Retatrutide
Also known as: LY3437943, GGG Triple Agonist, Eli Lilly Triple G
Retatrutide is an investigational triple hormone receptor agonist (GIP/GLP-1/glucagon) developed by Eli Lilly. In Phase II trials, it achieved up to 24.2% body weight reduction at 48 weeks; the highest weight loss reported for any single pharmacological agent in clinical trials.
Retatrutide is a ~4,500 Da (estimated, 39 amino acids with fatty acid modification) research peptide. Retatrutide is an investigational triple hormone receptor agonist (GIP/GLP-1/glucagon) developed by Eli Lilly. In Phase II trials, it achieved up to 24.2% body weight reduction at 48 weeks; the highest weight loss reported for any single pharmacological agent in clinical trials.
Also called: LY3437943, GGG Triple Agonist, Eli Lilly Triple G
~4,500 (estimated, 39 amino acids with fatty acid modification)
Molecular Weight
Daltons
0
Strong Evidence
benefits
5
Studies Cited
peer-reviewed
500-500
Typical Dose
mcg
Overview
Retatrutide (LY3437943) is a novel investigational peptide that represents the next evolution in incretin-based therapeutics. While tirzepatide activates two receptors (GIP and GLP-1), retatrutide activates three: GIP, GLP-1, and glucagon receptors simultaneously. Developed by Eli Lilly, it is the first triple incretin receptor agonist to reach advanced clinical development. The addition of glucagon receptor agonism provides a unique metabolic advantage, glucagon promotes hepatic fat oxidation, increases energy expenditure through thermogenesis, and reduces hepatic lipid accumulation. The Phase II trial (published in the New England Journal of Medicine in 2023) produced the most dramatic weight loss results ever reported for a pharmaceutical agent, with participants on the highest dose losing an average of 24.2% of body weight at 48 weeks, and approximately 26% extrapolated at the pre-specified 24-week treatment continuation. Phase III trials (TRIUMPH program) are underway for obesity and type 2 diabetes. Retatrutide also demonstrated notable efficacy against metabolic-associated steatohepatitis (MASH/NASH), with up to 90% of patients showing resolution of liver steatosis. If approved, it would represent a change in obesity pharmacotherapy.
Key Takeaways: Retatrutide
- Research doses typically range from 500 to 500 mcg via subcutaneous injection
- 0 benefits with strong evidence, 5 moderate, 1 preliminary
- Half-life: Approximately 6 days (enabling once-weekly dosing)
- 5 cited research studies in this guide
Mechanism of Action
Retatrutide activates three distinct G-protein coupled receptors in a balanced manner: GLP-1R (glucagon-like peptide-1 receptor), GIPR (glucose-dependent insulinotropic polypeptide receptor), and GCGR (glucagon receptor). Each receptor contributes distinct metabolic effects. GLP-1R activation provides appetite suppression through hypothalamic signaling, enhanced glucose-dependent insulin secretion, delayed gastric emptying, and beta-cell preservation. GIPR activation enhances insulin secretion, improves adipose tissue insulin sensitivity, and may potentiate central satiety signaling through complementary hypothalamic pathways. Glucagon receptor activation — the novel third component, promotes hepatic glycogenolysis and gluconeogenesis (counterbalanced by the insulin-promoting effects of GLP-1 and GIP), increases hepatic fat oxidation, stimulates energy expenditure through thermogenesis (both in brown and beige adipose tissue), and reduces hepatic lipid accumulation. The glucagon component is believed to be the key driver of retatrutide's superior efficacy over dual agonists, providing an increase in resting energy expenditure that accelerates fat loss beyond appetite suppression alone. The molecule incorporates a fatty acid modification enabling albumin binding for extended half-life and once-weekly dosing. The balanced multi-receptor activation produces combined metabolic effects greater than the sum of individual receptor activation.
Research Benefits
Retatrutide at a Glance
Retatrutide activates three distinct G-protein coupled receptors in a balanced manner: GLP-1R (glucagon-like peptide-1 receptor), GIPR (glucose-dependent insulinotropic polypeptide receptor), and GCGR (glucagon receptor).
Record-Breaking Weight Loss
Moderate EvidencePhase II trial demonstrated 24.2% mean body weight reduction at the highest dose (12 mg) over 48 weeks; the largest weight loss ever reported for a pharmacological agent. Over 25% of participants lost ≥30% body weight.
