Eli Lilly's next-generation weight-loss medicine, currently in late-stage trials. Activates three hormone receptors at once. In the first phase-3 trial (Dec 2025), patients lost an average of 28.7% of body weight at 68 weeks — about 70 pounds. Not yet FDA-approved — expected submission 2026.
LY3437943 — once-weekly SC investigational triagonist of GIP, GLP-1, and glucagon receptors. Single 39-amino-acid peptide with C20 fatty-diacid linker for albumin binding (~6-day half-life). Currently phase 3. TRIUMPH-4 (knee OA + obesity): −28.7% weight at 12 mg, 75.8% pain reduction, Dec 2025 topline. Seven additional TRIUMPH readouts expected through 2026.
Single 39-AA peptide engineered from a GIP backbone with three non-coded residues (Aib2, αMeL13, Aib20) and a γ-Glu-AEEA-C20 diacid moiety at Lys17 enabling albumin binding. Adds glucagon-receptor agonism on top of dual GIP/GLP-1 activity — glucagon increases REE and lipolysis, hypothesized to extend the weight-loss ceiling vs dual agonism. Cryo-EM-resolved binding at all three Class B1 GPCRs; receptor affinities (EC50): GLP-1R ≈ 6 pM, GIPR ≈ 9 pM, GCGR ≈ 1.5 nM.
The most-cited numbers across phase 2 and phase 3 read-outs — the metrics that define why retatrutide is being talked about as the highest-ceiling weight-loss molecule in development.
Retatrutide hits three hormone receptors at once. Each does something different — together they reduce appetite, improve insulin response, increase the calories your body burns at rest, and break down stored fat. That four-axis attack on energy balance is why the weight loss is bigger than any prior drug.
Glucagon receptor agonism is a calculated tradeoff. In isolation, glucagon raises blood sugar. But paired with strong GIP/GLP-1 stimulation, the net insulin response masks glucagon-driven gluconeogenesis. The benefit retained: ~5% increase in basal metabolic rate, marked lipolysis of visceral and hepatic fat depots. Hepatic steatosis reduces faster than with any prior incretin.
Receptor binding affinities (EC50): GLP-1R ≈ 6 pM, GIPR ≈ 9 pM, GCGR ≈ 1.5 nM. Balanced activation profile contrasts with cotadutide (highly glucagon-biased) and tirzepatide (zero glucagon activity). Mendelian randomization studies suggest glucagon-receptor agonism contributes additively rather than synergistically to weight loss — but with significant impact on liver-fat reduction (−85% MRI-PDFF at 24 wks in phase 2). Open questions: long-term glycemic safety, cardiovascular outcomes, hepatic biopsy data.
Retatrutide is administered as a once-weekly subcutaneous injection across every published and active trial. Because it carries no approved prescribing information as of May 2026, the architecture below is a speculative hypothesis layer (Grade D/P) derived from investigational trial protocols and incretin-class practice patterns — not a validated label. Each protocol is built to the same skeleton: starting dose, escalation cadence, dose ladder, maintenance target, cycle/continuation structure, dose math, monitoring overlay, and explicit evidence grade — anchored by a pharmacokinetic panel, a global dose-band table, a weight-band reference, engine-ready titration logic, and a biomarker monitoring scaffold. Weight-loss outcomes at each tier are Grade A (Phase 2/3 RCTs); the protocol mechanics wrapped around them remain Grade D until a label exists.
Retatrutide is engineered for weekly dosing the same way tirzepatide is: a C20 fatty-diacid moiety at Lys₁₇ drives reversible albumin binding, and Aib substitutions at positions 2 and 20 block DPP-4 cleavage — together yielding a terminal half-life of roughly 6 days (~144 h), dose-proportional across the studied range. Steady state is reached after ~4–5 half-lives (≈ 4–5 weeks), which is the basis for the 4-week titration step. Several parameters (Tmax, absolute bioavailability, clearance route) were not formally published from Phase 2 and are flagged Grade D.
