Retatrutide Clinical Trials: Phase 3 Results Explained

Retatrutide (LY3437943) is one of the most closely watched investigational drugs in obesity medicine. Developed by Eli Lilly, it belongs to a new class of triple-hormone-receptor agonists - meaning it simultaneously activates three key metabolic pathways: GIP (glucose-dependent insulinotropic polypeptide), GLP-1 (glucagon-like peptide-1), and glucagon receptors.

While semaglutide (Wegovy) targets one receptor and tirzepatide (Mounjaro/Zepbound) targets two, retatrutide’s triple mechanism has produced the most dramatic weight loss results ever recorded in obesity drug trials. This article breaks down every major clinical trial, from the early dose-finding studies through to the Phase 3 TRIUMPH programme, and explains what the data actually shows.

What Is the TRIUMPH Programme?

TRIUMPH is the name given to Eli Lilly’s Phase 3 registrational clinical development programme for retatrutide. Launched in 2023, the programme encompasses multiple large-scale trials designed to evaluate retatrutide across a range of conditions linked to obesity and metabolic dysfunction.

The TRIUMPH programme has enrolled more than 5,800 participants worldwide and includes trials targeting:

• TRIUMPH-1: Obesity and overweight (with nested protocols for obstructive sleep apnoea and knee osteoarthritis)
• TRIUMPH-2: Type 2 diabetes with obesity/overweight
• TRIUMPH-3: Cardiovascular and renal outcomes in people with established cardiovascular disease
• TRIUMPH-4: Obesity/overweight with knee osteoarthritis (the first trial to report Phase 3 results)

Additional Phase 3 studies are also evaluating retatrutide in metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as NAFLD/NASH), chronic low back pain, and maintenance dosing strategies. In total, Lilly expects seven additional Phase 3 readouts in 2026.

Phase 1: Dose-Finding and First-in-Human Studies

Retatrutide’s clinical journey began with two Phase 1 studies. The first was a single ascending dose study conducted in Singapore, involving 47 healthy participants who received retatrutide or placebo (Coskun et al.). This established the drug’s basic safety profile and confirmed that its pharmacokinetics supported once-weekly dosing.

The Phase 1b trial, published in The Lancet in 2022 (Urva, Coskun, Loh et al., Volume 400, pp. 1869–1881), was a multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose study in people with type 2 diabetes. It demonstrated:

• Clinically meaningful glucose-lowering effects
• Significant body weight reduction even at 12 weeks
• A safety profile consistent with the GLP-1 receptor agonist class (primarily gastrointestinal side effects)
• Pharmacokinetic data confirming once-weekly subcutaneous injection was feasible

These early findings provided the rationale for the larger Phase 2 programme that would go on to make headlines worldwide.

Phase 2 Trial: The Breakthrough Results

The Obesity Trial (Jastreboff et al., NEJM 2023)

The Phase 2 trial that put retatrutide on the map was published by Jastreboff and colleagues in the New England Journal of Medicine in June 2023 (NCT04881760). This randomised, double-blind, placebo-controlled trial enrolled 338 adults with obesity (BMI ≥30) or overweight (BMI ≥27 with at least one weight-related condition). Approximately 51.8% of participants were men.

Participants were randomly assigned to receive weekly subcutaneous injections of retatrutide at doses of 1 mg, 4 mg, 8 mg, or 12 mg, or placebo, for 48 weeks. For those assigned to 4 mg or higher, treatment started at a lower dose (2 mg or 4 mg) with gradual escalation every 4 weeks for up to 12 weeks to improve tolerability.

At the highest dose of 12 mg, participants lost an average of 24.2% of their body weight over 48 weeks - equivalent to roughly 26 kg (58 lbs). This was the largest weight reduction ever reported for an anti-obesity medication at the time of publication, and the weight loss curves had not yet plateaued, suggesting even greater losses might be achievable with longer treatment.

