Compound reference
Retatrutide
Also known as LY3437943
An investigational once-weekly triple agonist of the GLP-1, GIP, and glucagon receptors, with some of the largest weight-loss results yet reported for an incretin drug — and no regulatory approval anywhere.
- CAS
- 2381089-83-2
- Half-life
- About 6 days (once-weekly dosing)
Investigational; not approved as a medicine in Canada or the United States.
Mode of action
Retatrutide is a single engineered peptide that activates three receptors at once — GLP-1, GIP, and glucagon. That is what separates it from single-agonist drugs (semaglutide) and dual agonists (tirzepatide). Receptor-pharmacology work characterises it as a unimolecular triple agonist built on a GIP backbone, with roughly nine-fold greater potency than native GIP and deliberately attenuated activity at the GLP-1 and glucagon receptors so the three signals stay balanced. A fatty-acid chain extends its half-life to about six days, which supports once-weekly subcutaneous dosing.
The three arms do different work. GLP-1 and GIP suppress appetite and slow gastric emptying; the glucagon arm adds energy expenditure and hepatic effects — thermogenesis and glycogenolysis — that, in obese rodent models, pushed weight loss beyond dual agonism. The glucagon component is also the most double-edged: it is the proposed basis for the large liver-fat reductions seen in trials, and the reason hepatic and metabolic effects need close human study.
Main intended effect
Retatrutide is developed for weight reduction and glycemic control, with obesity and type 2 diabetes as the lead indications. Its standout signal is the magnitude of weight loss — among the largest reported for any incretin agonist in Phase 2.
Areas of interest
The Phase 3 program is unusually broad. Beyond obesity and type 2 diabetes, Eli Lilly has active trials in metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular and kidney outcomes, knee osteoarthritis, obstructive sleep apnea, and chronic low back pain. The early liver-fat and kidney-marker signals are a large part of why interest reaches past weight loss alone.
Evidence for intended effects
Unlike most research peptides, retatrutide has a substantial, controlled human evidence base — though it is not yet approved and the pivotal Phase 3 data are still arriving.
The Phase 1b multiple-ascending-dose trial in type 2 diabetes established safety, roughly six-day pharmacokinetics, and early efficacy. The pivotal Phase 2 obesity trial (NEJM 2023, 338 adults) then showed dose-dependent weight loss reaching −24.2% at 48 weeks on 12 mg, with 83% of that group losing at least 15% of body weight versus 2% on placebo. A Phase 2a substudy in MASLD reported liver-fat reductions up to −82% by MRI, with most higher-dose participants normalising liver fat. Meta-analyses pooling the randomised trials put mean weight loss near 14% and HbA1c reductions close to 1%, and a kidney-focused analysis noted reduced albuminuria.
The Phase 3 TRIUMPH program is where approval-grade evidence is being built. Lilly's topline release for TRIUMPH-1 — the pivotal obesity trial in about 2,335 adults — reported strong 80-week weight loss in May 2026, but the full peer-reviewed dataset is pending. A head-to-head diabetes trial against semaglutide, a maintenance trial, a MASLD liver-outcome trial, and a large cardiovascular and kidney outcomes trial are all ongoing, with the outcomes trial not due to complete until 2029.
| Indication | Strongest evidence so far | Status |
|---|---|---|
| Obesity / overweight | Phase 2 RCT (−24.2% at 48 wk); Phase 3 TRIUMPH-1 topline | Phase 3 (full data pending) |
| Type 2 diabetes | Phase 1b + Phase 2; Phase 3 head-to-head vs semaglutide | Phase 3 (ongoing) |
| MASLD (liver fat) | Phase 2a substudy (−82% liver fat) | Phase 3 outcomes ongoing |
| Cardiovascular & kidney | Event-driven Phase 3 (~10,000 adults) | Ongoing to 2029 |
Studied amounts (literature dosing context)
Retatrutide is given as a once-weekly subcutaneous injection with stepwise dose escalation to manage gastrointestinal effects. The doses that appear in the trials are study facts, not recommendations: the Phase 2 obesity trial tested 1, 4, 8, and 12 mg once weekly, and Phase 1b escalated through comparable levels. There is no approved dose or regimen — retatrutide is investigational — and this page does not provide dosing guidance.
