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Retatrutide Trial Endpoints Explained: Primary, Secondary, and Responder Measures

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PBIPeptide Bio Index Editorial DeskSource-labeled research summary
Source-limited10 min readUpdated Sep 9, 2026
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  1. Overview: endpoint categories used in retatrutide trials
  2. Primary endpoints reported in key phase 2 studies
  3. Secondary and exploratory endpoints commonly used
  4. Responder measures and typical thresholds reported
  5. Safety, tolerability, and safety-related endpoints reported alongside efficacy
  6. Trial design features that affect endpoint interpretation
  7. Implications for ongoing development and evidence gaps
  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 deep dive summarizes how retatrutide trial endpoints have been defined and measured in reported phase 2 studies and associated substudy and review literature, with emphasis on primary endpoints, secondary/exploratory endpoints, and the responder thresholds used to classify weight-loss outcomes.

Overview: endpoint categories used in retatrutide trials

Published phase 2 trials and substudies of retatrutide have used conventional clinical-trial endpoint categories: primary endpoints focused on a single prespecified efficacy measure (for example, percentage change in body weight or change in HbA1c at a defined week), secondary endpoints that extend efficacy assessment over longer timepoints or different measures (for example, bodyweight at additional weeks), and responder measures that report the proportions of participants meeting predefined percent weight-loss thresholds; systematic reviews and meta-analyses have synthesized these endpoints across trials. (Sources: definitions and endpoint framing in the phase 2 obesity and diabetes trials, and pooled reviews.) [S2] [S3] [S5] [S7]

Primary endpoints reported in key phase 2 studies

In the phase 2 obesity trial reported in NEJM, the prespecified primary endpoint was the percentage change in body weight from baseline to 24 weeks. (S2) [S2]

In the phase 2 trial conducted in people with type 2 diabetes and reported in Lancet, the prespecified primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to 24 weeks. (S3) [S3]

The body-composition substudy prespecified a different primary endpoint: percent change from baseline to week 36 in total fat mass measured by dual-energy X-ray absorptiometry (DXA). (S5) [S5]

Secondary and exploratory endpoints commonly used

In the obesity phase 2 trial, secondary endpoints included percentage change in body weight at 48 weeks and categorical responder outcomes (the proportions achieving ≥5%, ≥10%, or ≥15% weight loss), in addition to safety assessments. (S2) [S2]

In the type 2 diabetes phase 2 trial, secondary endpoints included change in HbA1c and bodyweight at 36 weeks, with efficacy comparisons to an active comparator (dulaglutide) in addition to placebo. (S3) [S3]

The body-composition substudy treated DXA-derived percent change in total fat mass at week 36 as the prespecified primary substudy endpoint and also reported lean-mass outcomes relative to total weight loss. (S5) [S5]

Responder measures and typical thresholds reported

Responder measures in the reported trials used categorical thresholds of percent body-weight reduction: commonly ≥5%, ≥10%, and ≥15% (and in pooled analyses sometimes ≥20%). The NEJM phase 2 obesity trial reported the proportions achieving these thresholds at 48 weeks by dose arm, and a systematic review/meta-analysis summarized increases in the proportions meeting these thresholds versus placebo across trials. (S2; S7) [S2] [S7]

Example responder results from the NEJM obesity trial at 48 weeks (by dose, as reported): for the pooled 4 mg group 92% achieved ≥5%, 75% ≥10%, and 60% ≥15%; for the pooled 8 mg group 100% ≥5%, 91% ≥10%, and 75% ≥15%; for the 12 mg group 100% ≥5%, 93% ≥10%, and 83% ≥15%; and for placebo 27% ≥5%, 9% ≥10%, and 2% ≥15%. (S2) [S2]

A pooled meta-analysis of randomized trials reported increased relative rates of achieving these responder thresholds with once-weekly subcutaneous retatrutide versus placebo (statistical estimates were provided in the meta-analysis for ≥5%, ≥10%, ≥15%, and ≥20% thresholds). (S7) [S7]

