Semaglutide is often optimized to maximize weight loss, yet it remains unclear whether long-term cardiovascular benefit is more closely associated with achieved weight reduction or therapeutic exposure. We conducted a retrospective observational study using a federated, de-identified U.S. electronic health record network comprising 47,199 patients with pre-existing cardiovascular disease who initiated semaglutide. Among 12,519 patients with at least two years of follow-up after initiation, dose escalation and weight change during the first two years (pre-landmark period) were evaluated in relation to cardiovascular outcomes during the subsequent two years (post-landmark period). Higher maximum semaglutide dose was strongly associated with greater weight loss during the pre-landmark period (3.15% additional weight loss per 1 mg increase; r = -0.97, P < 0.001) and with lower post-landmark risks of all-cause mortality (RR 0.42, P < 0.001), composite cardiovascular events (death, myocardial infarction, or stroke; RR 0.51, P < 0.001), cerebrovascular disease (RR 0.50, P < 0.001), and heart failure (RR 0.55, P < 0.001). In contrast, achieved weight loss was not significantly associated with subsequent all-cause mortality (P = 0.14) or composite cardiovascular events (P = 0.55), despite being strongly associated with improvements in hemoglobin A1c and blood pressure (both P < 0.001). In propensity-matched analyses, semaglutide was associated with lower cardiovascular event rates than metformin, DPP-4 inhibitors, and SGLT2 inhibitors. Transcriptomic analyses further demonstrated high GLP1R expression in cardiac tissue, particularly within cardiomyocytes and cardiac endothelial cells. Together, these findings suggest that semaglutide-associated cardiovascular benefit may align more closely with dose exposure than with the magnitude of weight loss achieved.
