Network meta-analysis ranks liraglutide last of the three obesity GLP-1 drugs

A systematic review and network meta-analysis published in the Journal of Endocrinological Investigation compared liraglutide, semaglutide, and tirzepatide head-to-head using data pooled across 24 randomized controlled trials, and it found liraglutide 3.0 mg came in last for weight loss while also carrying higher risks of side effects and treatment dropout ^[1].

The researchers combined phase 3 trial data from adults age 18 and older with a body mass index of 25 or higher, using trials that lasted at least 52 weeks ^[1]. Of the 24 studies identified, 23 were included in the network meta-analysis itself, which let the team rank drugs against each other even when they hadn't been tested directly head-to-head in the same trial ^[1]. The analysis was pre-registered with PROSPERO, a public registry for systematic reviews ^[1].

Tirzepatide 15 mg, the highest approved dose of the drug sold as Mounjaro for diabetes and Zepbound for weight management, ranked highest for both weight loss and waist circumference reduction across the analyses ^[1]. Semaglutide, sold as Ozempic, Wegovy, and Rybelsus depending on dose and use, showed a notable internal finding: the newer 7.2 mg dose ranked above the long-used 2.4 mg dose on every efficacy measure studied ^[1]. But the researchers cautioned that a statistically significant edge in percentage body weight change for the 7.2 mg dose only showed up in the subgroup of patients who had diabetes, and they estimated the average extra benefit of the higher dose at roughly 2 to 3 percentage points of body weight, calling it a "modest" difference given the limited number of statistically significant comparisons ^[1].

Liraglutide 3.0 mg, by contrast, produced the smallest weight loss of the three drug classes examined ^[1]. It also stood out on the safety side: the analysis found liraglutide carried a higher risk of any adverse event and a higher risk of patients stopping treatment because of side effects, compared with the other drugs ^[1]. Tirzepatide, meanwhile, was linked to a higher risk of injection site reactions specifically, though the study found no significant differences between the drugs in serious adverse events overall ^[1].

The study authors noted considerable variation, or heterogeneity, in how trials measured efficacy outcomes, though they found limited evidence that the overall network of comparisons was internally inconsistent; safety-related comparisons showed low to moderate heterogeneity ^[1].

Why it matters for patients

For people choosing among GLP-1 and GLP-1/GIP obesity drugs, this analysis adds comparative evidence beyond what any single trial can show, since it statistically links results across dozens of studies that didn't always test the drugs against one another directly ^[1]. The finding that liraglutide produced less weight loss and more side-effect-driven discontinuation than semaglutide or tirzepatide may be relevant to people currently using it, though the study did not evaluate cost, insurance coverage, or individual medical history — factors that also shape real-world drug choices. The modest edge of semaglutide's higher 7.2 mg dose over the standard 2.4 mg dose, mostly detectable in patients with diabetes, suggests that dose escalation alone may not deliver dramatically more weight loss for everyone, and the authors say tolerability and personal preference should factor into that decision ^[1]. The higher rate of injection site reactions with tirzepatide is a tolerability detail that some patients may weigh against its stronger weight-loss ranking ^[1].

What happens next

The study's authors say more head-to-head trials and real-world studies are needed to refine dose selection and confirm long-term safety patterns, since much of this analysis relies on indirect statistical comparisons across separate trials rather than drugs tested directly against each other in the same study population ^[1]. No specific timeline for such trials was given in the study ^[1].