Semaglutide 2.4 mg significantly cuts MACE risk by 41% in overweight/obese adults without diabetes

While semaglutide 2.4 mg is approved for secondary prevention of major adverse cardiovascular events (MACE) in individuals with overweight/obesity, its role in primary prevention for those without established atherosclerotic cardiovascular disease (ASCVD) but with risk factors remained less clear. Current standards of care for ASCVD primary prevention often involve lifestyle modifications and lipid-lowering agents, but a significant unmet need exists for interventions that simultaneously address obesity and reduce cardiovascular risk before an event occurs. This study investigates whether semaglutide 2.4 mg offers a benefit in this crucial primary prevention setting.

Researchers conducted a real-world retrospective cohort study using a U.S. database (01/01/2016-12/31/2024). They identified adults (≥45 years) with overweight/obesity and ≥3 risk factors for ASCVD but without diabetes. Patients initiating semaglutide 2.4 mg were propensity-score matched 1:2 to those not on semaglutide 2.4 mg. Primary outcomes included revised 3-point MACE (rMACE-3: myocardial infarction, stroke, and all-cause mortality) and revised 5-point MACE (rMACE-5: rMACE-3 plus coronary revascularization and hospitalization for heart failure [HF]). Secondary outcomes included standard MACE-3 and MACE-5 (replacing all-cause mortality with cardiovascular-related mortality), and composite HF outcomes.

The study matched 48,184 individuals on semaglutide 2.4 mg to 96,368 individuals not on the drug, demonstrating well-balanced baseline characteristics. Over a mean follow-up of 9 months, semaglutide 2.4 mg was significantly associated with lower risks across all measured cardiovascular endpoints. The most impactful finding was:

Semaglutide 2.4 mg was associated with a 41% lower risk of rMACE-3 (HR: 0.59; p < 0.001), indicating substantial reductions in myocardial infarction, stroke, and all-cause mortality. Furthermore, the drug reduced rMACE-5 risk by 35% (HR: 0.65; p < 0.001), which includes coronary revascularization and HF hospitalization. Reductions were also observed for MACE-3 (HR: 0.73; p < 0.01) and MACE-5 (HR: 0.75; p < 0.01), with composite HF outcomes also significantly lowered. These results suggest a broad protective effect against various cardiovascular events in this high-risk population.