Indirect Comparative Efficacy and Safety of Tirzepatide Versus Oral Semaglutide for the Treatment of Overweight and Obesity.

AIMS: Tirzepatide, an injectable glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA), is approved for weight management in several regions. Oral GLP-1 RAs, such as semaglutide, are under investigation to improve convenience, acceptance and adherence versus injectable formulations. Currently, no studies have compared the efficacy and safety of tirzepatide with oral semaglutide for weight management. This study aimed to indirectly compare the efficacy and safety of weekly injectable tirzepatide 5, 10 and 15 mg for weight management in obesity and overweight versus daily oral semaglutide 50 mg. MATERIALS AND METHODS: Pivotal trials SURMOUNT-1 (tirzepatide, Week 72) and OASIS 1 (oral semaglutide, Week 68) were compared using multilevel network meta-regression (ML-NMR) to adjust for differences in sex, ethnicity and outcome baselines between trial populations. Participants were adults without type 2 diabetes and with obesity (BMI ≥ 30 kg/m), or overweight (BMI ≥ 27 kg/m) with ≥ 1 obesity-related complication. RESULTS: Tirzepatide 10 and 15 mg were associated with statistically significantly greater reductions in weight (mean difference: -4.48% [-6.35, -2.61] and -5.59% [-7.52, -3.77]) and waist circumference (-3.60 cm [-5.59, -1.72] and -4.32 cm [-6.30, -2.40]), and higher odds of achieving ≥ 5%/10%/15%/20% weight reduction compared with oral semaglutide. Cardiometabolic benefits and safety profiles were improved or generally comparable for tirzepatide versus oral semaglutide. CONCLUSIONS: This ML-NMR provides an indirect comparison of injectable tirzepatide with oral semaglutide for weight management. Tirzepatide was associated with statistically significantly greater weight and waist circumference reduction versus oral semaglutide and improved or similar cardiometabolic benefits and safety.