Tirzepatide, a once‑weekly injection, cuts weight dramatically – about 9 kg in people with diabetes and up to 18 kg in those without – while also improving body‑measurements, blood pressure, blood sugar and cholesterol, and it does so with mostly mild side effects.

To conduct a systematic review and meta-analysis comparing tirzepatide versus placebo for weight management, with analyses stratified by diabetes status to precisely assess its efficacy and safety in individuals with and without diabetes. We systematically searched MEDLINE, Embase, and Cochrane Library for randomized controlled trials comparing once-weekly tirzepatide (5-15 mg) versus placebo in adults with or without diabetes for at least 26 weeks. For each subpopulation analysis, the random-effects model was used to calculate pooled risk ratios (RRs) and mean differences (MDs), with their 95% confidence intervals, for dichotomous and continuous endpoints, respectively. Statistical significance was considered at p < 0.05. We included five trials (n = 2,174) in patients with diabetes (BMI ≥ 23 kg/m²) and five (n = 4,467) in patients without diabetes (BMI ≥ 27 [≥24 in Asia] kg/m²). Compared with placebo, tirzepatide led to significantly greater relative and absolute weight reductions in patients with (RR -9.54%, p < 0.01; MD -9.06 kg, p < 0.01) and without diabetes (RR -17.15%, p < 0.01; MD -18.11 kg, p < 0.01). In both subpopulations, tirzepatide also significantly increased the probability of achieving weight reductions of ≥5%, ≥10%, and ≥15%, as well as improved BMI, waist circumference, blood pressure, hemoglobin A1c, and lipid levels. Notably, weight-related benefits with tirzepatide were significantly greater in patients without diabetes, whereas its safety was similar across subpopulations and predominantly consisted of mild to moderate, well-tolerated adverse events. Compared with placebo, tirzepatide resulted in statistically significant and clinically meaningful weight reduction, especially in patients without diabetes (with overweight/obesity), with an acceptable safety profile.