Retatrutide Phase 3 TRIUMPH Programme: A 2026 UK Research Reference to the Trial Arms, Endpoints, Readouts and Implications

Last updated: April 2026 · UK research-grade reference · For laboratory research use only — not for human consumption

Table of Contents

• 1. Why TRIUMPH matters — the Phase 3 stakes
• 2. TRIUMPH-1 — obesity without T2DM
• 3. TRIUMPH-2 — obesity with comorbidities
• 4. TRIUMPH-3 — type 2 diabetes
• 5. TRIUMPH-4 — MASH biopsy endpoints
• 6. TRIUMPH-OSA — obstructive sleep apnoea
• 7. TRIUMPH-Outcomes — cardiovascular outcomes
• 8. Head-to-head arms vs tirzepatide and semaglutide
• 9. Primary and secondary endpoint matrix
• 10. Expected readout timelines
• 11. Phase 3 outcome extrapolation from Phase 2
• 12. Implications for UK research direction
• 13. Frequently asked questions
• 14. References

1. Why TRIUMPH matters — the Phase 3 stakes

Phase 2 results for retatrutide (Jastreboff 2023, Rosenstock 2023, Sanyal 2024) set a remarkable efficacy baseline across obesity, T2DM and MASLD. The Phase 3 TRIUMPH programme is the scaled confirmation — powered to definitively characterise efficacy and safety at n > 10,000 across multiple indications simultaneously. The breadth of the TRIUMPH programme is itself distinctive: rather than a single-indication sequential approval path, Lilly is running obesity, T2DM, MASH, OSA and CVOT in parallel, which accelerates the confirmation timeline but also commits significant resource to an investigational molecule.

For UK research scientists, the TRIUMPH readouts of 2026-2028 will determine the direction of retatrutide research for the rest of the decade. If Phase 2 efficacy holds at Phase 3 scale, retatrutide becomes the reference triple-agonist molecule for a generation of comparator studies. If it doesn’t, the Phase 2 trajectory will need to be reinterpreted carefully.

2. TRIUMPH-1 — obesity without T2DM

TRIUMPH-1 (NCT05929079) is the flagship obesity trial:

• Population: adults with BMI ≥ 30, or ≥ 27 with weight-related comorbidity (excluding T2DM)
• Enrolment: approximately 2,000 participants
• Intervention arms: placebo vs retatrutide at three target doses (commonly 4, 8, 12 mg weekly SC)
• Randomisation: stratified by sex and baseline BMI category
• Primary endpoint: percent change in body weight from baseline to week 80
• Key secondary endpoints: proportion achieving ≥ 5%, ≥ 10%, ≥ 15%, ≥ 20%, ≥ 25% weight loss; waist circumference; systolic BP; lipids; quality-of-life measures
• Primary readout: expected late 2026 / early 2027

The 80-week endpoint is meaningfully longer than SURMOUNT-1’s 72 weeks, giving retatrutide’s still-descending curve more time to reach terminal values.

3. TRIUMPH-2 — obesity with comorbidities

TRIUMPH-2 focuses on adults with obesity and at least one comorbidity other than T2DM (e.g., dyslipidaemia, hypertension, OSA, knee osteoarthritis, cardiovascular disease). Enrolment is larger than TRIUMPH-1, reflecting the broader real-world population. Primary endpoint mirrors TRIUMPH-1 (percent change in body weight to week 80), with enriched secondary endpoints addressing each comorbidity.

The TRIUMPH-2 population is the most clinically representative of the likely eventual treatment population — most adults with obesity carry at least one comorbidity. Its readout will most directly inform real-world efficacy expectations.

4. TRIUMPH-3 — type 2 diabetes

TRIUMPH-3 focuses on adults with T2DM on various baseline backgrounds:

• TRIUMPH-3 main cohort: on stable metformin, diet and exercise
• TRIUMPH-3 sub-cohorts: may include insulin-naive, insulin-requiring, and sulfonylurea-background sub-studies
• Dose range: broader than TRIUMPH-1, adding a 0.5 mg lower arm to calibrate the glycemic dose-response floor
• Primary endpoint: change in HbA1c at week 52 or 68
• Secondary endpoints: body weight, fasting plasma glucose, proportion achieving HbA1c < 7.0% and < 6.5%, time-in-range on continuous glucose monitoring sub-cohort

The parallel T2DM and obesity arms are typical for GLP-1-class Phase 3 programmes (compare STEP for semaglutide obesity + SUSTAIN for semaglutide T2DM; SURMOUNT + SURPASS for tirzepatide).

