RT3 — Peptide Protocol Wiki reference

However, retatrutide has higher discontinuation rates and a novel dysesthesia safety signal.

Is retatrutide FDA approved?

It has not yet received FDA approval for any indication.

vation enhances energy expenditure and liver fat reduction • Significant knee osteoarthritis pain reduction (~75%) demonstrated • Once-weekly subcutaneous injection Community-Reported Side Effects Anecdotal ?

Retatrutide 2026: 28.7% Weight Loss in Phase 3 TRIUMPH-4 | Peptide Protocol Wiki Skip to main content 🧬 Peptide Protocol Wiki Peptides Side Effects New Learn Directory Tools Blog News About ⌘K ⌘K 🌱 New to Peptides?

In December 2025, the first Phase 3 results from TRIUMPH-4 showed 28.7% mean body weight loss at 68 weeks with the 12 mg dose -- the highest weight loss ever reported in a Phase 3 obesity trial 1 .

Events were generally mild per Eli Lilly, though the 20.9% rate at 12 mg requires further characterization in remaining TRIUMPH readouts.

Start the 7-step beginner guide Peptides Side Effects New Directory Learn Tools Blog News About Retatrutide 📋 Overview 🧬 Molecule 🔄 Similar ⚠️ Side Effects 💉 Dosing 🔬 Research 🚨 Risks 👥 Community 📊 Community Data Home Peptides Retatrutide Weight Loss & Metabolism Anti-Obesity phase3 Retatrutide Also known as: LY3437943, ELI-002, Reta, Retatuitide Compare with 6 peptide s Research compiled by Peptide Protocol Wiki 📅 Updated March 7, 2026 Citations Verified TL;DR Retatrutide (Eli Lilly LY3437943) is an investigational triple GIP/GLP-1/ glucagon receptor agonist for obesity and type 2 diabetes.

In the Phase 3 TRIUMPH-4 trial (December 2025; PMID 41090431), the 12 mg dose produced 28.7% mean body weight loss at 68 weeks -- the highest ever reported in a Phase 3 obesity trial.

Retatrutide is not FDA-approved as of June 2026; seven additional TRIUMPH Phase 3 readouts are expected throughout 2026, with the earliest possible approval in mid-2027.

Browse all metabolic peptides → Table of Contents 📌 TL;DR • Triple GIP/GLP-1/glucagon receptor agonist with novel mechanism • 28.7% body weight loss in Phase 3 TRIUMPH-4 (highest ever in obesity Phase 3) • Glucagon receptor acti

📋 Protocol Quick-Reference Investigational triple agonist (GIP/GLP-1/glucagon) for obesity and type 2 diabetes 💉 Dosing Amount 0.5 mg starting dose, escalating to target of 8-12 mg Frequency Once weekly Duration 48 weeks in Phase 2 trials (ongoing therapy anticipated) Step-wise Titration (12 weeks) 💊 Administration Route SC Schedule Once weekly Timing Same day each week, any time of day ✓ Rotate injection sites 📅 Cycle Duration 48 weeks in Phase 2 trials (ongoing therapy anticipated) Repeatable Yes Preparation & Storage ✓ Ready-to-use — no reconstitution required Storage: Investigational product; storage per clinical trial protocol ⚗️ Suggested Bloodwork ( 6 tests) HbA1c and fasting glucose When: Baseline Why: Baseline glycemic status Lipid panel When: Baseline Why: Baseline cardiovascular risk markers CMP with liver enzymes When: Baseline Why: Liver function (glucagon component affects hepatic metabolism) Thyroid panel (TSH, free T4) When: Baseline Why: GLP-1 agonist class has MTC black box warning Amylase and lipase When: Baseline Why: Baseline pancreatic function HbA1c When: 12 weeks Why: Monitor glycemic improvement 💡 Key Considerations → Contraindication: Avoid with personal/

family history of medullary thyroid carcinoma or MEN2 syndrome; caution with history of pancreatitis Subscribe to unlock this content Get weekly peptide research summaries, new study alerts, and protocol updates — free.