The Type 2 Diabetes Trial (Rosenstock et al., The Lancet 2023)

A parallel Phase 2 trial, published in The Lancet in 2023, evaluated retatrutide in 281 adults with type 2 diabetes (mean HbA1c 8.3%, mean BMI 35.0 kg/m²). This 36-week trial included doses of 0.5 mg through 12 mg, with dulaglutide 1.5 mg as an active comparator.

Key findings included:

• HbA1c reduction: 1.3% to 2.0% across the 4–12 mg dose groups, compared to no change with placebo and 1.4% with dulaglutide
• 82% of participants in higher-dose groups achieved HbA1c ≤6.5%
• HbA1c reductions were significantly greater than both placebo (p<0.0001) and dulaglutide at the 8 mg and 12 mg doses
• Improvements in blood pressure, triglycerides, waist circumference, and an 82% reduction in hepatic steatosis (liver fat)

The Liver Sub-Study (Harrison et al., Nature Medicine 2024)

A dedicated sub-analysis of liver outcomes was published in Nature Medicine in 2024, focusing on 98 participants from the Phase 2 trial who had elevated liver fat at baseline. The results were remarkable:

• Liver fat reduction at 24 weeks: −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg), −82.4% (12 mg) vs +0.3% (placebo)
• Liver fat reduction at 48 weeks: −81.7% (8 mg), −86.0% (12 mg) vs +4.6% (placebo)
• Normal liver fat (<5%) achieved at 48 weeks: 89% (8 mg) and 93% (12 mg) vs 0% (placebo)

These liver fat reductions were the largest ever reported for a pharmacological intervention in MASLD, and they correlated strongly with improvements in insulin sensitivity, liver function markers, and lipid metabolism. This data directly led to the inclusion of MASLD as a target indication in Lilly’s Phase 3 programme.

Phase 3: TRIUMPH-1 - Obesity and Overweight

ClinicalTrials.gov: NCT05929066

TRIUMPH-1 is the centrepiece of the registrational programme - the trial most likely to form the basis of regulatory submissions to the FDA and MHRA for an obesity indication. It is a Phase 3, multicentre, randomised, double-blind, placebo-controlled study evaluating retatrutide in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related complication.

What we know:

• Estimated enrolment: 2,300 participants
• Duration: Approximately 89 weeks, with up to 24 visits
• Nested protocols: Subsets of participants with knee osteoarthritis or obstructive sleep apnoea are being evaluated within the same trial framework
• Optional extension: Approximately 500 participants may continue treatment for an additional 24 weeks to study maintenance dosing
• Primary endpoint: Percentage change from baseline in body weight
• Expected completion: Results anticipated in 2026

Given the Phase 2 results showing 24.2% weight loss at 48 weeks (with the curve still declining), and the TRIUMPH-4 results showing 28.7% at 68 weeks, TRIUMPH-1 is expected to demonstrate even larger absolute weight losses over its longer treatment period.

Phase 3: TRIUMPH-2 - Type 2 Diabetes

ClinicalTrials.gov: NCT05929079

TRIUMPH-2 evaluates retatrutide in people with type 2 diabetes who are obese or overweight. This trial is particularly important because it will determine whether retatrutide can serve as both a weight management and glucose-lowering therapy - potentially replacing or complementing existing diabetes medications.

What we know:

• Estimated enrolment: Approximately 1,000 participants
• Duration: Approximately 89 weeks
• Includes: A subset of participants with obstructive sleep apnoea
• Key endpoints: HbA1c change, percentage body weight change, and proportion of participants achieving HbA1c <7.0% and ≤6.5%
• Expected completion: Mid-2026

The Phase 2 diabetes trial showed HbA1c reductions of up to 2.0% - substantially better than dulaglutide (a GLP-1 agonist already approved for type 2 diabetes). If TRIUMPH-2 confirms these results at scale, retatrutide could become a first-line therapy for people with both type 2 diabetes and obesity.

