Compounds / GLP-1 agonists

Retatrutide

Retatrutide (LY3437943)

Investigational once-weekly triple agonist at GIP, GLP-1, and glucagon receptors. The most efficacious obesity drug ever tested in phase 3. TRIUMPH-4 (Dec 2025) showed 28.7% mean weight loss at 12mg over 68 weeks in obesity + knee OA, exceeding tirzepatide's SURMOUNT-1 (-20.9%) and the prior phase 2 result (-24.2% at 48wk). Glucagon agonism adds direct hepatic fat oxidation and energy expenditure increase to incretin effects. Lilly Q4 2026 NDA filing target.

At a glance

Half-life

~6 days ~6 days. Dose-proportional PK confirmed in phase 1b. Steady state in 4 weeks of weekly dosing. Tmax 12-49h.

Tmax

~30.5 h

Routes

SubQ

Evidence base

4 studies 4 human

Mechanism

Single-peptide triple agonist of GIP receptor, GLP-1 receptor, and glucagon receptor (GCGR). Receptor potency: GIPR > GLP-1R > GCGR. GLP-1R drives standard incretin effects (insulin secretion, gastric emptying, central appetite suppression). GIPR reinforces glucose-dependent insulin secretion and may reduce GI side effects vs pure GLP-1. GCGR increases resting energy expenditure, hepatic lipid oxidation, and ketogenesis: the weight loss accelerator believed to drive the additional 5-10 percentage points vs tirzepatide; hepatic fat reduction 81-86% at 8/12mg by week 24. Dose-proportional PK confirmed; t½ ~6 days. Phase 2: 12mg -24.2% at 48 weeks. TRIUMPH-4: 12mg -28.7% at 68 weeks; dysesthesia 8.8-20.9% at 9-12mg.

Dosing

Where a study reports an amount, it appears in that study's entry below, attributed to the source.

Published evidence

1. Human RCT 2025

   TRIUMPH-4 topline results

   Eli Lilly investor release Lilly investor news

   Phase 3 obesity + knee OA, 68 weeks: retatrutide 12mg -28.7% body weight (-71.2 lbs avg). WOMAC pain reduction 75.8%. Dysesthesia signal: 8.8% at 9mg, 20.9% at 12mg vs 0.7% placebo. First successful phase 3 readout.

2. Human RCT 2024

   Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial

   Sanyal AJ, Bedossa P, Fraessdorf M, et al. Nat Med

   MASLD phase 2a: hepatic fat reduction 81-86% at 8/12mg by week 24. Glucagon agonism's signature.

   PMID 38858523

3. Human RCT 2023

   Triple-Hormone-Receptor Agonist Retatrutide for Obesity: A Phase 2 Trial

   Jastreboff AM, Kaplan LM, Frias JP, et al. NEJM

   Phase 2 obesity, 48 weeks, n=338. 24-week weight changes: 1mg -7.2%, 4mg -12.9%, 8mg -17.3%, 12mg -17.5% vs placebo -1.6%. 48-week: 12mg -24.2% vs placebo -2.1%. The largest weight loss reported for any obesity drug at the time.

   PMID 37366315

4. Human RCT 2022

   LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b multiple-ascending dose trial

   Urva S, Coskun T, Loh MT, et al. Lancet

   Phase 1b T2D, 12 weeks: dose-proportional PK, t½ ~6 days. HbA1c reductions and weight loss across all doses; well tolerated with mild/transient GI AEs.

   PMID 36354040

Reported side effects

Nausea

Very common Moderate · Phase 2: 35-50% across 4-12mg arms; mostly mild-moderate, dose-dependent, peaks during titration. Lower starting dose (2mg vs 4mg) attenuates.

Vomiting

Common Moderate · Dose-related; phase 2: ~15-25% at 8-12mg.

Diarrhea

Common Mild · Phase 2: 17-26%.

Constipation

Common Mild · Phase 2: 9-14%.

Dysesthesia

Common Moderate · NOVEL TO RETATRUTIDE. TRIUMPH-4 phase 3: 8.8% at 9mg, 20.9% at 12mg vs 0.7% placebo. Believed to relate to glucagon-receptor agonism in peripheral nerves. Manifests as paresthesia, burning, abnormal sensation. Often resolves with dose reduction.

Heart rate increase

Common Moderate · Dose-dependent rise; peaked at 24 weeks then declined. Mean +5-15 bpm at 12mg in phase 2.

Decreased appetite

Very common Mild · Wanted effect; reported as AE in 20-30% across doses.

Hepatic fat reduction (PD effect)

Very common Mild · Phase 2a MASLD trial: hepatic fat reduction 81-86% at 8/12mg by week 24. Glucagon agonism's signature effect: desired, not adverse.

Pancreatitis

Rare Serious · Class warning; rates not reported as elevated in phase 2/3 to date.

Hypoglycemia

Rare Moderate · T2D patients in TRIUMPH-2 may have increased risk; non-DM patients minimal.

Thyroid C-cell tumors

Rare Serious · Class warning expected at approval (rodent GLP-1 RA carcinogenicity).

Interactions

• Insulin or sulfonylurea Synergy

  Hypoglycemia risk when combined with insulin or sulfonylureas. Triple agonism includes glucose-dependent insulin secretion + glucagon receptor activity; net glucose effect is lowering.

• Oral medications (general) Absorption interference

  GLP-1 + GIP component slows gastric emptying. Magnitude likely between semaglutide and tirzepatide.

• Tirzepatide Redundant

  Overlapping GIP/GLP-1 agonism. No efficacy benefit; AE burden additive.

• Semaglutide (SC) Redundant

  Overlapping GLP-1 agonism. Concurrent GLP-1 RA use not recommended.

• Oral hormonal contraceptives Absorption interference

  Class effect; tirzepatide reduces ethinyl estradiol Cmax 59%. Retatrutide likely similar magnitude. Oral contraceptive efficacy may be compromised.

• Tesamorelin Caution

  Off-label combination some operators run for body recomposition. Reta drives weight loss + visceral fat via triple agonism while Tesamorelin preserves lean mass and accelerates visceral fat loss via GH pulsatility. Glucose dynamics push in opposite directions: GLP-1/GIP agonism improves insulin sensitivity, GH antagonizes it. Reta's glucose-lowering effect can mask early GH-induced glucose intolerance, so the metabolic interaction warrants closer monitoring than either compound alone.

Reconstitution and storage

N/A pre-approval. Likely SC pen at launch (Lilly's standard platform).

N/A pre-approval; expect refrigerated unused, room temp in-use (class standard).

Open the reconstitution calculator for Retatrutide