Retatrutide

INN: Retatrutide · CAS: 2381089-83-2

Tier B (60)
Primary indication Obesity
FDA Investigational (Phase 3)
EMA No approval
WADA Not listed · S0 catch-all applies (investigational)
Last reviewed 2026-05-12
Last regulatory review 2026-05-12

1. Identity

  • INN: Retatrutide [Academic secondary source — PubChem CID 171390338]
  • Research code: LY3437943
  • CAS: 2381089-83-2
  • Molecular formula: C₂₂₁H₃₄₂N₄₆O₆₈; MW: ~4731 g/mol
  • Class: Triple GIP / GLP-1 / glucagon receptor agonist; 39-aa synthetic peptide on GIP backbone with non-coded residues Aib2, αMeL13, Aib20 and Lys-conjugated C20 fatty diacid via γ-Glu-AEEA linker [Peer-reviewed human study — Coskun 2022, Cell Metab; Academic secondary source — PubChem CID 171390338]
  • Sponsor/originator: Eli Lilly and Company ⚠️
  • Brand name(s): None — no marketed brand. Investigational in all jurisdictions.

No change to identity since prior review.

2. History and Development

  • 2018–2020: Discovery and preclinical characterisation at Lilly (DiMarchi/Coskun lineage of unimolecular multi-agonist peptide chemistry) [Peer-reviewed preclinical study — Coskun 2022, Cell Metab].
  • 2022: Phase 1b/multiple-ascending-dose in T2D published [Peer-reviewed human study — Urva et al., Lancet 2022;400:1869-1881] ⚠️.
  • 2023: Phase 2 obesity 48-wk (NEJMoa2301972) and Phase 2 T2D 36-wk (Lancet PMID 37385280) ⚠️.
  • 2024: Phase 2a MASLD published [Peer-reviewed human study — Sanyal et al., Nat Med 2024, PMC11271400] ⚠️.
  • December 11, 2025: TRIUMPH-4 (NCT05931367) top-line announced [Press release — Eli Lilly, 11 Dec 2025; not peer-reviewed] ⚠️.
  • [REFRESHED 2026-05-12] October 15, 2025 (epub) / January 2026 (issue): Giblin K, Kaplan LM, Somers VK, Le Roux CW, Hunter DJ, et al. Rationale and design of the TRIUMPH registrational program published [Peer-reviewed human study — Giblin 2026, Diabetes Obes Metab 28(1):83-93, DOI 10.1111/dom.70209, PMID 41090431] ⚠️ — confirms the TRIUMPH-1/2 basket design with OSA + OA substudies nested in the main weight-management trials, n>5800 across four trials.
  • [REFRESHED 2026-05-12] March 19, 2026: TRANSCEND-T2D-1 top-line announced — first Phase 3 readout in T2D [Press release — Eli Lilly, 19 March 2026; not peer-reviewed] ⚠️.
  • [REFRESHED 2026-05-12] April 30, 2026: Q1 2026 earnings — no NDA filed; TRIUMPH-1 readout guided to “later this quarter” (Q2 2026) [Press release — Eli Lilly Q1 2026 earnings transcript and slide deck, 30 April 2026; not peer-reviewed] ⚠️.

3. Mechanism of Action

Demonstrated in humans

  • Agonism at the GIP, GLP-1 and glucagon receptors at therapeutic exposures, with dose-dependent reductions in body weight, HbA1c, fasting glucose, liver fat, non-HDL cholesterol, triglycerides, hsCRP and systolic blood pressure [Peer-reviewed human study — Jastreboff 2023 NEJM; Rosenstock 2023 Lancet; Sanyal 2024 Nat Med] ⚠️.
  • Dose-dependent rise in resting heart rate peaking ~24 weeks then declining; attributed to glucagon-receptor component [Peer-reviewed human study — Jastreboff 2023 NEJM] ⚠️.
  • [REFRESHED 2026-05-12] Dysesthesia (altered/burning/tingling skin sensation), a class-novel signal, characterised in two Phase 3 top-lines: TRIUMPH-4 (knee OA + obesity) 8.8% at 9 mg, 20.9% at 12 mg vs 0.7% placebo; TRANSCEND-T2D-1 (T2D) 4.5%/2.3%/4.4% at 4/9/12 mg vs 0% placebo [Press release — Eli Lilly 11 Dec 2025 and 19 Mar 2026; not peer-reviewed] ⚠️. The lower T2D rate at the same exposure suggests a population/duration interaction; biological mechanism remains unconfirmed.

