A comprehensive overview of every major study, trial, and publication on retatrutide — from preclinical origins to ongoing Phase 3 trials.
From Eli Lilly's internal discovery programme to global Phase 3 trials — the full history of retatrutide's clinical development.
Eli Lilly researchers design LY3437943 — a single peptide molecule engineered to simultaneously activate three receptors: GLP-1, GIP, and glucagon. Preclinical animal studies in rodents and primates demonstrate significant weight reduction and metabolic improvement, providing the basis for human trials. The compound is disclosed in Lilly patent filings around 2019.
First-in-human Phase 1 trials assess safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy volunteers and participants with type 2 diabetes. Studies confirm a favourable safety profile, establish the approximately 6-day half-life enabling once-weekly dosing, and identify appropriate dose escalation schedules for Phase 2. NCT04143802 and NCT04521153 registered on ClinicalTrials.gov.
The landmark Phase 2 obesity efficacy trial enrolls 338 participants with BMI ≥27 without diabetes. Participants are randomised to retatrutide doses of 1mg, 4mg, 8mg, or 12mg weekly, or placebo, for 48 weeks. Results published in the New England Journal of Medicine in June 2023 show unprecedented weight loss across all active dose groups.
A parallel Phase 2 trial in 281 participants with type 2 diabetes evaluates retatrutide's glycaemic control alongside weight loss. Results show significant HbA1c reductions across all dose groups, with the compound outperforming comparator arms. Published alongside the obesity trial results in 2023, supporting development across both indications.
Following the Phase 2 results, Eli Lilly launches the TRIUMPH (TRIple hormone receptor agonist for obesity Management and Potential cardiometabolic Health improvement) Phase 3 programme. Six or more large-scale global trials are initiated covering obesity, type 2 diabetes, cardiovascular outcomes, and liver disease. Enrolment begins across trial sites worldwide.
Subject to TRIUMPH Phase 3 trial outcomes, Eli Lilly is expected to file for regulatory approval with the FDA and EMA/MHRA. If Phase 3 results confirm Phase 2 efficacy and safety, retatrutide could become the first triple receptor agonist approved for obesity — potentially surpassing tirzepatide as the market-leading weight loss medication.
Phase 1 trials established retatrutide's safety profile, dosing schedule, and pharmacological behaviour in humans.
The SAD study administered single escalating doses of retatrutide to healthy adult volunteers to assess safety, tolerability, and pharmacokinetic profile. The study confirmed the compound's approximately 6-day half-life — enabling once-weekly subcutaneous injection — and demonstrated a dose-proportional pharmacokinetic profile. The side effect profile was consistent with GLP-1 class compounds, primarily GI-related and dose-dependent. No serious adverse events were attributable to the study drug.
The MAD study assessed multiple weekly doses over several weeks to characterise steady-state pharmacokinetics and early pharmacodynamic signals including glucose control and early body weight changes. Results supported the dose escalation regimen ultimately used in Phase 2, beginning at 2mg and escalating to target doses of up to 12mg. Early efficacy signals for both weight loss and glycaemic improvement were observed across dose groups, building the case for the larger Phase 2 programme.
The Phase 2 programme produced some of the most significant weight loss results ever recorded in a clinical trial setting.
This randomised, double-blind, placebo-controlled trial is the definitive Phase 2 study for retatrutide in obesity. Participants were adults with a BMI of 27 or higher without type 2 diabetes, randomised to one of four active dose groups or placebo. The primary endpoint was percentage change in body weight from baseline to week 48.
At the 12mg dose, 26% of participants lost more than 30% of body weight — a threshold previously unachievable with any approved medication. The trial was 48 weeks, shorter than competitor Phase 3 trials (tirzepatide's SURMOUNT ran to 72 weeks), suggesting longer treatment may yield even greater results in Phase 3. All active dose groups significantly outperformed placebo (p<0.001). GI side effects were the most common adverse events, consistent with the class, and were generally mild to moderate.
