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.
Yan. Kangling K; Yu. Haichuan H; Blaise. Benoît B
Key Findings
- Retatrutide produced the largest average weight loss (MD ≈ -8.6%) among all incretin-based agents studied.
- Tirzepatide showed the strongest reductions in fasting glucose (≈ -57 mg/dL) and HbA1c (≈ -1.9%).
- Both tirzepatide and cotadutide were linked to higher rates of adverse events, whereas semaglutide reduced serious adverse events.
Practical Outcomes
- For biohackers interested in weight‑loss or metabolic optimization, retatrutide looks promising but is still experimental and not widely available. Tirzepatide may be a more accessible option with solid glucose‑lowering and weight‑loss data, though users should watch for side‑effects. Until larger, longer trials confirm safety and efficacy, these peptides should be approached cautiously and preferably under medical supervision.
Summary
A recent analysis of many diabetes drug trials found that the experimental peptide retatrutide caused the biggest drop in body weight (about 8.6% on average) compared to other drugs, while tirzepatide was best at lowering blood sugar. However, the studies were small and short, so we still need more proof before recommending these drugs for everyday use.
Abstract
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. 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. Systematic searches in PubMed, Web of Science, Cochrane Library, and Embase (up to July 2024) identified RCTs. Trials assessing dual or triple incretin therapies in T2DM with outcomes on weight, HbA1c, FBG, AEs, and SAEs were included. Data on efficacy and safety were extracted by independent reviewers and assessed for quality using the NIH Quality Assessment Tool. 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. 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. 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. CRD42024532368.
Study Information
pubmed
2025
2025-06-05T00:00:00.000Z
10.1007/s00592-025-02534-y
3
37