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Peptide

Retatrutide (GLP-3 Triple Agonist)

Retatrutide (also known as GLP-3 or LY3437943) is an investigational triple hormone receptor agonist (GIP/GLP-1/glucagon) by Eli Lilly for obesity, T2DM, and MASLD. Phase 2: 24.2% weight loss at 48 weeks (NEJM 2023). Phase 3 TRIUMPH-4: 28.7% weight loss at 68 weeks. T2DM Phase 2: HbA1c reduction of 2.2%, 82% achieved HbA1c ≤6.5%. MASLD: 86% liver fat reduction at 48 weeks, 93% achieved <5% liver fat. SAFETY: GI side effects common - nausea (43%), diarrhea (33%), vomiting (21%). Dysesthesia reported in ~20% at higher doses. Seven Phase 3 readouts expected 2026.

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Best evidence
Grade A
Conditions studied
4
Outcomes
13
Graded outcomes
5413

Evidence by condition

  • Strong
  • Moderate
  • Limited
  • Very limited

4 conditions, plus general outcomes

Obesity

Obesity: outcomes studied for Retatrutide (GLP-3 Triple Agonist)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Body Weight Reduction

Phase 2 (n=338): 24.2% mean weight loss at 48 weeks with 12mg. 100% achieved ≥5%, 93% achieved ≥10%, 83% achieved ≥15% weight loss. Phase 3 TRIUMPH-4: 28.7% weight loss at 68 weeks. Most effective weight loss drug in clinical trials to date.

Improves (the measure goes down)Large effect23 studies

Studies that measured body weight reduction

and 13 more in the citations list

Gastrointestinal Side Effects

SAFETY CONCERN: Phase 3 TRIUMPH-4: Nausea 38-43%, diarrhea 33-35%, constipation 22-25%, vomiting 20-21%, decreased appetite 18-19%. Generally mild-moderate and manageable with dose titration. Higher dropout rates than placebo.

Worsens (the measure goes up)Moderate effect19 studies

Studies that measured gastrointestinal side effects

and 9 more in the citations list

Dysesthesia

SAFETY CONCERN: Unusual side effect - unpleasant skin sensations in ~20% at 12mg dose. Described as mild for most patients, rarely causing discontinuation. Mechanism unclear - may relate to glucagon receptor activation.

Worsens (the measure goes down)Small effect18 studies

Studies that measured dysesthesia

and 8 more in the citations list

Type 2 Diabetes

Type 2 Diabetes: outcomes studied for Retatrutide (GLP-3 Triple Agonist)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Glycemic Control (HbA1c)

Phase 2 T2DM (n=281): HbA1c reduction of 2.0-2.2% at 36 weeks. 82% achieved HbA1c ≤6.5%. Superior to 1.5mg dulaglutide comparator. Fasting glucose significantly improved across all doses.

Improves (the measure goes down)Large effect20 studies

Studies that measured glycemic control (hba1c)

and 10 more in the citations list

Fatty Liver Disease

  • Liver Fat Reduction: improves
Fatty Liver Disease: outcomes studied for Retatrutide (GLP-3 Triple Agonist)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Liver Fat Reduction

Phase 2a MASLD (n=98): 82-86% relative reduction in liver fat at 48 weeks with 8-12mg. 89-93% achieved normal liver fat (<5%). Driven by glucagon receptor activation promoting hepatic lipid oxidation.

Improves (the measure goes down)Large effect16 studies

Studies that measured liver fat reduction

and 6 more in the citations list

Osteoarthritis (OA)

  • Osteoarthritis Pain: improves
Osteoarthritis (OA): outcomes studied for Retatrutide (GLP-3 Triple Agonist)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Osteoarthritis Pain

Phase 3 TRIUMPH-4: WOMAC pain score reduced by 4.5 points (75.8%) at 68 weeks. 12% of patients on 12mg achieved complete pain freedom vs 4.2% placebo. Likely secondary to weight loss reducing joint stress.

Improves (the measure goes down)Large effect15 studies

Studies that measured osteoarthritis pain

and 5 more in the citations list

General

  • Blood Glucose Control: improves
  • Safety/Tolerability: improves
  • Kidney Function: improves
General: outcomes studied for Retatrutide (GLP-3 Triple Agonist)
GradeOutcomeEffectSizeStudiesPeopleStudies list
Blood Glucose Control

19 human trials and systematic reviews support this finding. Evidence includes systematic reviews/meta-analyses. Human clinical trial data available.

Improves (the measure goes down)Moderate effect19 studies

Studies that measured blood glucose control

and 9 more in the citations list

Safety/Tolerability

11 human trials and systematic reviews support this finding. Evidence includes systematic reviews/meta-analyses. Human clinical trial data available.

Improves (the measure goes up)Moderate effect16 studies

Studies that measured safety/tolerability

and 6 more in the citations list

Kidney Function

6 human trials and systematic reviews support this finding. Evidence includes systematic reviews/meta-analyses. Human clinical trial data available.

