Retatrutide
Once-weekly triple agonist of GIP, GLP-1 and glucagon receptors delivering unprecedented weight loss and metabolic improvements in obesity trials.
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Next-gen triple agonist frame
Retatrutide (LY3437943) is a 39–amino acid, once-weekly peptide engineered to activate three key metabolic hormone receptors:
the glucose-dependent insulinotropic polypeptide receptor (GIPR), the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR).
By simultaneously suppressing appetite and increasing energy expenditure, retatrutide produces weight loss far beyond current GLP-1 or GIP/GLP-1 dual agonists in Phase 2 trials,
with up to roughly 24% mean loss at 48 weeks in people with obesity and about 17% in type 2 diabetes, along with robust improvements in glycemia and cardiometabolic markers.
Gastrointestinal side effects and heart-rate increases are common but resemble those seen with potent incretin-based therapies, making retatrutide a leading candidate in the “triple G” obesity drug class.
Mechanism stack
How triple receptor agonism amplifies weight loss beyond GLP-1 and dual agonists.
Receptor profile
GIPR-dominant with GLP-1R & GCGR support
Retatrutide agonizes GIP, GLP-1 and glucagon receptors, with relatively stronger potency at the human GIPR and somewhat attenuated but clinically relevant activity at GLP-1R and GCGR.
This balance is designed to maximize metabolic benefits while moderating glucagon-driven hyperglycemia risk.
Appetite & intake
GLP-1R & GIPR-mediated satiety
Through GLP-1R activation, retatrutide slows gastric emptying, enhances satiety and increases glucose-dependent insulin secretion, reducing caloric intake and improving postprandial glycemia.
Strong GIPR agonism further boosts insulinotropic effects and may aid lipid clearance and adipose tissue signalling.
Energy expenditure
Glucagon-driven fat oxidation
GCGR activation increases hepatic glucose output between meals, stimulates lipolysis and fatty-acid oxidation, and may increase overall energy expenditure.
In a triple-agonist context, this is harnessed alongside incretin-mediated appetite suppression to drive deeper weight loss than with GLP-1R agonism alone.
Pharmacology
Once-weekly fatty-acid–linked peptide
Retatrutide is a 39–amino acid peptide linked to a C20 fatty diacid, prolonging half-life for once-weekly subcutaneous dosing.
This supports steady triple receptor engagement with dose titration schemes to manage tolerability in early weeks.
Efficacy snapshot
Key numerical outcomes from obesity and type 2 diabetes trials.
| Population / dose | Weight loss outcomes | Metabolic effects |
|---|---|---|
|
Obesity without diabetes (Phase 2, 48 weeks)
BMI ≥30 or ≥27 + comorbidity
|
Least-squares mean percentage change in body weight at 48 weeks: −8.7% (1 mg), −17.1% (4 mg), −22.8% (8 mg), −24.2% (12 mg) vs −2.1% with placebo. At 48 weeks, ≥5%, ≥10% and ≥15% weight loss occurred in 92%, 75% and 60% (4 mg); 100%, 91% and 75% (8 mg); 100%, 93% and 83% (12 mg) vs 27%, 9% and 2% with placebo. | Broad improvements in cardiometabolic markers including blood pressure and lipids; higher doses showed no clear plateau in weight loss by week 48, suggesting ongoing downward trajectory. |
|
Type 2 diabetes (Phase 2, 36 weeks)
T2D with overweight/obesity
|
Roughly 17% body weight reduction at 36 weeks with 8–12 mg doses, without showing a plateau. Magnitude of weight loss exceeds that seen with prior T2D pharmacotherapies. | A1c <6.5% achieved in up to about 82% of participants and A1c <5.7% in up to about 31% vs placebo and dulaglutide 1.5 mg. Strong normalization of glycemic control plus large weight reduction not previously shown with other T2D medications. |
|
Phase 3 obesity program (interim/press)
Emerging data
|
Phase 3 TRIUMPH-4 results report mean weight loss approaching 28–29% at higher doses over roughly one year in some cohorts, building on Phase 2 efficacy. | Full peer-reviewed outcomes, including cardiovascular and long-term safety endpoints, are pending; early readouts are consistent with Phase 2 results. |
Safety & tolerability
Where retatrutide aligns with GLP-1/GIP class effects, and where triple agonism adds nuance.
Common adverse events
- Gastrointestinal events: nausea, vomiting, diarrhea, constipation and abdominal pain were the most frequent adverse events, dose-dependent, mostly mild to moderate, and occurred mainly during dose escalation.
- Heart rate: dose-dependent increases in resting heart rate peaked around week 24 and declined thereafter; the clinical significance is still under evaluation.
- Class-typical risks: rare pancreatitis, gallbladder events, possible thyroid C-cell concerns (as with GLP-1 receptor agonists) and hypersensitivity reactions remain areas of monitoring; so far, overall safety resembles potent GLP-1/GIP agents.
- Long-term unknowns: data beyond about 1–2 years, including cardiovascular outcome trials and post-discontinuation weight regain profiles, are not yet fully available.
This dossier summarizes mechanistic, preclinical and clinical findings on retatrutide for scientific and educational purposes only.
It does not provide medical advice, treatment guidance or dosing recommendations.