Tirzepatide drives 5.16 percentage points greater weight loss than semaglutide post-MBS; incretins show no MACE impact.

Long-term weight management after metabolic and bariatric surgery (MBS) remains a significant challenge, with many patients experiencing weight regain. Current standard-of-care often falls short in sustaining optimal weight loss. Given the proven efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RA) and dual GIP/GLP-1 receptor agonists (GIP/GLP-1RA) in primary obesity and type 2 diabetes, there is growing interest in their role as adjunctive therapy to improve and maintain weight loss and potentially reduce cardiovascular events post-MBS.

This retrospective cohort study analyzed a de-identified US electronic health record dataset from 2018 to 2025, including 208,155 people who underwent MBS. Of these, 39,750 received postoperative incretin-based therapy. Researchers compared long-term weight and cardiometabolic outcomes among those who received semaglutide or tirzepatide for at least one year, using propensity score matching to adjust for variables like dose, timing, and surgical anatomy. Secondary analyses used inverse probability of censoring-weighted Cox models to compare major adverse cardiovascular events (MACE) between matched cohorts of incretin users vs. non-users.

Among patients who remained on therapy for at least one year, tirzepatide was associated with significantly greater percent total weight loss (%TWL) compared to semaglutide. Specifically, tirzepatide users achieved 17.2% TWL versus 12.0% TWL for semaglutide users, an adjusted difference of 5.16 percentage points (95% CI 4.17-6.16, p < 0.001), in a dose-dependent manner. Incretin-based therapy-associated %TWL was also greater when therapy was initiated later in the postoperative course. > Patients initiating therapy between postoperative months 53-79 achieved 15.4% TWL, compared to 13.5% TWL for those initiating earlier (postoperative months 12-24; p < 0.001). Pooled incretin-based therapy use was not significantly associated with MACE risk (HR 0.91, 95% CI 0.80-1.05, p = 0.19) in propensity score-matched landmark analyses.