Improves (the measure goes up)Small effect11 studies

Studies that measured kidney function

and 1 more in the citations list

Liver Protection

6 systematic reviews and preclinical studies support this finding. Evidence includes systematic reviews/meta-analyses. Primarily preclinical evidence.

Improves (the measure goes up)Small effect11 studies

Studies that measured liver protection

and 1 more in the citations list

Anti-Cancer Activity

2 systematic reviews and preclinical studies support this finding. Evidence includes systematic reviews/meta-analyses. Primarily preclinical evidence.

Improves (the measure goes up)Small effect10 studies

Studies that measured anti-cancer activity

Muscle Mass/Function

2 preclinical studies support this finding. Primarily preclinical evidence.

Improves (the measure goes up)Small effect8 studies
GI Protection

2 preclinical studies support this finding. Primarily preclinical evidence.

Improves (the measure goes up)Small effect7 studies

Key findings

  • Body Weight ReductionObesityImproves (the measure goes down)
  • Glycemic Control (HbA1c)Type 2 DiabetesImproves (the measure goes down)
  • Gastrointestinal Side EffectsObesityWorsens (the measure goes up)

Safety notes in the studies

  • SAFETY CONCERN: Unusual side effect - unpleasant skin sensations in ~20% at 12mg dose.

Studies cited

61 studies from PubMed

  1. 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
  2. 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 trialLancet Diabetes Endocrinol, 2025 · PMID 40609566
  3. Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes : A Systematic Review of Randomized Controlled Trials.Annals of internal medicine, 2025 · PMID 39761578
  4. Comparative efficacy of incretin drugs on glycemic control, body weight, and blood pressure in adults with overweight or obesity and with/without type 2 diabetes: a systematic review and network meta-analysis.Frontiers in endocrinology, 2025 · PMID 39968298
  5. What is the pipeline for future medications for obesity?International journal of obesity (2005), 2025 · PMID 38302593
  6. Efficacy of GLP-1-based Therapies on Metabolic Dysfunction-associated Steatotic Liver Disease and Metabolic Dysfunction-associated Steatohepatitis: A Systematic Review and Meta-analysis.The Journal of clinical endocrinology and metabolism, 2025 · PMID 40489581
  7. Antiobesity medications in adult and pediatric obesity and metabolic dysfunction-associated steatotic liver disease.Pharmacological reviews, 2025 · PMID 40554267
  8. Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review.World journal of gastroenterology, 2025 · PMID 41025003
  9. Retatrutide improves steatohepatitis in an accelerated mouse model of diet-induced steatohepatitis with a fructose binge.American journal of physiology. Gastrointestinal and liver physiology, 2025 · PMID 41056349
  10. Efficacy and safety of triple hormone receptor agonist retatrutide for the management of obesity: a systematic review and meta-analysis.Expert review of clinical pharmacology, 2025 · PMID 39817343
  11. Comparative efficacy and safety of GLP-1 receptor agonists for weight reduction: A model-based meta-analysis of placebo-controlled trials.Obesity pillars, 2025 · PMID 39980735
  12. Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials.Proceedings (Baylor University. Medical Center), 2025 · PMID 40291085
  13. Beyond GLP-1: efficacy and safety of dual and triple incretin agonists in personalized type 2 diabetes care-a systematic review and network meta-analysis.Acta diabetologica, 2025 · PMID 40471293
  14. 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
  15. 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
  16. Efficacy and safety of incretin co-agonists: Transformative advances in cardiometabolic healthcare.World journal of cardiology, 2025 · PMID 40949933
  17. Comparison of the effects of Liraglutide, Tirzepatide, and Retatrutide on diabetic kidney disease in db/db mice.Endocrine, 2025 · PMID 39212900
  18. The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity.Kidney international reports, 2025 · PMID 40630318
  19. Rationale, Design, and Baseline Characteristics of the TRANSCEND-CKD trial of Retatrutide in Patients with Chronic Kidney Disease.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2025 · PMID 41160422
  20. Diabetes Mellitus and Chronic Kidney Disease: The Future Is Being Surpassed.Journal of clinical medicine, 2025 · PMID 41375628
  21. Efficacy and Safety of Retatrutide in the Treatment of Diabetes and/or Obesity Comorbid with Chronic Kidney disease: a Systematic Review and Meta-Analysis.Maedica, 2025 · PMID 41537067
  22. Saving muscle while losing weight: A vital strategy for sustainable results while on glucagon-like peptide-1 related drugs.World journal of diabetes, 2025 · PMID 40980310
  23. Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression.npj metabolic health and disease, 2025 · PMID 40094000
  24. Evaluating the Rates of Pancreatitis and Pancreatic Cancer Among GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.Endocrinology, diabetes & metabolism, 2025 · PMID 40988099
