Network Meta-Analysis Finds Tirzepatide and Semaglutide Most Effective for Weight Loss in Adults

This systematic review and network meta-analysis evaluated the comparative efficacy and safety of obesity management medications (OMMs) in adults. The analysis included 63,909 patients (34,861 receiving active compound and 29,048 receiving placebo) from randomized controlled trials. The primary outcome was percentage total body weight loss (TBWL%) at the end of the study, with secondary outcomes assessed at 1, 2, and 3 years, including anthropometric, metabolic, mental health, and quality of life outcomes, as well as cardiovascular morbidity and mortality, remission of obesity-related complications, serious adverse events, and all-cause mortality.

All OMMs demonstrated significantly greater TBWL% compared with placebo. Notably, tirzepatide and semaglutide exceeded 10% TBWL, indicating substantial weight reduction. These two agents also showed the most favourable glycaemic effects. Semaglutide was associated with a reduction in major adverse cardiovascular events and all-cause mortality, and both semaglutide and tirzepatide showed benefit for heart failure-related outcomes. Tirzepatide was associated with improved outcomes in obstructive sleep apnoea syndrome, while semaglutide was associated with improvement in knee osteoarthritis pain remission. For metabolic dysfunction-associated steatohepatitis, both tirzepatide and semaglutide were associated with improvements, and semaglutide was also associated with improvement in liver fibrosis.

Regarding safety, no OMMs were associated with an increased risk of serious adverse events. However, specific adverse event rates, discontinuation rates, and tolerability data were not reported in the analysis. The network meta-analysis did not provide exact effect sizes, confidence intervals, or p-values for the outcomes, limiting the precision of the comparative estimates.

Compared with prior landmark studies, these findings align with individual trials showing the efficacy of GLP-1 receptor agonists and dual GIP/GLP-1 agonists for weight loss and cardiometabolic benefits. The network meta-analysis extends these observations by providing a comprehensive comparison across multiple OMMs, though the lack of quantitative effect sizes reduces the ability to rank treatments precisely.

Key methodological limitations include the absence of reported effect sizes, confidence intervals, and p-values, which prevents assessment of statistical uncertainty. The analysis also did not report on specific adverse events, discontinuations, or tolerability, which are critical for clinical decision-making. Additionally, the network meta-analysis may be subject to heterogeneity across trials in populations, follow-up durations, and outcome definitions.

Clinically, these results support the use of tirzepatide and semaglutide as highly effective options for weight loss and associated complications in adults with obesity. The choice of OMM should be individualized based on weight loss efficacy, complication profile, and safety. For patients with cardiovascular disease, semaglutide may offer additional benefits in reducing major adverse cardiovascular events and mortality. For those with heart failure, obstructive sleep apnoea, knee osteoarthritis, or metabolic dysfunction-associated steatohepatitis, tirzepatide or semaglutide may be preferred.

Remaining questions include the long-term durability of weight loss beyond 3 years, comparative effectiveness in specific subgroups (e.g., by age, sex, comorbidities), and the impact of these medications on hard outcomes such as cardiovascular events and mortality for agents other than semaglutide. Further research is needed to clarify the safety profile of these medications in real-world settings and to identify predictors of response.