Retatrutide
Retatrutide scored 4.9 / 10 (⚖️ Neutral) on the BioHarmony scale as a Substance → Pharmaceutical / Drug. Triple GLP-1/GIP/glucagon agonist.
What It Is
Triple GLP-1/GIP/glucagon agonist. Best-in-class weight loss (24.2% at 48 wk) and liver fat clearance. But only ~700 published participants, 48-week max exposure, 100% Lilly-funded, and real-world supply is unregulated gray-market peptide with documented contamination.
Upside (3.67 / 5.00)
| Dimension | Weight | Score | Visual | Weighted |
|---|---|---|---|---|
| Efficacy | 25% | 4.9 | 1.225 | |
| Breadth of Benefits | 15% | 3.8 | 0.570 | |
| Evidence Quality | 25% | 2.5 | 0.625 | |
| Speed of Onset | 10% | 3.8 | 0.380 | |
| Durability | 10% | 1.5 | 0.150 | |
| Bioindividuality Upside | 15% | 4.8 | 0.720 | |
| Total | 3.670 |
Upside Rationale
Efficacy (4.9/5.0) — Jastreboff NEJM 2023 Phase 2: −24.2% body weight at 48 weeks at 12 mg, curve still descending, no plateau. HbA1c −2.02% in T2D (Rosenstock, Lancet 2023). Liver fat −82.4% relative at 12 mg (Sanyal, Nat Med 2024) with 86% achieving complete MASLD resolution. Systolic BP −8 mmHg, triglycerides −25 to −35%. Cohen’s d clears 1.0 for weight; unprecedented in the outpatient drug class.
Breadth of benefits (3.8/5.0) — Weight, glycemia, liver fat, BP, lipids proven. Cardiovascular hard endpoints not yet reported (TRIUMPH-OUTCOMES reads 2027–2028). Kidney outcomes unknown. Addiction/cognition signals not studied. Narrower proven breadth than semaglutide until Phase 3 delivers.
Evidence quality (2.5/5.0) — Only 3 published Phase 2 RCTs plus one Phase 1, ~700 participants dosed, maximum 48-week exposure. 100% Lilly-funded. Zero independent replication. No CV outcomes. No kidney outcomes. No post-marketing pharmacovigilance. −1.0 integrity penalty for industry-only funding without replication.
Speed of onset (3.8/5.0) — Appetite suppression within 1–2 weeks (class effect). Weight loss approximately linear through 24 weeks. HbA1c drops within 4–8 weeks. Liver fat near-maximal by week 48.
Durability (1.5/5.0) — Zero published off-drug data. Extrapolating from semaglutide’s STEP 1 extension (two-thirds regain in 12 months), retatrutide’s steeper loss likely means steeper regain.
Bioindividuality upside (4.8/5.0) — 100% of 12 mg completers hit ≥5% weight loss. 83% hit ≥15%. 63% hit ≥20%. 26% hit ≥30%. The responder curve is essentially universal at therapeutic dose.
Downside (3.45 / 5.00)
| Dimension | Weight | Score | Visual | Weighted |
|---|---|---|---|---|
| Safety Risk | 30% | 4.0 | 1.200 | |
| Side Effect Profile | 15% | 4.0 | 0.600 | |
| Financial Cost | 5% | 3.5 | 0.175 | |
| Time/Effort Burden | 5% | 1.5 | 0.075 | |
| Opportunity Cost | 5% | 2.5 | 0.125 | |
| Dependency / Withdrawal | 15% | 4.3 | 0.645 | |
| Reversibility | 25% | 2.5 | 0.625 | |
| Total | 3.445 | |||
| × 1.4 (risk asymmetry) | 4.823 |
Downside Rationale
Safety risk (4.0/5.0) — Catastrophic risk floor applies from class-level MTC rodent signal, pancreatitis class prior, and a novel glucagon arm unstudied beyond 48 weeks. Heart rate rise +6.7 bpm at 12 mg is the largest in the incretin class. Only ~700 participants and 48 weeks of exposure provide minimal statistical power to detect rare serious events. The intrinsic pharmacological profile warrants the floor; no supply-chain contamination is factored into this dimension.
Side effect profile (4.0/5.0) — Nausea ~45% at 12 mg (highest in the incretin class), vomiting ~16%, diarrhea ~27%, discontinuation 6% at top dose. Lean mass loss absolute magnitude is the largest in class (up to 6.5 kg in Phase 2 body-comp substudy) simply because total weight loss is the largest.
