We use essential cookies (authentication, your saved goals/stack) by default. With your permission we’ll also enable privacy-respecting analytics (Vercel Web Analytics, anonymous load-time metrics) and error-replay diagnostics (Sentry — DOM snapshots only when an error fires) so we can fix bugs faster. Learn more about cookies
Retatrutide (LY3437943)
An investigational once-weekly injectable peptide that activates THREE receptors at once — GIP, GLP-1 and glucagon. Honest framing: in a 48-week phase-2 obesity trial it produced the largest mean weight loss yet reported for an incretin-class drug (about -24% at the top dose), and it cut liver fat dramatically in a MASLD substudy. BUT the first phase-3 trial (a type-2-diabetes trial, TRANSCEND-T2D-1) has now reported but the phase-3 obesity and cardio-kidney-outcome (TRIUMPH) program is still ongoing as of 2026, so long-term safety and hard outcomes are unknown. It is a prescription-pathway drug, not a dietary supplement, and the 'retatrutide' sold grey-market online is especially risky.
Prescription medication — not a dietary supplement
Retatrutide is a prescription (or investigational) drug, not a supplement. It is included here for reference because people research and discuss it (often used off-label) — not as a recommendation. Take it only under a qualified clinician's supervision and only as prescribed; do not source it from grey-market vendors, where identity, purity, and dosing are unverified. The evidence below reflects its clinical trials.
What the evidence says
Retatrutide doesn't have enough studies with structured effect-size data yet to pool a verdict. Browse the studies below for individual findings.
Most evidence is from high-quality meta-analyses and randomised trials published 2022–2026.
Based on 52 studies · 12 meta-analyses · 11 RCTs
Confidence
High confidenceBy outcome
Scored Moderate (5.5) because phase-2 trials and one phase-3 type-2-diabetes RCT show striking, consistent weight and glycemic effects, but it remains an investigational, unapproved drug with no obesity-population phase-3 or cardiovascular-outcome data.
11 trials ongoing or recruiting · 21 completed on ClinicalTrials.gov
2 of the completed trials have posted results
Registered trials show research momentum for Retatrutide, not proof of effect — a registration is a plan, and posted results are sponsor-reported, not peer-reviewed. They are never counted toward the evidence rating above.
Browse these trials on ClinicalTrials.govClinicalTrials.gov · as of Nov 2026
Retatrutide (developmental code LY3437943) is a single synthetic peptide engineered by Eli Lilly to be a balanced triple agonist of three entero-pancreatic hormone receptors: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR).
The rationale is mechanistic stacking: GLP-1 and GIP agonism reduce appetite/food intake and improve insulin secretion (the same axis exploited by semaglutide and tirzepatide), while adding glucagon-receptor agonism is intended to increase energy expenditure and drive hepatic fat mobilisation — components the GLP-1/GIP drugs lack.
Protraction chemistry gives it a ~6-day half-life suitable for once-weekly subcutaneous dosing. The human evidence to date is genuinely striking but still early.
A phase-1b multiple-ascending-dose study in type 2 diabetes and a phase-2 type 2 diabetes trial showed dose-dependent HbA1c and weight reductions (top doses outperforming dulaglutide).
The headline result is the 48-week phase-2 obesity trial (NEJM 2023, n=338), where the 12 mg dose produced a least-squares mean weight loss of about 24.2% at 48 weeks — the largest reported for an incretin-class agent and approaching surgical-range loss.
A phase-2a substudy in metabolic dysfunction-associated steatotic liver disease (MASLD) showed liver-fat reductions of roughly -81% to -82% at the 8 and 12 mg doses, with most participants reaching normal liver fat. The honest caveats are substantial.
The headline efficacy (the ~24% obesity weight loss and the MASLD liver-fat data) is still PHASE-2: the first phase-3 trial to report (TRANSCEND-T2D-1, Lancet 2026, n=537) was a 40-week type-2-diabetes monotherapy study that confirmed the glycemic/weight signal (HbA1c -1.94%, weight -15.3% at 12 mg vs placebo), but the phase-3 obesity program and the cardio-kidney-outcome trial (TRIUMPH-Outcomes) are still ongoing, so there are still NO cardiovascular/renal/mortality outcome data and no phase-3 obesity-population confirmation of the ~24% figure as of 2026.
