Semaglutide Linked to Reduced Risk for MACE Months Before Weight Loss Begins: Post Hoc Analysis
Semaglutide was associated with a significant reduction in risk for major adverse cardiovascular events after just 3 months of treatment in a population with established CVD.
A new analysis from the landmark SELECT trial shows that treatment with semaglutide 2.4 mg (Wegovy; Novo Nordisk) is associated with a significant reduction in major adverse cardiovascular events (MACE) as early as 3 months after initiation—before patients experienced clinically meaningful weight loss.1
Presented at the European Congress on Obesity, the secondary, post hoc analysis reveals that adults with overweight or obesity and established cardiovascular disease (CVD) who received semaglutide 2.4 mg had a 37% reduced risk of MACE compared to placebo within the first 3 months of treatment (HR 0.63; 95% CI 0.41-0.95).1 Semaglutide was added to standard of care therapy.
By 6 months, additional benefits emerged. Participants taking semaglutide showed a 50% reduced risk of cardiovascular death (HR 0.50; 95% CI 0.26- 0.93), a 59% reduction in composite heart failure risk (HR 0.41; 95% CI 0.24-0.67), and a 40% lower risk of all-cause mortality (HR 0.60; 95% CI 0.36-1.01).1 (Note: Investigators cautioned that confidence intervals were not adjusted for multiplicity and should not be used to infer definitive treatment effects for this secondary analysis, Novo Nordisk noted in a company statement).2
“Cardiovascular disease is linked to two thirds of obesity-related deaths, and with obesity on the rise, there is an urgent need for effective treatments,” Jorge Plutzky, MD, lead study author and director of preventive cardiology at Brigham and Women's Hospital, in Boston said in the statement. “In this secondary analysis [of the SELECT trial], there was early reduction in heart disease events observed with semaglutide 2.4 mg prior to what is typically considered significant weight loss.”2
The SELECT trial, which began in 2018, enrolled 17,604 adults with overweight or obesity and pre-existing cardiovascular disease but no history of diabetes.¹ The multicenter, double-blind, placebo-controlled study assessed the impact of semaglutide 2.4 mg on top of standard cardiovascular care in preventing MACE—defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.3
The early cardiovascular benefits of semaglutide come at a time when obesity-related heart disease deaths are rising. In the US, cardiovascular disease accounts for 1 in every 3 deaths.4
“For people with obesity and existing cardiovascular disease, preventing another heart attack or stroke is vitally important,” Jason Brett, MD, principal medical head at Novo Nordisk Inc, said in the statement. “Seeing this SELECT secondary data demonstrate that patients experienced MACE risk reduction within 3 months is remarkable. These latest findings add to the growing evidence on the effect of [semaglutide] addressing cardiovascular disease.”2
Semaglutide 2.4 mg in June 2021 was the first GLP-1 receptor agonist approved in the US as as an adjunct to dietary change and increased exercise for chronic weight management in adults with obesity (BMI of 30 kg/m2 or greater) or with overweight (BMI of 27 kg/m2 or greater) and one weight-related comorbidity; it was later approved for children aged 12 years and older with an initial BMI at the 95th percentile or greater, standardized for age and sex.5 The first approval of the incretin mimetic was in 2017 at a dose of 0.5 mg to 1.0 mg as an adjunct to diet and exercise to lower hyperglycemia in persons with T2D. Novo Nordisk was granted a label expansion soon afterward for dose of 2.0 mg for persons with T2D whose hyperglycemia remained uncontrolled by other agents.5
Obesity remains a chronic, progressive disease associated with a range of complications, including type 2 diabetes, kidney disease, steatotic liver disease, cancer, hypertension, and heart disease.⁶ Despite this, effective treatment options for cardiovascular risk in this population have been limited.
References
1. Plutzky J, Ostrominski J, Aroda V, et al. Early clinical benefit of semaglutide in adults with overweight or obesity and cardiovascular disease: A secondary analysis of the SELECT trial. Oral presentation presented at the European Congress on Obesity; 11-14 May 2025; Palacio De Ferias Y Congresos De Málaga, Magala, Spain. Presentation AD15.04.
2. In new SELECT trial analysis, early reduction in cardiovascular events was observed with Wegovy®, before clinically meaningful changes in body weight. News release. Novo Nordisk. May 13, 2025. Accessed May 14, 2025. https://www.novonordisk-us.com/media/news-archive/news-details.html?id=916004
3. Halsey G. Antiobesity medication semaglutide 2.4 mg reduced risk of MACE by 20%: Topline results from landmark SELECT trial. Patient Care Online. August 8, 2023. Accessed April 1, 2025. https://www.patientcareonline.com/view/antiobesity-medication-semaglutide-2-4-mg-reduced-risk-of-mace-by-20-topline-results-from-landmark-select-trial
4. MillionHearts. Costs & Consequences. Last accessed: April 2025. Available at: https://millionhearts.hhs.gov/learn-prevent/cost-consequences.html.
5. Novo Nordisk A/S: Semaglutide 2.4 mg reduces the risk of major adverse cardiovascular events by 20% in adults with overweight or obesity in the SELECT trial. News release. Novo Nordisk. August 8, 2023. Accessed August 8, 2023. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html
How overweight and obesity impacts your health. Centers for Disease Control and Prevention. Last updated January 4, 2024. Accessed May 13, 2025. Available at: http://cdc.gov/healthy-weight-growth/food-activity/overweight-obesity-impacts-health.html