Safety and regulatory status
The safety signal across trials is dominated by dose-related gastrointestinal effects — nausea, vomiting, diarrhea, constipation — usually mild-to-moderate and managed with slow titration; a transient rise in heart rate has also been reported. Pooled analyses found treatment-emergent adverse events more common than placebo (driven by GI events), but serious adverse events not significantly increased. Those numbers come from supervised trials with titration. A published case report describes intractable diarrhea after unsupervised self-dosing of retatrutide bought online, where dose and purity were unknown.
Retatrutide is not approved by the FDA, Health Canada, or any other regulator. It is legally available only through Eli Lilly's clinical trials, and Lilly's own guidance states that any version obtained outside a registered trial is unauthorised. Health Canada lists retatrutide among online peptides it warns against injecting, noting that unauthorised products are not assessed for safety, quality, or purity.
Sources
LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept
Coskun and colleagues characterized the receptor pharmacology of retatrutide (LY3437943), an engineered unimolecular triple agonist of the GIP, GLP-1, and glucagon receptors. In vitro assays showed approximately 8.9-fold greater potency than native GIP at the GIP receptor, with attenuated activity at GLP-1R (~0.4-fold) and GCGR (~0.3-fold) relative to native ligands. In obese rodent models, the glucagon-mediated increase in energy expenditure combined with GIP/GLP-1-driven appetite suppression to augment body-weight loss compared to dual agonism. A first-in-human single-ascending-dose phase 1 study established pharmacokinetics supporting once-weekly dosing, with a single dose producing body-weight reduction persisting to day 43. Phase 3 human efficacy and long-term safety data are not reported in this paper.
Retatrutide—A Game Changer in Obesity Pharmacotherapy
Narrative review by Katsi et al. (National and Kapodistrian University of Athens) published in Biomolecules synthesizing preclinical and early clinical evidence on retatrutide as a triple GLP-1, GIP, and glucagon receptor agonist for obesity and type 2 diabetes. Key mechanisms include delayed gastric emptying, appetite suppression, and complementary thermogenic and glycogenolytic effects from glucagon receptor activation that enhance weight loss beyond other incretin therapies. Phase I–II trials demonstrated dose-dependent weight loss, HbA1c reductions, and improvements in hepatic steatosis and kidney disease markers; Phase III TRIUMPH studies are ongoing. The review identifies cost and the need to characterize quality of weight loss beyond BMI as important unresolved issues.
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
Phase 1b, multicentre, double-blind, placebo-controlled, randomized multiple-ascending-dose trial (Urva and colleagues, The Lancet 2022) in 72 adults aged 20–70 years with type 2 diabetes (HbA1c 7.0–10.5%, BMI 23–50 kg/m²), randomized to once-weekly subcutaneous retatrutide (0.5, 1.5, 3, 3/6, or 3/6/9/12 mg escalating), dulaglutide 1.5 mg, or placebo over 12 weeks. The highest dose groups achieved placebo-adjusted HbA1c reductions of approximately −1.2% to −1.6% and body weight reductions of up to −8.96 kg. Pharmacokinetic analysis reported a half-life of approximately 6 days with dose-proportional kinetics, supporting once-weekly dosing. Treatment-emergent adverse events occurred in 63% of retatrutide recipients, predominantly mild-to-moderate gastrointestinal disorders; 29 participants discontinued prematurely. The trial established the safety, tolerability, metabolic efficacy, and PK profile that supported Phase 2 development.
Triple–Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial
Phase 2, randomized, double-blind, placebo-controlled trial (Jastreboff and colleagues, NEJM 2023) in 338 adults with BMI ≥30 or ≥27 with weight-related comorbidities, evaluating once-weekly subcutaneous retatrutide at 1, 4, 8, or 12 mg versus placebo over 48 weeks. The primary endpoint of percent body weight change at 24 weeks showed dose-dependent reductions: −7.2% (1 mg), −12.9% (4 mg), −17.3% (8 mg), and −17.5% (12 mg) versus −1.6% placebo. At 48 weeks, weight loss reached −8.7%, −17.1%, −22.8%, and −24.2%, respectively; at 12 mg, 83% of participants achieved ≥15% weight loss versus 2% on placebo. The most common adverse events were dose-related mild-to-moderate gastrointestinal effects; dose-dependent transient heart rate increases peaked at 24 weeks then declined. The authors concluded that retatrutide produced substantial, dose-dependent weight loss in adults with obesity at 48 weeks.
Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial
Randomized, double-blind, placebo-controlled phase 2a substudy (Sanyal and colleagues, Nature Medicine 2024) of 98 adults with metabolic dysfunction-associated steatotic liver disease and baseline liver fat ≥10%, drawn from the NCT04881760 obesity trial, receiving once-weekly subcutaneous retatrutide at 1, 4, 8, or 12 mg or placebo over 48 weeks. The primary endpoint of relative liver fat reduction by MRI-PDFF at 24 weeks showed dose-dependent decreases: −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg), and −82.4% (12 mg) versus +0.3% for placebo (all active doses p < 0.001). Normalization of liver fat to below 5% was achieved in 27%, 52%, 79%, and 86% of participants at each respective dose versus 0% with placebo. Body weight reductions correlated significantly with liver fat improvements, and metabolic measures associated with insulin sensitivity and lipid metabolism also improved. The authors concluded that retatrutide produced dose-dependent, near-complete resolution of steatotic liver fat in most higher-dose participants.
Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials
Systematic review and meta-analysis in Baylor University Medical Center Proceedings pooling 3 randomized controlled trials (n=878) of retatrutide in adults with obesity with or without diabetes. Retatrutide produced a mean body weight reduction of 14.33%, BMI decrease of 5.38 points, waist circumference reduction of 10.51 cm, and systolic blood pressure reduction of 9.88 mm Hg (all p<0.00001); HbA1c fell 0.91% and fasting plasma glucose 23.51 mg/dL. Overall adverse-event risk was not significantly different from placebo (relative risk 1.11; p=0.24). The authors concluded retatrutide demonstrates significant metabolic benefit with an appropriate safety profile but called for larger, longer-term trials to confirm these findings.
7792 Efficacy of Retatrutide for Weight Reduction and Its Cardiometabolic Effects Among Adults: A Systematic Review and Meta-Analysis
Systematic review and meta-analysis published as a conference supplement in the Journal of the Endocrine Society pooling 3 randomized controlled trials (n=691) of retatrutide through December 2023. In patients with type 2 diabetes, retatrutide reduced body weight by a mean of 11.89 kg (95% CI −13.53 to −10.25) and HbA1c by 1.64% (95% CI −2.38 to −0.89) versus placebo; in non-diabetic obesity, least-squares mean body weight fell 24.2%, with 83% of participants achieving ≥15% weight loss at 48 weeks. The authors concluded there is low-to-moderate certainty evidence for substantial cardiometabolic benefit. Limitations include the abstract format, small trial count, and risk of bias rated as low to unclear across included studies.
Efficacy and Safety of Retatrutide in the Treatment of Diabetes and/or Obesity Comorbid with Chronic Kidney disease: a Systematic Review and Meta-Analysis
Systematic review and meta-analysis in Maedica pooling 8 randomized controlled trials of retatrutide in adults with type 2 diabetes and/or obesity comorbid with chronic kidney disease. Pooled analysis found a mean HbA1c reduction of 1.04% (95% CI −1.42 to −0.67), with lower doses (≤8 mg) yielding greater glycemic benefit (−1.39%) than higher doses (≥12 mg); body weight fell up to 24.2%, and reductions in albuminuria suggested renoprotective potential. The authors concluded that retatrutide demonstrates strong glycemic and weight-loss efficacy in this population but noted that dedicated long-term CKD outcome data remain limited. Gastrointestinal adverse events required active management across included trials.
