Retatrutide

Also known as: LY3437943

Retatrutide (LY3437943) is a synthetic peptide designed as a triple agonist at the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. Its mechanism of action integrates the complementary metabolic effects of each pathway: GLP-1 receptor activation enhances insulin secretion and delays gastric emptying; GIP receptor agonism potentiates insulinotropic effects and may improve adipose tissue metabolism; and glucagon receptor stimulation increases energy expenditure and hepatic lipid oxidation. This triple agonism is hypothesized to produce synergistic effects on weight loss and glycemic control beyond dual GLP-1/GIP or GLP-1/glucagon agonists. Phase 2 clinical trial data (e.g., Jastreboff et al., *The Lancet*, 2023) demonstrated that retatrutide at doses up to 12 mg weekly resulted in mean body weight reductions of up to 24.2% over 48 weeks, the largest weight loss reported for any incretin-based therapy to date. Significant improvements in HbA1c, fasting glucose, and lipid profiles were also observed in participants with type 2 diabetes. The safety profile was consistent with the incretin class, with gastrointestinal adverse events (nausea, vomiting, diarrhea) being most common, though generally manageable with dose titration. Retatrutide is currently in phase 3 clinical trials for obesity and type 2 diabetes, with potential to become a leading pharmacotherapy for these conditions. Its pronounced weight reduction efficacy may offer a non-surgical alternative for patients with severe obesity or metabolic syndrome. However, long-term cardiovascular outcome data and safety in diverse populations remain pending. For research purposes only — not medical advice.

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