Rankings / Metabolic Health

Retatrutide

Metabolic Health · GLP-1/GIP/glucagon agonist (triple)

Tier B+

Reviewed by Read Off Label · Last reviewed · How we grade

glp-1gipinvestigationalawaiting-readout
7.1 / 10
Tier B+
Ev 8 Bn 10 Sf 5

Bottom line

Read Off Label grades Retatrutide as B+ (7.1/10) based on strong evidence, very high benefit magnitude, and a med-risk safety profile.

Eli Lilly TRIUMPH-1 (May 21, 2026 topline): first Phase 3 readout in obesity, n=2,339 adults with obesity + ≥1 comorbidity (HTN/dyslipidemia/OSA/OA) but no diabetes, randomized 1:1:1:1 to retatrutide 4/9/12 mg or placebo SC weekly, 80-week primary with 104-week extension.

Studied, labeled, or reported-use context: Phase 2 used up to 12 mg SC weekly; Phase 3 weekly SC — Investigational; not individualized guidance.

What the evidence says

Eli Lilly TRIUMPH-1 (May 21, 2026 topline): first Phase 3 readout in obesity, n=2,339 adults with obesity + ≥1 comorbidity (HTN/dyslipidemia/OSA/OA) but no diabetes, randomized 1:1:1:1 to retatrutide 4/9/12 mg or placebo SC weekly, 80-week primary with 104-week extension. Mean weight loss: 19.0% / 25.9% / 28.3% vs 2.2% placebo at 80wk; 30.3% (85.0 lbs) at 104wk on 12 mg. 45.3% of the 12 mg arm reached ≥30% loss (vs 0.5% placebo); 65.3% reached BMI <30. GI events dominant and dose-dependent; AE-driven discontinuation 11.3% (12 mg) vs 4.9% (placebo). Novel dysesthesia signal at 12.5% (vs 0.9% placebo). Magnitude is bariatric-surgery-tier in a non-surgical pill/injection class — previously only ~30% loss seen with sleeve gastrectomy/RYGB. Tirzepatide SURMOUNT-1 reached ~22.5% at 72wk; semaglutide STEP-1 ~14.9% at 68wk. Phase 2 (Jastreboff 2023 NEJM) reached ~24% at 48 weeks with a trajectory still descending; TRIUMPH-1 confirms the trajectory holds. No FDA filing announced as of May 21 2026. Remaining program: TRIUMPH-2 (T2D), TRIUMPH-3 (established CVD), TRIUMPH-4 (knee OA), TRIUMPH-Outcomes CVOT (NCT06383390), TRANSCEND-CKD Ph2b (n=146, baseline characteristics Oct 2025), head-to-head vs tirzepatide (NCT06662383, n=800, completion Dec 2026). TRANSCEND-T2D-1 (Lancet, Jun 6 2026; n=537, type 2 diabetes monotherapy, 40 wk): HbA1c −1.94% and weight −15.3% at 12 mg vs −0.81% / −2.6% placebo — the program's first peer-reviewed Phase 3 publication, confirming efficacy in T2D. Obesity Phase 3 (TRIUMPH-1) topline only — peer-reviewed publication pending. Update Aug 2026: TRIUMPH-2 (obesity + type 2 diabetes) and TRIUMPH-3 (obesity + established cardiovascular disease) both met their primary endpoints, reported 23 Jul 2026 — roughly 21% and 23% mean weight loss at 80 weeks on the highest doses, lower than TRIUMPH-1 as expected in populations with these comorbidities. Lilly now guides to an FDA submission in Q1 2027, pushed back from an earlier end-of-2026 target while it completes the manufacturing and quality-control (CMC) package; Lilly and the FDA are also disputing whether retatrutide is regulated as a biologic (BLA, 12-year exclusivity) or a drug (NDA, 5-year). Separately, on 3-4 Aug 2026 Lilly formalized a compassionate-use/expanded-access route after physician pressure, but the criteria are narrow — refractory obesity at BMI >=35 despite the highest tolerated dose of an approved weight-management therapy, plus two or more serious or life-threatening obesity-related complications. Patients cannot apply directly; a treating physician must petition Lilly, and FDA plus IRB authorization is still required. Access remains effectively closed to almost everyone asking for it.

Mechanism

Triple agonist: GLP-1 + GIP + glucagon receptors; glucagon arm adds energy expenditure in addition to appetite suppression

Studied, labeled, or reported dose & route

Phase 2 used up to 12 mg SC weekly; Phase 3 weekly SC

This records doses and routes described in studies, approved labeling, clinical practice, or documented use. It is not individualized guidance and does not establish safety; context changes with indication, formulation, health history, monitoring, and other medicines.

Citations

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Common questions

What does the evidence show about Retatrutide's effects?
Read Off Label rates the evidence for Retatrutide as Strong and the benefit magnitude as very high, producing an overall grade of B+ (7.1/10). Eli Lilly TRIUMPH-1 (May 21, 2026 topline): first Phase 3 readout in obesity, n=2,339 adults with obesity + ≥1 comorbidity (HTN/dyslipidemia/OSA/OA) but no diabetes, randomized 1:1:1:1 to retatrutide 4/9/12 mg or placebo SC weekly, 80-week primary with 104-week extension.
What safety findings are reported for Retatrutide?
Retatrutide has a med risk profile in the database. Med (GI dominant — 12 mg vs placebo at 80wk: nausea 42.4% vs 14.8%, vomiting 25.3% vs 4.8%, diarrhea 32.0% vs 13.5%; AE discontinuation 11.3% vs 4.9%; dysesthesia 12.5% vs 0.9% — novel signal; CV/MACE awaited from TRIUMPH-Outcomes) Legal status: Investigational (Phase 3; FDA submission guided to Q1 2027).
What doses or routes are reported for Retatrutide?
Phase 2 used up to 12 mg SC weekly; Phase 3 weekly SC This is context from studies, approved labeling, clinical practice, or documented use; it is not individualized guidance and does not establish safety.
How does Retatrutide work?
Triple agonist: GLP-1 + GIP + glucagon receptors; glucagon arm adds energy expenditure in addition to appetite suppression

This is an independent synthesis of published research by a non-clinician. Scores are opinions supported by citations, not prescriptions. See the full disclaimer and methodology for how this score was produced and what it does and doesn't mean.