This parallel Phase 2 trial recruited adults with type 2 diabetes on stable background therapy. The primary endpoint was reduction in HbA1c from baseline to week 36. All three dose groups demonstrated significant glycaemic improvement, with the 12mg dose achieving a mean HbA1c reduction of approximately 2.6 percentage points — clinically meaningful and competitive with the most effective approved diabetes medications. Weight loss was a secondary endpoint, with similar reductions observed as in the obesity trial despite the shorter duration and diabetic population.
The combination of substantial HbA1c reduction and significant weight loss positions retatrutide as a compelling candidate for a dual obesity/diabetes indication, mirroring the regulatory path successfully taken by tirzepatide (Mounjaro).
Motivated by retatrutide's unique glucagon receptor activity — known to drive hepatic lipid clearance — this study examined liver fat reduction as measured by MRI proton density fat fraction (MRI-PDFF) in participants with metabolic-associated steatotic liver disease. Results demonstrated dramatic reductions in liver fat content, with approximately 80% of participants achieving a clinically meaningful response. This positions retatrutide as a strong candidate for MASH (metabolic dysfunction-associated steatohepatitis) — a liver disease with very limited approved treatments — and is likely to form the basis of a dedicated TRIUMPH liver disease trial.
TRIUMPH — Triple hormone receptor agonist for obesity Management and Potential cardiometabolic Health improvement — is Eli Lilly's Phase 3 programme for retatrutide, encompassing multiple large global trials across different patient populations and indications.
The most clinically significant results from the published retatrutide research programme to date.
Mean body weight reduction at the 12mg dose over 48 weeks — the highest figure ever recorded for a pharmaceutical obesity intervention in a Phase 2 trial.
Over a quarter of 12mg participants lost more than 30% of body weight — a threshold previously only achievable through bariatric surgery.
Mean HbA1c reduction at the highest dose in the diabetes trial — clinically meaningful and competitive with the most effective approved diabetes treatments.
Approximately 80% of participants in the MASLD study achieved a clinically meaningful reduction in liver fat, driven by the unique glucagon receptor component.
Unlike all other approved GLP-1 agents, retatrutide's glucagon component measurably increases resting metabolic rate — the body burns more calories at rest.
Consistent reductions in systolic blood pressure, triglycerides, and LDL cholesterol observed across Phase 2 trial cohorts.
The primary peer-reviewed publications and trial registrations underpinning the retatrutide evidence base.
The definitive Phase 2 publication for retatrutide in type 2 diabetes. Reports HbA1c, fasting glucose, and weight outcomes across dose groups with comparison to dulaglutide. Confirms retatrutide's potent dual benefit in glycaemic control and weight reduction in this population.
The landmark obesity efficacy paper. Reports the 24.2% mean weight loss at 48 weeks in the 12mg dose group, the 26% of participants exceeding 30% weight loss, and the full safety profile. This publication prompted Lilly to initiate the TRIUMPH Phase 3 programme and generated widespread scientific attention for the triple agonist class.
Official trial registration for the Phase 2 obesity study. Contains full protocol, eligibility criteria, primary and secondary endpoints, and results posting following trial completion. Available at clinicaltrials.gov.
Official trial registration for the Phase 2 type 2 diabetes study. Full protocol and results available. Provides detailed breakdown of HbA1c, body weight, fasting glucose, and safety outcomes across all dose groups and comparator arms.
Details the Phase 1 pharmacokinetic analysis establishing the ~6-day half-life, dose-proportional exposure, and early pharmacodynamic signals including weight and glucose changes. Formed the scientific basis for the Phase 2 dose selection and escalation schedule.
Reports results from the Phase 2 MASLD/MASH study demonstrating approximately 80% response rate for clinically meaningful liver fat reduction by MRI-PDFF. Supports a dedicated liver disease indication within the TRIUMPH Phase 3 programme and highlights the unique contribution of glucagon receptor agonism to hepatic outcomes.
The most potent GLP-1 class compound in clinical development — available now for UK research purposes, dispatched within 24 hours.
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