Phase 3: TRIUMPH-3 - Cardiovascular and Renal Outcomes

ClinicalTrials.gov: NCT06383390

TRIUMPH-3, sometimes referred to as the TRIUMPH-Outcomes trial, is a large cardiovascular and renal outcomes study. Unlike the other TRIUMPH trials that focus on weight loss as a primary endpoint, this trial is designed to determine whether retatrutide reduces the risk of major adverse cardiovascular events (MACE) and renal outcomes in people with established cardiovascular disease.

What we know:

• Population: Obese individuals with prior myocardial infarction or established cardiovascular disease
• Primary endpoints: Major adverse cardiovascular events (cardiovascular death, heart attack, stroke) and renal outcomes
• Study duration: Event-driven trial (likely to run for several years)
• Expected results: 2026 or later

Cardiovascular outcomes trials are increasingly important in obesity medicine. Semaglutide’s SELECT trial demonstrated a 20% reduction in MACE, which broadened its prescribing indications significantly. If retatrutide achieves similar or superior cardiovascular protection, it would be a major commercial and clinical advantage.

Early signals are encouraging: TRIUMPH-4 showed clinically meaningful reductions in non-HDL cholesterol, high-sensitivity C-reactive protein, triglycerides, and systolic blood pressure (reduced by 14.0 mmHg at the 12 mg dose).

Phase 3: TRIUMPH-4 - The First Phase 3 Results

ClinicalTrials.gov: NCT05931367

TRIUMPH-4 was the first TRIUMPH trial to report results, with topline data announced by Eli Lilly in December 2025. It is a 68-week, Phase 3, randomised, double-blind, placebo-controlled study evaluating retatrutide in 445 adults with obesity or overweight and moderate-to-severe knee osteoarthritis, without diabetes.

Participants were randomised 1:1:1 to receive retatrutide 9 mg, retatrutide 12 mg, or placebo. Mean baseline body weight was 112.7 kg.

Weight Loss Results

• Retatrutide 9 mg: −26.4% body weight (−29.1 kg) vs −2.1% (−2.1 kg) placebo
• Retatrutide 12 mg: −28.7% body weight (−32.3 kg / 71.2 lbs) vs −2.1% placebo
• Both doses met all primary and key secondary endpoints

Knee Osteoarthritis Outcomes

• WOMAC pain score reduction: up to −4.5 points (−75.8%) with retatrutide vs −2.4 points (−40.3%) with placebo
• 14.1% (9 mg) and 12.0% (12 mg) of participants became completely pain-free, compared with 4.2% on placebo

Cardiovascular Risk Factors

• Clinically meaningful improvements in non-HDL cholesterol, hs-CRP, and triglycerides
• Systolic blood pressure reduced by 14.0 mmHg at the 12 mg dose

Safety Profile

As with earlier trials, the most common adverse events were gastrointestinal:

• Nausea: 43%
• Diarrhoea: 33%
• Vomiting: 21%
• Discontinuation rates: 12.2% (9 mg) and 18.2% (12 mg) vs 4.0% (placebo). Some discontinuations were attributed to “perceived excessive weight loss.”

A new safety signal emerged: dysesthesia (an abnormal, unpleasant skin sensation) was reported in 8.8% of the 9 mg group and 20.9% of the 12 mg group, compared with just 0.7% on placebo. While generally mild and rarely leading to discontinuation, this is a novel finding not seen in Phase 2 trials and will be closely monitored in subsequent readouts.

MASLD/Fatty Liver Disease: The Liver Breakthrough

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as NAFLD/NASH, affects approximately 1 in 3 adults in the UK and is a leading cause of liver disease. There are currently very few approved treatments, making retatrutide’s liver data exceptionally significant.

