Evidence Grade C — Moderate human evidence. 142 published studies, 91 human. 32 registered clinical trials.
Medically reviewed by a licensed medical professional
Retatrutide is a once-weekly injection in Phase III development by Eli Lilly that simultaneously activates three gut hormone receptors — GIP, GLP-1, and glucagon — making it the first triple-action treatment for obesity. The first Phase III trial reported an average weight loss of 28.7% (about 71 pounds) at the highest dose, the largest ever recorded for any obesity medication in a clinical trial.
Retatrutide is also known by these brand and alternate names:
142 published studies: 91 human, 5 animal, 1 in-vitro, 91 reviews
Retatrutide is in Phase III development (not yet approved). In a Phase II trial (338 patients, 48 weeks), the highest dose achieved 24.2% body weight loss compared to 2.1% with placebo, with 100% of participants at higher doses achieving at least 5% weight loss. A sub-study showed dramatic liver fat reduction.
Phase III trials are ongoing. If approved, retatrutide would represent an escalation from dual to triple receptor targeting in the incretin-based obesity treatment approach. The glucagon receptor component's ability to increase energy expenditure and reduce liver fat addresses limitations of GLP-1-only approaches. Gastrointestinal side effects (nausea, diarrhoea) are the most common adverse events, consistent with the drug class.
Retatrutide activates three complementary metabolic pathways simultaneously. GLP-1 receptor activation suppresses appetite and slows gastric emptying (the mechanism used by semaglutide). GIP receptor activation enhances insulin secretion and may improve metabolic efficiency (as with tirzepatide). Glucagon receptor activation — the novel addition — increases the body's energy expenditure and promotes liver fat burning, potentially addressing metabolic liver disease alongside weight loss.
The first Phase III results (TRIUMPH-4, 445 patients, 68 weeks) confirmed and exceeded the already striking Phase II data. At the 12 mg dose, patients lost an average of 28.7% of their body weight, with nearly 40% of participants losing 30% or more. The trial also showed substantial improvements in knee osteoarthritis pain, systolic blood pressure reductions of 14 mmHg, and improvements in cardiovascular risk markers. A new safety signal emerged: dysesthesia (abnormal tingling or pain sensations) was reported in 21% of patients at the highest dose — a side effect not seen in Phase II. Gastrointestinal side effects were significant (nausea 43%, diarrhoea 33%, vomiting 21%). Discontinuation rates of 12-18% were driven partly by perceived excessive weight loss in some patients. Seven additional Phase III trials are expected to report in 2026, covering obesity, diabetes, sleep apnoea, liver disease, and cardiovascular outcomes. Approval is projected for late 2027 at earliest.
PeptideTrace tracks 32 registered clinical trials for Retatrutide sourced from ClinicalTrials.gov.
Effect of LY3437943 Versus Placebo in Participants Who Have Obesity or Are Overweight
A Study of Retatrutide (LY3437943) in Participants Without Type 2 Diabetes Who Have Obesity or Overweight
A Study of Retatrutide (LY3437943) in Participants With Obesity or Overweight
A Master Protocol of Multiple Agents in Adults With Metabolic Dysfunction-Associated Steatotic Liver Disease (SYNERGY-Outcomes)
A Study to Investigate the Response of Participants With Type 2 Diabetes Mellitus on Once-Weekly Retatrutide to Hypoglycemia
Retatrutide (LY3437943) is a first-in-class triple GIP/GLP-1/glucagon receptor agonist containing 39 amino acids. The fully conjugated molecular weight is approximately 4,731 Da with molecular formula C221H342N46O68 (CAS 2381089-83-2). The half-life is approximately 6 days, supporting once-weekly subcutaneous dosing. Key structural features include Aib at positions 2 and 20 for DPP-4 resistance, alpha-methyl-leucine at position 13, C20 fatty diacid conjugation at Lys-18 via PEG2-gammaGlu linker, and C-terminal amidation. Developed by Eli Lilly. Based on a GIP backbone with modifications enabling triple receptor agonism.
Retatrutide simultaneously activates three Gs-coupled GPCRs with demonstrated binding affinities: GIPR EC50 = 0.064 nM, GLP-1R EC50 = 0.78 nM, and GCGR EC50 = 5.79 nM. The GLP-1R component drives appetite suppression, gastric emptying delay, and glucose-dependent insulin secretion. The GIPR component regulates CNS hunger signals and synergistically enhances insulin secretion. The GCGR component — the key differentiator — promotes hepatic fat oxidation, increases energy expenditure and basal metabolic rate, and directly reduces hepatic steatosis. The GLP-1R activity offsets glucagon's hyperglycemic potential.
Phase 2 obesity trial (Jastreboff et al. 2023, NEJM, N=338, 48 weeks): -24.2% weight loss at 12 mg versus -2.1% placebo, with 100% achieving >=5% weight loss at higher doses. Phase 2 T2D (Rosenstock et al. 2023, Lancet, N=281): HbA1c -2.0% and weight -16.9% at 12 mg. MASLD substudy (Sanyal et al. 2024, Nature Medicine, N=98): 86% relative liver fat reduction at 12 mg, with 93% achieving steatosis resolution. First Phase 3 result, TRIUMPH-4 (December 2025, N=445, 68 weeks): -28.7% body weight at 12 mg. WOMAC pain improved -74.3% versus -40.3% placebo. Dysesthesia signal emerged at 20.9% at 12 mg. Discontinuation 18.2% at 12 mg.
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Semaglutide is one of the most extensively studied peptide medications available today, with clinical trial data spanning over 50,000 patients. It is sold as Ozempic for type 2 diabetes (approved 2017), Rybelsus as an oral tablet for diabetes (approved 2019), and Wegovy for weight management (approved 2021). Wegovy has since received additional approvals for reducing heart attack and stroke risk, for use in adolescents aged 12 and older, and for liver disease related to obesity. In clinical trials, patients taking Wegovy lost an average of 14.9% of their body weight over 68 weeks, and the SELECT trial demonstrated a 20% reduction in major cardiovascular events such as heart attack and stroke. Research is now exploring its potential in early Alzheimer's disease. The main side effects are gastrointestinal, particularly nausea, and a key limitation is that most weight tends to return after stopping treatment.
Bimagrumab is in Phase II/III development (not yet approved). A Phase II trial (75 patients with type 2 diabetes and obesity) showed 20.5% fat mass reduction with 3.6% lean mass increase — essentially reshaping body composition without net appetite suppression. The BELIEVE Phase IIb trial (507 patients) showed that bimagrumab plus semaglutide achieved 22% weight loss with the weight lost being 88% fat — significantly better body composition than semaglutide alone. Bimagrumab is not a peptide. Its strategic significance is as a combination partner to address the muscle loss problem inherent in weight loss with current obesity drugs. Eli Lilly's acquisition positions it alongside tirzepatide.
Pemvidutide is in Phase II/III development (not yet approved). In the MOMENTUM Phase II trial (391 patients, 48 weeks), the 2.4 mg dose achieved 15.6% weight loss. Body composition analysis showed 78% of weight lost was fat mass, with only 22% lean mass — a favourable ratio. A Phase IIb MASH trial (212 patients) showed MASH resolution in up to 75% of patients at the highest dose. Pemvidutide's balanced receptor profile and no-titration dosing regimen represent potential practical advantages. The high rate of MASH resolution in Phase II positions it as a candidate for liver disease indications alongside obesity.
Evidence Reviews
This content is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional before making decisions about your health.
