Retatrutide — Triple Agonist GLP-1 / GIP / Glucagon Profile
Eli Lilly’s unimolecular triple agonist and the deepest-weight-loss obesity candidate in late-stage development. Phase 2 NEJM data reported approximately 24.2% weight loss at 48 weeks at the 12 mg dose. Phase 3 TRIUMPH programme readouts begin in 2026.
Update History ▾
Retatrutide (LY3437943) is Eli Lilly’s investigational once-weekly subcutaneous peptide that activates three receptors in a single molecule: GLP-1, GIP, and glucagon. In the 48-week Phase 2 trial published in the New England Journal of Medicine (Jastreboff et al., 2023), retatrutide produced approximately 24.2% mean weight loss at the 12 mg dose with no apparent plateau at study end — the deepest weight loss reported for any obesity candidate to date. The Phase 3 TRIUMPH programme is fully enrolled with readouts beginning in 2026. Retatrutide is not yet approved in any territory.
- Architecture: Unimolecular triple agonist — a single engineered peptide activating GLP-1, GIP, and glucagon receptors.
- Sponsor: Eli Lilly — the company’s next-generation flagship beyond tirzepatide (Mounjaro / Zepbound).
- Phase 2 efficacy: ~24.2% weight loss at 48 weeks, 12 mg dose (NEJM 2023).
- Glucagon arm: Increases basal energy expenditure and reduces hepatic fat — mechanisms neither semaglutide nor tirzepatide addresses.
- Phase 3: TRIUMPH-1 through TRIUMPH-4 span obesity, type 2 diabetes, cardiovascular outcomes, and knee osteoarthritis.
- Regulatory status: Not approved in any major territory as of April 22, 2026. Earliest NDA filing contingent on TRIUMPH-1 and TRIUMPH-3 readouts.
What Is Retatrutide?
Retatrutide (development code LY3437943) is Eli Lilly’s investigational obesity and type 2 diabetes peptide. Unlike CagriSema, which co-formulates two separate molecules in one injection, retatrutide is a single engineered peptide that binds and activates three different receptors at once:
- GLP-1 receptor — the same target as semaglutide (Ozempic/Wegovy) and the GLP-1 arm of tirzepatide.
- GIP receptor — the same target as tirzepatide’s second arm.
- Glucagon receptor — a third arm not present in any currently approved obesity agent.
Dosing is once-weekly subcutaneous, matching the administration pattern of semaglutide and tirzepatide. Phase 2 tested 1, 4, 8, and 12 mg weekly maintenance doses. If approved, retatrutide would become the first triple agonist on market and Eli Lilly’s next-generation successor to tirzepatide. For regulatory tracking, see Is retatrutide approved?
Mechanism of Action
The retatrutide hypothesis is that the three receptor arms are mechanistically complementary, not redundant. Each arm addresses a different component of body-weight regulation:
- GLP-1 receptor: Central appetite suppression and slowed gastric emptying. This is the same mechanism driving semaglutide’s ~15% weight loss in STEP 1. Well-characterised; gastrointestinal tolerability is the dominant side-effect driver.
- GIP receptor: Adds insulinotropic and satiety effects that appear to blunt GLP-1-driven nausea while reinforcing satiety. This is the same arm that lifted tirzepatide above semaglutide in SURMOUNT-1 (~22.5% vs ~15%).
- Glucagon receptor: Increases basal energy expenditure and reduces hepatic fat. Glucagon also raises blood glucose; retatrutide’s balanced triple agonism is designed so the GLP-1 and GIP arms offset the glycemic impact of the glucagon arm, yielding a net glucose-neutral or glucose-lowering profile.
Compared to the obesity-pipeline alternatives, retatrutide is the only late-stage candidate that targets energy expenditure in addition to appetite. Tirzepatide and semaglutide work almost exclusively through appetite and satiety. Survodutide targets GLP-1 and glucagon (skipping GIP). CagriSema targets GLP-1 and amylin (skipping GIP and glucagon). Retatrutide is the mechanistic superset.
Development Stage & TRIUMPH Programme
Retatrutide is in Phase 3 across the TRIUMPH programme, which spans four indications. The programme is fully enrolled, with topline readouts beginning in 2026 and extending into 2027. Eli Lilly has signaled regulatory filing will follow the pivotal TRIUMPH-1 obesity readout and, depending on design, a coordinated TRIUMPH-3 cardiovascular outcomes readout.
| Trial | Population | Design | Primary readout |
|---|---|---|---|
| TRIUMPH-1 | Adults with obesity | Placebo-controlled, 80+ weeks | Expected 2026 |
| TRIUMPH-2 | Obesity + type 2 diabetes | Placebo-controlled | Expected 2026–2027 |
| TRIUMPH-3 | Obesity + cardiovascular disease | CVOT design | Expected 2027 |
| TRIUMPH-4 | Obesity + knee osteoarthritis | Function + weight loss | Expected 2026–2027 |
Regulatory outlook: The earliest realistic NDA submission window opens after TRIUMPH-1. A cardiovascular outcomes readout from TRIUMPH-3 would strengthen label positioning versus approved competitors. For a running timeline, see the TRIUMPH trial tracker and the broader obesity drug pipeline timeline.
Retatrutide Pen 30mg — 300 clicks, 99.262% HPLC purity (Janoshik Batch RETP002). Ships from Dubai.
