Retatrutide
InvestigationalA triple GIP/GLP-1/glucagon receptor agonist. Phase 2 data show 24.2% weight loss at 48 weeks (12mg), the largest reduction reported for an incretin-based therapy. The Phase 3 TRIUMPH registrational program is ongoing.
LY3437943 · GGG Triple Agonist
15 human studies
- Preclinical
- 5%
- Clinical
- 12%
Based on 124 cited sources
clinically demonstrated · moderate confidence
Demonstrated effect magnitude — not a recommendation or safety claim.
Research Depth 89: Phase 1b/2 RCTs (Jastreboff 37366315 obesity N=338, Rosenstock 37385280 T2D N=281, Urva 36354040 Phase 1b), a published Phase 3 RCT (Bajaj 42250575 TRANSCEND-T2D-1 N=537), plus a systematic review/meta-analysis (40291085, 3 RCTs/878 pts) -> 1A meta-analysis tier 35; double-blind placebo/active-controlled low-RoB design 1B 19; total human N >1,000 across the program 1C 14; direct population/route/outcome match for obesity/T2D/MASLD 1D 14; substantial multi-model preclinical base incl. GLP-1R-KO rodent work (41997446) 1E 7. Mechanism 95: three named receptors (GIP/GLP-1/GCGR) with binding + functional cAMP data and GLP-1R knockout confirming GLP-1-independent weight loss (2A 40); pathway largely mapped (2B 26); monotonic dose-response across Phase 1b/2/3 and in vivo (2C 19); confirmed in mammalian models (2D 10). Plausibility 97: full mechanism->surrogate->clinical chain supported for weight, HbA1c (37385280) and liver fat (Sanyal 38858523) (3A 38); fully coherent with incretin/glucagon biology (3B 25); same-class analogues semaglutide/tirzepatide reliably produce the effect (3C 20); tightly scoped metabolic claims (3D 14). Global Coverage 70: Phase 3 now spans USA/Mexico/India and independent meta-analytic groups exist, but pivotal RCTs remain Lilly-sponsored (4A 24); multi-country trials + independent reviews (4B 18); >100 studies and growing (4C 23); investigational/Phase 3-registered, no approval yet (4D 5). Community Experience 47: anticipated pipeline drug with emerging off-label discussion (42219269) but no approved real-world use (5A 17); ~2-3 yr discussion window (5B 10); broadly consistent themes (5C 13); minor GI/dysesthesia signal noted (5D 7). Effectiveness clinical 92 (moderate confidence): 24.2% weight loss at 48 wk (12mg, 37366315) is transformative (d>>0.8, E1 30), far exceeds the obesity MCID by >=2x (E2 25), on a hard patient-relevant outcome (E3 15), and is the largest reduction of any incretin therapy with head-to-head superiority over dulaglutide though no head-to-head vs tirzepatide/semaglutide yet (E4 22); confidence moderate as Phase 3 obesity (TRIUMPH) efficacy results are not yet published.
The mechanisms of retatrutide are well-characterized through Phase 2/3 clinical trials and preclinical studies. It is the first triple GIP/GLP-1/Glucagon receptor agonist in late-stage development.
How It Works (Simplified)
Retatrutide activates three hormone receptors simultaneously, providing comprehensive metabolic effects:
Reduces appetite, slows gastric emptying, and enhances insulin secretion. Same target as Ozempic/Wegovy.
Works synergistically with GLP-1 to boost insulin, improves fat cell function, and enhances satiety. Added by Mounjaro.
Unique to retatrutide. Increases liver fat burning, boosts metabolic rate, and activates brown fat thermogenesis.
GLP-1/GIP counterbalance glucagon’s glucose-raising effects, resulting in improved glycemia alongside maximum weight loss.
Key Research: Jastreboff AM et al. (2023) demonstrated 24.2% weight loss at 48 weeks in Phase 2. PMID:37366315
Phase 3 Clinical Program (TRIUMPH)
TRIUMPH registrational program: The Phase 3 TRIUMPH program consists of four multicenter, randomized, double-blind trials enrolling over 5,800 participants, evaluating weekly subcutaneous retatrutide against placebo for obesity and two related complications — obstructive sleep apnea (OSA) and knee osteoarthritis (OA). It uses a basket trial design: two weight-management trials (TRIUMPH-1 and TRIUMPH-2) with OSA/OA protocols nested within, one weight-management trial in a population with cardiovascular disease (TRIUMPH-3), and one stand-alone knee OA trial (TRIUMPH-4). The primary weight-management endpoint is percent change in body weight. PMID:41090431
Status: Published Phase 3 efficacy and safety results were not yet available in the peer-reviewed literature at the time of this review; the program is ongoing.
