Retatrutide
Retatrutide (LY3437943) is a triple agonist of GIP, GLP-1, and glucagon receptors developed by Eli Lilly for obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Phase 2 data demonstrated up to 24.2% weight loss at 48 weeks.
Retatrutide (LY3437943) is a synthetic 39-amino-acid peptide that acts as a triple agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. Developed by Eli Lilly, it is the first triple incretin receptor agonist to reach Phase 3 clinical development and represents a novel approach to treating obesity, type 2 diabetes mellitus, and metabolic liver disease by engaging three complementary metabolic pathways simultaneously.
Overview
Retatrutide uniquely engages three metabolic hormone receptors — GIP, GLP-1, and glucagon — in a single molecule. While dual GIP/GLP-1 agonists like tirzepatide have demonstrated remarkable efficacy in obesity and diabetes, retatrutide adds glucagon receptor agonism to drive hepatic lipid oxidation, increase energy expenditure, and enhance thermogenesis. Its extended half-life of approximately six days is achieved through fatty acid acylation that promotes albumin binding, enabling convenient once-weekly subcutaneous dosing.
The addition of glucagon receptor agonism distinguishes retatrutide from all approved incretin-based therapies. Glucagon stimulates hepatic glycogenolysis, gluconeogenesis, and fatty acid oxidation while increasing resting energy expenditure. The GLP-1 and GIP components counterbalance glucagon's hyperglycemic effects, resulting in net improvements in glycemic control alongside enhanced fat metabolism and energy expenditure.
Mechanism of Action
Retatrutide activates three distinct receptor pathways through coordinated physiological mechanisms:
GLP-1 Receptor Agonism: Like selective GLP-1 receptor agonists, retatrutide stimulates glucose-dependent insulin release from pancreatic beta cells, suppresses glucagon secretion from alpha cells (at the pancreatic level), slows gastric emptying, and promotes satiety through central nervous system GLP-1 receptor activation in the hypothalamus and brainstem.
GIP Receptor Agonism: Retatrutide binds GIP receptors on pancreatic beta cells to enhance glucose-dependent insulin secretion through mechanisms partially distinct from GLP-1. GIP receptor activation also influences lipid metabolism in adipose tissue, potentially improving fat storage efficiency and reducing ectopic lipid deposition in the liver and muscle.
Glucagon Receptor Agonism: The glucagon component activates hepatic glucagon receptors to stimulate fatty acid oxidation, reduce hepatic lipid content, and increase energy expenditure via thermogenesis. Glucagon receptor activation increases resting metabolic rate by 5-10%, contributing to the greater weight loss observed with triple agonism compared to dual agonism. The hyperglycemic effect of glucagon is offset by the concurrent GLP-1 and GIP receptor activation.
Triple Agonist Synergy: The combination of all three receptor activations produces metabolic effects that exceed those achieved by dual GIP/GLP-1 agonism alone. The glucagon component adds a catabolic dimension — hepatic fat burning and increased energy expenditure — to the appetite suppression and insulin sensitization provided by GLP-1 and GIP agonism.
Central Appetite Regulation: Retatrutide acts on hypothalamic and brainstem receptors to reduce appetite and caloric intake. The combination of GLP-1 and GIP receptor engagement in the CNS may produce complementary satiety signals that contribute to the substantial reduction in food intake observed in clinical trials.
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Research
Liver Fat Reduction (MASLD/MASH)
Retatrutide has shown pronounced reductions in liver fat content in both the obesity and diabetes Phase 2 trials. The glucagon receptor agonist component is thought to drive hepatic lipid oxidation directly, complementing the weight-loss-mediated improvements in liver fat. Reductions in liver fat of up to 80-90% from baseline were observed in some dose groups, positioning retatrutide as a promising candidate for metabolic dysfunction-associated steatohepatitis (MASH). A dedicated Phase 3 MASH trial is underway.
Cardiovascular Risk Factors
Across Phase 2 studies, retatrutide produced improvements in multiple cardiovascular risk factors, including reductions in systolic blood pressure, triglycerides, LDL cholesterol, and waist circumference. These cardiometabolic benefits are consistent with the weight loss achieved and suggest potential for cardiovascular risk reduction, though dedicated cardiovascular outcomes trials have not yet been completed.
