Obesity in non-diabetic adults remains a significant clinical challenge, prompting the need for effective pharmacological therapies that achieve meaningful weight loss with acceptable tolerability. Semaglutide, a selective glucagon-like peptide-1 (GLP-1) receptor agonist, and tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, have shown promise in recent trials. However, direct comparisons across their dose ranges are lacking. This systematic network meta-analysis (NMA) compared multiple doses of tirzepatide (5 mg, 10 mg, 15 mg, and maximum tolerated dose (MTD)) and semaglutide (2.4 mg and MTD) versus placebo in non-diabetic adults with obesity. Eight randomized controlled trials comprising 7,179 participants were included. The primary outcome was the percentage change in body weight. Secondary outcomes included changes in waist circumference, the proportion achieving ≥15% weight loss, and safety outcomes such as discontinuation due to adverse events and gastrointestinal side effects. A random-effects model was used for all analyses, and small-study effects were assessed using comparison-adjusted funnel plots and Egger-type regression. All active interventions resulted in significantly greater weight loss compared to placebo. Tirzepatide MTD demonstrated the greatest effect (mean difference (MD): -20.90%; 95% confidence interval (CI): -24.93 to -16.87), followed by tirzepatide 15 mg (MD: -18.08%; 95% CI: -20.38 to -15.78), tirzepatide 10 mg (MD: -14.93%; 95% CI: -17.23 to -12.63), semaglutide MTD (MD: -14.40%; 95% CI: -19.82 to -8.98), semaglutide 2.4 mg (MD: -11.78%; 95% CI: -13.91 to -9.64), and tirzepatide 5 mg (MD: -11.49%; 95% CI: -14.65 to -8.34). Similar dose-dependent effects were observed for waist circumference and the likelihood of achieving ≥15% weight loss. The certainty of evidence for this ≥15% weight loss outcome, assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework applied to our NMA estimate threshold, was high for most interventions, except moderate for semaglutide MTD and tirzepatide 5 mg. The highest odds of treatment discontinuation due to adverse events were observed with semaglutide MTD (odds ratio (OR): 7.36; 95% CI: 2.56 to 21.15) and tirzepatide MTD (OR: 5.56; 95% CI: 2.28 to 13.58). Gastrointestinal side effects were more common with higher-dose regimens. No publication bias was detected. Tirzepatide at 15 mg and MTD offers the greatest efficacy for weight loss in non-diabetic adults with obesity, though at the cost of increased gastrointestinal side effects and higher discontinuation rates. These findings support a clear dose-response relationship and underscore the importance of tailoring treatment decisions to individual patient tolerability and goals.