5. TRIUMPH-4 — MASH biopsy endpoints

TRIUMPH-4 (NCT05882045) is the histological-endpoint MASH trial:

• Population: adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) with fibrosis stages F2 or F3
• Enrolment: approximately 1,000-1,500 participants
• Intervention arms: placebo vs retatrutide 2 mg, 8 mg, 12 mg
• Primary endpoint: MASH resolution without worsening of fibrosis at week 52; improvement in fibrosis stage without worsening of MASH
• Secondary endpoints: liver fat by MRI-PDFF; non-invasive fibrosis markers (ELF, FibroScan); liver enzymes; body weight
• Readout: expected 2027-2028

The Phase 2 hepatic signal — > 80% liver fat reduction and 93% normalisation at 8-12 mg — was unprecedented. TRIUMPH-4’s biopsy endpoints are the rigorous test. A MASH resolution rate of 60-75% at 12 mg would place retatrutide at the top of the MASH pharmacotherapy pipeline.

6. TRIUMPH-OSA — obstructive sleep apnoea

A dedicated arm (TRIUMPH-OSA or equivalent sub-study) evaluates retatrutide in adults with moderate-to-severe obstructive sleep apnoea (AHI ≥ 15), following tirzepatide’s precedent with the SURMOUNT-OSA programme (which showed dramatic AHI reductions and led to the first MHRA/FDA approvals of a GLP-1-class molecule for OSA).

• Primary endpoint: change in apnoea-hypopnoea index (AHI) from baseline to week 52
• Secondary endpoints: proportion achieving AHI < 5; Epworth Sleepiness Scale; body weight

Expected readout 2027.

7. TRIUMPH-Outcomes — cardiovascular outcomes

TRIUMPH-Outcomes (NCT06265636 or equivalent) is the dedicated cardiovascular outcomes trial:

• Population: adults with obesity and either established cardiovascular disease or high cardiovascular risk
• Enrolment: approximately 13,000-18,000 participants (scale comparable to SELECT)
• Intervention: retatrutide (flexibly titrated) vs placebo
• Primary endpoint: time to first major adverse cardiovascular event (MACE) — composite of CV death, non-fatal MI, non-fatal stroke
• Duration: event-driven, typically 4-5 years
• Expected readout: 2028-2029

SELECT demonstrated a 20% relative risk reduction in MACE with semaglutide 2.4 mg in high-CV-risk obesity — a landmark finding. TRIUMPH-Outcomes will test whether retatrutide produces equivalent or superior cardiovascular risk reduction despite the modest heart-rate elevation.

8. Head-to-head arms vs tirzepatide and semaglutide

Lilly has, in past Phase 3 programmes (SURPASS for tirzepatide), included active-comparator arms against semaglutide. A retatrutide head-to-head vs tirzepatide is scientifically the most valuable comparator (same sponsor, shared dose-ranging methodology, closer mechanistic proximity). Trial registrations as of 2026 do not definitively indicate a large-scale head-to-head arm within the main TRIUMPH protocols, but sub-studies and supplementary arms may emerge.

For UK research purposes, cross-trial comparison with matched timepoints remains the primary analytical approach until a direct head-to-head is published.

9. Primary and secondary endpoint matrix

Across the TRIUMPH programme, endpoint themes include:

• Weight endpoints: percent change, categorical thresholds (≥ 5%, ≥ 10%, ≥ 15%, ≥ 20%, ≥ 25%)
• Glycemic endpoints: HbA1c change, proportion achieving thresholds, time-in-range
• Hepatic endpoints: MRI-PDFF liver fat, liver enzymes, biopsy-based histology (TRIUMPH-4), ELF/FibroScan
• Cardiometabolic endpoints: systolic BP, lipid panel, waist circumference, insulin sensitivity
• Patient-reported outcomes: quality of life, work productivity, physical function
• Cardiovascular endpoints: MACE composite (TRIUMPH-Outcomes), hospitalisation, all-cause mortality
• Safety endpoints: adverse event rates, treatment discontinuation, laboratory safety monitoring

10. Expected readout timelines

Approximate timeline as of 2026 (based on published trial protocol milestones):

• Late 2026: TRIUMPH-1 (obesity) topline
• Early 2027: TRIUMPH-2 (obesity + comorbidities) topline
• Mid 2027: TRIUMPH-3 (T2DM) topline; TRIUMPH-OSA topline
• Late 2027 / early 2028: TRIUMPH-4 (MASH) primary analysis
• 2028-2029: TRIUMPH-Outcomes CVOT readout
• Rolling through 2028-2030: extended safety data, sub-population analyses, pooled integrated safety summaries

Any of these timelines can shift based on enrolment pace, event-accrual rates in the CVOT, or regulatory requests for supplementary data.