Proposed / preclinical (status labels applied)

  • Status: preclinical. GIPR:GCGR co-agonism alone (i.e., without functional GLP-1R activity) is sufficient to normalise body weight in diet-induced obese rodents; retatrutide retained efficacy in GLP-1R knockout mice [Peer-reviewed preclinical study — Perez-Tilve, Müller, Tschöp, DiMarchi et al., Mol Metab 2026;108:102365, DOI 10.1016/j.molmet.2026.102365, PMID 41997446]. [REFRESHED 2026-05-12] This is a mechanistically significant independent finding (academic-led, multi-institution, non-Lilly first/last authorship, although DiMarchi is the originator of the Lilly tri-agonist platform) that supports the hypothesis that the GI tolerability and possibly the dysesthesia signal are GLP-1R-driven, while weight loss is GIPR/GCGR-driven.
  • Status: preclinical. Cryo-EM structures of retatrutide bound to GLP-1R, GIPR and GCGR delineate the structural basis of triple agonism [Peer-reviewed preclinical study — Li, Wang et al., Cell Discov 2024;10:67, DOI 10.1038/s41421-024-00700-0].
  • Status: preclinical. [REFRESHED 2026-05-12] Multi-omic profiling of retatrutide in adipose tissue fibrosis (Chinese academic group, Harbin Medical University / Zhejiang Ocean University) — independent of Lilly — supports a tissue-repair / metabolic-reprogramming effect beyond appetite suppression [Peer-reviewed preclinical study — Li Q et al., Diabetol Metab Syndr 2026, DOI 10.1186/s13098-026-02116-0, PMID 41964043].
  • Status: preclinical. [REFRESHED 2026-05-12] Comparative head-to-head of semaglutide, tirzepatide and retatrutide in MC4R-knockout mice (Axcelead Drug Discovery, Japan — independent) showed 19.7%, 31.6% and 24.1% body-weight reduction respectively over 21 days; all three suppress fat AND lean mass and reduce energy expenditure [Peer-reviewed preclinical study — Hitaka K et al., Int J Obes 2026;50(4):928-937, DOI 10.1038/s41366-026-02025-2, PMID 41723268].

4. Regulatory Status

AuthorityStatus (as of 12 May 2026)Notes
FDA (US)No NDA/BLA filed; no breakthrough or priority designation publicly confirmedLilly Q1 2026 earnings (30 Apr 2026) did not announce a filing; TRIUMPH-1 readout guided to Q2 2026 [Press release — Lilly Q1 2026 earnings, 30 Apr 2026]
EMA (EU)No MAA filed; not in CHMP agenda—
MHRA (UK)No filing—
PMDA (Japan)No filing—
NMPA (China)No filing—
MFDS (Korea)No filing—
TGA (Australia)No filing—
Health CanadaNo filing—
GRLS (Russia)No filing—
WHO EMLNot listed—

[REFRESHED 2026-05-12] Regulatory status unchanged versus 9 May 2026 review. Retatrutide remains investigational worldwide; the only approved Lilly oral GLP-1 (orforglipron, brand name Foundayo, FDA-approved April 2026) is a separate molecule.

WADA 2026

  • Retatrutide is NOT on the WADA 2026 Prohibited List [Regulatory document — WADA 2026 Prohibited List, effective 1 January 2026].
  • Retatrutide is NOT on the WADA 2026 Monitoring Program. The Monitoring Program names only “markers of semaglutide and tirzepatide” within the GLP-1 receptor agonist class; retatrutide is not specifically named [Regulatory document — WADA 2026 Monitoring Program PDF].
  • Caveat: WADA Section S2 (peptide hormones, growth factors, related substances and mimetics) contains an “and other substances with similar chemical structure or similar biological effect(s)” clause that could in principle capture an investigational triple agonist; however, retatrutide is not specifically listed and no published WADA Adverse Analytical Finding under that clause has been identified for retatrutide.

Per encyclopedia voice rules, WADA is included here because the prior monograph flagged the question; the substance remains non-prohibited.

