Retatrutide
GIP / GLP-1 / Glucagon triple receptor agonist
First-in-class triple agonist — the frontier of incretin therapy.
Half-life
~ several days (once-weekly dosing)
Mol. weight
~ 4.7 kDa (peptide + fatty diacid conjugate)
Sequence
GIP/GLP-1/glucagon-based triple agonist (modified peptide)
Discussions
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Overview
Retatrutide (LY3437943, Eli Lilly) is an investigational once-weekly triple hormone receptor agonist that activates GIP, GLP-1, and glucagon receptors simultaneously — adding glucagon agonism to the dual GIP/GLP-1 concept. In the phase 2 obesity trial, the 12 mg dose produced a mean weight reduction of 24.2% at 48 weeks, with participants still losing weight at trial's end. In the pivotal phase 3 TRIUMPH-1 trial, the 12 mg dose delivered an average 70.3 lb (28.3%) weight loss at 80 weeks, with 45.3% of participants losing ≥30% of body weight — a level long associated with bariatric surgery.
Mechanism of action
Retatrutide is a single peptide conjugated to a fatty diacid moiety with agonism at GIP, GLP-1, and glucagon (GCG) receptors. The rationale for adding glucagon: GCG receptor agonism may further reduce energy intake, increase energy expenditure, and improve substrate utilization beyond what GLP-1 or dual agonism alone can achieve. Relative to endogenous ligands it is less potent at GCG and GLP-1 but more potent at GIP. The triple action produces weight loss that, in phase 3, approached bariatric-surgery magnitude, alongside cardiometabolic improvements (waist circumference, non-HDL cholesterol, triglycerides, BP, hsCRP).
Researched benefits
- Phase 3: −28.3% body weight (−70.3 lb) at 12 mg / 80 weeks (TRIUMPH-1)
- 45.3% of 12 mg participants achieved ≥30% weight loss — bariatric-surgery territory
- Phase 2: −24.2% at 48 weeks (12 mg), with no plateau reached
- 100% of 8 mg+ participants lost ≥5% body weight (phase 2)
- Improvements in waist circumference, triglycerides, BP, hsCRP
Considerations
- Investigational — legally available only to clinical-trial participants
- Dose-dependent GI effects (nausea, diarrhea, constipation, vomiting)
- Dysesthesia and urinary tract infections reported at higher doses
- Adding glucagon agonism introduces a novel safety profile under study
- Requires medical supervision if/when approved
Key Academic Literature & Studies
Search more in PubMedPeer-reviewed citations and clinical trials evaluating Retatrutide in scientific literature.
Articles & logs
TRIUMPH-1: The Phase 3 Trial That Rivals Surgery
70 pounds lost on average, 45% of participants losing ≥30% of body weight — inside the phase 3 data.
By Dr. M. Reyes
Why Three Receptors? The Glucagon Rationale
Adding glucagon agonism to GIP+GLP-1 — what the extra receptor may do for energy expenditure.
By Editorial Team