Phase 2 Obesity Trial
The pivotal Phase 2 trial evaluated retatrutide at multiple doses (1, 4, 8, and 12 mg) in adults with obesity (BMI ≥30 or ≥27 with comorbidities) without type 2 diabetes. At 48 weeks, participants receiving retatrutide 12 mg achieved a mean body weight reduction of 24.2%, with some participants losing more than 30% of their body weight. This exceeded the weight loss observed with any previously studied anti-obesity pharmacotherapy in a randomized controlled trial at that time point. Jastreboff AM et al. (2023) — N. Engl. J. Med. 389, 514-526.
Type 2 Diabetes
In a Phase 2 trial enrolling adults with type 2 diabetes, retatrutide demonstrated dose-dependent HbA1c reductions of up to 2.16% at 36 weeks (12 mg dose), with concurrent body weight reductions of up to 16.9%. These glycemic improvements were comparable to or exceeded those observed with tirzepatide in the SURPASS program, suggesting that triple agonism provides robust glucose control alongside substantial weight loss. Rosenstock J et al. (2023) — Lancet 402, 529-544.
Comparison to Related Compounds
| Parameter | Retatrutide (12 mg) | Tirzepatide (15 mg) | Semaglutide 2.4 mg | Survodutide (GLP-1/Glucagon) |
|---|---|---|---|---|
| Receptor targets | GIP + GLP-1 + Glucagon | GIP + GLP-1 | GLP-1 only | GLP-1 + Glucagon |
| Dosing frequency | Once weekly | Once weekly | Once weekly | Once weekly |
| Weight loss (obesity) | −24.2% (48 wk, Phase 2) | −22.5% (72 wk, Phase 3) | −15.8% (68 wk) | −14.9% (46 wk, Phase 2) |
| HbA1c reduction (T2DM) | −2.16% (Phase 2) | −2.46% (Phase 3) | −1.86% (1 mg dose) | N/A |
| Liver fat reduction | Pronounced (80-90% relative) | Moderate | Moderate | Significant |
| Development stage | Phase 3 | Approved | Approved | Phase 3 |
Retatrutide vs. Tirzepatide: Both are Eli Lilly compounds sharing GIP and GLP-1 receptor agonism, but retatrutide adds glucagon receptor activation. In cross-trial comparisons (with inherent limitations), retatrutide achieved comparable or greater weight loss at 48 weeks (−24.2%) versus tirzepatide at 72 weeks (−22.5%), despite a shorter treatment duration. The glucagon component is hypothesized to drive superior liver fat reduction and energy expenditure. Phase 3 data will provide more definitive comparisons.
Retatrutide vs. Semaglutide: Retatrutide's triple agonism engages two additional receptor pathways beyond semaglutide's GLP-1-only mechanism. Cross-trial comparisons suggest approximately 50% greater weight loss with retatrutide (−24.2% vs ~−16%) and potentially greater improvements in hepatic steatosis due to direct glucagon-mediated hepatic lipid oxidation.
Retatrutide vs. Survodutide (BI 456906): Survodutide is a GLP-1/glucagon dual agonist (without GIP) developed by Boehringer Ingelheim for MASH and obesity. Retatrutide adds GIP receptor agonism, which may provide additional insulin-sensitizing effects and potentially better gastrointestinal tolerability.
Ongoing & Future Research
Several large-scale trials are actively investigating retatrutide:
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TRIUMPH-1 (NCT05929066): Pivotal Phase 3 trial evaluating retatrutide in adults with obesity (BMI ≥30 or ≥27 with comorbidity) without type 2 diabetes. Randomized, double-blind, placebo-controlled design. Primary endpoints: percent change in body weight and proportion achieving ≥5% weight loss. Estimated enrollment: ~1,600 participants. Estimated completion: 2025-2026.
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TRIUMPH-2 (NCT05881005): Phase 3 trial evaluating retatrutide in adults with obesity and type 2 diabetes. This trial will help establish the dual indication (obesity + diabetes) and enable comparisons with approved therapies. Estimated completion: 2025-2026.
-
MASLD/MASH Trial (NCT06094244): Phase 3 trial evaluating retatrutide for metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Given the pronounced liver fat reductions observed in Phase 2, this is a key indication for retatrutide. Histological endpoints include MASH resolution and fibrosis improvement.
-
TRIUMPH-3 (NCT06154304): Additional Phase 3 obesity trial with extended treatment duration to assess durability of weight loss and long-term safety.