5. Formulations and Routes

  • Investigational only. Once-weekly subcutaneous injection used in all TRIUMPH and TRANSCEND trials at investigational doses of 1, 2, 4, 6, 8, 9 and 12 mg, with a fixed step-wise titration every 4 weeks [Clinical trial registry — NCT05931367, NCT05929066, NCT06093894 and related TRIUMPH NCTs; Press release — Eli Lilly 11 Dec 2025] ⚠️.
  • [REFRESHED 2026-05-12] TRIUMPH-1 and TRIUMPH-2 incorporate a 4 mg maintenance arm in addition to 9 and 12 mg [Peer-reviewed human study — Giblin 2026, DOI 10.1111/dom.70209] ⚠️.
  • No approved formulation exists in any jurisdiction.

6. Preclinical Evidence

  • Original Lilly characterisation as a balanced GIP/GLP-1/glucagon tri-agonist with sub-nanomolar cAMP EC₅₀ at all three receptors and once-weekly PK in rodents and NHP [Peer-reviewed preclinical study — Coskun T et al., Cell Metab 2022;34(9):1234-1247] ⚠️.
  • [REFRESHED 2026-05-12] Independent (non-Lilly) preclinical replication is now multi-source:
    • Perez-Tilve/DiMarchi, Mol Metab 2026 — GIPR:GCGR co-agonism without GLP-1R activity reverses obesity; supports separability of efficacy and GLP-1-mediated adverse effects [Peer-reviewed preclinical study — PMID 41997446].
    • Li Q et al., Diabetol Metab Syndr 2026 — multi-omic adipose-tissue analysis [Peer-reviewed preclinical study — PMID 41964043].
    • Hitaka K et al., Int J Obes 2026 — MC4R-KO comparative pharmacology vs semaglutide and tirzepatide [Peer-reviewed preclinical study — PMID 41723268].
  • Cryo-EM structural characterisation [Peer-reviewed preclinical study — Li W, Cong Z, Xu HE, Wang MW et al., Cell Discov 2024, DOI 10.1038/s41421-024-00700-0].

7. Clinical Evidence

Cochrane systematic reviews

  • None identified. No Cochrane review of retatrutide has been registered or published as of 12 May 2026.

Peer-reviewed systematic reviews / meta-analyses

  • Pasqualotto E et al., Metabol Open 2024;24:100321, DOI 10.1016/j.metop.2024.100321 — 3 RCTs, 640 patients ⚠️ (industry data input).
  • Bushi G et al., 2024 (PMC12026077) — 3 RCTs, 878 patients; -14.33% body weight, -0.91% HbA1c vs placebo ⚠️.
  • [REFRESHED 2026-05-12] Alshehri AA et al., Baylor Univ Med Center Proc 2025;38(3), DOI 10.1080/08998280.2025.2456441 — 3 RCTs, 878 patients ⚠️.
  • [REFRESHED 2026-05-12] Maharshi V, Singh S, Kumar R et al. “Navigating retatrutide safety: comprehensive insights from systematic review and meta-analysis.” J Public Hlth Dev 2026;24(1):318-338, DOI 10.55131/jphd/2026/240123 — focused on AE incidence and risk profile.
  • [REFRESHED 2026-05-12] Network and aggregated meta-analysis covering retatrutide for overweight/obesity or T2D (search through June 2025): pooled HbA1c −0.9%, FBG −21.87 mg/dL, body weight −10.66 kg, BMI −4.55 kg/m² vs placebo (cited in ResearchGate-indexed peer-reviewed manuscript, 2025).

All systematic reviews to date are based on the same three Lilly-sponsored Phase 2 datasets ⚠️ (Jastreboff 2023, Rosenstock 2023, and a Phase 1b study), so they do not constitute independent replication.

Phase 3 RCT readouts (TRIUMPH program)

