Real-World Study of Cardiac Remodeling on Semaglutide and Tirzepatide Therapy Using Longitudinal Echocardiography

Background: Glucagon-like peptide-1 (GLP-1) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists reduce cardiovascular events, but the underlying cardiac structural remodeling remains unclear. Objectives: This study evaluated longitudinal cardiac remodeling associated with semaglutide and tirzepatide in a real-world cohort and determined its weight-loss dependency. Methods: Using electronic health records from a federated network, we analyzed longitudinal echocardiograms of patients prescribed semaglutide or tirzepatide, stratified by 12-month weight loss into super-responders (>15%), moderate-responders (5%-15%), and minimal-responders (<5%). Additionally, GLP-1/GIP patients with >5% weight loss were propensity-matched with non-GLP-1/GIP weight-loss medication control patients on demographics and baseline body mass index. Results: Among 3,500 GLP-1/GIP patients (422 weight-loss super-responders, 1,426 moderate-responder, 1,652 minimal-responders), left ventricular (LV) mass decreased across all groups proportional to weight loss (super-responders: 198.4 ± 69.6 to 176.6 ± 66.0 g; moderate-responders: 210.7 ± 74.0 to 195.8 ± 68.1 g; minimal-responders: 216.1 ± 68.4 to 204.8 ± 67.4 g; p < 0.001). Left atrial volume and LV systolic and diastolic function did not change. Among weight-loss super-responders, semaglutide (n = 159) showed greater LV mass reduction than tirzepatide (n = 89) (Cohen’s d = -0.389 vs. -0.263), while tirzepatide showed small improvements in right ventricular function. Compared to matched non-GLP-1/GIP controls (n = 118/group), GLP-1/GIP patients exhibited significant LV mass reduction not observed in controls despite similar weight loss. Conclusions: Real-world findings demonstrate that incretin-based therapies are associated with reverse cardiac remodeling characterized by weight-loss-dependent and incretin-specific mechanisms, with potentially distinct structural targets among agents.