RETATRUTIDE (GLP/GIP/GLUCAGON)

Mechanism of Action
Retatrutide is a triple agonist that activates the GLP-1, GIP, and glucagon receptors, designed to mimic three key metabolic hormones. GLP-1 + GIP signaling increases glucose-dependent insulin secretion, reduces appetite, and delays gastric emptying (including central nervous system effects mediated by GLP-1). Activation of the glucagon receptor may promote increased energy expenditure and fat oxidation, helping counteract the metabolic slowdown typically seen with weight loss. Structurally, retatrutide is a synthetic peptide derived from GIP sequences with an acylated side chain that allows for prolonged half-life and once-weekly subcutaneous administration. It should be noted that some mechanisms (e.g., increased energy expenditure via glucagon signaling) are derived mainly from animal studies, and their magnitude in humans is still under investigation.
 
Clinical Uses
As of 2025, retatrutide is not approved for general clinical use and remains under investigation. Its primary potential indications are obesity and possibly type 2 diabetes. It has completed phase II trials in obesity and is currently in phase III for obesity/overweight (the TRIUMPH program). In type 2 diabetes, although published studies have focused mainly on weight loss, Eli Lilly is evaluating its glycemic effects; in early phase II studies involving patients with diabetes and obesity, significant reductions in HbA1c were observed alongside weight loss. Early improvements in hepatic steatosis and some renal biomarkers have also been reported, suggesting possible utility in metabolic syndrome, but definitive phase III evidence and regulatory approval are still pending.
 
Side Effects and Safety
Adverse events resemble those of other incretin-based agonists, with gastrointestinal symptoms predominating: nausea, diarrhea, vomiting, constipation, decreased appetite, and abdominal discomfort, in a dose-dependent manner. These effects are generally mild to moderate and transient, and gradual dose escalation improves tolerability. Approximately 5–7% of participants discontinued treatment due to adverse events at medium/high doses versus ~2% with placebo. A modest, dose-dependent increase in heart rate has also been reported (peaking around 24 weeks, with a tendency to decline by 48 weeks). No major cardiovascular events attributable to the drug were observed during the available short-term follow-up.
 
Main Clinical Evidence
Human evidence comes primarily from a phase II trial published in 2023 in The New England Journal of Medicine, involving 338 adults with obesity (BMI ≥30, or ≥27 with comorbidities) treated for 48 weeks. Weight loss was substantial: up to −22.8% (8 mg) and −24.2% (12 mg) compared with ~−2.1% with placebo; the 4 mg dose achieved −17.1%. In terms of clinical response, ≥91% of participants in the 8 mg and 12 mg groups achieved ≥10% weight loss; with 12 mg, approximately 83% exceeded ≥15%, and more than half exceeded 20%. In the placebo group, only 2% achieved ≥15%. Improvements were also reported in glycemic measures (in participants with prediabetes/diabetes), waist circumference, blood pressure, and lipid profile. Many participants were still losing weight at week 48 (without a clear plateau), supporting longer-term studies (72 weeks or more), and a phase III trial evaluating up to 88 weeks is already underway. Preliminary favorable signals were also observed for fatty liver disease (liver enzymes and imaging-based hepatic fat), insulin resistance, and some renal parameters, although these findings require confirmation.
 
References – Retatrutide (GLP-1/GIP/Glucagon)
Badman, M.K. et al. (2023). Retatrutide—A Novel Triple-Receptor Agonist in Obesity Treatment. Biomolecules, 15(6), 796.
Jastreboff, A.M. et al. (2023). Triple–Hormone-Receptor Agonist Retatrutide for Obesity – Phase 2 Trial. N Engl J Med, 389(6), 514–526.
MedlinePlus. General information on experimental treatments for obesity (updated September 2025).