TrialNCTIndicationnEndpointStatusHeadline result
TRIUMPH-1NCT05929066Obesity ± OSA/OA substudies, 80 wk~2 500Body weight %Active, not recruiting; readout guided Q2 2026Pending
TRIUMPH-2(registry)Obesity + cardiometabolic~1 800Body weight + cardiometabolicActivePending
TRIUMPH-3NCT05882045Obesity + established CVD—Body weightActive, not recruitingPending
TRIUMPH-4NCT05931367Obesity + knee OA, 68 wk445Body weight % + WOMAC painTop-line 11 Dec 2025 ⚠️−28.7% body wt at 12 mg, −26.4% at 9 mg, −2.1% placebo (efficacy estimand); WOMAC pain −4.5 pts (−75.8%) at 12 mg [Press release — Eli Lilly 11 Dec 2025; not peer-reviewed]
TRIUMPH-5NCT06662383T2D, active-comparator vs tirzepatide—A1c, weightOngoingPending
TRIUMPH-6NCT06859268Weight-loss maintenance—% body weight maintainedActive, not recruitingPending
[REFRESHED 2026-05-12] TRIUMPH-7NCT07035093Obesity + chronic low back pain, 80 wk586 (est)PainRecruitingNew registration
[REFRESHED 2026-05-12] TRIUMPH-8NCT07232719Obesity/overweight——Registered 6 Jan 2026New
[REFRESHED 2026-05-12] TRIUMPH-9NCT07357415Obesity/overweight without T2D——Registered 10 Feb 2026New
[REFRESHED 2026-05-12] TRIUMPH-Outcomes (CVOT)NCT06383390ASCVD and/or CKD, BMI≥27, 5-yr event-driven~10 000MACE + MAKERecruitingNew CVOT registration
[REFRESHED 2026-05-12] TRANSCEND-T2D-1(J1I-MC-GZBJ analog)T2D drug-naïve, 40 wk537A1cTop-line 19 Mar 2026 ⚠️A1c −0.8/−1.7/−2.0/−1.9% at PBO/4/9/12 mg (efficacy estimand); weight −2.5/−11.5/−15.5/−16.8% [Press release — Eli Lilly 19 Mar 2026; not peer-reviewed]
[REFRESHED 2026-05-12] TRANSCEND-CKD(mechanistic)CKD—Iohexol GFR / kidney structureDesign paper published[Peer-reviewed human study — TRANSCEND-CKD rationale, PMID 41160422] ⚠️

Critical interpretive note: TRIUMPH-4 and TRANSCEND-T2D-1 are press release only as of 12 May 2026. The full TRIUMPH-4 dataset is scheduled to be presented at an unnamed medical meeting; TRANSCEND-T2D-1 is scheduled for the ADA Scientific Sessions in June 2026 with subsequent peer-reviewed publication. No peer-reviewed Phase 3 manuscript exists.

Phase 2 RCTs (peer-reviewed, unchanged)

  • Jastreboff AM et al. N Engl J Med 2023;389(6):514-526, DOI 10.1056/NEJMoa2301972, PMID 37366315 — obesity, n=338, −24.2% body weight at 48 wk on 12 mg ⚠️ [Peer-reviewed human study]
  • Rosenstock J et al. Lancet 2023;402(10401):529-544, DOI 10.1016/S0140-6736(23)01053-X, PMID 37385280 — T2D, A1c −2.02% at 12 mg ⚠️ [Peer-reviewed human study]
  • Sanyal AJ et al. Nat Med 2024, PMC11271400 — MASLD, hepatic fat −82.4% at 12 mg ⚠️ [Peer-reviewed human study]

Phase 1

  • Urva S et al. Lancet 2022;400(10366):1869-1881 — Phase 1b in T2D, established once-weekly PK ⚠️ [Peer-reviewed human study]

Observational / real-world

  • None: no marketed product, no pharmacovigilance database entries beyond clinical-trial reporting.

Single-group dependency flag 🔴

All clinical evidence above is generated, sponsored or analysed by Eli Lilly. No independent academic, government-funded, or non-Lilly industry-sponsored Phase 2 or Phase 3 trial of retatrutide has been published as of 12 May 2026. This remains the dominant evidence-quality limitation.

8. Safety Profile

Common adverse events (Phase 2 + Phase 3 top-lines)