Safety Profile
Common adverse effects include gastrointestinal symptoms such as nausea (varying by dose, up to ~25%), diarrhea, vomiting, constipation, and decreased appetite, which are typically mild to moderate in severity and tend to diminish with continued treatment and gradual dose escalation. The overall GI tolerability profile appears similar to other incretin-based therapies. Dose-dependent increases in heart rate (1-4 bpm) have been observed, consistent with the GLP-1 receptor agonist class. Retatrutide carries precautionary warnings for thyroid C-cell tumors based on the class effect observed in rodent studies with GLP-1 receptor agonists; clinical relevance in humans has not been determined. Additional monitoring includes pancreatitis, gallbladder disease, and hypoglycemia when used with insulin or sulfonylureas. Discontinuation rates due to adverse events in Phase 2 trials were generally low (5-7%).
Pharmacokinetic Profile
Retatrutide — Pharmacokinetic Curve
Subcutaneous injection (once weekly)Quick Start
- Typical Dose
- 0.5mg starting, titrate up to 8-12mg weekly
- Frequency
- Once weekly (same day each week)
- Route
- Subcutaneous injection (once weekly)
- Cycle Length
- Continuous therapy as prescribed
- Storage
- Reconstituted: 2-8°C, use within 28 days
Molecular Structure
- Formula
- C221H342N46O68
- Weight
- 4,731.33 Da Da
- Length
- 39 amino acids
- PubChem CID
- 171390338
- Exact Mass
- 4730.4785 Da
- LogP
- -6.3
- TPSA
- 1780 Ų
- H-Bond Donors
- 58
- H-Bond Acceptors
- 70
- Rotatable Bonds
- 159
- Complexity
- 11500
Identifiers (SMILES, InChI)
InChI=1S/C221H342N46O68/c1-23-124(11)179(208(322)241-144(83-88-176(291)292)192(306)245-150(105-134-69-75-137(276)76-70-134)196(310)244-148(100-121(5)6)194(308)243-147(99-120(3)4)193(307)240-142(82-87-175(289)290)187(301)230-110-169(282)229-113-173(286)264-92-51-61-161(264)206(320)253-158(116-270)203(317)251-157(115-269)189(303)232-111-170(283)233-128(15)212(326)266-94-53-63-163(266)214(328)267-95-54-64-164(267)213(327)265-93-52-62-162(265)207(321)250-156(114-268)183(226)297)258-200(314)152(103-131-55-41-39-42-56-131)242-185(299)127(14)235-216(331)219(18,19)262-205(319)145(80-85-166(225)279)237-184(298)126(13)234-190(304)140(60-48-50-90-227-172(285)119-335-98-97-334-96-91-228-167(280)86-81-146(215(329)330)236-168(281)65-45-37-35-33-31-29-27-25-26-28-30-32-34-36-38-46-66-174(287)288)238-191(305)141(59-47-49-89-222)239-198(312)154(107-177(293)294)247-195(309)149(101-122(7)8)256-218(333)221(22,109-123(9)10)263-211(325)180(125(12)24-2)259-204(318)160(118-272)252-197(311)151(106-135-71-77-138(277)78-72-135)246-199(313)155(108-178(295)296)248-202(316)159(117-271)254-210(324)182(130(17)274)260-201(315)153(104-132-57-43-40-44-58-132)249-209(323)181(129(16)273)257-171(284)112-231-188(302)143(79-84-165(224)278)255-217(332)220(20,21)261-186(300)139(223)102-133-67-73-136(275)74-68-133/h39-44,55-58,67-78,120-130,139-164,179-182,268-277H,23-38,45-54,59-66,79-119,222-223H2,1-22H3,(H2,224,278)(H2,225,279)(H2,226,297)(H,227,285)(H,228,280)(H,229,282)(H,230,301)(H,231,302)(H,232,303)(H,233,283)(H,234,304)(H,235,331)(H,236,281)(H,237,298)(H,238,305)(H,239,312)(H,240,307)(H,241,322)(H,242,299)(H,243,308)(H,244,310)(H,245,306)(H,246,313)(H,247,309)(H,248,316)(H,249,323)(H,250,321)(H,251,317)(H,252,311)(H,253,320)(H,254,324)(H,255,332)(H,256,333)(H,257,284)(H,258,314)(H,259,318)(H,260,315)(H,261,300)(H,262,319)(H,263,325)(H,287,288)(H,289,290)(H,291,292)(H,293,294)(H,295,296)(H,329,330)/t124-,125-,126-,127-,128-,129+,130+,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,151-,152-,153-,154-,155-,156-,157-,158-,159-,160-,161-,162-,163-,164-,179?,180?,181-,182-,221+/m0/s1
MLOLQJNKXBNWFW-SAGGEDDASA-NResearch Indications
Weight Loss
Clinical trials show 17.5% weight loss at 24 weeks and 24.2% at 48 weeks.