Retatrutide is INVESTIGATIONAL — it is not a dietary supplement.
Adverse effects are class-typical (dose-related gastrointestinal events) plus glucagon-agonism-specific signals: dose-dependent increases in heart rate were seen, and glucagon agonism can transiently raise glucose, so the net metabolic effect depends on receptor balance.
Like the whole GLP-1 class it carries expected concerns about gallbladder events, pancreatitis, lean-mass loss alongside fat loss, and a class thyroid C-cell warning.
Crucially, unregulated 'retatrutide' is already being sold grey-market online; using an investigational drug with no clinical oversight, no identity/purity guarantee and no safety monitoring is especially dangerous.
Because it is a prescription-pathway investigational drug rather than a supplement to recommend, it is sandboxed out of goal-based and stack recommendations here.
Like the approved incretin drugs, retatrutide activates the GLP-1 and GIP receptors, which reduce appetite and food intake, slow gastric emptying, and enhance glucose-dependent insulin secretion. This is the shared backbone of the incretin class and drives much of the glycemic and weight effect.
The distinguishing third arm: adding glucagon-receptor agonism is intended to raise energy expenditure and mobilise hepatic fat. Preclinical work attributes the augmented weight loss specifically to this glucagon component layered on top of GLP-1/GIP-driven calorie-intake reduction — but glucagon agonism can also transiently raise glucose and heart rate.
Retatrutide was tuned to an empirically optimised receptor potency ratio across GCGR, GIPR and GLP-1R (in vitro it shows balanced glucagon/GLP-1 activity with relatively more GIP activity). The clinical effect therefore depends on the net balance of three signals, not a single target — a key uncertainty that phase-3 trials are meant to resolve.
How Retatrutide works — from molecular targets to health outcomes. Click an edge to see supporting research.This visualization is in beta — pathways are being refined and expanded.
Obtaining or using grey-market 'retatrutide' means taking an investigational drug with no clinical oversight, dosing standard, or product-quality guarantee. Strongly discouraged.
High hypoglycemia risk if combined; only relevant under trial-level medical supervision with secretagogue adjustment.
The dose-dependent heart-rate increase and absence of cardiovascular-outcome data make unsupervised use particularly unwise.
Contraindicated — not studied; weight-loss pharmacotherapy is avoided in pregnancy.
Incretin-class agonism slows gastric emptying, which can reduce the rate/extent of absorption of co-administered oral drugs — relevant for time-critical or narrow-therapeutic-index oral medicines.
Combining a glucose-lowering incretin agonist with insulin or sulfonylureas increases hypoglycemia risk; dose reduction of the secretagogue is typically required in supervised use.
Stacking retatrutide with another GLP-1/GIP incretin agonist compounds gastrointestinal toxicity and glucose-lowering with no evidence of benefit; this combination is not studied and is dangerous.
Tip: Dose-related; mitigated by a lower starting dose and slow escalation. Most cases mild-to-moderate.
Tip: Class-typical GI effects; generally transient and dose-related.
Tip: Dose-dependent rise peaking ~24 weeks then declining; long-term cardiovascular significance unknown. Requires clinical monitoring.
Tip: Marked appetite suppression; as with the GLP-1 class, part of the weight lost is lean mass — adequate protein and resistance exercise are advised in supervised settings.
Tip: Rapid weight loss and incretin-class effects are associated with gallbladder events; report severe abdominal pain.
Tip: A class concern for incretin drugs; discontinue and seek care for persistent severe abdominal pain. Long-term incidence unknown without phase-3 data.
Retatrutide has an evidence score of 5.5/10 — moderate evidence based on 52 indexed studies. An investigational once-weekly injectable peptide that activates THREE receptors at once — GIP, GLP-1 and glucagon. Honest framing: in a 48-week phase-2 obesity trial it produced the largest mean weight loss yet reported for an incretin-class drug (about -24% at the top dose), and it cut liver fat dramatically in a MASLD substudy. BUT the first phase-3 trial (a type-2-diabetes trial, TRANSCEND-T2D-1) has now reported but the phase-3 obesity and cardio-kidney-outcome (TRIUMPH) program is still ongoing as of 2026, so long-term safety and hard outcomes are unknown. It is a prescription-pathway drug, not a dietary supplement, and the 'retatrutide' sold grey-market online is especially risky. Representative study: PMID 42250575.
