Retatrutide (RETA, LY-3437943) is an acylated peptide, the first triple agonist of GLP-1, GIP, and glucagon (GCGR) receptors. Its structure incorporates a fatty diacid moiety, enabling albumin binding, conferring a half-life of approximately 6 days and supporting once-weekly dosing.
OVERVIEW
Retatrutide simultaneously activates three complementary metabolic receptors: GLP-1R suppresses appetite and slows gastric emptying, GIPR enhances insulin secretion and insulin sensitivity, and GCGR increases energy expenditure, promotes fat oxidation, and reduces liver fat.
This coordinated activation of three complementary hormonal pathways produces synergistic effects on glycemia, weight loss, and overall metabolism—results that exceed those of single (semaglutide) and dual (tirzepatide) agonists in head-to-head comparisons.
MECHANISM OF ACTION
GLP-1R — appetite suppression, delayed gastric emptying, glucose-dependent insulin secretion stimulation, glucagon inhibition.
GIPR — amplification of insulin response, improved insulin sensitivity, potential lipid metabolism support, potential reduction of GLP-1-induced nausea.
GCGR — increased basal energy expenditure, promotion of fatty acid oxidation, reduction of liver fat (hepatic gluconeogenesis and glycogenolysis).
CLINICAL DATA
Weight loss (Phase 2 obesity) — average 24.2% body weight reduction at 48 weeks (12 mg dose, NEJM 2023); highest results ever recorded for an anti-obesity drug.
Glycemic control (T2D) — HbA1c reduction of 2.0–2.5% in T2D patients; up to 16.94% weight loss in the diabetes trial (The Lancet 2023).
Liver fat (MASLD) — 81–82% reduction in liver fat at 8 mg and 12 mg doses over 24 weeks (Nature Medicine 2024, Phase 2a substudy).
Lipid profile — significant reductions in triglycerides, LDL-C, and liver fat content; improvement of HOMA-IR and fasting insulin levels.
Energy expenditure — increased basal metabolic rate and fat oxidation via glucagon receptor activation.
CHEMICAL DATA
| Other names |
Retatrutide, LY-3437943 |
| Structure |
Acylated peptide + C20 fatty diacid moiety |
| Half-life |
~6 days · once-weekly dosing |
| Form |
Lyophilized powder |
| Purity |
>99% HPLC |
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