Phase III: Large-scale Efficacy
Retatrutide
Also known as: LY3437943, Eli Lilly Triple Agonist
At a Glance
Retatrutide (LY3437943) is a novel investigational peptide developed by Eli Lilly that simultaneously activates three receptors involved in metabolism: GIP (glucose-dependent insulinotropic polypeptide), GLP-1 (glucagon-like peptide-1), and glucagon receptors. This “triple agonist” mechanism distinguishes it from dual agonists like tirzepatide (GIP/GLP-1) and single agonists like semaglutide (GLP-1 only).
⚠️ Investigational Drug: Retatrutide is not approved for any use. It is currently in Phase 3 clinical trials. The data below comes from Phase 1 and Phase 2 trials only.
Mechanism of Action
Retatrutide’s triple agonism creates a unique metabolic profile:
GLP-1 Receptor Agonism
- Reduces appetite and food intake via hypothalamic satiety centers
- Slows gastric emptying, promoting fullness
- Enhances glucose-dependent insulin secretion
GIP Receptor Agonism
- Works synergistically with GLP-1 on appetite and glucose control
- May enhance fat oxidation and energy expenditure
- Potentially reduces GLP-1-associated nausea
Glucagon Receptor Agonism
- Increases energy expenditure and thermogenesis
- Promotes hepatic lipid oxidation
- May contribute to greater fat mass reduction vs. GLP-1 alone
Key Insight: The glucagon component is what differentiates retatrutide from tirzepatide. While glucagon can raise blood glucose, the GLP-1/GIP effects appear to counterbalance this in clinical trials.
Evidence Summary
Weight Loss (Phase 2 Trial)
Moderate Confidence RCT ≤3 YearsThe Phase 2 trial (published in NEJM, 2023) randomized 338 adults with obesity to retatrutide or placebo for 48 weeks.
[PMID: 37366315]Key Results:
| Dose | Mean Weight Loss |
|---|---|
| Placebo | -2.1% |
| 1 mg | -7.2% |
| 4 mg | -12.9% |
| 8 mg (escalation) | -17.5% |
| 12 mg (escalation) | -24.2% |
- The 12 mg dose achieved the highest weight loss ever reported in a Phase 2 obesity trial
- 100% of participants on 12 mg lost ≥5% body weight
- 83% lost ≥15% body weight
- 63% lost ≥20% body weight
Limitations: Phase 2 data only; 48-week duration; predominantly White participants (75%); industry-sponsored.
Metabolic Effects
Moderate Confidence RCT ≤3 YearsSecondary endpoints from the Phase 2 trial showed:
- Significant reductions in HbA1c (even in non-diabetic participants)
- Improvements in blood pressure and lipid profiles
- Reductions in liver fat (measured by MRI in a subset)
Phase 3 Program (Ongoing)
High Confidence RCT ≤3 YearsRetatrutide is being studied in the Phase 3 TRIUMPH registrational program, encompassing weight management, obstructive sleep apnea, and knee osteoarthritis. [PMID: 41090431] In January 2026, Lilly initiated an additional Phase 3b Dosing Study to optimize dose-escalation schemes and potentially mitigate gastrointestinal and neurologic side effects.
Phase 3 (TRIUMPH-4) — Topline Results
Moderate Confidence RCT ≤3 YearsLilly reported positive topline Phase 3 results for TRIUMPH-4 (Dec 2025). This registrational study focused on adults with obesity/overweight and knee osteoarthritis. [lilly-pr-triumph-4-topline-2025-12-11]
Co-primary endpoints (efficacy estimand, week 68):
| Endpoint | Retatrutide 12 mg | Placebo |
|---|---|---|
| Mean weight loss | -28.7% (-71.2 lbs) | -2.1% |
| WOMAC pain change | -4.5 points (-75.8%) | -2.1 points (-35.1%) |
Unprecedented Efficacy: This represents the highest weight reduction efficacy reported in any registrational anti-obesity trial to date. Percent changes in WOMAC pain and physical function were estimated from post-hoc analyses. [lilly-pr-triumph-4-topline-2025-12-11]
Safety & Unknowns
Adverse Events (Phase 2 Trial)
Moderate Confidence RCT ≤3 YearsIn the Phase 2 trial, common adverse events included dose-dependent nausea, diarrhea, and vomiting. Dose-dependent increases in heart rate were observed (peaking early and then declining). [PMID: 37366315]
Dysesthesia Signal (Neurologic)
Moderate Confidence RCT ≤3 YearsA new safety signal emerged from Phase 3: Dysesthesia (an abnormal sense of touch, often described as burning or tingling) was reported in 20.9% of participants on the 12 mg dose and 8.8% on the 9 mg dose, compared to only 0.7% in the placebo group. [lilly-pr-triumph-4-topline-2025-12-11] Lilly’s 2026 dosing study aims to investigate if different titration schedules can reduce this neurologic side effect.
Unknowns & Concerns
- Long-term safety: Extended data expected from ongoing TRIUMPH trials
- Cardiovascular outcomes: No dedicated CV outcomes trial yet (TRIUMPH-3 may provide data)
- Muscle mass preservation: Unknown if weight loss is fat-preferential
- Rebound weight regain: Not yet studied after discontinuation
- Thyroid risk: Class-wide boxed warning for GLP-1 agonists (rodent thyroid tumors)
Regulatory Status
| Region | Status |
|---|---|
| FDA | Not approved; Phase 3 ongoing (first positive results Dec 2025) |
| EMA | Not approved; Phase 3 ongoing |
| WADA | Not listed (not yet on market) |
Key Studies
| Year | Type | Finding | Citation |
|---|---|---|---|
| 2023 | Phase 2 RCT | 24.2% weight loss at 48 weeks (12 mg) | [PMID: 37366315] |
| 2026 | Trial Design | TRIUMPH program rationale and endpoints | [PMID: 41090431] |
| 2025 | Press Release | TRIUMPH-4 topline Phase 3 results (pending publication) | [lilly-pr-triumph-4-topline-2025-12-11] |
Related Compounds
- Tirzepatide (Mounjaro/Zepbound): Dual GIP/GLP-1 agonist (approved)
- Semaglutide (Ozempic/Wegovy): GLP-1 agonist (approved)
- Survodutide: Dual glucagon/GLP-1 agonist (in trials)
Changelog
| Date | Change |
|---|---|
| 2026-01-25 | Updated Phase 3 results, added dysesthesia signal, and noted Jan 2026 dosing study |
| 2026-01-22 | Added Phase 3 TRIUMPH sources (design paper + press release) |
| 2026-01-21 | Initial dossier created |