Comparative Effects of Antidiabetic Drugs on Body Composition: A Systematic Review and Network Meta-Analysis

This systematic review and network meta-analysis compared antidiabetic drugs for their effects on body composition. It found that GLP-1 and dual GIP/GLP-1 receptor agonists, especially tirzepatide, produced the largest reductions in fat mass but also decreased lean mass, while metformin, insulin, and DPP-4 inhibitors had minimal impact.

Systematic review — systematic review and network meta-analysis. Population: people with type 2 diabetes from randomized controlled trials. Sample size: 2906 participants across 41 trials. Interventions: tirzepatide; semaglutide; liraglutide; liraglutide plus exercise; metformin; insulin glargine; insulin regimens; alogliptin.

Across 41 trials with 2906 participants, tirzepatide reduced fat mass most versus placebo (MD -10.70 kg; 95% CI: -13.42 to -7.99), followed by liraglutide plus exercise. Semaglutide and liraglutide produced moderate reductions, while insulin glargine and alogliptin were associated with fat mass gain relative to metformin and exenatide. For lean body mass, tirzepatide (MD -4.40 kg; 95% CI: -7.58 to -1.22) and liraglutide (MD -1.54 kg; 95% CI: -2.55 to -0.52) showed significant losses. SGLT2 inhibitors caused minor lean mass losses; metformin, insulin regimens, and DPP4 inhibitors were neutral.

Researchers working on semaglutide, tirzepatide, or liraglutide need to know that these drugs reduce fat mass but also decrease lean mass in type 2 diabetes. This paper quantifies those effects head-to-head and shows exercise may mitigate liraglutide-related lean loss, but it does not establish dose-response relationships, optimal durations, or long-term functional implications.

Key findings

• Tirzepatide showed the greatest fat mass reduction versus placebo (MD -10.70 kg; 95% CI: -13.42 to -7.99).
• Liraglutide plus exercise reduced fat mass after tirzepatide, while semaglutide and liraglutide alone produced moderate reductions.
• Insulin glargine and alogliptin were associated with fat mass gain relative to metformin and exenatide.
• Tirzepatide reduced lean body mass (MD -4.40 kg; 95% CI: -7.58 to -1.22) and liraglutide reduced lean body mass (MD -1.54 kg; 95% CI: -2.55 to -0.52).
• SGLT2 inhibitors caused minor lean mass losses, whereas metformin, insulin regimens, and DPP4 inhibitors showed neutral effects.

Limitations

• Authors state further research on dose, duration and lifestyle influences is warranted.
• Network meta-analysis relies on indirect comparisons across different trials.
• Heterogeneity in trial designs, exercise co-interventions, and patient populations may affect comparability.
• No information on long-term outcomes or functional consequences of body composition changes.

The record

• Journal: Diabetes, obesity & metabolism 28(9): 7689-7704
• Published: 2026-06-16
• PMID: 42304171 — DOI: 10.1111/dom.70957
• MeSH terms: Humans, Diabetes Mellitus, Type 2, Metformin, Hypoglycemic Agents, Body Composition, Randomized Controlled Trials as Topic, Insulin Secretagogues, Tirzepatide, Semaglutide
• Funding: Chronic Diseases Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences
• Author countries: Iran

Peptide profiles: Semaglutide, Tirzepatide, Liraglutide.

All indexed evidence: Semaglutide trials & papers, Tirzepatide trials & papers, Liraglutide trials & papers.

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