Restore access No thanks, continue reading Related Reading Peptide Tirzepatide dual GIP/GLP-1 receptor agonist Peptide Semaglutide GLP-1 receptor agonist Peptide Survodutide dual glucagon/GLP-1 receptor agonist How Retatrutide works at the cellular level Overview of Retatrutide benefits and applications Scientific Details Molecular Formula C221H342N46O68 Molecular Weight 4731.41 Da CAS Number 2381089-83-2 Sequence His(Aib)QGTFTSDVSSYLEGQAAKEFIAWLVKGR(C18 fatty acid via Lys30-linker)-NH2 Retatrutide Weight Loss 2026: 28.7% Phase 3 Results, Dosing & Side Effects # Retatrutide (LY3437943) is an investigational triple GIP/GLP-1/glucagon receptor agonist developed by Eli Lilly that, in the Phase 3 TRIUMPH-4 trial reported December 2025, produced 28.7% mean body weight loss at 68 weeks with the 12 mg dose -- the highest weight loss ever reported in a Phase 3 obesity trial (TRIUMPH-4; Giblin K et al., Diabetes, Obesity and Metabolism 2026; PMID 41090431; DOI: 10.1111/dom.70209 ) 1 .

# Retatrutide (LY3437943) is an investigational triple-hormone receptor agonist developed by Eli Lilly.

It is a synthetic peptide that simultaneously activates three metabolically important receptors: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR).

Retatrutide targets three receptors (GIP, GLP-1, and glucagon) versus tirzepatide's two (GIP and GLP-1).

Mechanism of Action # Retatrutide's triple receptor agonism leverages complementary metabolic pathways to produce weight loss that exceeds any single or dual agonist therapy tested to date.

Three-Receptor Activation # GLP-1R activation : Suppresses appetite via hypothalamic signaling, enhances glucose-dependent insulin secretion, slows gastric emptying -- the same mechanism that drives semaglutide's efficacy GIPR activation : Potentiates insulin secretion, modulates fat distribution and adipose tissue function, and may improve GI tolerability of GLP-1 agonism -- the addition that distinguishes tirzepatide from

semaglutide GCGR activation : Increases hepatic energy expenditure through fatty acid oxidation, promotes thermogenesis in brown adipose tissue, and reduces liver fat content -- the novel third receptor unique to retatrutide Key Differentiator: Glucagon Component # The inclusion of glucagon receptor agonism is retatrutide's primary differentiator.

Glucagon increases energy expenditure by activating thermogenesis and promotes hepatic glycogenolysis and gluconeogenesis.

While glucagon alone would raise blood glucose, the combined GLP-1R/GIPR activity counterbalances potential hyperglycemia, allowing net metabolic benefit.

This three-receptor approach appears to explain the substantially greater weight loss observed with retatrutide compared to dual agonists.

The glucagon component is also hypothesized to drive hepatic fat reduction, which is being evaluated in a dedicated TRIUMPH trial for metabolic dysfunction-associated steatohepatitis (MASH).

All trials test retatrutide 9 mg and 12 mg versus placebo with dose escalation starting at 2 mg weekly.

Key findings: 12 mg dose: 28.7% mean weig

ht loss (-32.3 kg / -71.2 lbs) at 68 weeks 9 mg dose: 26.4% mean weight loss (-29.1 kg / -64.2 lbs) at 68 weeks Placebo: 2.1% weight loss 58.6% of patients on 12 mg achieved 25%+ weight loss 39.4% of patients on 12 mg achieved 30%+ weight loss WOMAC knee pain reduced by approximately 75% (both doses) Systolic blood pressure reduced by 14.0 mmHg at 12 mg Remaining TRIUMPH Trials (Expected 2026) # Trial Population Duration Key Question TRIUMPH-1 Obesity (general) 80 weeks Will weight loss exceed 30%?

TRIUMPH-3 Obesity + CV disease ~68-80 weeks Cardiovascular outcomes?