See UAE Pricing & Formats →Efficacy Data — Phase 2 NEJM Trial
The Phase 2 dataset anchoring retatrutide’s positioning is the 48-week randomised, double-blind, placebo-controlled trial published by Jastreboff and colleagues in the New England Journal of Medicine (June 2023). The trial enrolled 338 adults with obesity without type 2 diabetes and tested four retatrutide doses (1, 4, 8, 12 mg) against placebo.
| Dose | Mean weight change | ≥15% weight loss |
|---|---|---|
| Placebo | −2.1% | Minimal |
| 1 mg | −8.7% | — |
| 4 mg | −17.1% | — |
| 8 mg | −22.8% | — |
| 12 mg | −24.2% | 83% of participants |
Two features of the Phase 2 readout shaped retatrutide’s Phase 3 positioning. First, the dose-response was steep and orderly — every dose step produced meaningfully greater weight loss, which is a strong signal that the mechanism is active at the receptor level. Second, the 12 mg weight-loss curve had not plateaued at 48 weeks, implying longer dosing windows (as in TRIUMPH) could push efficacy higher still.
For cross-class context, semaglutide 2.4 mg produced ~15% weight loss at 68 weeks in STEP 1, and tirzepatide 15 mg produced ~22.5% at 72 weeks in SURMOUNT-1. Retatrutide’s 48-week number exceeds both, and the triple-agonist architecture provides a plausible mechanism. For a three-way breakdown, see Retatrutide vs Tirzepatide vs CagriSema.
Safety & Tolerability
Retatrutide’s Phase 2 safety profile was consistent with the GLP-1 class, layered with glucagon-related signals requiring further characterisation in Phase 3:
- Most common AEs: nausea, diarrhea, vomiting, constipation, decreased appetite — the standard GLP-1/GIP agonist profile, concentrated in dose-escalation phases.
- Heart rate: A modest dose-dependent increase in resting heart rate was observed, consistent with glucagon-receptor activation. The clinical significance is being monitored in TRIUMPH.
- Glycemic control: The balanced triple agonism produced neutral to favourable glycemic effects in Phase 2; HbA1c was not adversely affected.
- Hepatic fat: Retatrutide reduced hepatic fat content in Phase 2 substudy participants, consistent with the glucagon-arm mechanism.
No unexpected safety signals were reported in Phase 2. Long-term tolerability, cardiovascular outcomes, and discontinuation rates at commercial-intent doses are being characterised in TRIUMPH. For a focused breakdown, see retatrutide side effects.
How It Compares — Retatrutide vs Tirzepatide vs CagriSema
Retatrutide sits at the mechanistic top of the obesity pipeline. Tirzepatide (Eli Lilly, approved as Mounjaro and Zepbound) is a dual GLP-1/GIP agonist. CagriSema (Novo Nordisk, NDA filed December 2025) is a GLP-1/amylin co-formulation. Retatrutide adds a glucagon arm that neither of those candidates has, which is the source of its weight-loss ceiling advantage in cross-trial comparison.
On efficacy, retatrutide’s Phase 2 12 mg result (~24.2% at 48 weeks) exceeds tirzepatide 15 mg in SURMOUNT-1 (~22.5% at 72 weeks) and CagriSema in REDEFINE 1 (~22.7% at 68 weeks). Timeline position is inverted: CagriSema is closest to market (FDA decision expected ~October 2026), tirzepatide is already approved, and retatrutide is still working through TRIUMPH. For a full comparative breakdown, see retatrutide vs tirzepatide vs CagriSema, and for orforglipron-specific context, see retatrutide vs orforglipron.
Research Use Notes
Remy Peptides supplies HPLC-verified retatrutide pens for in-vitro laboratory research. Current batch flow: Retatrutide Pen 30 mg, 300 clicks at 0.1 mg per click, 99.262% HPLC purity, Janoshik Analytical Batch RETP002. Reference the COA library for batch documents. For reconstitution and handling, see the bacteriostatic water guide and the reconstitution calculator.
Retatrutide is not approved for human therapeutic use in any territory. Remy Peptides material is supplied strictly for in-vitro research. For regional research context, see the retatrutide in Dubai guide and Retatrutide UAE availability page.
All Remy Peptides products are supplied for in-vitro laboratory research only. Not for human or veterinary use. UAE MoHAP Circular 17/2022 compliance statement.
Our Research Standards
This article cites peer-reviewed studies, FDA filings, and ClinicalTrials.gov data. All claims are cross-referenced against primary sources. We update articles when new trial data or regulatory decisions are published. Read our editorial policy →
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. nejm.org
- Eli Lilly. TRIUMPH programme: Phase 3 clinical trials of retatrutide in obesity. Pipeline overview. investor.lilly.com
- ClinicalTrials.gov. TRIUMPH-1: A Study of Retatrutide (LY3437943) in Participants With Obesity (NCT05929066). clinicaltrials.gov
- ClinicalTrials.gov. TRIUMPH-3: A Study of Retatrutide in Participants With Obesity and Cardiovascular Disease (NCT05882045). clinicaltrials.gov
- ClinicalTrials.gov. TRIUMPH-4: A Study of Retatrutide in Participants With Obesity and Osteoarthritis of the Knee (NCT05816642). clinicaltrials.gov
- Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 2022;34(9):1234-1247. cell.com
Retatrutide Pen 30 mg — Dubai
99.262% HPLC purity, Janoshik Analytical. 300 clicks per pen, ships from Dubai across the UAE and GCC.
See UAE Formats & Pricing →