| Parameter | Value | Note |
|---|---|---|
| Route | Subcutaneous only | Abdomen, thigh, or upper arm; rotate sites. No oral/IM/intranasal form in any trial. |
| Half-life (t½) | ~6 days (~144 h) | Terminal elimination; Phase 2 PK + Nat Med 2024. Enables once-weekly dosing. |
| Dosing interval | Once weekly (7-day) | Phase 2 + Phase 3 (TRIUMPH) protocols. |
| Tmax (SC) | Not formally published | Slow absorption expected from albumin-binding acylation (class behavior). Grade D. |
| Bioavailability (SC) | Not published (~70–90% class range) | Estimated from peptide SC class data; not retatrutide-specific. Grade D. |
| Protein binding | High (albumin) | Via C20 fatty-diacid moiety — the mechanism for the extended half-life. |
| DPP-4 resistance | Aib at positions 2 & 20 | Non-coded α-aminoisobutyric-acid substitutions protect against proteolytic cleavage. |
| Clearance | Renal / proteolytic (data not published) | Dose-proportional PK; no intact-peptide accumulation expected. Grade D. |
| Steady state | ~4–5 weeks weekly dosing | ~4–5 half-lives; the basis for the 4-week titration step. |
| Renal / hepatic impairment | Not established | TRANSCEND-T2D-3 studying moderate/severe renal impairment; await data. |
2 mg once weekly, weeks 1–4. Lower than the 0.5 mg starting dose used in earlier Phase 2 work — chosen to balance tolerability and titration time.4 weeks until target maintenance reached. TRIUMPH protocols typically reach 12 mg maintenance by week 20–24.2 → 4 → 6 → 9 → 12 mg in TRIUMPH-1 / TRIUMPH-4. Some active arms use 2 → 4 → 8 → 12 mg compressed schedule.9 mg or 12 mg weekly — both arms studied in TRIUMPH-4. 12 mg delivers maximum weight loss; 9 mg balances effect with side-effect burden.0.5 mg, 1 mg, 2 mg, or 4 mg once weekly (study arms used varying starts). 1 mg was the most-studied starting dose in this trial.4 weeks. Phase 2 used multiple titration schemes — slow titration arms reduced GI events without reducing 48-week weight loss outcome.1 mg, 4 mg, 8 mg, 12 mg — full dose-ranging design (placebo + 4 active arms).2 mg once weekly (standard) or 0.5 mg in slow-titration arms. Lower starts preferred in patients with high baseline HbA1c or insulin-treated T2DM.4 mg, 9 mg, or 12 mg — TRIUMPH-2 / TRANSCEND-T2D-1 study three target doses. 4 mg often sufficient for HbA1c control in moderate T2DM.0.5 mg or 1 mg once weekly. Used in phase 2 slow-titration arms and recommended for elderly, low-BMI, or GLP-1-naïve patients.6–8 weeks rather than 4. Allows full PK steady-state plus an additional cycle of tolerance before next increase.0.5 → 1 → 2 → 4 → 6 → 9 → 12 mg — seven steps, ~10–12 months to reach 12 mg if escalation is held at any tolerability checkpoint.4–8 mg without need to reach 12 mg. Phase 2 weight loss at 4 mg (−17.5%) already exceeds semaglutide max.4 mg, 9 mg, or 12 mg weekly. Choice depends on baseline BMI, weight-loss goal, comorbidities, and tolerability ceiling.For reference only. Not medical dosing advice. Verify peptide purity and sterility — only use product from a licensed source for any injection protocol.
There is no approved retatrutide pen. Unlike tirzepatide (fixed-concentration prefilled pen, no reconstitution), the only material available outside trials is unregulated research-grade lyophilized powder requiring reconstitution — so this calculator is vial-only by design. Common research vial sizes are 5, 10, 20, and 30 mg; default BAC water is 2 mL. Worked reference: a 10 mg vial + 2 mL BAC = 5 mg/mL, so a 2 mg dose draws 0.40 mL (40 U), a 4 mg dose 0.80 mL (80 U), and a 9 mg dose 1.80 mL (180 U — requires a 2 mL syringe or two U-100 draws; a 30 mg vial avoids waste at 9–12 mg). Compounding retatrutide is explicitly prohibited under FDA 503A/503B.
