Retatrutide is a once-weekly injectable peptide that activates three gut and metabolic hormone receptors simultaneously — GLP-1, GIP, and glucagon. No compound in the GLP-1 class had targeted all three at once in human trials before it. Developed by Eli Lilly, it showed the highest weight reduction percentages recorded in a peptide-based clinical trial when its phase 2 data were published in 2023, generating significant research and medical interest.
Weight Management Research
The phase 2 JAMA trial published in 2023 tested retatrutide in adults with obesity. The highest dose group (12mg weekly) showed a mean weight reduction of 24.2% at 48 weeks — the highest recorded in a peptide-based obesity trial at that time. The trial was randomized and placebo-controlled.
Type 2 Diabetes
Phase 2 trials also examined retatrutide in type 2 diabetes patients, showing significant HbA1c reductions consistent with GLP-1 receptor activation alongside the weight effects.
NASH and Liver Research
The liver stores excess fat when the body's metabolic signals are out of balance, and glucagon is one of the hormones involved in telling the liver to burn that fat. Retatrutide's glucagon component may make it useful for non-alcoholic fatty liver disease — a condition where excess fat builds up in liver tissue and can lead to inflammation over time. Research examining retatrutide specifically for this indication is underway.
Cardiovascular Research
Phase 3 trials are now underway including cardiovascular outcomes research, following the established pattern of GLP-1 class development where metabolic benefits are followed by cardiovascular trials.
Phase 2 trial: 24.2% mean weight reduction at 48 weeks at the highest dose — highest in a peptide obesity trial at time of publication.
Significant HbA1c reductions in type 2 diabetes patients.
Dose-dependent effects across GLP-1, GIP, and glucagon pathways.
Phase 3 trials underway.
Not yet FDA-approved.
Retatrutide has not completed phase 3 trials. Phase 2 data, while striking, do not constitute approval evidence. GI side effects were common — nausea, vomiting, diarrhea — consistent with the GLP-1 class and amplified by the additional glucagon component. The glucagon component also produces a modest increase in resting heart rate — a known effect of glucagon receptor activation that was monitored in the trials and is factored into ongoing phase 3 safety assessments. Long-term data beyond 48 weeks are not available from published trials.
Retatrutide activates three receptors at once. GLP-1 receptor activation reduces appetite, slows stomach emptying, and improves insulin secretion. GIP receptor activation appears to enhance the effects of GLP-1, reduce fat storage, and improve metabolic flexibility. Glucagon receptor activation increases the rate at which the liver burns fat and raises energy expenditure — glucagon is normally a counter-regulatory hormone that raises blood sugar, but when balanced with the insulin-supporting effects of GLP-1 and GIP, the glucagon component appears to add significant fat-burning activity without causing problematic blood sugar elevations. The combination of all three effects working simultaneously appears to explain the unusually large weight reduction seen in the trial.
Retatrutide is not FDA-approved. In phase 2 trials the GI side effect profile was consistent with GLP-1 class compounds, with significant nausea during uptitration. Heart rate increases consistent with glucagon receptor activation were observed and require monitoring. Phase 3 long-term safety data are still being collected.
High Evidence
This compound has been studied in multiple large randomized controlled trials with human subjects. The evidence base is strong and consistent across independent research groups.
Published Research Ranges
1–12mg weekly in Phase 2 trials
Research Context Only: These are ranges reported in published scientific studies for educational reference. They are not dosing recommendations. This is not medical advice. Always consult a qualified healthcare professional.
Sources listed here are from the platform research library. All links open the original publication. No citations are generated by AI.
Retatrutide, a GIP, GLP-1 and Glucagon Receptor Agonist, for People with Type 2 Diabetes
The Lancet • 2023
• DOI: 10.1016/S0140-6736(23)01053-X
Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA
Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: Effects on weight loss and safety in adults with overweight or obesity
LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial
Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes : A Systematic Review of Randomized Controlled Trials
Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials
Efficacy and safety of once-weekly tirzepatide for weight management compared to placebo: An updated systematic review and meta-analysis including the latest SURMOUNT-2 trial
Comparison of the efficacy and safety of 10 glucagon-like peptide-1 receptor agonists as add-on to metformin in patients with type 2 diabetes: a systematic review
Effect of a Low-Calorie Dietary Intervention on Liver Health and Body Weight in Adults with Metabolic-Dysfunction Associated Steatotic Liver Disease (MASLD) and Overweight/Obesity: A Systematic Review and Meta-Analysis
New advances in novel pharmacotherapeutic candidates for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) between 2022 and 2024
Adipocentric origin of the common cardiometabolic complications of obesity in the young up to the very old: pathophysiology and new therapeutic opportunities
Research Education Only: This profile is for educational purposes only. All information is sourced from published scientific literature. This is not medical advice. Not for human consumption. Consult qualified medical professionals for any health decisions.
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