Comparative Efficacy of Dual and Triple GLP-1, GIP, and Glucagon Receptor Agonists: A Systematic Review and Network Meta-analysis

Qiannan Jia; Yuqing Wang; Jinhong Li; Zhe Gao

doi:10.54097/9576k069

Authors

Qiannan Jia
Yuqing Wang
Jinhong Li
Zhe Gao

DOI:

https://doi.org/10.54097/9576k069

Keywords:

Type 2 Diabetes Mellitus, GLP-1 Receptor Agonists, Glucose-dependent Insulinotropic Polypeptide, Glucagon Receptors

Abstract

Dual and triple agonists targeting GLP-1, GIP, and glucagon receptors have emerged as promising therapies for obesity and type 2 diabetes mellitus (T2DM). Although individual trials have demonstrated substantial metabolic benefits, the comparative efficacy across available multi-receptor agonists remains uncertain. A systematic search of PubMed, Embase, and Scopus was conducted through January 27, 2024, to identify randomized controlled trials evaluating dual or triple incretin- and glucagon-pathway receptor agonists versus placebo in adults with overweight, obesity, or T2DM. Primary outcomes were changes in body weight and HbA1c. Secondary outcomes included fasting plasma glucose, fasting insulin, waist circumference, blood pressure, and lipid parameters. A frequentist random-effects network meta-analysis was performed, and treatment rankings were estimated using surface under the cumulative ranking curve (SUCRA). Heterogeneity was explored with subgroup and meta-regression analyses. Twenty-one trials involving 5568 participants were included. All seven agonists significantly improved weight and glycemic outcomes compared with placebo. Tirzepatide, particularly at 10–15 mg, achieved the greatest reductions in HbA1c, fasting glucose, and waist circumference. Retatrutide 12 mg produced the strongest lipid improvements, including total cholesterol, triglycerides, LDL-C, and VLDL-C. Mazdutide 6 mg achieved the largest decreases in systolic and diastolic blood pressure. Dual and triple receptor agonists confer broad metabolic benefits but differ in their efficacy profiles. Tirzepatide exhibits superior glycemic and weight-lowering effects, Retatrutide offers greater lipid improvements, and Mazdutide provides enhanced blood pressure reduction. These distinctions support individualized therapeutic selection in obesity and T2DM management.

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