All retatrutide trials use flat weekly milligram dosing, not body-weight adjustment. The engine anchors every protocol to the discrete trial steps. The weight-loss figures per band are Grade A (Phase 2/3 RCT outcomes); the per-kg figures are reference framing only (Grade D) — weight-based dosing has never been validated for this molecule. Half-life ≈ 6 days drives once-weekly dosing with steady state by ~4–5 weeks per step.
| Band | Weekly dose (SC) | ≈ µg/kg/day (80 kg ref) | Expected weight loss (48–80 wk) | Primary basis | Grade |
|---|---|---|---|---|---|
| Low | 1–4 mg/week | ~2–8 | −8.7% (1 mg) to −17.1% (4 mg) at 48 wk | Phase 2b (Jastreboff, NEJM 2023). | A |
| Standard | 4–9 mg/week | ~8–18 | −17.1% (4 mg) to −23.7% (9 mg) at 80 wk | Phase 3 TRIUMPH-1. | A |
| High / maximum | 12 mg/week | ~24 | −24.2% at 48 wk; −25.0 to −28.3% at 80 wk; −30.3% in BMI ≥35 at 104 wk | Phase 2b + Phase 3 (max studied dose; highest AE burden). | A |
µg/kg/day estimates assume an 80 kg reference and are not a dosing instruction. Doses above 12 mg/week have not been studied and carry no data (Grade D).
| Body weight | 4 mg/week | 9 mg/week | 12 mg/week |
|---|---|---|---|
| 55 kg (121 lb) | ~104 µg/kg/day | ~234 µg/kg/day | ~312 µg/kg/day |
| 65 kg (143 lb) | ~88 µg/kg/day | ~198 µg/kg/day | ~263 µg/kg/day |
| 75 kg (165 lb) | ~76 µg/kg/day | ~171 µg/kg/day | ~228 µg/kg/day |
| 85 kg (187 lb) | ~67 µg/kg/day | ~151 µg/kg/day | ~201 µg/kg/day |
| 95 kg (209 lb) | ~60 µg/kg/day | ~135 µg/kg/day | ~181 µg/kg/day |
| 105 kg (231 lb) | ~54 µg/kg/day | ~122 µg/kg/day | ~163 µg/kg/day |
Trials do not use weight-based dosing; doses are flat at 2/4/9/12 mg regardless of body weight. Per-kg values are for research comparison only and are not validated for weight-adjusted dosing.
These rules are extrapolated from TRIUMPH-program protocols and incretin-class standards (Grade D) — retatrutide has no label, so the cadence and hold logic here are borrowed, not validated. Escalation is gated on completing the minimum interval at the current step and adequate tolerability. Hard stops reflect class contraindications and the novel Phase 3 dysesthesia signal unique to this molecule.
| Decision node | Rule | Rationale | Grade |
|---|---|---|---|
| Escalate | After ≥4 weeks at current dose AND tolerating well → step to next tier (2→4→9→12 mg). | Phase 3 titration schedule; allows steady state before reassessment. | D |
| Hold | Grade 2 GI effects (nausea/vomiting limiting activity) → hold current tier an additional 4 weeks before escalating; slower titration carries no efficacy penalty. | GI events peak during escalation and plateau at steady state. | D |
| De-escalate | Grade 3 GI (hospitalization-level) or persistent intolerance at 9/12 mg → reduce to last tolerated dose as new maintenance. | Matches incretin-class protocols; lower maintenance is acceptable. | D |
| Dysesthesia (mild–moderate) | Tingling / burning / numbness → continue, monitor, document onset. | TRIUMPH-4 signal: 20.9% at 12 mg; majority resolve during treatment. | B |
| Dysesthesia (severe / progressive) | Hard-stop escalation → de-escalate to 9 mg or hold; evaluate neurological cause. | Mechanism unknown; glucagon-receptor neural expression hypothesized but unconfirmed. | B |
| Hold (combination) | With insulin → reduce basal ~30–40%; with sulfonylurea → reduce 50% or discontinue. Monitor glucose/CGM during titration. | Glucose-dependent secretion means monotherapy rarely causes hypoglycemia, but secretagogue/insulin combinations elevate risk. | D |
| Response check | No meaningful loss at maintenance dose × 3 months → escalate if tolerating; rule out adherence/dietary causes first. | Dose-response relationship confirmed across trials. | D |
| Permanent stop (hard) | Personal/family history of MTC or MEN2A/2B → contraindicated; do not initiate. Suspected pancreatitis → discontinue. Pregnancy identified → discontinue. | GLP-1R class boxed-warning analog (rodent C-cell tumors); class pancreatitis risk; no human pregnancy safety data. | B |
Special populations: renal/hepatic dosing not established (TRANSCEND-T2D-3 ongoing); favor conservative (6–8 week) titration in elderly or low-BMI patients. Discontinue well before any planned conception — investigational status means no reproductive safety margin is defined.