Dosing for Retatrutide: SupStack does not provide a self-directed dosing protocol for Retatrutide. A dose used in a clinical trial does not establish a safe consumer dose. Phase-2 trials used once-weekly subcutaneous injection with stepwise escalation (e.g. start 2 mg) up to 8-12 mg maintenance.
Timing is flexible for Retatrutide — consistent daily use matters more than the time of day. Trials dosed once weekly subcutaneously with gradual dose escalation to limit gastrointestinal effects; the ~6-day half-life supports once-weekly administration.
No consumer dose of Retatrutide is endorsed, so there is no dose at which it can be called safe. Talk to a healthcare provider before taking it. Reported side effects include pancreatitis, nausea / vomiting, increased heart rate. How often they occur is not established for all of them. Use caution if any of these apply to you: Not a dietary supplement and not an approved drug — investigational; do not self-source grey-market vials; Personal/family history of medullary thyroid carcinoma or MEN 2 (expected GLP-1-class thyroid C-cell precaution, not a product-label contraindication: this investigational drug has no label, and not every approved GLP-1 product carries the US thyroid boxed warning); History of pancreatitis.
Semaglutide
Too few graded studiesAn FDA-approved GLP-1 receptor agonist (Ozempic/Rybelsus for type 2 diabetes, Wegovy for chronic weight management) with genuinely strong, large-RCT evidence for glycemic control and substantial weight loss, plus a cardiovascular-outcomes benefit. Honest appraisal: this is a real prescription medicine with real efficacy AND real risks — a US FDA boxed warning for thyroid C-cell tumors, pancreatitis and gallbladder risk, very common GI side effects, and growing concern about grey-market/compounded versions. It is a prescription drug, not a supplement, and is never auto-recommended.
Tirzepatide
Too few graded studiesAn FDA-approved prescription medication (Mounjaro for type 2 diabetes, Zepbound for obesity and obstructive sleep apnea), not a dietary supplement. Honest appraisal: in head-to-head phase-3 trials it is the most effective approved weight-loss drug to date — up to ~21% body-weight loss over 72 weeks and superior to semaglutide — but it is a real medicine with real risks: a US FDA boxed warning for thyroid C-cell tumors, common GI side effects, and pancreatitis/gallbladder signals. Do not source or use it outside a prescription.
Liraglutide
Too few graded studiesAn FDA-approved, once-daily GLP-1 receptor agonist (Victoza for type 2 diabetes, Saxenda for chronic weight management). Honest appraisal: a real prescription medicine with genuinely strong large-RCT evidence for glycemic control and moderate weight loss, plus a cardiovascular-outcomes benefit (LEADER). It also carries real risks — a US FDA boxed warning for thyroid C-cell tumors, pancreatitis and gallbladder risk, very common GI side effects, and lean-mass loss with weight loss. It is a prescription medicine, NOT a supplement, and is not auto-recommended.
Orforglipron
Too few graded studiesAn ORAL, non-peptide small-molecule GLP-1 receptor agonist for obesity, also studied in type 2 diabetes — the headline is the convenience of a once-daily pill (no injection, no cold chain, no food/water restrictions) delivering GLP-1-class glycemic and weight benefit. In the US, orforglipron is approved as Foundayo for long-term weight management in adults with obesity, or overweight with at least one weight-related condition, together with a reduced-calorie diet and increased physical activity. FDA approval was granted on 1 April 2026. An EMA list dated 5 October 2026 places orforglipron under evaluation. Honest appraisal: the phase-2 data are strong and the phase-3 read-outs (ATTAIN/ACHIEVE) are promising, but it has the full GLP-1-class side-effect burden (very common dose-dependent nausea/vomiting/diarrhea, higher discontinuation than injectables in some comparisons), the US label carries a boxed warning about thyroid C-cell tumours, and long-term outcomes are unsettled. It is NOT a dietary supplement.
Explore: Best supplements for Vitality & Longevity
Reviewed by Dr. Baher Al Hakim · Last reviewed June 2026 · evidence from 52 studies · how we score · editorial policy
This information is for educational purposes only. It is not a substitute for professional medical advice. Always consult a qualified healthcare provider before starting, stopping, or changing any supplement or medication.
Tap node to isolate • Pinch to zoom • Tap edge for research