Important Limitations
- Retatrutide is an investigational drug not yet approved by FDA/EMA
- Long-term safety beyond the 48-week Phase 2 data is still being evaluated in the Phase 3 program
- Gastrointestinal adverse events were dose-related and the most common in Phase 2 trials
- Cardiovascular, kidney, and hepatic outcomes data from the Phase 3 program are pending
- Head-to-head comparisons against approved incretin therapies are not yet published
- Not available outside clinical trials; any other source is illegitimate
Reported positives
- Impressive weight loss results in clinical trials generating excitement
- Triple agonism mechanism viewed as next-generation approach
- Strong media coverage increasing awareness
- Potential for muscle-sparing weight loss discussed
Reported negatives
- Not yet available outside clinical trials
- GI side effects expected to be significant based on trial data
- Dysesthesia safety signal concerning to community
- No real-world user data yet
“Highly anticipated pipeline drug. Community following trial results closely. No real-world user reports yet.”
Self-reported, unverified accounts — not clinical evidence and no substitute for the cited research. Anecdotes are prone to selection bias and placebo effects.
| NCT ID | Title | Peptide | Phase | Status | Completion |
|---|---|---|---|---|---|
| NCT04867785 | Phase 2 T2D Trial Type 2 Diabetes | Retatrutide | Phase 2 | Completed | Jul 2022 |
| NCT04881760 | Phase 2 Obesity Trial Obesity, Overweight | Retatrutide | Phase 2 | Completed | May 2022 |
| NCT05929066 | TRIUMPH-1: Obesity without T2D Obesity, Overweight +2 more | Retatrutide | Phase 3 | Active | Apr 2026 |
| NCT05929079 | TRIUMPH-2: Obesity with T2D Type 2 Diabetes, Obesity +2 more | Retatrutide | Phase 3 | Active | May 2026 |
| NCT05882045 | TRIUMPH-3: Obesity with CVD Obesity, Cardiovascular Diseases | Retatrutide | Phase 3 | Active | Apr 2026 |
| NCT05931367 | TRIUMPH-4: Obesity with Knee OA Obesity, Overweight +1 more | Retatrutide | Phase 3 | Completed | Nov 2025 |
| NCT06662383 | TRIUMPH-5: Head-to-head vs Tirzepatide Obesity | Retatrutide | Phase 3 | Active | Dec 2026 |
| NCT06859268 | TRIUMPH-6: Long-term Maintenance (116 weeks) Obesity | Retatrutide | Phase 3 | Active | Apr 2028 |
| NCT06383390 | TRIUMPH-Outcomes: CV/Kidney Outcomes Atherosclerotic Cardiovascular Disease (ASCVD), Chronic Kidney Disease (CKD) | Retatrutide | Phase 3 | Active | Feb 2029 |
| NCT07467447 | Effect of LY3437943 Versus Placebo in Participants Who Have Obesity or Are Overweight Obesity | Retatrutide | Phase 2 | Recruiting | Mar 2027 |
| NCT07357415 | A Study of Retatrutide (LY3437943) in Participants Without Type 2 Diabetes Who Have Obesity or Overweight Obesity, Overweight | Retatrutide | Phase 3 | Recruiting | Oct 2028 |
| NCT07232719 | A Study of Retatrutide (LY3437943) in Participants With Obesity or Overweight Obesity, Overweight | Retatrutide | Phase 3 | Active | Jul 2027 |
| NCT07165028 | A Master Protocol of Multiple Agents in Adults With Metabolic Dysfunction-Associated Steatotic Liver Disease (SYNERGY-Outcomes) Metabolic Dysfunction-Associated Steatotic Liver Disease | Retatrutide | Phase 3 | Recruiting | Aug 2030 |
| NCT06982846 | A Study to Investigate the Response of Participants With Type 2 Diabetes Mellitus on Once-Weekly Retatrutide to Hypoglycemia Type 2 Diabetes Mellitus | Retatrutide | Phase 1 | Active | May 2026 |
| NCT06982859 | A Study to Evaluate the Effect of Retatrutide on Insulin Secretion and Insulin Sensitivity in Adult Participants With Type 2 Diabetes Mellitus Diabetes Mellitus, Insulin Sensitivity | Retatrutide | Phase 1 | Recruiting | Nov 2026 |
| NCT07035093 | A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight and Chronic Low Back Pain Obesity, Overweight +1 more | Retatrutide | Phase 3 | Recruiting | Sep 2027 |
| NCT06808802 | To Investigate the Effect of Retatrutide (LY3437943) on Metoprolol Pharmacokinetics in Healthy Participants Healthy | Retatrutide | Phase 1 | Completed | Apr 2025 |
| NCT06354660 | Effect of Retatrutide Compared With Placebo in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Diet and Exercise Alone (TRANSCEND-T2D-1) Diabetes Type 2 | Retatrutide | Phase 3 | Completed | Jan 2026 |
| NCT06313528 | A Study to Measure Calorie Consumption and Usage in Participants With Obesity Using LY3437943 Obesity | Retatrutide | Phase 1 | Completed | Aug 2025 |
