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Retatrutide Phase 3 TRIUMPH Program: A Trial-by-Trial Research Index

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PBIPeptide Bio Index Editorial DeskSource-labeled research summary
Source-limited10 min readUpdated Sep 4, 2026
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  1. Program overview (TRIUMPH Phase 3 program design)
  2. TRIUMPH-1 and TRIUMPH-2 (weight-management basket trials with OSA and OA nesting)
  3. TRIUMPH-3 (weight management in a cardiovascular-disease population)
  4. TRIUMPH-4 (stand-alone knee osteoarthritis trial)
  5. Phase 2 evidence that informed phase 3 dose selection
  6. Safety and tolerability signals reported in phase 2
  7. What to expect from the TRIUMPH Phase 3 program (reporting and endpoints)
  8. Reported study-design details from cited sources
  9. Limitations and research gaps
  10. Documentation checklist
  11. Related research supplies
  12. More Retatrutide research
  13. Sources and references

Disclosure: Peptide Bio Index is affiliated with SourcePoint Research and may earn from qualifying purchases or affiliate links.

This article summarizes published research and reported study designs. It is not medical advice, dosing guidance, or a personal-use recommendation.

Source-limited research note: The reviewed sources were incomplete, ambiguous, or insufficient for a normal article. This page labels missing details rather than guessing.

This trial-by-trial research index compiles the publicly reviewed, peer-reviewed descriptions of the TRIUMPH Phase 3 clinical-development program for retatrutide and the phase 2 data that informed it. The index focuses on trial design features reported in the reviewed sources (trial structure, primary endpoints, populations) and on phase 2 efficacy/safety evidence cited by the program designers. This document does not report any Phase 3 results (none are published in the reviewed records).

Program overview (TRIUMPH Phase 3 program design)

TRIUMPH is a registrational clinical-development program described as four Phase 3, multicenter, randomized, double-blind studies of once-weekly subcutaneous retatrutide versus placebo conducted in conjunction with healthy-diet and physical-activity interventions, with a planned combined enrollment of over 5,800 participants (program-level enrollment figure reported in the trial-design publication). [S4]

The program uses a basket-trial approach that evaluates weight-management outcomes and nests protocols for two adiposity-related complications (obstructive sleep apnea and knee osteoarthritis) within weight-management trials, while also including a dedicated trial in a cardiovascular-disease population and a stand-alone osteoarthritis trial. [S4]

TRIUMPH-1 and TRIUMPH-2 (weight-management basket trials with OSA and OA nesting)

TRIUMPH-1 and TRIUMPH-2 are described as weight-management 'basket' trials that include nested study protocols evaluating retatrutide for obstructive sleep apnea (OSA) and/or knee osteoarthritis (OA) within the weight-management framework. [S4]

At the basket level the primary endpoint for weight management is percent change in body weight; the OSA nested protocol uses change in the Apnea–Hypopnea Index as its primary endpoint, and the OA nested protocol uses change in the WOMAC pain subscale score as its primary endpoint. [S4]

TRIUMPH-3 (weight management in a cardiovascular-disease population)

TRIUMPH-3 is described as a weight-management Phase 3 study specifically recruiting participants with cardiovascular disease (CVD) to evaluate safety and efficacy of weekly subcutaneous retatrutide versus placebo, with percent change in body weight designated as the weight-management primary endpoint. [S4]

TRIUMPH-4 (stand-alone knee osteoarthritis trial)

TRIUMPH-4 is described as a stand-alone knee osteoarthritis trial within the overall program; the primary knee-OA endpoint is the WOMAC pain subscale score (Western Ontario and McMaster Universities Osteoarthritis Index). [S4]

Phase 2 evidence that informed phase 3 dose selection

Multiple phase 2 randomized trials of retatrutide reported dose-dependent, clinically meaningful reductions in body weight and improvements in metabolic measures that the program designers cited when selecting phase 3 doses. In a 48-week phase 2 obesity trial, least-squares mean percent weight changes at 48 weeks were −8.7% (1 mg), −17.1% (combined 4 mg), −22.8% (combined 8 mg), and −24.2% (12 mg) versus −2.1% with placebo (reported in the NEJM phase 2 obesity randomized trial publication). [S1] [S7] [S6]

In a phase 2 diabetes trial, retatrutide produced dose-dependent HbA1c reductions at 24 weeks and dose-dependent bodyweight reductions at 36 weeks (examples reported included ~16–17% weight reduction at higher tested doses versus ~3% with placebo at 36 weeks), and those phase 2 data were reported to have informed phase 3 dose selection. [S7]

