Incretin-based therapies outperform placebo for glycemic control and weight loss in type 2 diabetesNewer diabetes drugs outperform for blood sugar and weight loss

ObjectivesThis 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.MethodsA 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.Results102 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.ConclusionIBTs 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 Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD420251152746.