Retatrutide
Retatrutide is an investigational once-weekly triple agonist acting at GLP-1, GIP and glucagon receptors. In phase-2 obesity trials it produced the largest mean weight loss reported for any incretin-based drug to date (~24% at the highest dose over 48 weeks), and it is in phase-3 development. Not yet approved for any indication.
01 Overview
Retatrutide (LY3437943) is a synthetic peptide engineered to activate three metabolic receptors simultaneously: GLP-1 and GIP (both incretins that improve insulin secretion and reduce appetite) and glucagon (which increases energy expenditure and hepatic fat oxidation). The addition of glucagon agonism is what distinguishes it from dual agonists like tirzepatide and is thought to drive its unusually large effect on body weight and hepatic steatosis.
As of 2026 retatrutide remains investigational, with phase-3 trials (the TRIUMPH programme) ongoing in obesity, type-2 diabetes, and metabolic dysfunction-associated steatohepatitis. Published phase-2 data are robust for a drug at this stage, but long-term safety and cardiovascular outcome data are not yet available. All human dosing to date has occurred within clinical trials.
02 Mechanism
Balanced triple agonist at GLP-1, GIP and glucagon receptors. GLP-1/GIP agonism suppresses appetite and improves glycaemic control; glucagon agonism raises resting energy expenditure and promotes hepatic lipolysis, together producing large reductions in fat mass and liver fat.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Trial starting dose | 1–2 mg/wk | SubQ | Initiation dose in phase-2/3 trials before titration. |
| Trial maintenance | 4–8 mg/wk | SubQ | Titrated maintenance range used across trial arms. |
| Highest trial dose | 12 mg/wk | SubQ | Highest arm in phase-2, ~24% mean weight loss at 48 weeks. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Weight lossDose-dependent mean body-weight reduction at 48 weeks in phase-2 obesity trial, the largest reported for an incretin drug. | -17% to -24% | Clinical | |
| Reduced hepatic fatMarked reduction in liver fat content, with normalisation of hepatic steatosis in a majority of participants at higher doses. | near-complete resolution in many | Clinical | |
| Improved glycaemic controlSubstantial HbA1c reduction in type-2 diabetes participants. | HbA1c -1.3% to -2.0% | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Gastrointestinal upsetNausea, vomiting, diarrhoea and constipation, most frequent during dose escalation and largely dose-dependent. | Moderate | Most users during titration | Clinical | |
| Increased heart rateModest dose-dependent rise in resting heart rate, partly attributed to glucagon agonism. | Mild | Dose-dependent | Clinical |
06 Commonly used with
What retatrutide is combined with, and why. This is about intent rather than safety — the interactions table below covers what is dangerous. Nothing here is listed without what it costs.
| Compound | Frequency | Purpose & trade-off |
|---|---|---|
| Stacked compounds | ||
| Semaglutide or tirzepatidetransition between incretins | Some users move to retatrutide from an earlier incretin (with brief overlap) seeking the added glucagon-driven fat loss.Trade-off: Overlapping incretin agonists compounds GI and hypoglycaemia risk, and doing so with an investigational agent that lacks full safety data magnifies the uncertainty. | |
| Support & ancillaries | ||
| Resistance training + high-protein dietmuscle preservation | Essential alongside retatrutide because its triple GLP-1/GIP/glucagon action produces some of the largest weight losses seen, and without training/protein a large fraction comes off as lean mass.Trade-off: The same potent appetite suppression that drives the fat loss makes eating adequate protein very difficult, so muscle preservation is an uphill battle. | |
| Metformininsulin-sensitiser | Added for additional glycaemic support via a separate mechanism during retatrutide use.Trade-off: Both are GI-heavy and, since retatrutide is still investigational with only trial-stage human data, the combination's real-world safety profile is largely uncharacterised. | |
| Heart-rate / blood-pressure monitoringcardiovascular check | Used because the glucagon component and trial data are associated with modest heart-rate increases, so vitals are tracked during dose escalation.Trade-off: Monitoring only detects a problem; it does not prevent the tachycardia or other effects, and retatrutide's long-term cardiovascular outcome data does not yet exist. | |