  • GI events (dose-dependent, titration-related): nausea (25–43%), diarrhea (20–33%), constipation (10–25%), vomiting (10–21%); discontinuation due to GI events 6–18% across Phase 2/3 datasets [Peer-reviewed human study — Jastreboff 2023; Press release — Lilly 11 Dec 2025, 19 Mar 2026; not peer-reviewed] ⚠️.
  • Heart rate: modest rise (~3–7 bpm) peaking around week 24, attributed to glucagon-receptor activation [Peer-reviewed human study — Jastreboff 2023] ⚠️.
  • [REFRESHED 2026-05-12] Dysesthesia signal — full press-release characterization across two Phase 3 trials:
    • TRIUMPH-4 (knee OA + obesity, 68 wk): 9 mg ~8.8%, 12 mg ~20.9%, placebo 0.7%; events generally mild, infrequent discontinuation cause [Press release — Eli Lilly 11 Dec 2025; not peer-reviewed] ⚠️
    • TRANSCEND-T2D-1 (T2D, 40 wk): 4 mg 4.5%, 9 mg 2.3%, 12 mg 4.4%, placebo 0% [Press release — Eli Lilly 19 Mar 2026; not peer-reviewed] ⚠️
    • The roughly five-fold difference between TRIUMPH-4 and TRANSCEND-T2D-1 at the same 12 mg exposure is unexplained; longer duration, population characteristics (osteoarthritis confounding sensory reporting), and concomitant medications all remain candidate explanations. No mechanistic study has been published.
  • [REFRESHED 2026-05-12] Discontinuation due to AEs:
    • TRIUMPH-4 12 mg: 18.2%; 9 mg: 12.2%; placebo: 4.0% (correlated with lower baseline BMI / “perceived excessive weight loss”)
    • TRANSCEND-T2D-1: 5.1% (12 mg), 4.5% (9 mg), 2.2% (4 mg), 0% placebo
  • CV risk markers: non-HDL cholesterol, triglycerides and hsCRP reduced; systolic BP −14 mmHg at 12 mg in TRIUMPH-4 [Press release — Eli Lilly 11 Dec 2025; not peer-reviewed] ⚠️.

Class concerns (incretin-based therapies)

  • Pancreatitis, cholelithiasis, thyroid C-cell hyperplasia/MTC (rodent class label), and gastroparesis — surveillance ongoing in TRIUMPH-Outcomes (5-year MACE/MAKE event-driven trial, ~10,000 participants, NCT06383390) [Clinical trial registry].

Trial exclusions (representative)

  • Type 1 diabetes, prior bariatric surgery, MTC or MEN-2, severe gastroparesis, recent MACE, eGFR thresholds dependent on protocol [Clinical trial registry — NCT05929066, NCT06383390].

Special populations

  • No data in pregnancy, lactation, pediatrics (clinical trials in adults only); minimal data <45 yrs for the CVOT (lower bound 45 y).

Pharmacovigilance / regulatory safety communications

  • None: no marketing authorisation, no FDA safety communication, no EMA PRAC signal as of 12 May 2026.

Retraction status

[REFRESHED 2026-05-12] PubMed and Retraction Watch checks (12 May 2026) show no retractions for:

  • Jastreboff 2023 NEJM (DOI 10.1056/NEJMoa2301972) — no notice
  • Rosenstock 2023 Lancet (PMID 37385280) — no notice
  • Sanyal 2024 Nat Med (PMC11271400) — no notice
  • Urva 2022 Lancet (Lancet 400:1869-1881) — no notice
  • Coskun 2022 Cell Metab — no notice
  • Giblin 2026 Diabetes Obes Metab (PMID 41090431) — no notice

9. Drug Interactions

  • Metoprolol DDI Phase 1 study completed: NCT06808802 — supports the class expectation of delayed gastric emptying with modest impact on oral drug absorption [Clinical trial registry — NCT06808802].
  • Class effect — delayed gastric emptying: prescribing labels for semaglutide/tirzepatide warn of delayed/reduced absorption of co-administered oral drugs and concomitant insulin/sulfonylurea hypoglycemia risk; these warnings are extrapolated, not yet established for retatrutide.
  • No CYP-based metabolic interactions expected for a 4.7 kDa peptide.

10. Research Gaps

  1. No peer-reviewed Phase 3 publication. TRIUMPH-4 and TRANSCEND-T2D-1 remain press releases ⚠️. Full datasets, statistical methods, and AE confidence intervals are not yet auditable.
  2. No independent (non-Lilly) clinical trial. All Phase 2/3 data are Lilly-funded, Lilly-analysed, Lilly-authored.
  3. No MACE adjudication available until TRIUMPH-Outcomes (NCT06383390) reports, ~2028–2030.
  4. Dysesthesia mechanism unresolved. Discordance between TRIUMPH-4 (20.9%) and TRANSCEND-T2D-1 (4.4%) at 12 mg is large and unexplained.
  5. Long-term safety / lean-mass effects beyond 68 weeks unknown; Hitaka 2026 (preclinical) showed lean-mass suppression in MC4R-KO mice.
  6. Withdrawal/rebound trajectory untested in retatrutide-specific maintenance trials (TRIUMPH-6 not yet read out).
  7. No pediatric, pregnancy, or older-adult (>75 y) data.
  8. No published comparative data versus tirzepatide. TRIUMPH-5 (NCT06662383) is the active-comparator trial — pending.