In a randomized phase 2a substudy in participants with metabolic dysfunction-associated steatotic liver disease, 24-week reductions in liver fat were dose-dependent (examples reported included −81.4% at 8 mg and −82.4% at 12 mg versus +0.3% with placebo), and liver-fat normalization rates at 24 weeks were higher at the higher retatrutide doses. [S6]

Safety and tolerability signals reported in phase 2

Phase 2 reports consistently describe predominantly gastrointestinal adverse events (nausea, diarrhea, vomiting, constipation) that were dose-related and mostly mild to moderate; in the obesity phase 2 trial these events were partially mitigated by using a lower starting dose in escalation schedules, and dose-dependent increases in heart rate were observed that peaked around 24 weeks and declined thereafter. [S1] [S7] [S6]

In the phase 2 diabetes trial, gastrointestinal adverse events occurred across retatrutide dose groups at higher frequency than placebo, and no severe hypoglycaemia or deaths were reported during that study. [S7]

What to expect from the TRIUMPH Phase 3 program (reporting and endpoints)

The TRIUMPH program is framed as a registrational effort to evaluate retatrutide for obesity and two related complications (OSA and knee OA) using randomized, double-blind, placebo-controlled trials with prespecified primary endpoints and type I error control across the basket design; peer-reviewed reporting of TRIUMPH trial results was not included in the reviewed program-design manuscript (the reviewed program-design record describes the trials but does not present Phase 3 results). [S4] [S2]

The TRIUMPH manuscript reports that the program-wide type I error rate is controlled at α = 0.05 and is split between the overarching weight-management analysis and each nested basket trial, reflecting a pre-specified multiplicity control plan described for the program. [S4]

Reported study-design details from cited sources

The following table summarizes protocol details reported in cited studies. These details are provided as literature context only and are not recommendations or instructions.

Source Study Type Model / Subject Amount Reported Route Reported Frequency Duration Notes
[S4] Phase 3, randomized, double-blind, placebo-controlled (basket trial with nested OSA/OA protocols) Weight management basket trial participants (TRIUMPH-1; adults with obesity; OSA/OA protocols nested) not reported in the reviewed source subcutaneous once weekly not reported in the reviewed source Primary endpoint for weight management: percent change in body weight. OSA primary endpoint: change in Apnea–Hypopnea Index. OA primary endpoint: WOMAC pain subscale. Program-level enrollment reported as part of the multi-trial design.
[S4] Phase 3, randomized, double-blind, placebo-controlled (basket trial with nested OSA/OA protocols) Weight management basket trial participants (TRIUMPH-2; adults with obesity; OSA/OA protocols nested) not reported in the reviewed source subcutaneous once weekly not reported in the reviewed source Primary endpoint for weight management: percent change in body weight. OSA primary endpoint: change in Apnea–Hypopnea Index. OA primary endpoint: WOMAC pain subscale.
[S4] Phase 3, randomized, double-blind, placebo-controlled (CVD subgroup weight-management trial) Weight management in participants with cardiovascular disease (TRIUMPH-3) not reported in the reviewed source subcutaneous once weekly not reported in the reviewed source Primary endpoint: percent change in body weight. Designed to assess safety and efficacy in a CVD population.
[S4] Phase 3, randomized, double-blind, placebo-controlled (stand-alone OA trial) Stand-alone knee osteoarthritis trial participants (TRIUMPH-4) not reported in the reviewed source subcutaneous once weekly not reported in the reviewed source Primary endpoint: change in WOMAC pain subscale score.
[S1] Phase 2, randomized, double-blind, placebo-controlled trial (obesity) Adults with obesity (BMI ≥30 or BMI 27– 1 mg, 4 mg (with different starting-dose escalation schedules), 8 mg (with different starting-dose escalation schedules), and 12 mg (varied starting dose schedules) as once-weekly maintenance doses (dosing schedules and starting-dose escalation details reported in the source). subcutaneous once weekly 48 weeks Primary endpoint reported as percent change in body weight at 24 weeks; secondary endpoints included 48-week weight change and categorical weight-loss thresholds. Safety assessed; gastrointestinal adverse events dose-related; heart-rate increases noted (peak at 24 weeks).
[S7] Phase 2, randomized, double-blind, placebo- and active-controlled (dulaglutide) trial in type 2 diabetes Adults with type 2 diabetes (HbA1c 7.0–10.5%, BMI 25–50 kg/m2) Reported maintenance doses included 0.5 mg, 4 mg (with and without escalation), 8 mg (with different escalation schedules), and 12 mg (escalation schedules reported); initial starting doses varied by escalation arm (details provided in the source). subcutaneous once weekly 24 weeks (primary endpoint); 36 weeks reported for some secondary endpoints Primary endpoint: change in HbA1c at 24 weeks; secondary endpoints included change in HbA1c and bodyweight at 36 weeks. Safety assessed; GI adverse events reported more frequently with active doses.
[S6] Phase 2a, randomized, double-blind, placebo-controlled trial (liver-fat substudy nested within phase 2 obesity trial) Participants with metabolic dysfunction-associated steatotic liver disease and ≥10% liver fat 1 mg, 4 mg, 8 mg, and 12 mg once-weekly maintenance doses reported in the source. subcutaneous once weekly 48 weeks (trial-wide); primary liver-fat substudy reported at 24 weeks Primary objective of the substudy: mean relative change from baseline in liver fat at 24 weeks. Liver-fat reductions reported to be dose-dependent and correlated with bodyweight and metabolic changes.

