Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus: a network meta-analysis based on clinical trials.

OBJECTIVES

This study systematically assessed the efficacy and safety of 15 incretin-based therapies (IBTs) for type 2 diabetes mellitus (T2DM), including mono- (GLP-1RA), dual- (GIP/GLP-1RA or GLP-1/GCGR), and triple- (GIP/GLP-1/GCGR) receptor agonists, and explored how dosage and treatment duration affect clinical outcomes to support individualized treatment decisions.

METHODS

A systematic review and Bayesian network meta-analysis were performed following PRISMA 2020 and PRISMA-NMA guidelines (PROSPERO: CRD420251152746). We searched MEDLINE, Cochrane Library, and Embase up to 1 August 2025, for randomized controlled trials (RCTs). Study selection, data extraction, risk-of-bias assessment (Cochrane RoB 2.0) and CINeMA framework were conducted. Analyses included SUCRA ranking, sensitivity, subgroup, and meta-regression in R Studio 4.4.3.

RESULTS

102 RCTs (98,693 T2DM patients) with low overall bias were included. IBTs were superior to placebo in glycemic control (tirzepatide, orforglipron, semaglutide best), weight loss (retatrutide best), lipid, blood pressure, cardiorenal, and insulin function improvement. The most common adverse events were mild, transient gastrointestinal reactions, and the risk of hypoglycemia was low. Higher doses improved efficacy but increased adverse events; 45 mg orforglipron balanced benefits and tolerability. Optimal duration and combination efficacy varied by agent.

CONCLUSION

IBTs provide comprehensive benefits in T2DM. Efficacy and safety differ across agents, doses, durations, and combinations, supporting individualized therapy. Long-term high-quality RCTs are needed. Cardiovascular protection may stem from synergistic improvements in lipids, blood pressure, renal function, and insulin sensitivity.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD420251152746.