Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial

Abstract

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 per cent 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 .

Fig. 1. Trial profile.

SURMOUNT-3 CONSORT flow diagram. MTD, maximum tolerated dose (10 or 15 mg). TZP, tirzepatide.

Fig. 2. Effect of once-weekly tirzepatide on body weight in comparison with placebo.

a, Least-square mean (LSM) (s.e.) per cent 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.) per cent 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) per cent 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.

Extended Data Fig. 1. Body weight in kg over time.

Mean (standard error) body weight (kg) over time from randomization to 72 weeks derived from a mixed-model for repeated measures (MMRM) analysis for the efficacy estimand. Only participants with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis. MTD, maximum tolerated dose (10 or 15 mg).

Extended Data Fig. 2. Blood pressure change from start of lead-in period over time.

Panel A, mean (95% confidence interval) change from baseline over time in systolic blood pressure from start of intensive-lifestyle intervention lead-in period (week -12) to 72 weeks using observed means. Week 72 estimates for the efficacy estimand (EFF) are also shown. Panel B, mean (95% confidence interval) change from baseline over time in diastolic blood pressure from start of intensive-lifestyle intervention lead-in period (week -12) to 72 weeks using observed means. Week 72 estimates for the efficacy estimand (EFF) are also shown.

Extended Data Fig. 3. Incidence of nausea, vomiting, and diarrhea over time.

The percentage of participants receiving tirzepatide or placebo who reported nausea, vomiting, or diarrhea are presented. Percentages are based on number of participants at risk at specific observation time. Events were classed as mild (shown in green), moderate (shown in orange), or severe (shown in red). MTD, maximum tolerated dose (10 or 15 mg); TZP, tirzepatide.

Extended Data Fig. 4. SURMOUNT-3 study design.

This is a phase 3, multicenter, randomized, placebo-controlled, double- blinded clinical trial investigating the efficacy and safety of maximum tolerated dose (MTD) of tirzepatide (10 mg or 15 mg) administered once weekly (QW) subcutaneously compared with placebo for body weight management, in participants who have obesity, or overweight with at least 1 obesity-related complication (excluding type 2 diabetes), and with at least 5% weight reduction following a 12-week intensive lifestyle intervention lead-in. All randomized participants were planned to undergo a 72-week treatment period.