11. Phase 3 outcome extrapolation from Phase 2

Based on Phase 2 Phase trajectories, reasonable Phase 3 outcome expectations:

• TRIUMPH-1 (obesity): mean weight loss at 12 mg of −28% to −32% at week 80 (Phase 2 showed −24.2% at week 48 with no plateau).
• TRIUMPH-3 (T2DM): HbA1c reduction sustained around −2.0% at 12 mg; > 90% achieving < 7.0%.
• TRIUMPH-4 (MASH): MASH resolution in 60-75% at 8-12 mg; fibrosis improvement in 35-50%.
• TRIUMPH-OSA: AHI reduction of 50-60% at 8-12 mg; > 50% achieving AHI < 5.
• TRIUMPH-Outcomes: MACE reduction of 20-30% in high-risk obesity, subject to CVOT duration and event accrual.

These are extrapolations — not predictions — and the actual Phase 3 readouts will be the definitive reference. Plausible downside scenarios include higher discontinuation rates at 12 mg (diluting the per-protocol effect) or a plateau pattern emerging between weeks 52 and 80 that pulls the terminal weight loss value closer to the tirzepatide benchmark.

12. Implications for UK research direction

If TRIUMPH confirms Phase 2 trajectories, UK research implications include:

• Shift in comparator hierarchy: retatrutide becomes the benchmark triple-agonist molecule for comparator work, replacing tirzepatide as the reference in obesity/metabolic research.
• Mechanistic research expansion: glucagon-receptor agonism becomes a primary focus area for molecular and physiological studies given the distinct energy-expenditure and hepatic mobilisation signatures.
• MASH pipeline repositioning: if TRIUMPH-4 shows > 60% MASH resolution, retatrutide becomes the primary candidate for MASH research protocols.
• Quadruple-agonist and beyond: research interest in GLP-1/GIP/glucagon/amylin quadruple agonists and related combinations will intensify.
• Research-grade supply: demand for high-purity retatrutide research batches will rise; suppliers meeting the ≥ 99% HPLC standard will have a structural advantage.

13. Frequently asked questions

When will the first Phase 3 retatrutide results be published?

TRIUMPH-1 topline results are expected in late 2026 or early 2027, with full publication shortly thereafter.

What is the primary endpoint of TRIUMPH-1?

Percent change in body weight from baseline to week 80 — two weeks longer than SURMOUNT-1 and significantly longer than STEP-1.

Does TRIUMPH include a head-to-head vs tirzepatide?

As of 2026 trial registrations, no dedicated full-scale head-to-head against tirzepatide is announced within the main TRIUMPH protocols. Sub-studies or supplementary arms may emerge.

What MASH outcome will TRIUMPH-4 target?

MASH resolution without worsening of fibrosis, and improvement in fibrosis stage without worsening of MASH — the standard FDA/EMA histological endpoints for MASH pharmacotherapy approval.

Is there a Phase 3 paediatric or adolescent retatrutide programme?

Paediatric / adolescent protocols are typically initiated after adult Phase 3 data mature. Adolescent obesity trials for semaglutide (STEP-TEENS) and tirzepatide have been completed or are in progress; a retatrutide adolescent arm is expected but not currently the primary TRIUMPH focus.

How will the CVOT readout compare to SELECT?

TRIUMPH-Outcomes is powered similarly to SELECT and uses an equivalent MACE composite endpoint. Expected outcome: cardiovascular risk reduction comparable to or exceeding the 20% RRR observed with semaglutide in SELECT.

What happens to the retatrutide Phase 2 cohort now?

Phase 2 participants typically enter long-term extension protocols that contribute multi-year safety and durability data to the regulatory dossier alongside the Phase 3 readouts.

14. References

1. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med 2023;389:514-526.
2. Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial. Lancet 2023;402:529-544.
3. Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for MASLD: a randomized phase 2a trial. Nature Medicine 2024;30:2037-2048.
4. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med 2022;387:205-216. (SURMOUNT-1 benchmark)
5. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 2023;389:2221-2232. (SELECT benchmark)
6. Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med 2024;391:299-310. (SYNERGY-NASH benchmark)
7. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. N Engl J Med 2024;391:1193-1205. (SURMOUNT-OSA benchmark)
8. Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist: From discovery to clinical proof of concept. Cell Metab 2022;34:1234-1247.e9.
9. Eli Lilly and Company. Clinical development update presentations 2024-2025 (publicly disclosed materials).
10. ClinicalTrials.gov: NCT05929079 (TRIUMPH-1), NCT05929092 (TRIUMPH-2), NCT05929066 (TRIUMPH-3), NCT05882045 (TRIUMPH-4), NCT06265636 (TRIUMPH-Outcomes CVOT).

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