Safety endpoints in the NEJM phase 2 obesity trial included adverse-event reporting, with gastrointestinal events the most common and described as dose-related; the report also documented dose-dependent increases in heart rate that peaked at 24 weeks and declined thereafter. (S2) [S2]

In the type 2 diabetes phase 2 trial and the body-composition substudy, investigators reported rates of mild-to-moderate gastrointestinal adverse events and other safety outcomes across arms, noted no severe hypoglycaemia or deaths in the diabetes trial, and reported overall adverse-event frequencies by dose group in the substudy. (S3; S5) [S3] [S5]

Systematic reviews and pooled analyses have highlighted that gastrointestinal adverse effects are the most consistently reported safety signals across trials and that phase 3 trials are expected to add longer-term safety data. (S7; S6) [S7] [S6]

Trial design features that affect endpoint interpretation

Key design elements across the reported phase 2 trials that influence endpoint interpretation include randomized, double-blind, placebo-controlled and (in one diabetes trial) active-comparator-controlled parallel-group designs; multiple fixed-dose retatrutide arms with specified starting-dose escalation regimens; once-weekly subcutaneous dosing; and prespecified analysis timepoints (24, 36, and 48 weeks depending on the endpoint and study). (S2; S3; S5) [S2] [S3] [S5]

Where body-composition endpoints were evaluated, a prespecified imaging modality (DXA) and defined on-treatment analysis set were used for the primary substudy endpoint. (S5) [S5]

Implications for ongoing development and evidence gaps

Reviews and pooled evidence note that phase 2 findings show robust, dose-dependent efficacy on weight and glycaemic endpoints, but that phase 3 programmes (for example, trials referenced as TRIUMPH in review summaries) are ongoing and will be needed to better define long-term efficacy, safety, and outcomes in broader populations; network and systematic reviews emphasize the need to balance efficacy endpoints with safety outcomes in comparative assessments. (S1; S6; S8) [S1] [S6] [S8]

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
[S2] Randomized, double-blind, placebo-controlled Phase II clinical trial (obesity population) Adults with obesity (BMI ≥30 or BMI 27- Dose arms included 1 mg; 4 mg (initial dose 2 mg or initial dose 4 mg); 8 mg (initial dose 2 mg or initial dose 4 mg); 12 mg (initial dose 2 mg) Subcutaneous Once weekly 48 weeks Primary endpoint prespecified as percent change in body weight from baseline to 24 weeks; secondary endpoints included percent change in body weight at 48 weeks, categorical weight-loss responder thresholds (≥5%, ≥10%, ≥15%), and safety assessments. Multiple dose arms were randomized including 1 mg, 4 mg (with different starting-dose regimens), 8 mg (with different starting-dose regimens), and 12 mg.
[S3] Randomized, double-blind, double-dummy, placebo- and active-controlled Phase II clinical trial (type 2 diabetes population) Adults with type 2 diabetes (age 18–75, HbA1c 7.0–10.5%, BMI 25–50 kg/m2), treated with diet/exercise ± stable metformin Maintenance dose arms included 0.5 mg, 4 mg (starting 2 mg or no escalation), 8 mg (starting 2 mg or starting 4 mg), and 12 mg (starting 2 mg) Subcutaneous Once weekly 24 weeks (primary endpoint at 24 weeks); efficacy also reported at 36 weeks Primary endpoint prespecified as change in HbA1c from baseline to 24 weeks; secondary endpoints included change in HbA1c and bodyweight at 36 weeks, and comparisons versus active comparator (dulaglutide 1.5 mg). Multiple retatrutide maintenance doses were randomized with specified starting-dose escalation regimens.
[S5] Phase II randomized, double-blind, parallel-group, placebo-controlled body-composition substudy Adults with type 2 diabetes enrolled in the body-composition substudy (subset of main Phase II trial participants; HbA1c 7.0–10.5%, BMI 25–50 kg/m2) Maintenance dose arms included 0.5 mg, 4 mg (2 mg initial dose or 4 mg initial dose), 8 mg (2 mg initial dose or 4 mg initial dose), and 12 mg Subcutaneous Once weekly 36 weeks (primary substudy endpoint measured at week 36) Prespecified primary substudy endpoint was percent change from baseline to week 36 in total fat mass measured by DXA; trial reported on-treatment analyses for participants with non-missing DXA scans and presented comparisons versus placebo and dulaglutide.

