Tirzepatide Once Weekly for the Treatment of Obesity

This is the SURMOUNT-1 trial, the pivotal Phase III randomized controlled trial behind tirzepatide's FDA approval as Zepbound for chronic weight management. Investigators randomized 2,539 adults with overweight or obesity (BMI ≥30, or ≥27 with at least one weight-related comorbidity) without diabetes to once-weekly subcutaneous tirzepatide (5, 10, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation phase. The trial used a 1:1:1:1 randomization across the four arms. Mean percent change in body weight at 72 weeks was -16.0% on 5 mg, -21.4% on 10 mg, and -22.5% on 15 mg versus -3.1% on placebo. More than half of participants in the 10-mg and 15-mg groups lost more than 20% of body weight — magnitudes that had previously been confined to bariatric surgery in non-trial populations. Cardiometabolic risk factors improved across all tirzepatide doses. Gastrointestinal adverse events (nausea, vomiting, diarrhea, constipation) were most common, concentrated during dose escalation, and typically mild-to-moderate. Treatment discontinuation due to adverse events ranged from 2.6% on placebo to 7.1% on 10-mg tirzepatide. The trial was conducted at 119 sites across nine countries.

The trial population skews younger and healthier than the broader population that will use tirzepatide off-label — exclusions included diabetes, severe psychiatric disease, and a range of cardiovascular conditions, all of which are present at higher rates in real-world prescribing. The 72-week duration is long for an obesity trial but short relative to the chronic-therapy framing the drug now carries; longer-term efficacy and safety are addressed in extension cohorts and the SURMOUNT-4 maintenance design rather than in this paper. Body-composition substudies are reported in companion analyses; this primary paper focuses on body weight rather than fat-versus-lean-mass partitioning. Industry sponsorship by Eli Lilly is disclosed; the primary endpoint is regulatory-grade and the manuscript is consistent with the EMA and FDA reviews. Generalizability to non-White populations is a known concern across the SURMOUNT program — recruitment skewed predominantly White (~71%) consistent with U.S. obesity-trial baselines, and the broader generalizability literature is still being built.