Gastrointestinal tolerability and weight reduction associated with tirzepatide in adults with obesity or overweight with and without type 2 diabetes in the SURMOUNT‐1 to ‐4 trials

Abstract Aims This analysis evaluated whether gastrointestinal (GI) adverse events (AEs) including nausea, vomiting, diarrhoea (N/V/D) and dyspepsia were associated with weight reduction with tirzepatide across the SURMOUNT‐1 to ‐4 trials. Materials and Methods SURMOUNT‐1 to ‐4 were global Phase 3 clinical trials evaluating the safety and efficacy of tirzepatide among participants with obesity or overweight with or without type 2 diabetes (T2D). Participants were randomly assigned to receive once weekly subcutaneous tirzepatide or placebo. This post hoc analysis investigated weight change at the primary endpoint from baseline among participants who self‐reported no N/V/D, any N/V/D or nausea alone. Mediation analyses evaluated the contribution of N/V/D and dyspepsia on weight reduction. Time to first use of antidiarrheal and antiemetic usage was reported by time intervals. Results Baseline characteristics were similar between participants who reported N/V/D and those who did not. More participants reported GI AEs in the tirzepatide treatment arms (27.8%–72.8%) than with placebo (12.2%–32.5%). Most GI AEs were non‐serious and occurred during dose escalation. Between 1.0% and 10.5% of tirzepatide‐treated participants discontinued treatment due to GI AEs. Weight reduction with tirzepatide was similar among participants reporting no nausea, nausea alone, or any N/V/D. Mediation analyses suggested that N/V/D and dyspepsia were associated with up to 3.1% of total weight reduction. When required, first use of antidiarrheal and antiemetic medication was most commonly reported during dose escalation. Conclusions In this post hoc analysis, GI AEs appeared to contribute slightly to the weight reduction seen with tirzepatide in participants with obesity or overweight with or without T2D.