Limitations and research gaps

  • Most detailed endpoint data in the reviewed sources derive from phase 2 trials; longer-term and larger phase 3 outcome data were still pending in reviewed sources (review articles reference ongoing phase 3 programmes).
  • Heterogeneity of endpoint timepoints across studies (24, 36, and 48 weeks) complicates direct comparisons without careful attention to the prespecified primary and secondary timing.
  • Safety and rare-event assessment are limited by sample sizes and duration reported in phase 2 studies; pooled and phase 3 data will be required for a fuller safety profile.
  • Some syntheses (systematic reviews, meta-analyses, and network meta-analyses) pool across different populations (people with obesity alone vs people with type 2 diabetes), which can modify effect sizes and responder rates.

Documentation checklist

  • Confirm primary endpoint definition and timepoint in the protocol (e.g., percent change in body weight at 24 weeks vs change in HbA1c at 24 weeks).
  • Verify secondary and exploratory endpoint schedules (e.g., bodyweight at 36 or 48 weeks, DXA at week 36) before analysis.
  • Document responder thresholds used in reporting (≥5%, ≥10%, ≥15%, and when reported ≥20%) and the numerator/denominator for each timepoint.
  • Confirm exact dosing groups and any starting-dose escalation regimens as reported in each study arm.
  • Record adverse-event definitions, severity grading, and specific safety timepoints (e.g., heart-rate changes measured through week 24 and beyond).
  • Where body-composition endpoints are used, confirm imaging modality and analysis method (DXA was prespecified in the substudy).
  • Clinical trial protocol templates and endpoint definitions (editable document)
  • DXA imaging operator manual and calibration/quality-control logs
  • Cold-chain temperature monitoring logs for investigational-product storage
  • Case report forms (CRFs) and electronic data-capture templates for endpoint collection
  • Laboratory sample labeling supplies and tracking logs
  • Site filing and source-document organization materials
  • Surface disinfectant wipes and device-safe cleaning supplies for imaging rooms

Research organization supplies: Common tools used for research documentation workflows may include lab notebooks, label makers, sample storage boxes, inventory stickers, and temperature log sheets.

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More Retatrutide research

Sources and references

  1. [S1] 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
  2. [S2] 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
  3. [S3] 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
  4. [S4] Abdul-Rahman T, Roy P, Ahmed FK, Mueller-Gomez JL, Sarkar S, Garg N. The power of three: Retatrutide's role in modern obesity and diabetes therapy.. European journal of pharmacology. 2024. PMID: 39515565. DOI: 10.1016/j.ejphar.2024.177095
  5. [S5] Coskun T, Wu Q, Schloot NC, Haupt A, Milicevic Z, Khouli C. Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial.. The lancet. Diabetes & endocrinology. 2025. PMID: 40609566. DOI: 10.1016/S2213-8587(25)00092-0
  6. [S6] Misra S, Narayan RK, Kaur M. Efficacy and safety of retatrutide for the treatment of obesity: a systematic review of clinical trials.. Journal of basic and clinical physiology and pharmacology. 2025. PMID: 40728138. DOI: 10.1515/jbcpp-2025-0113
  7. [S7] Pasqualotto E, Ferreira ROM, Chavez MP, Hohl A, Ronsoni MF, Pasqualotto T. Effects of once-weekly subcutaneous retatrutide on weight and metabolic markers: A systematic review and meta-analysis of randomized controlled trials.. Metabolism open. 2024. PMID: 39318607. DOI: 10.1016/j.metop.2024.100321
  8. [S8] Sinha B, Ghosal S. Efficacy and Safety of GLP-1 Receptor Agonists, Dual Agonists, and Retatrutide for Weight Loss in Adults With Overweight or Obesity: A Bayesian NMA.. Obesity (Silver Spring, Md.). 2025. PMID: 40685589. DOI: 10.1002/oby.24360

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