| NCT06297603 | Effect of Retatrutide Compared With Placebo in Participants With Type 2 Diabetes and Moderate or Severe Renal Impairment, With Inadequate Glycemic Control on Basal Insulin, With or Without Metformin and/or SGLT2 Inhibitor (TRANSCEND-T2D-3) Type 2 Diabetes | Retatrutide | Phase 3 | Active | Oct 2026 |
| NCT06260722 | Effect of Retatrutide Compared With Semaglutide in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Metformin With or Without SGLT2 Inhibitor (TRANSCEND-T2D-2) Diabetes Mellitus, Type 2 | Retatrutide | Phase 3 | Active | Aug 2026 |
| NCT06039826 | A Study of LY3437943 in Postmenopausal Female Participants Who Are Overweight or Obese Overweight | Retatrutide | Phase 1 | Completed | Jul 2024 |
| NCT06003465 | A Research Study Looking at Similarity Between LY3437943 Versions for Different Injection Devices Healthy | Retatrutide | Phase 1 | Completed | Feb 2024 |
| NCT05936151 | A Study of Retatrutide (LY3437943) on Renal Function in Participants With Overweight or Obesity and Chronic Kidney Disease With or Without Type 2 Diabetes Overweight or Obesity, CKD +1 more | Retatrutide | Phase 2 | Completed | Oct 2025 |
| NCT05959096 | A Study of LY3437943 in Healthy Participants With a High Body Mass Index Healthy | Retatrutide | Phase 1 | Completed | Jul 2024 |
| NCT05916560 | A Study of LY3437943 in Participants With Impaired and Normal Liver Function Healthy, Hepatic Insufficiency | Retatrutide | Phase 1 | Completed | Mar 2025 |
| NCT05757531 | A Study of Carbon-14-Labelled [14C] LY3437943 in Healthy Male Participants Healthy | Retatrutide | Phase 1 | Completed | Jun 2023 |
| NCT05611957 | A Study of LY3437943 in Healthy Participants and Participants With Impaired Renal Function Healthy, Renal Insufficiency | Retatrutide | Phase 1 | Completed | Sep 2023 |
| NCT05548231 | A Study of LY3437943 in Chinese Participants With Obesity Or Overweight Overweight, Obesity | Retatrutide | Phase 1 | Completed | Jul 2023 |
| NCT05445232 | A Drug-Drug Interaction (DDI) Study of LY3437943 in Obese Participants Obesity | Retatrutide | Phase 1 | Completed | Feb 2023 |
| NCT04823208 | A Study of LY3437943 in Japanese Participants With Type 2 Diabetes Mellitus (T2DM) Diabetes Mellitus, Type 2 | Retatrutide | Phase 1 | Completed | Jun 2022 |
| NCT04143802 | A Study of LY3437943 in Participants With Type 2 Diabetes Mellitus (T2DM) Diabetes Mellitus, Type 2 | Retatrutide | Phase 1 | Completed | Dec 2020 |
| NCT03841630 | A Safety Study of LY3437943 Given as a Single Injection in Healthy Participants Healthy | Retatrutide | Phase 1 | Completed | Jul 2019 |
Effect of LY3437943 Versus Placebo in Participants Who Have Obesity or Are Overweight
A Study of Retatrutide (LY3437943) in Participants Without Type 2 Diabetes Who Have Obesity or Overweight
A Study of Retatrutide (LY3437943) in Participants With Obesity or Overweight
A Master Protocol of Multiple Agents in Adults With Metabolic Dysfunction-Associated Steatotic Liver Disease (SYNERGY-Outcomes)
A Study to Investigate the Response of Participants With Type 2 Diabetes Mellitus on Once-Weekly Retatrutide to Hypoglycemia
A Study to Evaluate the Effect of Retatrutide on Insulin Secretion and Insulin Sensitivity in Adult Participants With Type 2 Diabetes Mellitus
A Study of Retatrutide (LY3437943) in Participants Who Have Obesity or Overweight and Chronic Low Back Pain
To Investigate the Effect of Retatrutide (LY3437943) on Metoprolol Pharmacokinetics in Healthy Participants
Effect of Retatrutide Compared With Placebo in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Diet and Exercise Alone (TRANSCEND-T2D-1)
A Study to Measure Calorie Consumption and Usage in Participants With Obesity Using LY3437943
Effect of Retatrutide Compared With Placebo in Participants With Type 2 Diabetes and Moderate or Severe Renal Impairment, With Inadequate Glycemic Control on Basal Insulin, With or Without Metformin and/or SGLT2 Inhibitor (TRANSCEND-T2D-3)
Effect of Retatrutide Compared With Semaglutide in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Metformin With or Without SGLT2 Inhibitor (TRANSCEND-T2D-2)
A Study of LY3437943 in Postmenopausal Female Participants Who Are Overweight or Obese
A Research Study Looking at Similarity Between LY3437943 Versions for Different Injection Devices
A Study of Retatrutide (LY3437943) on Renal Function in Participants With Overweight or Obesity and Chronic Kidney Disease With or Without Type 2 Diabetes
