professor of Medicine
Leon H. Charney Division of Cardiology
NYU Grossman School of Medicine
Disclosures: Heffron reports no relevant financial disclosures.
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