Navigating retatrutide safety: comprehensive insights from systematic review and meta-analysis
Systematic review and meta-analysis in the Journal of Public Health and Development pooling 4 randomized controlled trials to characterize the safety profile of retatrutide, a triple GIP/GLP-1/glucagon receptor agonist. Treatment-emergent adverse events were significantly more frequent with retatrutide than placebo (RR 1.87; 95% CI 1.25–2.80; p=0.003), driven primarily by gastrointestinal disturbances including nausea, vomiting, and constipation; adverse events of special interest occurred at RR 2.94 (95% CI 1.85–4.69). Serious adverse events were not significantly different from placebo (RR 0.81; 95% CI 0.36–1.83; p=0.61). The authors recommend careful patient selection, dose titration, and monitoring in vulnerable populations and note that long-term comparative safety data remain lacking.
https://he01.tci-thaijo.org/index.php/AIHD-MU/article/view/277028
A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight (TRIUMPH-1)
Phase 3 randomized, double-blind, placebo-controlled trial sponsored by Eli Lilly, enrolling 2,335 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with comorbidities but without type 2 diabetes. Three subcutaneous dose levels of once-weekly retatrutide are compared with placebo over a main phase of approximately 89 weeks, with an optional 24-week extension. Co-primary endpoints are percent change from baseline in body weight at week 80 and at week 104 for extension participants; pre-specified subsets track osteoarthritis pain and sleep apnea. Primary completion occurred in April 2026 and results have not yet been posted to the registry.
Lilly's triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial
Official press release (Eli Lilly) reporting topline phase 3 TRIUMPH-1 results for investigational retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, studied in adults with obesity or overweight plus at least one weight-related comorbidity and without diabetes. It reports the 80-week primary weight-loss outcome together with cardiometabolic secondary endpoints and the overall adverse-event profile. The release also describes a pre-specified 104-week extension cohort limited to participants with a baseline BMI of at least 35. As a sponsor-issued topline summary, the specific endpoint figures precede the full peer-reviewed dataset, which is pending publication. TRIUMPH-1 is the pivotal efficacy readout in retatrutide's phase 3 obesity program.
A Study of Retatrutide Compared With Semaglutide in Adults With Type 2 Diabetes (TRANSCEND-T2D-2)
Phase 3 randomized, multicenter, open-label, parallel-group trial sponsored by Eli Lilly comparing two dose levels of once-weekly subcutaneous retatrutide against once-weekly semaglutide in approximately 1,250 adults with type 2 diabetes inadequately controlled on metformin (≥1,500 mg/day) with or without an SGLT2 inhibitor; eligible participants had HbA1c 7.0–10.5% and BMI ≥25 kg/m². The primary endpoint is change from baseline in HbA1c at week 80, with estimated primary completion in August 2026. The trial was active but not recruiting as of April 2026, and no efficacy results have been posted.
A Study of Retatrutide on Cardiovascular and Kidney Outcomes in Adults Living With Obesity (TRIUMPH-Outcomes)
Phase 3, randomized, double-blind, placebo-controlled, event-driven outcomes trial sponsored by Eli Lilly, enrolling approximately 10,000 adults aged ≥45 with BMI ≥27 kg/m² and established atherosclerotic cardiovascular disease and/or chronic kidney disease. Participants receive escalating doses of subcutaneous retatrutide or matched placebo. Co-primary endpoints are time to first cardiovascular event (nonfatal MI, nonfatal stroke, cardiovascular death, or urgent heart failure visit) and time to first renal event (end-stage kidney disease, ≥40% sustained eGFR decline, cardiovascular death, or renal death). The trial started April 2024 with estimated completion in February 2029; no results have been posted.
A Master Protocol of Multiple Agents in Adults With MASLD at Risk of Major Adverse Liver Outcomes (SYNERGY-Outcomes)
Phase 3 randomized, single-blind, master-protocol outcomes trial sponsored by Eli Lilly and Company, enrolling approximately 4,500 adults with MASLD identified as high risk for disease progression via non-invasive testing. Parallel arms test subcutaneous retatrutide, tirzepatide, and two separate placebo comparators. The primary endpoint is time to first major adverse liver outcome (MALO) — a composite including cirrhosis progression, varices, ascites, hepatic encephalopathy, variceal hemorrhage, meaningful MELD score increase, liver transplantation, or all-cause mortality — over approximately 224 weeks. The trial began recruiting in October 2025 and no efficacy results have been posted.
