Novo Nordisk's semaglutide 2.4 mg demonstrated significant cardiovascular risk reduction in patients with obesity or overweight and established cardiovascular disease, according to new real-world data presented at the American College of Cardiology Annual Scientific Session and Expo (ACC.25) on March 30, 2025.
The retrospective, observational SCORE study analyzed 27,963 patients and found that compared to non-users, semaglutide 2.4 mg users experienced a 57% lower risk of major adverse cardiovascular events (MACE), defined as heart attack, stroke, or all-cause death (HR: 0.43; 95% CI: 0.31-0.61; p < 0.001).
"Real-world analyses such as SCORE complement randomized controlled trials by offering healthcare professionals additional information about how therapies perform in routine clinical practice as they partner with patients on individualized treatment decisions," said Jason Brett, MD, Acting Principal Medical Head at Novo Nordisk Inc.
Study Design and Key Findings
The SCORE study analyzed patients aged 45 years or older with overweight or obesity (diagnosis or BMI ≥ 27 kg/m²) and established cardiovascular disease (prior heart attack, ischemic stroke, or peripheral arterial disease) but no diabetes. Researchers compared 9,321 patients who initiated semaglutide 2.4 mg with 18,642 matched non-users.
The primary endpoint of revised MACE-3 (heart attack, stroke, or all-cause death) occurred in only 42 patients (0.45%) in the semaglutide group compared to 175 patients (0.94%) in the non-user group during a mean follow-up of 7.1 months for semaglutide users and 6.4 months for non-users.
For the expanded MACE-5 composite endpoint (heart attack, stroke, hospitalization for heart failure, evidence of coronary revascularization procedure, or all-cause death), semaglutide 2.4 mg was associated with a 45% risk reduction (HR: 0.55; 95% CI: 0.43-0.70; p < 0.001). The MACE-5 endpoint occurred in 88 patients (0.94%) in the semaglutide group versus 288 patients (1.54%) in the non-user group.
Notably, semaglutide 2.4 mg use was also associated with significantly lower risks of hospitalization for heart failure, cardiovascular-related death, and all-cause death compared to non-users.
Context Within the Treatment Landscape
The SCORE findings build upon results from the landmark SELECT trial, which previously demonstrated that semaglutide 2.4 mg reduced the risk of serious cardiovascular events by 20% in people with overweight or obesity and established cardiovascular disease.
Semaglutide 2.4 mg is currently approved for adults and children aged 12 years and older with obesity, or some adults with overweight who also have weight-related medical problems, to help with weight management and to reduce the risk of major cardiovascular events in adults with known heart disease and either obesity or overweight.
Stephen Gough, senior vice president and head of the chief medical office at Novo Nordisk, emphasized that while the SCORE study builds on SELECT trial results, the two studies are not directly comparable. "SCORE is a retrospective, observational, real-world evidence study, and SELECT was a randomized phase 3 cardiovascular outcomes trial," he noted.
Limitations and Implications
While real-world studies provide valuable insights into treatment effects outside controlled clinical settings, they have inherent limitations. The SCORE analysis may reflect residual unmeasured confounding, and causal relationships cannot be definitively established. Additionally, the relatively recent approval of semaglutide 2.4 mg limited follow-up duration, restricting assessment of long-term benefits.
It's important to note that semaglutide 2.4 mg carries a Boxed Warning for possible thyroid tumors, including cancer, and should not be used in those with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2. Currently, semaglutide is not approved in the U.S. specifically to reduce heart failure outcomes, coronary revascularization, or all-cause death.
Clinical Significance
For healthcare providers treating patients with obesity and cardiovascular disease, the SCORE study offers compelling evidence that the cardiovascular benefits of semaglutide 2.4 mg observed in clinical trials may translate to real-world practice.
"Our mission is to drive change in how obesity is seen and treated, and the real-world evidence from SCORE provides actionable insights that can ultimately help improve patient care for people living with obesity at risk for CV events," said Dr. Brett.
The consistent cardiovascular risk reduction across multiple endpoints suggests that semaglutide 2.4 mg may offer comprehensive cardiovascular protection for this high-risk population, potentially changing the treatment paradigm for obesity management in patients with established cardiovascular disease.