Safety Profile # Gastrointestinal Side Effects # GI adverse events in TRIUMPH-4 were the most common, consistent with all incretin-based therapies but at higher rates than seen with semaglutide or tirzepatide: Nausea: 43.2% (12 mg), 38.1% (9 mg) vs 10.7% placebo Diarrhea: 33.1% (12 mg), 34.7% (9 mg) vs 13.4% placebo Vomiting: 20.9% (12 mg), 20.4% (9 mg) vs 0.0% placebo Constipation: 25.0% (12 mg), 21.8% (9 mg) vs 8.7% placebo Dysesthesia: Novel Safety Signal # The most notable finding was d

ose-dependent dysesthesia (abnormal touch sensations): 12 mg: 20.9% incidence 9 mg: 8.8% incidence Placebo: 0.7% This signal was not observed in Phase 2 and has not been reported with GLP-1 or dual agonists.

Discontinuation Rates # Treatment discontinuation due to adverse events was 18.2% at 12 mg and 12.2% at 9 mg, compared to 4.0% with placebo.

Notably, patients with BMI 35+ had lower discontinuation rates (12.1% at 12 mg).

An NDA submission is anticipated in late 2026 or early 2027, with potential FDA approval in mid-2027 under optimistic timelines.

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Phase 2 Data # The Phase 2 trial (Jastreboff et al., NEJM 2023; PMID: 37366315) enrolled 338 adults with obesity over 48 weeks: 12 mg dose: 24.2% mean weight loss Clear dose-response across 1 mg, 4 mg, 8 mg, and 12 mg groups 26% of participants on 12 mg lost 30%+ body weight GI adverse events common but manageable with dose escalation Dysesthesia was not reported as a significant signal A separate Phase 2 trial in type 2 diabetes (Rosenstock et al., The Lancet 2023; PMID: 37385280) showed HbA1c reductions of up to 2.0% from baseline, with significant weight loss and superiority over dulaglutide 1.5 mg comparator.

Retatrutide vs Tirzepatide vs Semaglutide # Parameter Retatrutide Tirzepatide Semaglutide Mechanism Triple (GIP/GLP-1/GCG) Dual (GIP/GLP-1) Single (GLP-1) Max Phase 3 Weight

Loss -28.7% (68 wk) -20.9% (72 wk) -14.9% (68 wk) Approval Status Phase 3 FDA-approved (2023) FDA-approved (2021) Nausea Rate 43% ~31% ~44% Discontinuation (AEs) 18.2% ~6.2% ~7.0% For a detailed analysis of these comparisons, see Retatrutide Phase 3 Results: TRIUMPH Trial Weight Loss Data .

Regulatory Timeline # Phase 3 data: Seven remaining TRIUMPH readouts expected throughout 2026 NDA submission: Anticipated late 2026 or early 2027 FDA review: 6-12 months depending on standard vs priority review Earliest possible approval: Mid-2027 (optimistic); late 2027 or 2028 (conservative) Important Considerations # Investigational compound -- NOT FDA-approved for any indication Phase 3 results available from TRIUMPH-4 only; additional trials pending Novel dysesthesia safety signal requires further characterization Higher discontinuation rates than approved alternatives GI adverse events are common, particularly at higher doses Should not be used outside of clinical trials Key Research Findings # TRIUMPH registrational clinical trials design paper , published in Diabetes, Obesity and Metabolism (Giblin K et al., 2026; PMID: 41090431): Four-study Phase 3 program evaluating retatrutide in 5,800+ participants across obesity, OSA, and knee OA TRIUMPH-4 results: 28.7% weight loss at 68 weeks with 12 mg dose Triple-hormone-receptor agonist retatrutide for obesity -- a Phase 2 trial , published in New England Journal of Medicine (Jastreboff AM et al.,

2023; PMID: 37366315): 24.2% mean weight loss at 48 weeks with 12 mg dose in 338 adults with obesity Retatrutide Phase 2 in type 2 diabetes , published in The Lancet (Rosenstock J et al., 2023; PMID: 37385280): HbA1c reductions of up to 2.0% from baseline with significant weight loss References # Related Reading # Retatrutide Phase 3 Results: TRIUMPH Trial Data Retatrutide research studies and evidence Retatrutide dosing protocols Retatrutide side effects profile Amycretin research guide CT-388 research guide Survodutide research guide Footnotes # Giblin K, Boehnke A, Brown C, et al.

Triple-hormone-receptor agonist retatrutide for obesity -- a Phase 2 trial.