A Study of Retatrutide (LY3437943) in the Maintenance of Weight Reduction in Individuals With Obesity (TRIUMPH-6)
Phase 3b randomized, double-blind, placebo-controlled maintenance trial sponsored by Eli Lilly, enrolling an estimated 643 adults with obesity who have not responded adequately to dietary weight loss. After an open-label lead-in, participants are randomized to one of three subcutaneous retatrutide strategies over 116 weeks: continued dose-level 1 throughout, a dose-level 1 to dose-level 2 escalation at week 80, or dose-level 1 followed by placebo at week 80. The primary endpoint is percent change from baseline in body weight at week 116. The trial was verified active in February 2026 and no efficacy results have been posted.
Effect of retatrutide on body weight, lipid profile, liver function, oxidative stress, and inflammation in experimental obesity in male rats
Diet-induced obesity study in male Sprague-Dawley rats (n = 28) fed a high-fat/sucrose diet for 12 weeks, followed by 4 weeks of subcutaneous retatrutide at 25 nmol/kg. Treated animals showed approximately 25% body-weight reduction, blood glucose falling from 107 ± 6 to 86 ± 5 mg/dL, triglycerides dropping from 112 to 30 mg/dL, and LDL from 172 to 51 mg/dL (all p < 0.0001), while HDL rose from 38 to 66 mg/dL. Hepatic oxidative stress markers improved: malondialdehyde decreased from 5.4 to 3.1 nmol/mL and glutathione increased from 1.2 to 2.9 ng/mL; TNF-α fell from 116 to 93 pg/mL. These findings indicate antioxidant and anti-inflammatory hepatic effects of the GIP/GLP-1/glucagon triple agonism beyond weight loss alone, though translation to human hepatic outcomes requires prospective clinical assessment.
Retatrutide-Induced Intractable Diarrhea
Case report published in Annals of Internal Medicine: Clinical Cases (April 2026) documenting intractable diarrhea following unsupervised self-administration of retatrutide — a triple GIP/GLP-1/glucagon receptor agonist — obtained online without medical oversight. The patient self-determined the dose, and the resulting severe gastrointestinal toxicity required clinical evaluation. Retatrutide is an investigational agent without regulatory approval; unregulated online sources carry unknown peptide purity and concentration. The case serves as a safety signal for the GI risks associated with potent multi-receptor incretin agonism at uncontrolled doses, and underscores the hazards of self-administering unapproved peptides outside clinical supervision.
What to know about retatrutide
Eli Lilly public information page confirming that retatrutide, a once-weekly investigational triple hormone receptor agonist that simultaneously activates GIP, GLP-1, and glucagon receptors, has not received FDA approval and remains legally available only through Lilly's clinical trials. As of May 2026, retatrutide has completed several Phase 3 studies and has additional Phase 3 trials ongoing across multiple indications including obesity and overweight, type 2 diabetes, knee osteoarthritis, obstructive sleep apnea, chronic low back pain, cardiovascular and renal outcomes, and metabolic dysfunction-associated steatotic liver disease. The page explicitly states that retatrutide is investigational and not approved by the FDA. Any version obtained outside of a registered clinical trial is unauthorized, and this resource underscores the drug's unapproved investigational status as of the publication date.
https://www.lilly.com/news/stories/what-to-know-about-retatrutide
Think twice before injecting peptides bought online: unauthorized products can seriously harm you
Health Canada public safety advisory published April 9, 2026 warning consumers against injecting peptides purchased online. The advisory explicitly names numerous peptides commonly available through unregulated channels, including BPC-157, CJC-1295, GHK-Cu, Ipamorelin, Melanotan I and II, MOTS-c, SS-31, TB-500, and Retatrutide, among others. Health Canada confirms that peptides are generally regulated as prescription drugs in Canada and that unauthorized products have not been assessed for safety, efficacy, or quality. Identified risks include hormonal imbalance, blood sugar dysregulation, liver or kidney damage, blood clots, tumor growth, infections, and contaminants including heavy metals and bacteria. The advisory explicitly states that "For Research Use Only" labeling does not exempt a product from Canadian drug regulations, and that lawfully authorized Canadian drugs display an eight-digit Drug Identification Number (DIN).