Limitations and research gaps

  • The reviewed program-design publication (S4) describes Phase 3 protocols but does not report any Phase 3 results; all TRIUMPH outcome data are unavailable in the reviewed records.
  • Dose, escalation schedule, exact per-trial sample sizes, statistical analysis plans beyond the high-level multiplicity control, and treatment durations for the Phase 3 TRIUMPH trials are not fully reported in the reviewed program-design record (details are reported as 'not reported in the reviewed source' in protocol rows where applicable).
  • Phase 2 efficacy and safety findings derive from separate randomized trials in selected populations (obesity, type 2 diabetes, and participants with metabolic steatotic liver disease) and should not be assumed to predict Phase 3 results or safety profile in all TRIUMPH populations.

Documentation checklist

  • This index summarizes design elements of the TRIUMPH Phase 3 program as described in the reviewed peer-reviewed trial-design record.
  • Phase 3 TRIUMPH trials are randomized, double-blind, placebo-controlled and evaluate weekly subcutaneous retatrutide plus lifestyle counseling versus placebo plus lifestyle counseling.
  • Primary endpoints vary by nested indication: percent change in body weight (weight management), Apnea–Hypopnea Index (OSA), and WOMAC pain subscale (knee OA).
  • Phase 2 randomized trials reported dose-dependent weight loss and metabolic effects that were used to inform phase 3 dose selection.
  • Published phase 2 data describe dose-related gastrointestinal adverse events and transient increases in heart rate.
  • temperature-monitored investigational-product storage unit (per manufacturer labeling and trial pharmacy procedures)
  • trial drug accountability and dispensing logs (investigator site documentation)
  • randomization and blinding kit materials (trial-specific labeling and code envelopes per protocol)
  • clinical data capture and electronic case-report form (eCRF) systems
  • surface disinfectant wipes and clinical-area cleaning supplies (site environmental controls)

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More Retatrutide research

Sources and references

  1. [S1] Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial.. The New England journal of medicine. 2023. PMID: 37366315. DOI: 10.1056/NEJMoa2301972
  2. [S2] Katsi V, Koutsopoulos G, Fragoulis C, Dimitriadis K, Tsioufis K. Retatrutide-A Game Changer in Obesity Pharmacotherapy.. Biomolecules. 2025. PMID: 40563436. DOI: 10.3390/biom15060796
  3. [S3] Drucker DJ. Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity.. Diabetes care. 2024. PMID: 38843460. DOI: 10.2337/dci24-0003
  4. [S4] Giblin K, Kaplan LM, Somers VK, Le Roux CW, Hunter DJ, Wu Q. Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials.. Diabetes, obesity & metabolism. 2026. PMID: 41090431. DOI: 10.1111/dom.70209
  5. [S5] Locatelli JC, Costa JG, Haynes A, Naylor LH, Fegan PG, Yeap BB. Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition?. Diabetes care. 2024. PMID: 38687506. DOI: 10.2337/dci23-0100
  6. [S6] Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.. Nature medicine. 2024. PMID: 38858523. DOI: 10.1038/s41591-024-03018-2
  7. [S7] Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA.. Lancet (London, England). 2023. PMID: 37385280. DOI: 10.1016/S0140-6736(23)01053-X
  8. [S8] Melson E, Ashraf U, Papamargaritis D, Davies MJ. What is the pipeline for future medications for obesity?. International journal of obesity (2005). 2025. PMID: 38302593. DOI: 10.1038/s41366-024-01473-y

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