Scientific Reference

Retatrutide (LY3437943)

Evidence profile: Human Phase 3 evidence

Retatrutide (LY3437943) is a novel triple hormone receptor agonist targeting GLP-1, GIP, and glucagon receptors simultaneously. The Phase III TRIUMPH-4 trial (December 2025) achieved 28.7% weight loss (71.2 lbs) at 68 weeks with the 12 mg dose — the highest weight reduction recorded for any obesity medication. Currently in late-stage Phase III development by Eli Lilly, with FDA approval anticipated in 2026–2027. By combining GLP-1-mediated appetite suppression, GIP-mediated insulin sensitivity, and glucagon-mediated energy expenditure, retatrutide addresses obesity through three complementary pathways simultaneously. Phase II results showed 17.5% weight loss at 24 weeks and 24.2% at 48 weeks — with no plateau reached — suggesting greater long-term potential than current single- or dual-agonist therapies.

Mechanism of Action

Retatrutide activates three hormone receptors in parallel: GLP-1 receptors suppress appetite and slow gastric emptying; GIP receptors enhance insulin sensitivity and glucose-dependent insulin secretion; glucagon receptors increase energy expenditure and hepatic fat oxidation. A C20 fatty acid conjugation with alpha-aminoisobutyric acid (Aib) residues provides DPP-4 resistance and extends the half-life to approximately 6 days, enabling once-weekly dosing. This multi-receptor synergy produces superior metabolic outcomes compared to mono- or dual-agonist approaches.

Molecular Information

Type: Triple GLP-1/GIP/glucagon receptor agonist
Length: 39 amino acids

Pharmacokinetics

The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. Across dose levels, the maximum observed drug concentration (Cmax) occurred between ~1 and 3 days postdose, while the mean terminal half-life was ~5 to 7 days, thus supporting a QW dosing regimen.

Published Research

Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial
Jastreboff AM et al. · The New England journal of medicine · 2023 · Clinical
PMID 37366315 — View on PubMed
Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial
Bajaj HS et al. · Lancet (London, England) · 2026 · Clinical
PMID 42250575 — View on PubMed
Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA
Rosenstock J et al. · Lancet (London, England) · 2023 · Clinical
PMID 37385280 — View on PubMed
LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial
Urva S et al. · Lancet (London, England) · 2022 · Clinical
PMID 36354040 — View on PubMed
Efficacy and safety of triple hormone receptor agonist retatrutide for the management of obesity: a systematic review and meta-analysis
Tewari J et al. · Expert review of clinical pharmacology · 2025 · Review
PMID 39817343 — View on PubMed
Efficacy and safety of retatrutide for the treatment of obesity: a systematic review of clinical trials
Misra S et al. · Journal of basic and clinical physiology and pharmacology · 2025 · Review
PMID 40728138 — View on PubMed