Beyond GLP-1: efficacy and safety of dual and triple incretin agonists in personalized type 2 diabetes care-a systematic review and network meta-analysis.
This systematic review and network meta-analysis evaluated the comparative efficacy and safety of dual and triple incretin-based agonists — compounds targeting combinations of GLP-1, GIP, and glucagon receptors — versus standard therapies for type 2 diabetes mellitus (T2DM). Researchers searched PubMed, Web of Science, Cochrane Library, and Embase through July 2024, identifying randomized controlled trials assessing outcomes including body weight, HbA1c, fasting blood glucose (FBG), adverse events (AEs), and serious adverse events (SAEs). The analysis found that Retatrutide (a triple agonist) was associated with the greatest weight reduction, while Tirzepatide (a dual GLP-1/GIP agonist) showed the largest reductions in both FBG and HbA1c. Regarding safety, Tirzepatide and Cotadutide were associated with increased AEs, whereas Semaglutide was associated with reduced SAEs. The authors suggest that receptor-specific targeting may help personalize T2DM treatment. Key limitations include small sample sizes in some included trials, short study durations, and reliance on indirect comparisons in the network meta-analysis. The authors acknowledge that direct head-to-head trials are needed to confirm these findings. The study was prospectively registered (PROSPERO: CRD42024532368).
Why this grade: Although this meta-analysis synthesizes human RCT data, confidence is moderated by acknowledged small sample sizes, short durations, and reliance on indirect network comparisons rather than direct head-to-head trials for several key findings.
Background Dual 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. Purpose This 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 sources Systematic searches in PubMed, Web of Science, Cochrane Library, and Embase (up to July 2024) identified RCTs. Study selection Trials assessing dual or triple incretin therapies in T2DM with outcomes on weight, HbA1c, FBG, AEs, and SAEs were included. Data extraction Data on efficacy and safety were extracted by independent reviewers and assessed for quality using the NIH Quality Assessment Tool. Data synthesis Retatrutide 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. Limitations Small 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. Conclusion Receptor-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 number CRD42024532368.
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