The Phase 2a liver sub-study (Harrison et al., Nature Medicine 2024) demonstrated that retatrutide produced the most dramatic liver fat reductions ever recorded for a drug treatment:

Eli Lilly has included MASLD as a target indication in its Phase 3 programme, with a dedicated liver disease trial (NCT06859268) expected to report results in 2026. This trial will evaluate whether retatrutide can resolve steatohepatitis (liver inflammation) and fibrosis, not just reduce liver fat, which would be required for regulatory approval in MASLD specifically.

The glucagon receptor agonism in retatrutide is believed to be a key contributor to these liver benefits. Glucagon promotes hepatic fat oxidation (the liver’s ability to burn stored fat), which is not a mechanism present in GLP-1-only or dual GIP/GLP-1 agonists like semaglutide and tirzepatide.

How Retatrutide Compares: TRIUMPH vs STEP vs SURMOUNT

The obesity treatment landscape now has three major trial programmes to compare. While head-to-head trials between all three drugs have not been conducted, cross-trial comparisons give a clear picture of relative efficacy:

Key takeaway: Retatrutide’s triple agonism appears to produce substantially greater weight loss than either single or dual agonists, with the addition of glucagon receptor activation also driving superior liver fat reduction. However, cross-trial comparisons have inherent limitations - different patient populations, study designs, and endpoints make direct comparison imperfect. A head-to-head trial would be needed for definitive conclusions.

What Comes Next? Regulatory Timeline

As of early 2026, the regulatory path for retatrutide is becoming clearer but remains subject to trial outcomes:

• December 2025: TRIUMPH-4 reported first successful Phase 3 results
• Throughout 2026: Seven additional Phase 3 readouts expected, including TRIUMPH-1 (the important obesity trial), TRIUMPH-2 (type 2 diabetes), and MASLD data
• Q4 2026 / Q1 2027 (estimated): New Drug Application (NDA) submission to the FDA
• Late 2027 (estimated): Potential FDA approval (10-month standard review timeline)
• 2027–2028 (estimated): MHRA approval in the UK (typically 6–12 months after FDA)
• 2028–2029 (estimated): NICE technology appraisal and potential NHS coverage

Important caveat: No official regulatory timeline has been confirmed by Eli Lilly or any regulatory agency. These estimates are based on typical drug development timelines and analyst projections. Unexpected safety signals, manufacturing challenges, or regulatory requests for additional data could delay the timeline.

Blood Tests in Clinical Trials: What Researchers Monitored

Across all retatrutide clinical trials, researchers relied on comprehensive blood testing to track both the efficacy and safety of the drug. The biomarkers monitored in these trials are the same ones that anyone on a weight management programme, whether medicated or not, should track regularly:

• HbA1c (glycated haemoglobin): The primary endpoint in the diabetes trials. Measures average blood sugar control over 2–3 months. Essential for anyone with or at risk of type 2 diabetes.
• Liver function markers (ALT, AST, GGT): Monitored extensively in the MASLD sub-study and across all trials. Elevated liver enzymes can indicate liver stress, inflammation, or fatty liver disease.
• Lipid panel (total cholesterol, LDL, HDL, triglycerides): TRIUMPH-4 showed significant improvements in non-HDL cholesterol and triglycerides. These markers are critical for assessing cardiovascular risk.
• Kidney function (creatinine, eGFR): Monitored across all trials, and a primary focus in TRIUMPH-3. Weight loss medications can affect kidney function, and renal health is closely linked to both diabetes and cardiovascular disease.
• Inflammatory markers (hs-CRP): High-sensitivity C-reactive protein was significantly reduced in TRIUMPH-4, reflecting decreased systemic inflammation with weight loss.
• Fasting glucose and insulin: Monitored to assess improvements in insulin resistance, a key driver of both obesity and type 2 diabetes.

For a more detailed panel that also includes vitamins, hormones, and advanced metabolic markers, our Peak Insights 70 test covers 70 biomarkers — providing a thorough baseline that mirrors the breadth of monitoring used in Phase 3 clinical research.

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