Because retatrutide is investigational, most markers below are flagged validated_for_retatrutide = false — the inverse of an approved-drug page. A minority (HbA1c, body weight, MRI-PDFF liver fat, triglycerides, non-HDL, systolic BP) are trial-validated, drawn from the Phase 3 TRIUMPH endpoints and the Phase 2a MASLD biomarker panel. The rest are class-borrowed surveillance markers checked on clinical indication only.
| Biomarker | Frequency | Threshold / action | Validated? |
|---|---|---|---|
| HbA1c (glycemic) | Baseline; wk 12, 24; then q6 mo | Target <7% (T2DM); primary endpoint TRANSCEND-T2D-1 (−2.0% at 12 mg) | Yes |
| Body weight / BMI (efficacy) | Weekly (self); clinic q4 wk | <1% monthly loss = consider escalation; primary metric all trials | Yes |
| Waist circumference | Baseline; q12 wk | Correlated with visceral & liver-fat reduction (Phase 2a) | Yes |
| MRI-PDFF liver fat | Baseline & wk 24 (research settings) | Gold-standard MASLD response; −82.4% at 24 wk (12 mg) | Yes |
| Triglycerides | Baseline; wk 12, 24; q6 mo | ↓35–49% in MASLD cohort; >500 mg/dL → evaluate pancreatitis risk | Yes |
| Non-HDL cholesterol | Baseline; q6 mo | Key secondary in TRIUMPH-4 & TRANSCEND-T2D-1 | Yes |
| Systolic BP | Every clinic visit | −14 mmHg at 12 mg (TRIUMPH-4); target <130 mmHg | Yes |
| Fasting insulin / HOMA-IR | Baseline; wk 24, 48 | ↓ up to 70.9% at wk 48 (MASLD substudy) | Substudy |
| ALT / AST | Baseline; wk 12, 24; q6 mo | >3× ULN → evaluate hepatotoxicity (no signal in trials) | Not validated |
| Amylase / lipase | Symptom-triggered only — not routine | Acute elevation + abdominal pain → suspend & evaluate | Not validated |
| Neurological (dysesthesia) | Patient self-report each visit | Grade 2+ → document; Grade 3 → de-escalate | Signal only |
| Heart rate | Every clinic visit | >100 bpm resting sustained → investigate (mild HR rise at high dose) | Not validated |
| Gallbladder ultrasound | Baseline; symptom-triggered | Class biliary risk; 1 cholecystitis SAE in MASLD trial | Not validated |
Architecture note: store each biomarker with a source_endpoint tag and a validated_for_retatrutide boolean. For an investigational molecule most resolve to false — the inverse of the tirzepatide page — which is exactly what distinguishes a speculative entry from an approved-drug one.
Retatrutide is investigational and not approved — formal combination clinical-trial data is sparse. The pairings below reflect mechanistic complementarity, observed lean-mass and metabolic concerns during incretin therapy, and recovery / cardiometabolic strategies discussed in clinical practice. None are FDA-validated combinations. Combination use of investigational compounds requires physician oversight.
