Weight loss and cardiovascular outcomes with incretin-based therapies after metabolic and bariatric surgery: a nationwide US cohort study.

BACKGROUND: Long-term weight management after metabolic and bariatric surgery (MBS) remains a prevalent clinical challenge. Given the efficacy of glucagon-like peptide-1 receptor (GLP-1RA) and dual GIP/GLP-1 receptor agonists (GIP/GLP-1RA), there is increasing interest in their role as adjunctive therapy after MBS. We examined weight loss and major adverse cardiovascular events (MACE) in people who underwent MBS and subsequently received incretin-based therapy. METHODS: In this retrospective cohort study, we compared long-term weight and cardiometabolic outcomes among people who underwent MBS and received postoperative semaglutide or tirzepatide for at least one year, comparing agents by dose, timing, and surgical anatomy using propensity score matching. Secondary analyses compared MACE between propensity score-matched cohorts of incretin-based therapy users vs. non-users using inverse probability of censoring-weighted Cox models. Study cohorts were derived using a de-identified electronic health record dataset from 43 104 academic and private medical centres across the USA between 2018 and 2025. FINDINGS: Analyses included 208 155 people who underwent MBS, of whom 39 750 received postoperative incretin-based therapy. Among those who remained on therapy for one year, tirzepatide was associated with greater percent total weight loss (%TWL) than semaglutide (17.2% vs. 12.0%, adjusted difference 5.16 percentage points, 95% CI 4.17-6.16, p < 0.001) in a dose-dependent manner. Incretin-based therapy-associated %TWL was greater when therapy was initiated later in the postoperative course (postoperative month 53-79; 15.4% TWL) compared with earlier initiation (quartile 1: postoperative month 12-24; 13.5% TWL; p < 0.001). In propensity score-matched landmark analyses with inverse probability of censoring weighting, pooled incretin-based therapy use was not associated with MACE risk (HR 0.91, 95% CI 0.80-1.05, p = 0.19). INTERPRETATION: In this large nationwide cohort, incretin-based therapy post-MBS was associated with clinically meaningful augmented weight loss in a dose- and timing-dependent manner. Future prospective studies are needed to establish causality, assess longer-term durability of weight loss benefit, and determine whether incretin-based therapy provides additive cardiovascular protection in the post-MBS population. FUNDING: None.