Rates of overweight and obesity have climbed steeply worldwide, and so has scientific interest in the peptide-based medicines researchers are studying to address them. Three compounds have attracted the most attention in large clinical programs: liraglutide, semaglutide, and tirzepatide. Each works on receptors that regulate blood sugar and appetite, but they do so in slightly different ways and at different doses.
A systematic review and network meta-analysis published in the Journal of Endocrinological Investigation pooled evidence from 24 phase-3 randomized controlled trials, all lasting at least 52 weeks, to compare these agents head-to-head in adults with a body-mass index of 25 or above. The analysis used frequentist random-effects models and a statistical tool called P-scores to rank treatments across multiple endpoints simultaneously. The result is one of the more thorough comparative pictures available in the published literature.
What the three compounds do
Liraglutide and semaglutide both act on the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 is a hormone released in the gut after eating. When its receptor is activated, it slows the emptying of the stomach, reduces appetite signals in the brain, and prompts the pancreas to release insulin in a blood-sugar-dependent way. Researchers studying these effects have measured meaningful reductions in food intake and body weight across a range of trial populations.
Tirzepatide adds a second target to that picture. It is a dual agonist, meaning it activates both the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor. GIP is another gut hormone with its own role in energy balance. Whether the combined action is simply additive or produces something qualitatively different is a question researchers are still working out, but the clinical trial data included in this meta-analysis gave the authors a way to compare outcomes directly.
Overall findings on weight reduction
Across all 23 trials eligible for the network meta-analysis, every active treatment reduced body weight, waist circumference, and body-mass index compared with placebo. That finding held consistently regardless of which specific compound was being studied. The differences between placebo and active treatment were described in the abstract as clinically meaningful over the minimum one-year follow-up period.
When the three compounds were ranked against each other, tirzepatide at its highest studied dose came out on top by P-score for both overall weight reduction and waist circumference reduction. Semaglutide at the higher of the two doses examined ranked second across efficacy endpoints. Liraglutide produced the smallest weight loss of the three agents, ranking last for the weight-related outcomes.
The semaglutide dose comparison
One reason the authors conducted this particular analysis was the recent availability of a 7.2 mg maintenance dose of semaglutide, a step up from the 2.4 mg dose that had been studied more extensively in earlier trials. The network meta-analysis found that the 7.2 mg dose consistently ranked above 2.4 mg across all efficacy endpoints based on P-scores.
However, the authors were careful about how they framed that ranking. When they looked at statistically significant differences in percentage body weight change between the two doses, meaningful separation appeared only in the subgroup of participants who had type 2 diabetes. In the broader, non-diabetes population, the average incremental benefit of the higher dose was estimated at roughly two to three percentage points, but that gap did not consistently reach statistical significance. The authors concluded that the incremental benefit of the higher dose should be weighed against tolerability and individual patient preferences, and they called for more direct head-to-head trials.
Safety and tolerability patterns
None of the three compounds showed a statistically significant difference from the others in serious adverse events, which is a meaningful finding given that serious adverse events are the highest-stakes safety metric in clinical trials. That said, the three agents did differ in other safety signals.
Tirzepatide was associated with a higher risk of injection-site reactions compared with the other treatments. Liraglutide, on the other hand, was linked to a higher risk of any adverse events overall and to a higher rate of treatment discontinuation because of those adverse events. Researchers observing these patterns note that the tolerability profile of each compound is as relevant to long-term use as its efficacy ranking, because a treatment a participant stops taking early cannot demonstrate its full potential effect.
The safety networks in the meta-analysis showed low to moderate heterogeneity, meaning the results across individual trials were reasonably consistent for safety outcomes. Efficacy outcomes showed considerably more heterogeneity, which the authors flagged as a reason for caution when interpreting the rankings.
Study design and limitations
The meta-analysis drew on 24 phase-3 randomized controlled trials covering approved weight-management doses. The authors registered their protocol in advance through PROSPERO, a standard practice that helps prevent selective reporting of results. They used random-effects models, which account for the natural variation between trials rather than assuming all studies are measuring an identical effect.
Despite those methodological strengths, the authors noted several limitations. Considerable heterogeneity was present for the efficacy outcomes, which complicates direct comparisons. Most of the evidence comparing active treatments to each other came through the network structure rather than from direct head-to-head trials. The authors called for additional real-world studies and direct comparative trials, particularly to resolve questions about long-term safety and optimal dose selection in different patient populations.
What this means for research context
For researchers and science-curious readers, this network meta-analysis provides a useful framework for understanding where the three compounds sit relative to each other in the published trial evidence. Tirzepatide's dual receptor mechanism appears to translate into a quantifiable efficacy advantage at the doses studied. Semaglutide's higher dose shows a trend toward greater effect, but the magnitude of that trend is modest and the statistical picture is mixed outside the diabetes subgroup. Liraglutide, despite being the earliest of the three to reach large clinical trials, produces smaller average weight reductions than either of the other two.
The literature as a whole continues to evolve rapidly. The authors of this review are explicit that their findings should not be the final word on dose selection or compound choice. Head-to-head trial data, longer follow-up periods, and real-world registry studies will all contribute to a more complete picture. For now, this systematic review offers a well-structured synthesis of the strongest available evidence on how these three GLP-1 and GLP-1/GIP receptor agonists compare on the outcomes researchers care most about.