| Component | Role | Evidence |
|---|---|---|
| Retatrutide | Weight loss · triple agonism | Phase 3 (A) |
| Ipamorelin | GHSR · GH pulse | Off-label (C) |
| CJC-1295 | GHRH analog | Off-label (C) |
| RT + protein | Anabolic stimulus | Evidence-based (A) |
| Component | Target | Status |
|---|---|---|
| Retatrutide | Steatosis · weight | Investigational |
| Resmetirom | MASH fibrosis | FDA-approved (A) |
| SGLT2i | Hepatic TG · CV | FDA-approved (A) |
| Statin | LDL · ASCVD | FDA-approved (A) |
| Component | Mechanism | Evidence |
|---|---|---|
| Retatrutide | Triagonist · weight + glucose | Phase 2/3 (A) |
| Metformin | Insulin sensitizer · gluconeogenesis ↓ | 1L T2DM (A) |
| SGLT2i | Urinary glucose · CV/renal benefit | FDA (A) |
| Intervention | When |
|---|---|
| Ondansetron PRN | Acute nausea episodes |
| Ginger 1–2 g | Daily, prophylactic |
| B6 + doxylamine | Persistent nausea |
| Meal pattern adjust | Continuous · cornerstone |
| From → To | Washout | Start |
|---|---|---|
| Semaglutide → Reta | 1–2 weeks | 2 mg standard |
| Tirzepatide → Reta | 1–2 weeks | 2 mg standard |
| Liraglutide → Reta | 3–5 days | 2 mg standard |
| Agent | Receptor Profile | Max Weight Loss | HbA1c Reduction | Dosing | Status |
|---|---|---|---|---|---|
| Retatrutide | GIP · GLP-1 · GCG (triple) | −28.7% (Phase 3) | −2.02% (Phase 2, T2DM) | Weekly SC · 12 mg max | Phase 3 (A) |
| Tirzepatide (Mounjaro / Zepbound) | GIP · GLP-1 (dual) | −22.5% (SURMOUNT-1, 15 mg) | −2.46% (SURPASS-3, 15 mg) | Weekly SC · 15 mg max | FDA-approved (A) |
| Semaglutide (Ozempic / Wegovy) | GLP-1 only (mono) | −14.9% (STEP-1, 2.4 mg) | −1.6% (SUSTAIN-7, 1.0 mg) | Weekly SC · 2.4 mg max | FDA-approved (A) |
| Liraglutide (Saxenda / Victoza) | GLP-1 only (mono) | −8% (SCALE, 3.0 mg) | −1.2% | Daily SC · 3.0 mg max | FDA-approved (A) |
| Survodutide | GLP-1 · GCG (dual, GCG-biased) | −18.7% (Phase 2) | −1.5% (early data) | Weekly SC | Phase 3 (B/C) |
| CagriSema (cagrilintide + semaglutide) | Amylin + GLP-1 | −15.7% (REDEFINE-1) | −1.8% | Weekly SC | Phase 3 (B) |
| Cotadutide (MEDI0382) | GLP-1 · GCG (dual, GCG-biased) | ~−5% (terminated) | ~−0.6% | Daily SC | Discontinued |
| Mazdutide | GLP-1 · GCG (dual) | −10% (Phase 3 in China) | −1.5% | Weekly SC | Approved in China (B) |
Retatrutide's safety profile to date is consistent with the incretin class (GI side effects dominant, dose-dependent, peak with titration steps), with two retatrutide-specific signals: small transient heart-rate elevation and mild fasting-glucose increases at the highest doses. Long-term cardiovascular and oncology outcomes remain under phase-3 investigation.
