Tirzepatide for maintenance of bodyweight reduction in people with obesity in the USA (SURMOUNT-MAINTAIN): a multicentre, double-blind, randomised, placebo-controlled trial

Background: Obesity treatment improves long-term health and quality of life outcomes. Weight reduction and its maintenance play an important role in achieving these goals. We evaluated the efficacy and safety of continuing tirzepatide at the maximum tolerated dose (MTD) or lowering the dose to 5 mg compared with switching to placebo on the maintenance of bodyweight reduction obtained with tirzepatide MTD in adults with obesity. Methods: This phase 3b, placebo-controlled, 112-week trial, including a 60-week open-label weight-loss period and a 52-week, double-blind weight maintenance period, was conducted across 20 sites in the USA. After completing the initial weight-loss period with once weekly subcutaneous tirzepatide at the MTD (10 mg or 15 mg), adults (aged ≥18 years) with a BMI of 30 kg/m2 and above or 27 kg/m2 and above with one or more weight-related comorbidity, and a history of at least one self-reported unsuccessful dietary effort to lose bodyweight were randomly assigned in a 3:3:2 ratio to continue tirzepatide MTD, reduce to tirzepatide 5 mg, or switch to placebo for an additional 52 weeks. Starting at week 84 (24 weeks after random allocation), participants could receive rescue tirzepatide if their weight regain exceeded 50%. The primary endpoint was the percentage change in bodyweight from baseline to week 112. The primary estimand was the modified treatment-regimen estimand, which assumed that participants who initiated rescue tirzepatide would not have gained further benefit from their assigned study treatment and included all randomly allocated participants, regardless of treatment discontinuation or initiation of prohibited medications. The efficacy estimand was supportive. Safety was assessed in all participants who received at least one dose of study drug. This completed trial was registered at ClinicalTrials.gov (NCT06047548). Findings: From Sept 20, 2023, to Jan 20, 2026, 441 patients were enrolled in and took at least one dose of study treatment during the weight-loss period, with 378 participants randomly allocated at week 60 (140 to tirzepatide MTD; 144 to dose-reduction to 5 mg tirzepatide; and 94 to placebo). 372 received at least one dose of study drug during the weight maintenance period (139 for tirzepatide MTD; 142 for 5 mg tirzepatide; and 91 for placebo). 345 (91%) of 378 participants completed the study. The majority of participants were White (67%); 288 (65%) participants were female and 153 (35%) were male; and the mean age was 46·6 years (SD 13·0). At baseline, participants had a mean bodyweight of 113·8 kg (SD 27·0), a BMI of 40·1 kg/m2 (SD 8·1), and HbA1c 5·64% (SD 0·4; 38·2 mmol/mol [SD 4·0]). The model-based estimate percent change in bodyweight from baseline to week 112 was -21·9% (95% CI -23·5 to -20·3) with MTD (estimated treatment difference [ETD] -12·0% [95% CI -13s·8 to -10·1]), -16·6% (95% CI -18·0 to -15·1) with 5 mg tirzepatide (ETD -6·6 [95% CI -8·3 to -5·0]), versus -9·9% (95% CI -11·1 to -8·8) with placebo (p