Extensively Studied

Retatrutide

Triple GLP-1/GIP/Glucagon Agonist | Weight Loss & Diabetes

Retatrutide (LY3437943) is a novel triple hormone receptor agonist targeting GLP-1, GIP, and glucagon receptors. Phase III TRIUMPH-4 trial (Dec 2025) achieved 28.7% weight loss (71.2 lbs) at 68 weeks with 12mg dose - the highest recorded for any obesity medication. Currently in late-stage Phase III development by Eli Lilly with FDA approval expected 2026-2027.

Daily dose

0.5-12 mg weekly

Frequency

Once weekly

Cycle length

Continuous therapy

Storage

2-8°C

Key benefits

Triple hormone receptor activation provides superior weight loss (24.2%), improved glycemic control, and enhanced cardiovascular benefits compared to single or dual agonists

How it works

Activates GLP-1 for appetite suppression, GIP for insulin sensitivity, and glucagon for increased energy expenditure and hepatic fat oxidation

Dosage protocols

Goal

Weight Loss Initiation

Dose

2 mg weekly · Once weekly

Route

Subcutaneous injection

Goal

Moderate Weight Loss

Dose

4 mg weekly · Once weekly

Route

Subcutaneous injection

Goal

Advanced Weight Loss

Dose

8 mg weekly · Once weekly

Route

Subcutaneous injection

Goal

Maximum Efficacy (Clinical Supervision)

Dose

12 mg weekly · Once weekly

Route

Subcutaneous injection

Goal

Type 2 Diabetes Management

Dose

4-8 mg weekly · Once weekly

Route

Subcutaneous injection

Goal

Cardiovascular Risk Reduction

Dose

8 mg weekly · Once weekly

Route

Subcutaneous injection

Research indications

weight Loss

Superior Weight Reduction — Clinical trials demonstrate 17.5% at 24 weeks and 24.2% at 48 weeks - highest recorded for any obesity medication in development

Sustained Weight Management — Continuous weight loss throughout trials with no plateau reached at 48 weeks, suggesting greater long-term potential than current therapies

Triple Mechanism Obesity Treatment — Addresses obesity through appetite suppression, increased energy expenditure, and improved metabolic efficiency via three hormone pathways

diabetes

Superior Glycemic Control — HbA1c reductions up to 2.16% with 82% of participants achieving target levels below 6.5% - exceeding dual agonist performance

Glucose-Dependent Regulation — Glucose-dependent insulin secretion and glucagon suppression provide balanced glycemic control with minimal hypoglycemia risk

Insulin Sensitivity Enhancement — Marked improvements in insulin sensitivity with potential for significant reduction in exogenous insulin requirements

cardiovascular

Comprehensive Lipid Improvement — Non-HDL cholesterol reductions up to 26.9%, triglyceride reductions up to 40.6%, and ApoB reductions up to 24.2%

Blood Pressure Optimization — Consistent decreases in both systolic and diastolic blood pressure across clinical trials, supporting cardiovascular risk reduction

Hepatic Fat Reduction — Up to 82% reduction in liver fat with normalization in 90% of participants, addressing MASLD and reducing cardiovascular risk

Administration

injectable

Interactions

Avoid Combination

Tirzepatide — Do not combine with other dual/triple agonists - risk of severe hypoglycemia, excessive gastrointestinal effects, and unpredictable hormone interactions

Use Caution

Cagrilintide — Both cause significant GI effects (gastroparesis, nausea). Retatrutide (triple agonist) and Cagrilintide (amylin agonist) have different mechanisms but compounded GI side effects create substantial risk. Not recommended without specialist supervision.