Triple Receptor Mechanism
Moderate EvidenceFirst-in-class triple agonist (GIP/GLP-1/glucagon) providing additive metabolic benefits: appetite suppression (GLP-1), insulin sensitization (GIP), and increased energy expenditure (glucagon).
Liver Fat Reduction (MASH/NASH)
Moderate EvidencePhase II data showed up to 86-90% of patients achieved resolution of hepatic steatosis, with dramatic reductions in liver fat content. A potential breakthrough for MASH/NASH treatment.
Increased Energy Expenditure
Moderate EvidenceThe glucagon receptor component stimulates thermogenesis and fat oxidation, increasing resting energy expenditure — a mechanism not present in GLP-1-only or dual GIP/GLP-1 agonists.
Glycemic Control
Moderate EvidencePhase II diabetes data showed HbA1c reductions comparable to or exceeding tirzepatide, with the majority of participants achieving normoglycemia.
Cardiovascular Risk Factor Improvement
PreliminarySignificant improvements in blood pressure, triglycerides, and other cardiometabolic risk markers observed in Phase II, likely driven by both weight loss and direct metabolic effects.
Research Dosing Protocols
Research Purposes Only: All content is for informational and research purposes only. This site does not provide medical advice, diagnosis, or treatment. Consult a qualified healthcare professional before using any peptide or supplement.
| Research Protocol | Dose Range | Route |
|---|---|---|
| Starting dose (Phase II protocol) | 500–500 mcg | Subcutaneous injection |
| Dose escalation steps | 1000–8000 mcg | Subcutaneous injection |
| Maximum studied dose | 12000–12000 mcg | Subcutaneous injection |
Frequency
Once weekly
Timing
Any time of day, same day each week
Cycle Length
Ongoing; chronic treatment anticipated (same as tirzepatide/semaglutide)
Research Notes
- 1INVESTIGATIONAL, not yet approved. Phase III trials (TRIUMPH) are ongoing.
- 2Phase II used slow escalation: 0.5 mg → 1 mg → 2 mg → 4 mg → 8 mg → 12 mg over months.
- 3Gradual dose escalation is essential to manage GI tolerability.
- 4The 12 mg dose produced the most dramatic weight loss (24.2% at 48 weeks).
- 5GI side effects (nausea, diarrhea, vomiting) are the primary tolerability concern.
- 6The glucagon component raises theoretical concerns about hyperglycemia, but GLP-1/GIP co-agonism appears to effectively counterbalance this.
Reconstitution Guide
Standard Reconstitution
Vial Size
5 mg
Bacteriostatic Water
1 mL
Concentration
50 mcg
per 0.1 mL (10 units)
Step-by-Step Guide
Gather Materials
Retatrutide vial, bacteriostatic water, alcohol swabs, insulin syringes.
Equilibrate Temperature
Remove the vial from storage and allow it to reach room temperature (5-10 minutes).
Sanitize
Swab the rubber stopper of both the peptide vial and bacteriostatic water vial with alcohol.
Draw Water
Draw 1 mL of bacteriostatic water into a syringe.
Add Water to Vial
Insert the needle into the peptide vial and direct the water stream against the glass wall — not directly onto the powder.
Mix Gently
Swirl the vial gently until the powder is fully dissolved. Never shake. The solution should be clear and colorless.
Store Properly
Refrigerate at Refrigerated (2-8°C / 36-46°F). Per manufacturer/clinical protocol — investigational product.
Storage Temperature
Refrigerated (2-8°C / 36-46°F)
Shelf Life
Per manufacturer/clinical protocol — investigational product
Important Notes
- •Retatrutide is an investigational drug available only through clinical trials or compounding.
- •The approved pharmaceutical form (if/when approved) will likely be a pre-filled pen injector.
- •Compounded versions may require reconstitution from lyophilized powder with bacteriostatic water.
- •Handle with standard peptide precautions, refrigerate, protect from light.