Financial cost (3.5/5.0) — Current gray-market pricing $200–400/month. Post-approval pricing likely to match tirzepatide ($1,000+/month).
Time/effort burden (1.5/5.0) — Once-weekly subcutaneous injection. Negligible effort (same as semaglutide).
Opportunity cost (2.5/5.0) — Same behavioral crowd-out as other incretins: blunts food reward, training appetite. Moderate trade-off with lifestyle approaches.
Dependency/withdrawal (4.3/5.0) — Class effect rebound assumed from semaglutide/tirzepatide precedent. Steeper loss likely means steeper regain. Completely unstudied for this specific molecule.
Reversibility (2.5/5.0) — Most pharmacological effects reversible on discontinuation. Class-level risks (gastroparesis, pancreatitis) may persist but are rare. Lean mass lost tends to return as fat mass.
Verdict
✅ Best for: Patients in active TRIUMPH Phase 3 trials receiving Lilly-manufactured product with full adverse event monitoring. If retatrutide approves in late 2027 with a clean label, obese adults with MASH or T2D who have failed first-line interventions become the primary population.
❌ Avoid if: You have any thyroid, pancreatic, or cardiovascular history; you are treating this as a lifestyle recomp drug rather than a serious metabolic disease intervention; you are pregnant or of childbearing potential without contraception; you are not willing to resistance train and eat 1.6+ g/kg protein to protect lean mass through historic rates of weight loss.
⚠️ Supply chain warning: As of April 2026, retatrutide is not FDA approved and cannot be obtained through any legitimate pharmacy channel. Real-world use is entirely gray-market research peptide supply with documented quality issues including endotoxin contamination (~78% of samples exceeding limits by ~1000×), identity failures, and mass accuracy variations of ±50%. These supply risks are not reflected in the dimension scores above (which evaluate the compound itself), but they represent a separate and serious risk layer for anyone sourcing outside a clinical trial.
How This Score Could Change
BioHarmony scores are living assessments. New research, regulatory changes, or personal context can shift the score up or down. These are the most likely scenarios that would change this intervention's rating.
| Scenario | New Score | Tier |
|---|---|---|
| TRIUMPH-OUTCOMES 20%+ MACE reduction (Evidence 2.5→3.5, Breadth 3.8→4.3) | 5.1 / 10 | ⚖️ Neutral |
| FDA approves + 2yr clean safety (Evidence 2.5→4.0, Safety 4.0→3.5, Breadth 3.8→4.3) | 5.4 / 10 | ⚖️ Neutral |
| Phase 3 surfaces MTC or cardiac signal (Safety 4.0→5.0, Side effects 4.0→4.5) | 4.1 / 10 | ⚠️ Proceed with caution |
| FDA approval + 5yr clean safety + durability data (Evidence 2.5→4.5, Safety 4.0→3.5, Durability 1.5→2.5) | 5.7 / 10 | ⚖️ Neutral |
| Population: obese T2D with MASH only | 5.6 / 10 | ⚖️ Neutral |
Key Evidence Sources
- Jastreboff AM et al. Phase 2 obesity. NEJM 2023 — PMID 37366315
- Rosenstock J et al. Phase 2 T2D. Lancet 2023 — PMID 37356367
- Sanyal AJ et al. Phase 2 MASLD. Nat Med 2024 — PMID 38858523
- Coskun T et al. Preclinical pharmacology. Cell Metab 2022 — PMID 35914546
- Urva S et al. Phase 1. Lancet 2022 — PMID 35914548
- Phase 2 body composition. Lancet Diab Endo 2025 — PMID 40609566
- Systematic review/meta-analysis 2025 — PMC12026077
- NCT05929066 TRIUMPH-1 — Phase 3 obesity trial
- NCT05882045 TRIUMPH-OUTCOMES — CV outcomes trial
- FDA concerns re unapproved GLP-1 drugs — FDA safety communication
Other interventions for Cardiovascular
See all ratings →📊 How BioHarmony scoring works
BioHarmony translates a weighted expected-value calculation into a reader-facing 0–10 score. 5.0 is neutral (benefits and risks balance). Above 5 = benefits outweigh risks; below 5 = risks outweigh benefits. Every downside dimension is multiplied by 1.4 before subtraction because harm potential is more consequential than benefit potential — the precautionary principle encoded as math.
Upside: 3.670 / 5.00
Downside (post-1.4×): 3.450 / 5.00
EV = 0.220
Score = ((EV + 7) / 12) × 10 = 4.9 / 10