Avoid Combination

Semaglutide — Do not combine with other GLP-1 agonists - overlapping mechanisms increase risk of severe hypoglycemia and excessive side effects

Monitor Combination

Insulin — May significantly reduce insulin requirements due to improved glucose control - monitor blood glucose closely and adjust insulin doses accordingly

Compatible

Metformin — Safe combination tested in clinical trials with no significant interactions. Both work through different mechanisms to improve glucose control and weight management

Compatible

SGLT2 Inhibitors — Clinical trials included participants on SGLT2 inhibitors with no safety concerns. Complementary mechanisms for glucose control

Requires Timing

Oral Contraceptives — Space oral contraceptives by 1 hour before retatrutide injection due to delayed gastric emptying effects

Monitor Combination

Warfarin — Weight loss may affect warfarin requirements - monitor INR more frequently and adjust anticoagulation as needed

Compatible

BPC-157 — Safe combination - different therapeutic targets. BPC-157 promotes tissue repair via growth factors while Retatrutide targets metabolic hormone receptors. BPC-157 may provide GI protective benefits during Retatrutide use.

Compatible

NAD+ — Safe combination - different cellular systems. Retatrutide targets hormone receptors (GLP-1/GIP/glucagon) while NAD+ supports cellular energy and DNA repair. NAD+ may support metabolic adaptation during weight loss.

Safety notes

Most common side effects are gastrointestinal (nausea 43%, diarrhea 33% at 12mg) - typically mild to moderate and dose-dependent

NEW SIGNAL (Dec 2025): Dysesthesia (abnormal touch sensations) reported in 8.8-20.9% of participants at 9-12mg doses in TRIUMPH-4 trial

Start with 0.5mg weekly and escalate gradually every 4 weeks to minimize gastrointestinal side effects

Phase III discontinuation rates: 12.2% (9mg) and 18.2% (12mg) due to adverse events

Monitor for signs of pancreatitis (severe abdominal pain radiating to back) - discontinue immediately if suspected

Contraindicated in patients with personal/family history of medullary thyroid carcinoma or MEN2 syndrome

Research studies

Phase III TRIUMPH-4 Trial - Eli Lilly (Dec 2025)

Human | 9-12mg weekly | 68 weeks | 28.7% weight loss (71.2 lbs)

First successful Phase III trial in 445 adults with obesity and knee osteoarthritis. 12mg dose achieved 28.7% weight loss (71.2 lbs from 248.5 lb baseline) with 75.8% pain reduction. Discontinuation rates 12-18% due to GI effects; new dysesthesia signal in 8.8-20.9% of participants.

View study →

MASLD Substudy - Nature Medicine (2024)

Human | 8-12mg weekly | 24 weeks | 82% liver fat reduction

Metabolic dysfunction-associated steatotic liver disease study showing dramatic liver fat reductions with normalization in over 90% of participants at highest doses.

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TRIUMPH-Outcomes Cardiovascular Study (2024-2029)

Human | 8mg weekly | 248 weeks | 10,000 participants with ASCVD

Major cardiovascular outcomes trial assessing effects on MACE and kidney outcomes in participants with obesity and established cardiovascular or kidney disease.

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Phase II Obesity Trial - NEJM (2023)

Human | 1-12mg weekly | 48 weeks | 24.2% mean weight reduction

Landmark randomized controlled trial in 338 participants with obesity showing dose-dependent weight loss with 12mg achieving 24.2% reduction - the highest weight loss recorded for any obesity medication in clinical trials at the time.

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Phase II Type 2 Diabetes Study - Lancet (2023)

Human | 0.5-12mg weekly | 36 weeks | 16.9% weight loss, -2.02% HbA1c

Trial in 281 participants with type 2 diabetes demonstrating significant glycemic control improvements with HbA1c reductions up to 2.16% and concurrent substantial weight loss.

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TRIUMPH-1 Phase III Trial (2023-2026)

Human | 4-12mg weekly | 72 weeks | Obesity without comorbidities

Pivotal Phase III trial in participants with obesity without diabetes or osteoarthritis, evaluating maintenance dose (4mg) in addition to 9mg and 12mg. Results expected 2026.

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Phase I Pharmacokinetics - Cell Metabolism (2022)

Human | Single ascending dose | 12 weeks | Established 6-day half-life

First-in-human study establishing safety profile, dose-proportional pharmacokinetics, and the extended half-life enabling once-weekly administration.

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Related compounds

Tirzepatide Semaglutide Bioglutide Survodutide