| Condition / factor | Risk level | Applies to | Rationale |
|---|---|---|---|
| MTC / MEN2 (personal or family) | Avoid | All | Class boxed warning — rodent C-cell adenoma signal; absolute contraindication for any incretin therapy. |
| Pregnancy | Avoid | All | Animal teratogenicity reported. Discontinue ≥8 weeks pre-conception given ~6-day half-life. |
| Active pancreatitis | Avoid | All | Pancreatitis cases reported in retatrutide trials. Severe abdominal pain warrants drug hold and evaluation. |
| Type 1 diabetes | Avoid | All | Not studied. GCG agonism + endogenous insulin lack = hyperglycemia / DKA risk; insulin replacement essential. |
| Severe gastroparesis | Avoid | All | Additive slowed emptying. Risk of intractable nausea, dehydration, weight loss without benefit. |
| Prior severe pancreatitis | Caution | All | Recurrence risk uncertain on incretin therapy. Specialist consultation advised. |
| Active diabetic retinopathy (PDR/severe NPDR) | Caution | T2DM with DR | Class signal of DR progression with rapid HbA1c lowering. Stabilize retinopathy first; ophthalmology consult. |
| Poorly controlled T2DM (HbA1c > 9%) | Monitor | T2DM | CGM-guided titration. Adjust insulin/SU pre-emptively to avoid hypoglycemia. |
| Active gallbladder disease | Caution | All | Class effect of rapid weight loss; gallstone formation risk. Address symptomatic cholelithiasis before initiation. |
| Pheochromocytoma / paraganglioma | Avoid | All | Theoretical sympathetic-activation risk from GCG agonism. No safety data; avoid until catecholamine excess resolved. |
| Major depression / suicidality history | Monitor | All | EMA 2024 class signal under review. Monitor mood; engage mental-health provider during initiation. |
| Renal impairment (eGFR < 30) | Caution | All | Limited PK data. Dehydration from GI side effects can precipitate AKI. Maintain hydration; monitor function. |
| Hepatic impairment (Child-Pugh C) | Caution | All | GCG agonism modulates hepatic glucose output. Specialist consultation advised in advanced cirrhosis. |
| Concomitant GLP-1 RA or dual agonist | Avoid | All | Mechanistic overlap, additive AEs, no safety data on stacked incretins. Allow washout before transition. |
HbA1c, fasting glucose, lipid panel, CMP (LFTs, renal), TSH, lipase if symptomatic. Vital signs (HR, BP). Pregnancy test if reproductive potential. DEXA optional for body-composition tracking. ECG if cardiac history.
At each escalation: tolerability review (nausea, vomiting, diarrhea severity), HR/BP, glucose if T2DM. CGM data in diabetics. Decision: escalate, hold, or step back.
Repeat HbA1c (if T2DM), lipid panel, weight, blood pressure, HR. Vitamin/micronutrient screen if intake significantly reduced (B12, iron, vitamin D). Re-evaluate concomitant antidiabetic medications.
Full repeat panel: HbA1c, lipid, CMP, weight, BP, HR. ALT/AST trending (MASH context). Body-composition check (DEXA / BIA) if available. Discuss long-term plan: continue, dose-modify, or address tolerability ceiling.
Repeat full panel. Retinal exam (if T2DM). Gallbladder ultrasound if suggestive symptoms. Bone density (DEXA) if significant total weight loss + age > 50.
Severe abdominal pain (rule out pancreatitis), persistent vomiting impairing hydration, symptomatic tachycardia, new diagnosis of MTC/MEN2 in family member, planned pregnancy, severe psychiatric event, or any allergic reaction.
The TRIUMPH program covers obesity, T2DM, knee osteoarthritis, obstructive sleep apnea, chronic kidney disease, MASH, and cardiovascular outcomes. As of late 2025, TRIUMPH-4 has read out positively. Eight more pivotal trials are active. The breadth of indications targeted simultaneously is unprecedented for a single molecule.
N=338, 48 weeks, 5 dose arms. −17.5% / −22.8% / −24.2% at 4/8/12 mg; no plateau observed at 48 weeks. The published anchor evidence and the basis for the entire phase 3 program. NEJM 2023.
N=281, 36 weeks. HbA1c −2.02% at 12 mg, weight −16.94%. Triple agonist superior to dulaglutide 1.5 mg active comparator. Lancet 2023.
N=445, 68 weeks. 12 mg arm: −28.7% weight, WOMAC pain −75.8%, >1 in 8 pain-free. SBP and non-HDL-C also reduced. First successful phase 3 readout.
N≈2,100, 88 weeks. Active. Primary: % change body weight + ≥5% / ≥15% / ≥20% / ≥25% threshold responder rates. Readout expected 2026. Registrational anchor for obesity indication.
N≈1,800. Active. Primary co-endpoints: HbA1c + body weight. Will benchmark vs SURMOUNT-2 tirzepatide data in the same population. Read-out 2026.
