Retatrutide

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).

---

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 Years

The 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 Years

Secondary 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)

Moderate Confidence RCT ≤3 Years

Retatrutide is being studied in the Phase 3 TRIUMPH registrational program, including studies in weight management and nested “basket” protocols in obstructive sleep apnea and knee osteoarthritis. [PMID: 41090431]

Phase 3 (TRIUMPH-4) — Topline Results (Press Release; Not Peer Reviewed)

Low Confidence RCT ≤3 Years

Lilly reported positive topline Phase 3 results for TRIUMPH-4 in a press release, noting that detailed results will be presented and published later. Treat these numbers as preliminary until peer-reviewed publication. [lilly-pr-triumph-4-topline-2025-12-11]

Reported co-primary endpoints (efficacy estimand, week 68):

Endpoint	Retatrutide 9 mg	Retatrutide 12 mg	Placebo
Mean weight loss	-26.4% (-64.2 lbs)	-28.7% (-71.2 lbs)	-2.1%
WOMAC pain change	-4.0 points (-67.2%)	-3.7 points (-62.6%)	-2.1 points (-35.1%)

Note: the press release states percent change in WOMAC pain/physical function were not pre-specified and 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 Years

In the Phase 2 trial, the most commonly reported adverse events were gastrointestinal and were described as dose-related and mostly mild-to-moderate in severity. Dose-dependent increases in heart rate were observed (peaking earlier and declining thereafter). [PMID: 37366315]

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
2026-01-22	Added Phase 3 TRIUMPH sources (design paper + press release)
2026-01-21	Initial dossier created