Tirzepatide Efficacy and Tolerability According to Early Weight Response: A Post Hoc Analysis of the <scp>SURMOUNT</scp> ‐1 and <scp>SURMOUNT</scp> ‐2 Trials

AIMS: Obesity affects over 800 million people globally and is associated with complications including cardiovascular disease and type 2 diabetes (T2D). Early response to weight loss interventions may help optimize achievement of individual treatment goals. Tirzepatide has demonstrated significant weight reduction and improvement in cardiometabolic risk parameters (CRPs) in the SURMOUNT (SM)-1 (NCT04184622) and SM-2 (NCT04657003) trials. We aimed to assess weight reduction, CRPs, tolerability and hypoglycaemia according to early body weight response to tirzepatide in these studies. MATERIALS AND METHODS: SM-1 and SM-2 were phase 3, multicentre, randomized, placebo-controlled, double-blind trials evaluating the safety and efficacy of tirzepatide in individuals with obesity or overweight, without (SM-1) or with T2D (SM-2). Post hoc exploratory analyses included tirzepatide-treated participants from SM-1 (n = 1775) and SM-2 (n = 609), categorized as early responders (ERs; ≥ 5% weight reduction) or nonearly responders (non-ERs; < 5% weight reduction) at Week 8. Outcomes were assessed using the efficacy estimand with logistic regression and mixed models for repeated measures. RESULTS: Across both studies (N = 2384), ERs were more likely to be female, White and to have lower baseline HbA1c levels. Clinically meaningful weight reduction and improvements in CRPs, including HbA1c, were observed from baseline to Week 72, with significantly greater improvements in ERs compared with non-ERs. The pattern, severity and time course of gastrointestinal events were similar between groups. CONCLUSIONS: In this post hoc analysis of the SURMOUNT-1 and SURMOUNT-2 trials, tirzepatide-treated participants with obesity or overweight in both ER and non-ER groups achieved clinically meaningful weight reduction and improvements in CRPs at Week 72. However, ERs experienced greater weight reduction and improvements in CRP than non-ERs, with a comparable gastrointestinal tolerability profile. TRIAL REGISTRATION: SURMOUNT-1: ClinicalTrials.gov: NCT04184622 (https://clinicaltrials.gov/study/NCT04184622). SURMOUNT-2: ClinicalTrials.gov: NCT04657003 (https://clinicaltrials.gov/study/NCT04657003).