A Study of LY3437943 in Healthy Participants With a High Body Mass Index
A Study of LY3437943 in Participants With Impaired and Normal Liver Function
A Study of Carbon-14-Labelled [14C] LY3437943 in Healthy Male Participants
A Study of LY3437943 in Healthy Participants and Participants With Impaired Renal Function
A Study of LY3437943 in Chinese Participants With Obesity Or Overweight
A Drug-Drug Interaction (DDI) Study of LY3437943 in Obese Participants
A Study of LY3437943 in Japanese Participants With Type 2 Diabetes Mellitus (T2DM)
A Study of LY3437943 in Participants With Type 2 Diabetes Mellitus (T2DM)
A Safety Study of LY3437943 Given as a Single Injection in Healthy Participants
Initial dose titration period. GI adaptation occurs as GLP-1 pathway activates. Appetite suppression begins within first week. Early weight loss typically 2-4% during titration phase.
PMID:37366315Continued dose escalation to maintenance dose. Weight loss accelerates as full triple receptor activation achieved. Average 8-12% weight loss by week 12 at higher doses. GI side effects typically improve.
PMID:37366315Sustained weight loss trajectory. Metabolic improvements measurable including HbA1c reductions in diabetic patients. Liver fat reduction substantial in those with MASLD. Weight loss reaches 15-18% range.
PMID:37385280Continued linear weight loss without plateau at 48 weeks in Phase 2 trials. Maximum observed weight loss of 24.2% at 48 weeks. Metabolic parameters continue to improve.
PMID:37366315Long-term efficacy and maintenance beyond 48 weeks are being evaluated in the Phase 3 TRIUMPH registrational program; published results were not yet available at the time of review.
PMID:41090431Research-based observations
This timeline reflects observations from published clinical and preclinical studies. Individual responses may vary significantly. This is not a guarantee of effects or a dosing schedule. Consult qualified healthcare providers for personalized guidance.
Good Signs (6 indicators)
Warning Signs (5 indicators)
Bad Signs (6 indicators)
For Research Evaluation Only
These quality indicators are general guidelines based on typical peptide characteristics. Professional laboratory testing (HPLC, mass spectrometry) provides definitive quality verification. This checklist is for initial visual evaluation only.
Ipamorelin
CompatibleNon-overlapping mechanisms. Ipamorelin acts on ghrelin receptors while retatrutide targets incretin receptors. No known contraindications though combined effects on appetite are unstudied.
CJC-1295
CompatibleDifferent pathways (GHRH vs incretin). Theoretical complementary metabolic benefits. No interaction studies available.
BPC-157
CautionBoth affect GI function. Retatrutide slows gastric emptying while BPC-157 is gastroprotective. Unclear if effects interact; monitor GI symptoms if combined.
AOD-9604
CautionBoth target metabolic and lipolytic pathways. Combined effects on fat metabolism are unstudied. Exercise caution due to potential additive effects.
Tirzepatide
AvoidBoth are incretin-based therapies targeting overlapping receptors. Tirzepatide (GIP/GLP-1) and retatrutide (GIP/GLP-1/GCGR) should not be combined due to additive effects and increased risk of severe GI adverse events.
Semaglutide
AvoidBoth activate GLP-1 receptors. Combining would cause excessive GLP-1 pathway stimulation with high risk of severe nausea, vomiting, and potentially dangerous hypoglycemia.
Research Note: Interaction data is based on published literature, mechanistic understanding, and theoretical considerations. Most peptide combinations lack direct clinical study. This information is for educational purposes only and does not constitute medical advice. Always consult qualified healthcare providers.
Key Studies Cited
Full reference list available on request. All citations link to PubMed for verification.
This dossier synthesizes available evidence from peer-reviewed literature, regulatory documents, and clinical trial registries. Evidence strength ratings follow a modified GRADE approach.
For complete methodology details, see our Methodology page.
Important Disclaimer
This dossier is for educational purposes only and does not constitute medical advice. Always consult a qualified healthcare provider before making health decisions.
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