Two integrated study arms analogous to SURMOUNT-OSA design. Primary endpoint: apnea-hypopnea index (AHI) at 52 weeks. Will determine if triagonism extends benefit beyond AHI to broader cardiorespiratory metrics.
Primary: change in eGFR slope + UACR at 104 weeks. Tests whether weight loss + glucagon-driven hemodynamic changes preserve renal function in CKD.
Phase 2 hepatic fat reduction reached −85% (MRI-PDFF). TRIUMPH-MASH tests histological resolution + fibrosis improvement at 52 weeks. Could establish retatrutide as a MASH first-line therapy.
N≈12,000. Primary: 5-point MACE. Pivotal for the first triagonist label outside metabolic indications — direct comparison anchor to SELECT and SURMOUNT-MMO.
TRIUMPH-4 (Dec 2025) read-out demonstrated −28.7% weight loss with substantial WOMAC pain reduction — the first phase-3 confirmation that the phase 2 magnitude scales. The remaining 2026 read-outs will determine retatrutide's label breadth: T2DM, OSA, MASH (with histology), CKD, and CV outcomes. If positive across this set, retatrutide enters the market with potentially the broadest single-molecule indication portfolio in metabolic medicine.
Every section of this page rewrites itself for consumer, clinician, or researcher via the depth selector at the top. Below, the same summary is held at all three layers at once — the clearest way to see how the framing shifts with the reader.
Retatrutide is an experimental once-weekly injection being developed by Eli Lilly to treat obesity and type 2 diabetes — and in clinical trials, people have lost up to 30% of their body weight, an amount comparable to weight-loss surgery. It works by activating three separate hormone pathways at once (GLP-1, GIP, and glucagon), which cuts appetite, improves blood sugar, and directly burns fat stored in the liver and body. It is not yet approved — FDA clearance is not expected before late 2027, and compounding it is illegal.
Retatrutide (LY3437943) is a first-in-class GIP/GLP-1/GCGR triple receptor agonist in Phase 3 development (TRIUMPH program) for obesity and T2DM. Its GIP backbone carries Aib stabilizing substitutions and a C20 fatty diacid for albumin binding, yielding a ~6-day half-life supporting once-weekly SC dosing. Phase 3 TRIUMPH-1 (n=2,339) demonstrated 28.3% mean weight loss at 80 weeks (12 mg) and 30.3% in severe obesity at 104 weeks — exceeding tirzepatide's 22.5% benchmark. TRANSCEND-T2D-1 showed −2.0% A1C and −16.8% weight in T2DM. The safety profile is broadly incretin-consistent, with a novel dysesthesia signal (20.9% at 12 mg) requiring monitoring. FDA approval is not expected before late 2027; compounding is prohibited.
Retatrutide is a synthetic 39-amino-acid peptide (C221H342N46O68; MW ≈ 4731 Da; CAS 2381089-83-2) with a GIP-derived primary sequence bearing Aib substitutions at positions 2 and 20 conferring DPP-4 resistance, and a C20 fatty-diacid moiety at Lys₁₇ enabling reversible albumin binding for a ~144-hour half-life. As a full agonist of GIPR (8.9× supraphysiologic potency), GLP-1R (0.4× endogenous), and GCGR (0.3× endogenous), it drives convergent Gαs/cAMP signaling across pancreatic β-cells, hypothalamic ARC/VMH neurons, hepatocytes, and brown adipose tissue. Hepatic GCGR activation stimulates CPT1A-mediated β-oxidation and FGF21 secretion, raises β-hydroxybutyrate 181% at 12 mg, suppresses de novo lipogenesis, and produces −82.4% MRI-PDFF liver-fat reduction at 24 weeks in MASLD (Phase 2a, n=98). Central triple-receptor co-activation in AgRP/POMC neurons yields anorexigenic output exceeding GLP-1 monoagonism; adiponectin rises up to 44% and leptin falls up to 56%. Hard CV outcome data (TRIUMPH-Outcomes, ~10,000 pts) and MASH liver-endpoint data (SYNERGY-OUTCOMES, ~4,500 pts) remain pending through 2029–2030.