BackgroundDual and triple incretin-based agonists, targeting combinations of GLP-1, GIP, and glucagon receptors, represent an innovative approach in T2DM care. However, comparative efficacy and safety analyses tailored to receptor-specific strategies are limited.PurposeThis systematic review and network meta-analysis uniquely evaluates the efficacy and safety of dual and triple incretin agonists compared to standard therapies, offering insights into personalized, receptor-specific T2DM therapies.Data sourcesSystematic searches in PubMed, Web of Science, Cochrane Library, and Embase (up to July 2024) identified RCTs.Study selectionTrials assessing dual or triple incretin therapies in T2DM with outcomes on weight, HbA1c, FBG, AEs, and SAEs were included.Data extractionData on efficacy and safety were extracted by independent reviewers and assessed for quality using the NIH Quality Assessment Tool.Data synthesisRetatrutide achieved the greatest weight reduction (MD: - 8.601; 95% CrI: - 11.20 to - 5.95) while Tirzepatide was most effective in lowering FBG (MD: - 57.30) and HbA1c ( - 1.88), with 95% CrIs of - 65.41 to - 48.9 and - 2.15 to - 1.64 respectively. Tirzepatide (RR 1.15) and Cotadutide (1.38) increased AEs, while Semaglutide reduced SAEs (0.35); 95% Crls: 1.04-1.33, 1.16-1.68, and 0.13-0.78, respectively.LimitationsSmall sample sizes, short study durations, and reliance on indirect comparisons in some cases may limit the certainty of these findings. Direct head-to-head trials are needed to confirm these results.ConclusionReceptor-specific targeting optimizes T2DM treatment, with Semaglutide supporting glycemic control, Tirzepatide enhancing weight loss and glucose regulation, and Retatrutide potentially offering broader metabolic benefits, advancing receptor-targeted, personalized therapy.Prospero registration numberCRD42024532368.
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