(CSEMP016) TOLERABILITY AND WEIGHT REDUCTION OF TIRZEPATIDE IN ADULTS WITH OBESITY OR OVERWEIGHT

Background: Guidelines recommend anti-obesity medications as an adjunct to lifestyle in patients with BMI ≥30 kg/m2, or ≥27 kg/m2 with weight-related comorbidities. Incretin-based pharmacotherapies, including tirzepatide (TZP), which has been approved for type 2 diabetes and is currently in development for chronic weight management, have been associated with mild to moderate gastrointestinal (GI) adverse events (AEs). This post hoc analysis explored whether GI AEs contributed to the weight reduction (WR) effects of TZP in adults with obesity or overweight in the SURMOUNT-1 trial.

METHODS AND RESULTS: The 72-week, phase 3, double-blind, SURMOUNT-1 trial included adults with obesity, or overweight with weight-related comorbidities (excluding diabetes). Participants were randomized (1:1:1:1) to once-weekly TZP 5, 10, or 15mg, or placebo (PBO). WR was analyzed by presence/absence of GI AEs (nausea, vomiting, or diarrhea). Mediation analysis estimated the contribution of GI AEs to the overall effect of TZP on WR. Data for participants on treatment prior to discontinuation of study drug were used for analysis.

Results:
A total of 37%-45% of participants reported GI AEs across the TZP groups compared with 15% in the PBO group. WR was consistent in all treatment groups regardless of the presence/absence of GI AEs. The percent weight change from baseline (least squares mean [SE]) at week 72 for TZP 5, 10, and 15mg, and PBO, respectively, was: -17.2% (0.7), -22.2% (0.6), -22.8% (0.6), and -2.9% (1.1) in participants reporting GI AEs; -15.3% (0.5), -20.6% (0.5), -22.2% (0.5), and -2.4% (0.4) in participants not reporting GI AEs. WR was significantly greater with TZP than with PBO in the presence/absence of GI AEs (p < 0.001). The contribution of GI AEs (indirect effects) to WR with TZP versus PBO was minimal (≤1% of the total effect).

Conclusion: In a post hoc analysis of SURMOUNT-1 in adults with obesity or overweight, TZP-induced WR was independent of reported GI AEs.