“Tirzepatide After Intensive Lifestyle Intervention in Adults With Overweight or Obesity: the SURMOUNT-3 Phase 3 Trial”, Thomas A. Wadden, Ariana M. Chao, Sriram Machineni, Robert Kushner, Jamy Ard, Gitanjali Srivastava, Bruno Halpern, Shuyu Zhang, Jiaxun Chen, Mathijs C. Bunck, Nadia N. Ahmad, Tammy Forrester2023-10-15 ()⁠:

The effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on weight reduction after successful intensive lifestyle intervention are unknown. This double-blind, placebo-controlled trial randomized (1:1) adults with body mass index ≥30 or ≥27 kg⁄m2 and at least one obesity-related complication (excluding diabetes), who achieved ≥5.0% weight reduction after a 12-week intensive lifestyle intervention, to tirzepatide maximum tolerated dose (10 or 15 mg) or placebo once weekly for 72 weeks (n = 579).

The treatment regimen estimand assessed effects regardless of treatment adherence in the intention-to-treat population. The coprimary endpoint of additional mean % weight change from randomization to week 72 was met with changes of −18.4% (standard error (s.e.) 0.7) with tirzepatide and 2.5% (s.e. 1.0) with placebo: estimated treatment difference −20.8 percentage points (95% confidence interval (CI) −23.2%, −18.5%; p < 0.001).

The coprimary endpoint of the percentage of participants achieving additional weight reduction ≥5% was met with 87.5% (s.e. 2.2) with tirzepatide and 16.5% (s.e. 3.0) with placebo achieving this threshold (odds ratio 34.6%; 95% CI 19.2%, 62.6%; p < 0.001). The most common adverse events with tirzepatide were gastrointestinal, with most being mild to moderate in severity.

Tirzepatide provided substantial additional reduction in body weight in participants who had achieved ≥5.0% weight reduction with intensive lifestyle intervention. ClinicalTrials.gov registration: NCT04657016.

Figure 2: Effect of once-weekly tirzepatide on body weight in comparison with placebo[+diet+exercise]. (a) Least-square mean (LSM) (s.e.)% change in body weight from randomization to week 72 derived from an analysis of covariance model for the TRE (tirzepatide MTD, n = 287 participants; placebo, n = 292 participants), and from MMRM analysis for the efficacy estimand (tirzepatide MTD, n = 284 participants; placebo, n = 291 participants). (b) LSM (s.e.)% change in body weight over time from randomization to 72 weeks, derived from MMRM analysis for the efficacy estimand; week 72 estimates for the TRE are also shown. (c,d) LSM (s.e.) percentages of participants who had body weight reduction of at least 5, 10, 15, 20 or 25% from randomization to week 72. (c) Percentage of participants reaching weight reduction thresholds (TRE) was calculated using logistic regression with missing values imputed by hybrid imputation (tirzepatide MTD, n = 287 participants; placebo; n = 292 participants). (d) Percentage of participants reaching weight reduction thresholds (efficacy estimand) was obtained by logistic regression with missing values at week 72 imputed from MMRM analysis (tirzepatide MTD, n = 284 participants; placebo, n = 291 participants). (e) LSM proportion of participants that maintained ≥80% of body weight reductions achieved at the end of the lead-in period. Both TRE and efficacy estimand shown. (f) Mean (95% CI)% change in body weight over time from the start of the intensive lifestyle intervention lead-in period (–12 weeks) to 72 weeks, derived from observed values, irrespective of treatment adherence; week 72 estimates for TRE and efficacy estimand (EFF), are also shown.