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Tirzepatide Ranks Highest for Weight Loss; Semaglutide 7.2 mg Shows Modest Incremental Benefit
In a network meta-analysis of 23 phase 3 randomised controlled trials, tirzepatide 15 mg ranked highest for body weight and waist circumference reduction, while semaglutide 7.2 mg outranked semaglutide 2.4 mg across all efficacy endpoints, though its incremental advantage of approximately 2–3 percentage points in body weight was statistically significant only in adults with diabetes. No significant between-treatment differences were observed for serious adverse events, though the tolerability profiles of individual agents differed meaningfully.
What Was Studied
The review compared the efficacy and safety of three approved GLP-1 and GLP-1/GIP receptor agonists—liraglutide 3.0 mg, semaglutide 2.4 mg, semaglutide 7.2 mg, and tirzepatide 15 mg—for weight management in adults with overweight or obesity, with specific attention to whether the recently introduced 7.2 mg maintenance dose of semaglutide offers a meaningful clinical advantage over the established 2.4 mg dose. The primary outcome was percentage change in body weight over at least 52 weeks.
How It Was Studied
This pre-registered frequentist network meta-analysis (PROSPERO: CRD420251014401) synthesised evidence from 24 phase 3 randomised controlled trials, of which 23 met eligibility criteria for inclusion in the network. Eligible participants were adults aged 18 years or older with a BMI of at least 25 kg/m², and all trials had a minimum duration of 52 weeks. Comparators included placebo and active head-to-head comparisons among the included agents. Random-effects models were applied using the netmeta package, with treatment ranking performed via P-scores to account for uncertainty in the ordering of interventions.
What Was Observed
- Tirzepatide 15 mg achieved the highest efficacy ranking for both body weight reduction and waist circumference across all analyses based on P-scores, placing it above all semaglutide and liraglutide doses in the network for these outcomes.
- Semaglutide 7.2 mg ranked above semaglutide 2.4 mg for all efficacy endpoints, but the incremental benefit in percentage body weight change—approximately 2–3 percentage points—reached statistical significance only within the diabetes subgroup, limiting conclusions about the added value of the higher dose in the broader overweight and obese population.
- Liraglutide 3.0 mg produced the smallest weight loss among the active treatments, ranking lowest for weight and waist circumference reduction; it was also associated with higher risks of any adverse events and of treatment discontinuation due to adverse events compared with other agents in the network.
- No significant between-treatment differences were identified for serious adverse events (SAEs); however, tirzepatide was associated with a higher risk of injection site reactions relative to comparators, and the safety networks demonstrated low to moderate heterogeneity, in contrast to the considerable heterogeneity observed across efficacy outcomes.
Why This Matters
This analysis is notable for being the first network meta-analysis to incorporate the 7.2 mg semaglutide maintenance dose alongside the other approved agents, providing a comparative framework that was previously unavailable to clinicians and researchers. The finding that semaglutide 7.2 mg’s advantage is modest and statistically significant only in a diabetes subgroup has direct implications for dose-selection decisions and the design of future head-to-head trials. The divergent tolerability profiles across agents—despite similar SAE rates—highlight that treatment choice involves considerations beyond weight loss magnitude alone.
How to Read This Result
Although the analysis draws on a relatively large set of phase 3 trials and uses pre-registered methods, the considerable heterogeneity across efficacy outcomes, the restriction of semaglutide 7.2 mg’s statistically significant advantage to the diabetes subgroup, and the absence of direct head-to-head data for several comparisons mean that the efficacy rankings should be interpreted as indicative rather than definitive.
Limitations
Considerable heterogeneity was present across efficacy outcomes, complicating interpretation of pooled estimates. The statistically significant benefit of semaglutide 7.2 mg over 2.4 mg was observed only in the diabetes subgroup, not in the overall population. Direct head-to-head trial data between several agents were limited, increasing reliance on indirect comparisons. Long-term safety evidence beyond the trial durations remains sparse, and the possibility of network inconsistency could not be fully excluded.