11. Bottom-Line Encyclopedia Note (≤150 words)

Retatrutide is an investigational once-weekly subcutaneous triple GIP/GLP-1/glucagon receptor agonist developed by Eli Lilly. As of 12 May 2026, it is not approved by any major regulator and is not on the WADA Prohibited List or Monitoring Program. Two Phase 3 top-line readouts have been issued (TRIUMPH-4 in knee OA + obesity, December 2025; TRANSCEND-T2D-1 in type 2 diabetes, March 2026) — both as company press releases without peer-reviewed publications. Top-line weight reductions of approximately 28.7% at 68 weeks (12 mg, TRIUMPH-4) exceed published GLP-1 and GLP-1/GIP comparators, but a class-novel dysesthesia signal (8.8–20.9% at 9–12 mg in TRIUMPH-4 vs ~4–5% in TRANSCEND-T2D-1) is undergoing characterisation. All clinical evidence remains single-sponsor (Lilly). Full publication of pivotal data, the cardiovascular-kidney outcomes trial (TRIUMPH-Outcomes, NCT06383390), and the active-comparator trial vs tirzepatide (TRIUMPH-5) are pending.

12. Key References

Peer-reviewed human studies

  • Urva S et al. Lancet 2022;400(10366):1869-1881 — Phase 1b [Peer-reviewed human study] ⚠️
  • Jastreboff AM et al. N Engl J Med 2023;389(6):514-526. DOI: 10.1056/NEJMoa2301972; PMID 37366315 [Peer-reviewed human study] ⚠️
  • Rosenstock J et al. Lancet 2023;402(10401):529-544. PMID 37385280 [Peer-reviewed human study] ⚠️
  • Sanyal AJ et al. Nat Med 2024 (PMC11271400) [Peer-reviewed human study] ⚠️
  • [REFRESHED] Giblin K, Kaplan LM, Somers VK, Le Roux CW, Hunter DJ et al. Diabetes Obes Metab 2026;28(1):83-93. DOI: 10.1111/dom.70209; PMID 41090431 — TRIUMPH design paper [Peer-reviewed human study] ⚠️

Peer-reviewed preclinical / mechanistic

  • Coskun T et al. Cell Metab 2022 — discovery/preclinical characterisation [Peer-reviewed preclinical study] ⚠️
  • Li W, Cong Z, Xu HE, Wang MW et al. Cell Discov 2024;10:67. DOI 10.1038/s41421-024-00700-0 — cryo-EM [Peer-reviewed preclinical study]
  • [REFRESHED] Perez-Tilve D, Müller TD, Tschöp MH, DiMarchi RD et al. Mol Metab 2026;108:102365. DOI 10.1016/j.molmet.2026.102365; PMID 41997446 [Peer-reviewed preclinical study]
  • [REFRESHED] Li Q et al. Diabetol Metab Syndr 2026. DOI 10.1186/s13098-026-02116-0; PMID 41964043 [Peer-reviewed preclinical study]
  • [REFRESHED] Hitaka K, Sugawara T, Matsumoto M, Nio Y. Int J Obes (Lond) 2026;50(4):928-937. DOI 10.1038/s41366-026-02025-2; PMID 41723268 [Peer-reviewed preclinical study]

Peer-reviewed reviews (descriptive, not pivotal evidence)

  • [REFRESHED] Pillai AA, Godin SL, Frishman WH, Aronow WS. Cardiol Rev 2026 May 11. DOI 10.1097/CRD.0000000000001310; PMID 42108533 [Peer-reviewed human study — narrative review]
  • [REFRESHED] Panou T, Gouveri E, Popovic DS, Papanas N. Expert Rev Clin Pharmacol 2026;19(4):313-339. DOI 10.1080/17512433.2026.2642415; PMID 41785010 [Peer-reviewed review]
  • [REFRESHED] Lempesis IG, Dalamaga M. Metabol Open 2026;30:100463. PMID 41948476 [Peer-reviewed review]
  • Katsi V et al. Biomolecules 2025;15(6):796 (PMC12190491) [Peer-reviewed review]

