Cardiovascular Protection Beyond Weight Loss: Insights from the SELECT Trial on Semaglutide

The SELECT trial found that semaglutide reduced major adverse cardiovascular events (MACE) independent of weight loss, suggesting a cardioprotective effect beyond weight reduction.

The randomized, event-driven SELECT study enrolled approximately 17,604 adults and used MACE as the primary endpoint. Prespecified adiposity and biomarker subanalyses, together with mechanistic data, point to improved endothelial function, reduced systemic inflammation, and favorable lipid modulation as plausible non–weight-mediated pathways—providing biologic plausibility for relatively rapid-onset cardiovascular effects.

These data support shifting prescribing considerations from BMI-based thresholds toward cardiovascular-risk–guided use, while still assessing comorbidities, drug interactions, and contraindications. It's important to integrate the SELECT findings with individual risk profiles, tolerability, shared decision-making, and monitoring plans when semaglutide is used principally for cardioprotection.

Clinically, patients with established atherosclerotic cardiovascular disease (ASCVD) or those with high predicted ASCVD risk—regardless of BMI—stand to benefit most. Evidence remains limited for people with severe renal impairment or very recent stroke, where caution is warranted; it's key to prioritize cardiovascular-risk stratification in these groups.