  25. Quantitative Comparison of Glucagon-Like Peptide-1 Receptor Agonists on Weight Loss in Adults: A Systematic Review and Model-Based Meta-Analysis.Diabetes technology & therapeutics, 2025 · PMID 39911047
  26. Emerging pharmacotherapies for obesity: A systematic review.Pharmacological reviews, 2025 · PMID 39952695
  27. The promise of glucagon-like peptide 1 receptor agonists (GLP-1RA) for the treatment of obesity: a look at phase 2 and 3 pipelines.Expert opinion on investigational drugs, 2025 · PMID 40022548
  28. Sex Differences in the Efficacy of Glucagon-Like Peptide-1 Receptor Agonists for Weight Reduction: A Systematic Review and Meta-Analysis.Journal of diabetes, 2025 · PMID 40040445
  29. Comparative Effectiveness of Semaglutide, Liraglutide, Orlistat, and Phentermine for Weight Loss in Obese Individuals: A Systematic Review.Cureus, 2025 · PMID 40206909
  30. Efficacy of GLP-1 Receptor Agonist-Based Therapies on Cardiovascular Events and Cardiometabolic Parameters in Obese Individuals Without Diabetes: A Meta-Analysis of Randomized Controlled Trials.Journal of diabetes, 2025 · PMID 40207414
  31. Appetite, eating attitudes, and eating behaviours during treatment with retatrutide in adults with type 2 diabetes: Results of a phase 2 study.Diabetes, obesity & metabolism, 2025 · PMID 40916752
  32. Perceived benefits of treatment for obesity with retatrutide: A qualitative study of patients in a phase 2 clinical trial.Obesity pillars, 2025 · PMID 41216380
  33. Medical Management of Obesity: A Comprehensive Review of Food and Drug Administration (FDA)-Approved and Investigational Therapies.Cureus, 2025 · PMID 41393574
  34. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trialNat Med, 2024 · PMID 38858523
  35. A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesityObes Rev, 2024 · PMID 38367045
  36. Recent advances in the treatment of type 2 diabetes mellitus using new drug therapies.The Kaohsiung journal of medical sciences, 2024 · PMID 38183334
  37. Future is Brighter: New Potential Paradigm-Shifting Medications and Regimens for Diabetes and Obesity.Current diabetes reviews, 2024 · PMID 38275036
  38. Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now?Expert opinion on pharmacotherapy, 2024 · PMID 38753454
  39. Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity.Diabetes care, 2024 · PMID 38843460
  40. Comparative Meta-Analysis of Retatrutide Versus Placebo and Dulaglutide for Weight Loss and Diabetes Management: Insights From Clinical Trials.American journal of therapeutics, 2024 · PMID 38976545
  41. The power of three: Retatrutide's role in modern obesity and diabetes therapy.European journal of pharmacology, 2024 · PMID 39515565
  42. At ObesityWeek, More Data and Questions About Semaglutide, Tirzepatide, and Retatrutide.JAMA, 2024 · PMID 38055301
  43. Gut hormones and appetite regulation.Current opinion in endocrinology, diabetes, and obesity, 2024 · PMID 38511400
  44. Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions.Gastroenterology report, 2024 · PMID 38681750
  45. The impact of weight loss on fat-free mass, muscle, bone and hematopoiesis health: Implications for emerging pharmacotherapies aiming at fat reduction and lean mass preservation.Metabolism: clinical and experimental, 2024 · PMID 39481534
  46. Sex, race, and BMI in clinical trials of medications for obesity over the past three decades: a systematic review.The lancet. Diabetes & endocrinology, 2024 · PMID 38723646
  47. Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials.Metabolism: clinical and experimental, 2024 · PMID 39305981
  48. 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
  49. Approved and Emerging Hormone-Based Anti-Obesity Medications: A Review Article.Indian journal of endocrinology and metabolism, 2024 · PMID 39676791
  50. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 TrialN Engl J Med, 2023 · PMID 37366315
  51. 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 USALancet, 2023 · PMID 37385280
  52. Triple G Agonists - A Home Run for Obesity?N Engl J Med, 2023 · PMID 37419558
  53. GLP-1 receptor agonists for treatment of obesity: Efficacy and safety considerationsNat Rev Endocrinol, 2023 · PMID 36652991
  54. Is retatrutide (LY3437943), a GLP-1, GIP, and glucagon receptor agonist a step forward in the treatment of diabetes and obesity?Expert opinion on investigational drugs, 2023 · PMID 37086147
  55. Retatrutide showing promise in obesity (and type 2 diabetes).Expert opinion on investigational drugs, 2023 · PMID 37947489
  56. Triple-Hormone Combination Retatrutide Induces 24% Body Weight Loss.JAMA, 2023 · PMID 37405802
  57. Triple-Hormone-Receptor Agonist Retatrutide for Obesity.The New England journal of medicine, 2023 · PMID 37888925
  58. Triple-Hormone-Receptor Agonist Retatrutide for Obesity.The New England journal of medicine, 2023 · PMID 37888926
  59. Triple-Hormone-Receptor Agonist Retatrutide for Obesity. Reply.The New England journal of medicine, 2023 · PMID 37888927
  60. Retatrutide: a triple incretin receptor agonist for obesity management.Expert opinion on investigational drugs, 2023 · PMID 37902090
  61. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trialLancet, 2022 · PMID 35658024