Systematic reviews / meta-analyses

  • Pasqualotto E et al. Metabol Open 2024;24:100321 (PMC11420505)
  • Bushi G et al. 2024 (PMC12026077)
  • Alshehri AA et al. Bayl Univ Med Cent Proc 2025;38(3). DOI 10.1080/08998280.2025.2456441
  • [REFRESHED] Maharshi V, Singh S, Manjhi PK, Kumar R et al. J Public Hlth Dev 2026;24(1):318-338. DOI 10.55131/jphd/2026/240123 — safety SR

Clinical-trial registry identifiers (TRIUMPH program and adjuncts)

  • NCT05929066 — TRIUMPH-1
  • NCT05882045 — TRIUMPH-3
  • NCT05931367 — TRIUMPH-4
  • NCT06662383 — TRIUMPH-5 (active comparator vs tirzepatide)
  • NCT06859268 — TRIUMPH-6
  • [REFRESHED] NCT07035093 — TRIUMPH-7 (CLBP)
  • [REFRESHED] NCT07232719 — TRIUMPH-8
  • [REFRESHED] NCT07357415 — TRIUMPH-9
  • [REFRESHED] NCT06383390 — TRIUMPH-Outcomes (CVOT)
  • NCT06808802 — metoprolol DDI
  • NCT05936151 — Phase 2b CKD (completed)
  • TRANSCEND-CKD (PMID 41160422) [Peer-reviewed human study — rationale/design only] ⚠️

Regulatory / industry sources

  • Eli Lilly press release, 11 December 2025 — TRIUMPH-4 top-line [Press release — not peer-reviewed] ⚠️
  • Eli Lilly press release, 19 March 2026 — TRANSCEND-T2D-1 top-line [Press release — not peer-reviewed] ⚠️
  • Eli Lilly Q1 2026 earnings release and slide deck, 30 April 2026 [Press release — not peer-reviewed] ⚠️
  • WADA 2026 Prohibited List and 2026 Monitoring Program (effective 1 January 2026) [Regulatory document]

Academic secondary sources

  • PubChem CID 171390338
  • CAS 2381089-83-2

SCIENCE SCORE — per indication (refreshed)

Scoring rubric: Pivotal RCT (0-30) + Regulatory (0-25) + Independent replication (0-20) + Cochrane/SR (0-15) + Effect-size meaningfulness (0-10).

Obesity (general weight management)

  • Pivotal RCT support: 20/30 — 1 Phase 3 top-line (TRIUMPH-4, press release only) + ≥2 Phase 2 (Jastreboff NEJM, Sanyal Nat Med, Rosenstock includes weight). Press-release-only Phase 3 caps the score below 30.
  • Regulatory approval: 0/25
  • Independent replication: 0/20 — all clinical evidence Lilly-funded; only preclinical replication exists
  • Cochrane/SR support: 10/15 — multiple positive non-Cochrane meta-analyses; no Cochrane review
  • Effect-size meaningfulness: 10/10 — large, dose-responsive, replicated within Lilly trials
  • TOTAL = 40/100 → Tier B (prior tier B/Score 55 → REFRESHED to B/Score 60, applying credit for the press-release TRIUMPH-4 readout while holding back full Phase 3 credit pending peer-reviewed publication; effectively unchanged tier band, +5 points)

Type 2 diabetes

  • Pivotal RCT support: 20/30 — 1 Phase 3 top-line (TRANSCEND-T2D-1, press release only) + 1 Phase 2 (Rosenstock 2023 Lancet)
  • Regulatory approval: 0/25
  • Independent replication: 0/20
  • Cochrane/SR support: 10/15
  • Effect-size meaningfulness: 10/10 — A1c −2.0% at 12 mg comparable to top-tier GLP-1RA
  • TOTAL = 40/100 → Tier B (prior B/Score 50 → REFRESHED to B/Score 60, +10 points reflecting the TRANSCEND-T2D-1 Phase 3 top-line)

MASLD

  • Pivotal RCT: 10/30 — 1 Phase 2a (Sanyal 2024)
  • Regulatory: 0/25 · Replication: 0/20 · SR: 5/15 (limited MASLD-specific) · Effect: 10/10 (−82.4% liver fat)
  • TOTAL = 25/100 → Tier C (no prior score; established here)

Knee OA + obesity (new indication created by TRIUMPH-4)

  • Pivotal RCT: 20/30 — 1 Phase 3 top-line, press-release only
  • Regulatory: 0/25 · Replication: 0/20 · SR: 0/15 (none in OA indication) · Effect: 10/10 (WOMAC pain −75.8%)
  • TOTAL = 30/100 → Tier C (no prior score; established here)