Retatrutide Dosing Calculator
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Retatrutide Reconstitution Calculator
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Safety & Side Effects
Reported Side Effects
- !Nausea (most common, 16-45% depending on dose; usually transient with escalation)
- !Diarrhea (15-36%)
- !Vomiting (8-23%)
- !Decreased appetite (expected pharmacological effect)
- !Constipation
- !Dyspepsia
- !Injection site reactions
- !Increased heart rate (small, dose-dependent increase)
- !GI adverse events were the primary reason for discontinuation in trials
- !Theoretical risk: thyroid C-cell tumors (class warning for GLP-1 agonists, observed in rodents)
- !Long-term safety data still being collected (Phase III ongoing)
Potential Interactions
- ⚡Expected to slow gastric emptying (like all GLP-1 agonists); may affect oral medication absorption.
- ⚡Risk of hypoglycemia when combined with insulin or sulfonylureas.
- ⚡Not recommended with other GLP-1 or GIP receptor agonists.
- ⚡Oral contraceptive efficacy may be reduced due to delayed gastric emptying.
- ⚡The glucagon component may affect hepatic drug metabolism — interactions not fully characterized.
- ⚡Caution with medications that cause GI side effects (additive risk).
Important: Side effects and interactions listed here are compiled from published research and community reports. This is not a complete list. No formal drug interaction studies have been conducted for most research peptides. Always consult a qualified healthcare provider.
Research Studies
The following studies are referenced in this profile. PubMed IDs are provided where available for independent verification.
Retatrutide once weekly for the treatment of obesity (Phase II)
Landmark Phase II trial demonstrating 24.2% mean weight loss at 12 mg dose over 48 weeks, the highest weight reduction ever reported for a single pharmaceutical agent. >25% of participants lost ≥30% body weight.
Retatrutide for type 2 diabetes (Phase II)
Phase II diabetes trial showing HbA1c reductions of up to 2.02% and weight loss of up to 16.94% at 36 weeks. Over 70% of participants achieved HbA1c <5.7% at the highest dose.
Retatrutide and MASH: liver fat reduction
Showed retatrutide achieved resolution of hepatic steatosis in up to 86-90% of patients with MASH/NASH over 48 weeks, with dramatic reductions in liver fat measured by MRI-PDFF.
GIP/GLP-1/glucagon triple agonism: preclinical rationale
Described the preclinical pharmacology of LY3437943 (retatrutide), demonstrating that triple receptor engagement produces superior metabolic outcomes compared to mono or dual agonism in animal models.
Glucagon receptor agonism and energy expenditure in obesity treatment
Review of the scientific rationale for including glucagon receptor agonism in multi-receptor metabolic drugs, explaining how glucagon increases energy expenditure, promotes fat oxidation, and reduces liver fat.
Note: This is not an exhaustive list of all published research. Studies are selected for relevance and quality. Click PubMed IDs to verify sources independently. Inclusion does not imply endorsement of the peptide for any clinical use.
Frequently Asked Questions
Retatrutide is an investigational triple hormone receptor agonist (GIP/GLP-1/glucagon) being developed by Eli Lilly. It achieved 24.2% weight loss in Phase II trials; the most of any pharmaceutical agent ever studied. Phase III trials are ongoing.
Retatrutide activates three receptors (GIP, GLP-1, glucagon) versus tirzepatide's two (GIP, GLP-1). The added glucagon receptor increases energy expenditure and fat oxidation. Phase II showed 24.2% weight loss for retatrutide vs 22.5% for tirzepatide, though direct head-to-head data is needed.
No. As of 2025, retatrutide is investigational and has only completed Phase II trials. Phase III trials (TRIUMPH program) are underway for obesity and type 2 diabetes. Approval, if granted, is not expected before 2026-2027.
Glucagon can raise blood sugar, but in retatrutide, this effect is effectively counterbalanced by the GLP-1 and GIP components which promote insulin secretion. Phase II data showed excellent glycemic control, with most patients achieving normoglycemia.
GI side effects are the primary concern, nausea, diarrhea, and vomiting, similar to other incretin-based therapies. These are typically worst during dose escalation and improve with continued treatment. Slow titration helps manage tolerability.
Phase II data showed notable results — up to 86-90% of patients with MASH/NASH achieved resolution of liver steatosis. The glucagon receptor component drives hepatic fat oxidation, making retatrutide particularly potent against fatty liver. Dedicated MASH trials are ongoing.
Research & Educational Use Only
All content is for informational and research purposes only. This site does not provide medical advice, diagnosis, or treatment. Consult a qualified healthcare professional before using any peptide or supplement.
The information presented here is compiled from published research studies and is intended for informational purposes only. Individual results may vary. Always consult with a licensed healthcare provider.