Retatrutide
Retatrutide (triple GLP-1/GIP/glucagon agonist)
An investigational once-weekly triple receptor agonist producing the largest pharmacological weight loss reported to date in trials.
Overview
Retatrutide is an investigational triple agonist targeting the GLP-1, GIP, and glucagon receptors. Phase 2 trials reported up to ~24% body weight reduction at the highest dose. The glucagon receptor component is thought to add thermogenic and fat-oxidation effects beyond dual agonism. It is currently in Phase 3 development and is not yet approved. Update, September 2026: TRIUMPH-1 (NCT05929066; 2,339 participants randomized) reported up to 28.3% mean weight loss at 80 weeks on 12 mg versus 2.2% on placebo, with about 12.5% of top-dose participants reporting sensory disturbance (dysesthesia). TRIUMPH-4 in knee osteoarthritis showed 28.7% at 68 weeks. TRIUMPH-2 and 3 read out later in 2026.
Mechanism of action
Agonizes GLP-1, GIP, and glucagon receptors. The added glucagon activity increases energy expenditure and hepatic fat oxidation, complementing the appetite and insulin effects of the incretin receptors.
Key studies & citations
- Human2023
Triple-Hormone-Receptor Agonist Retatrutide for Obesity: A Phase 2 Trial
338 adults over 48 weeks: least-squares mean body weight change of -24.2% at 12 mg, -22.8% at 8 mg and -17.1% at 4 mg versus -2.1% with placebo.
New England Journal of Medicine - Human2024
Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial
Phase 2a substudy (NCT04881760): at 24 weeks, normal liver fat (below 5%) was reached by 86% of participants on 12 mg, 79% on 8 mg and 52% on 4 mg versus 0% on placebo.
Nature Medicine - Review2026
Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: rationale and design of the TRIUMPH registrational clinical trials
Describes the four Phase 3 TRIUMPH trials (over 5,800 participants) with weight-management, sleep apnea and knee osteoarthritis baskets; TRIUMPH-4 is the stand-alone osteoarthritis trial.
Diabetes, Obesity & Metabolism - Human2026
A Master Protocol to Investigate the Efficacy and Safety of LY3437943 Once Weekly in Participants Without Type 2 Diabetes Who Have Obesity or Overweight (TRIUMPH-1)
Registry record for the completed Phase 3 TRIUMPH-1 trial (2,335 enrolled per the registry). Lilly's May 21, 2026 topline release reported -28.3% at 80 weeks on 12 mg versus -2.2% on placebo; the peer-reviewed paper was not yet indexed at review time.
ClinicalTrials.gov NCT05929066
Frequently asked questions
Is retatrutide available by prescription?
No. It is investigational and still in clinical trials. It has not been approved by the FDA or other major regulators.