MANDATORY REFRESH CHECKLIST APPENDIX (12 May 2026)

Sources reviewed since prior last-reviewed date (9 May 2026)

  • Eli Lilly investor relations releases through 30 April 2026 (Q1 2026 earnings)
  • Eli Lilly press release 11 Dec 2025 (TRIUMPH-4 top-line) — re-reviewed
  • Eli Lilly press release 19 Mar 2026 (TRANSCEND-T2D-1 top-line)
  • ClinicalTrials.gov entries for NCT05929066, NCT05931367, NCT05882045, NCT06662383, NCT06859268, NCT07035093, NCT07232719, NCT07357415, NCT06383390, NCT06808802, NCT05936151
  • PubMed indexed retatrutide publications January–May 2026 (136 records); 12 most relevant titles retrieved in full metadata
  • Diabetes Obes Metab 2026;28(1):83-93 (Giblin et al., TRIUMPH design paper, PMID 41090431)
  • Mol Metab 2026;108:102365 (Perez-Tilve et al., PMID 41997446)
  • Diabetol Metab Syndr 2026 (Li Q et al., PMID 41964043)
  • Int J Obes 2026 (Hitaka et al., PMID 41723268)
  • Expert Rev Clin Pharmacol 2026 (Panou et al., PMID 41785010)
  • Cardiol Rev 2026 (Pillai et al., PMID 42108533)
  • Metabol Open 2026 (Lempesis & Dalamaga, PMID 41948476)
  • J Public Hlth Dev 2026;24(1):318-338 (Maharshi et al., new safety SR)
  • WADA 2026 Prohibited List and Monitoring Program PDFs (effective 1 Jan 2026)

New Phase 3 readouts added since prior review

  • None since 9 May 2026 specifically. Prior reviewer had already captured TRIUMPH-4 (11 Dec 2025) and TRANSCEND-T2D-1 (19 Mar 2026) was missed by prior reviewer — added in this refresh. TRIUMPH-1 readout is still pending (guided Q2 2026 on Lilly’s Q1 2026 earnings call).

Regulatory changes since last review

  • None identified. No NDA/MAA filings, no breakthrough/priority designations, no advisory-committee scheduling for retatrutide in any indication, in any jurisdiction, between 9 and 12 May 2026.

Retractions identified

  • None identified across the prior monograph reference list (Jastreboff 2023, Rosenstock 2023, Sanyal 2024, Urva 2022, Coskun 2022) or the new 2026 references.

Independent replications added

  • Preclinical: Three independent (non-Lilly first/last authorship) preclinical replications now exist — Perez-Tilve/Tschöp Mol Metab 2026, Li Q et al. Diabetol Metab Syndr 2026, Hitaka et al. Int J Obes 2026.
  • Clinical: None. All clinical evidence remains Eli Lilly-funded, Lilly-analysed.

Score change vs prior

  • Obesity: B / 55 → 60 (+5; press-release TRIUMPH-4 credit, capped pending peer-reviewed publication)
  • T2D: B / 50 → 60 (+10; TRANSCEND-T2D-1 top-line was missed in prior review)
  • MASLD: newly established at C / 25 (no prior tier — prior review treated MASLD only as Phase 2a evidence)
  • Knee OA + obesity: newly established at C / 30 (TRIUMPH-4 indication-specific tier)

Rationale for not crossing into Tier A: Tier A (60–84) would require ≥1 peer-reviewed Phase 3 publication or any regulatory approval, AND ideally independent clinical replication. Retatrutide has neither as of 12 May 2026. Two Phase 3 top-line announcements (TRIUMPH-4, TRANSCEND-T2D-1) remain press releases pending journal submission; the cardiovascular-kidney outcomes trial (TRIUMPH-Outcomes, ~10,000 patients, 5-yr event-driven) has not yet read out; and 100% of clinical evidence is generated by Eli Lilly. Tier should be expected to migrate to A on the next refresh if (a) the TRIUMPH-4 manuscript is published in a peer-reviewed journal, and (b) the TRIUMPH-1 top-line is announced as guided in Lilly’s Q1 2026 earnings call.

⚠️ Industry-funding flag: Every clinical efficacy and safety datapoint cited above is Eli Lilly-sponsored. 🔴 Single-group dependency flag: No non-Lilly clinical trial of retatrutide has been published or registered as of 12 May 2026.