Retatrutide

Administered as a once-weekly subcutaneous injection. Phase 2 trial protocol: start at 1 mg weekly for 2-4 weeks, escalate through 2, 4, 6, 8 mg every 4 weeks, up to a maximum of 12 mg weekly. Half-life is approximately 6 days. Gradual dose escalation is critical to minimize GI side effects (nausea, diarrhea, vomiting). Still investigational as of early 2026; not yet FDA-approved.

Activates glucagon-like peptide-1 receptors (EC50: 0.775 nM), enhancing glucose-stimulated insulin secretion, slowing gastric emptying, and promoting satiety through central appetite suppression.

Potently activates glucose-dependent insulinotropic polypeptide receptors (EC50: 0.0643 nM), the most potent of the three receptor activities. Contributes to insulin secretion and may enhance fat metabolism.

Activates glucagon receptors (EC50: 5.79 nM), reducing GI motility and acting on adipose tissue to decrease lipogenesis and induce lipolysis, contributing to enhanced energy expenditure.

Phase 2 trials demonstrated mean weight reduction of up to 24.2% (26.2 kg) at 48 weeks with 12 mg weekly dosing. 100% of participants on the highest dose achieved at least 5% weight loss, and 83% achieved at least 15%.

Phase 2 trials in type 2 diabetes showed significant HbA1c reductions through combined GLP-1 and GIP receptor activation enhancing insulin secretion.

Phase 2a trial showed substantial reduction in liver fat content in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Triple receptor activation produces robust appetite suppression through complementary central and peripheral mechanisms including delayed gastric emptying and hypothalamic satiety signaling.

Phase 3 trial (TRIUMPH-3) showed substantial relief from osteoarthritis pain alongside weight loss, with average weight loss of 71.2 lbs in that trial.

Retatrutide Shows Multiple Metabolic Benefits in Diet-Induced Obese MASH Mouse and Hamster Models.

Obesity (Silver Spring, Md.) · Briand F, Le Cudennec C, Grasset E

Efficacy of GLP-1 analog peptides, semaglutide, tirzepatide, and retatrutide on MC4R deficient obesity and their comparison.

International journal of obesity (2005) · Hitaka K, Sugawara T, Matsumoto M

Incretin-Based Dual and Triple Agonists in Overweight or Obese Individuals: A Systematic Review and Meta-Analysis.

Cardiology in review · Chan ZH, Omar AS, Gill K

Development of the Weight and Emotions Scale (WES).

Obesity science & practice · Kanu C, Kimel M, Goetz I

Effect of glucagon-like peptide-1 receptor agonists on heart rate in non-diabetic individuals with overweight or obesity: a systematic review and pair...

European journal of medical research · Zhang Y, Zhang C, Gong X