Continuous weight loss with no plateau at 48 weeks suggests greater long-term potential.
Addresses obesity through appetite suppression, energy expenditure, and metabolic efficiency.
Type 2 Diabetes
HbA1c reductions up to 2.16% with 82% achieving target levels below 6.5%.
Balanced glycemic control with minimal hypoglycemia risk.
Marked improvements in sensitivity with potential for reduced exogenous insulin requirements.
Cardiovascular/Metabolic
Non-HDL cholesterol reductions up to 26.9%, triglyceride reductions up to 40.6%.
Consistent decreases in systolic and diastolic blood pressure across trials.
Up to 82% reduction in liver fat with normalization in 90% of participants.
Research Protocols
subcutaneous Injection
Triple agonist (GIP/GLP-1/glucagon) administered once weekly with gradual escalation.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| Initiation | 2 mg | Once weekly | Weeks 1-4 |
| Escalation 1 | 4 mg | Once weekly | Weeks 5-8 |
| Escalation 2 | 6 mg | Once weekly | Weeks 9-12 |
| Standard dose | 8 mg | Once weekly | Weeks 13+(Advanced: up to 12 mg. Minimum 24 weeks.) |
Reconstitution Guide (5mg vial + 1mL BAC water)
- Wipe vial tops with alcohol swab
- Draw 1.0 mL bacteriostatic water into syringe
- Inject slowly down the inside wall of the peptide vial
- Gently swirl to dissolve — never shake
- Resulting concentration: 5.0 mg/mL
- For 2 mg dose: draw 40 units (0.40 mL)
- For 4 mg dose: draw 80 units (0.80 mL)
- For 6 mg dose: use multiple vials as needed
- Store reconstituted vial refrigerated at 2-8°C
Interactions
Peptide Interactions
Retatrutide uniquely engages three metabolic hormone receptors — GIP, GLP-1, and glucagon — in a single molecule.
Retatrutide uniquely engages three metabolic hormone receptors — GIP, GLP-1, and glucagon — in a single molecule.
These glycemic improvements were comparable to or exceeded those observed with tirzepatide in the SURPASS program, suggesting that triple agonism provides robust glucose control alongside substantial weight loss.
What to Expect
What to Expect
Initial appetite suppression and mild GI effects as body adapts to triple hormone activation
Noticeable food cravings reduction and portion size decrease; early weight loss (2-5%)
Significant appetite control and steady weight loss (5-10%); improved glucose control
Substantial weight reduction (10-18%) with enhanced energy expenditure
Major weight loss milestone (15-22%) with cardiovascular benefits and liver fat reduction
Maximum clinical efficacy (20-24.2%) with comprehensive metabolic improvements
Safety Profile
Common Side Effects
- Gastrointestinal effects (nausea, vomiting, diarrhea)—typically mild to moderate
- Heart rate increases—common especially in first 24 weeks
- Appetite suppression
- Mild dehydration
Contraindications
- Personal or family history of medullary thyroid carcinoma
- MEN2 syndrome
- Severe renal impairment
Discontinue If
- Severe persistent nausea or vomiting preventing adequate nutrition
- Signs of pancreatitis: severe abdominal pain radiating to back
- Severe hypoglycemia symptoms: confusion, dizziness, sweating
- Excessive weight loss (>3 lbs per week consistently or >25% total body weight)
- Gallbladder problems: severe right upper abdominal pain
Quality Indicators
What to look for
- Pharmaceutical-grade white powder with uniform texture
- Proper cold chain maintenance (2-8°C refrigeration)
- Clear, colorless reconstituted solution without particles
- Stable extended half-life effects (consistent appetite suppression between doses)
Caution
- Source verification critical—counterfeit versions circulate due to investigational status
Red flags
- Rapid tolerance or effectiveness loss suggests degraded or counterfeit product
- Unusual side effect profile may indicate contamination
Frequently Asked Questions
References (13)
- [11]
- [12]
- [1]Phase II Obesity Trial (2023)
- [2]Phase II Type 2 Diabetes Study (2023)
- [3]MASLD Substudy (2024)
- [5]Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs... in first successful Phase 3 trial (TRIUMPH-4) (2025)
- [8]
- [9]
- [10]
- [4]
- [6]
- [7]
- [14]Sanyal, A. J. et al A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis N. Engl. J. Med. (2024)
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Retinalamin
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