Retatrutide

Retatrutide is an investigational triple-receptor agonist peptide developed by Eli Lilly that simultaneously activates GLP-1, GIP, and glucagon receptors. This novel mechanism has demonstrated unprecedented weight loss results in clinical trials—up to 24.2% body weight reduction at 48 weeks and 28.7% at 68 weeks—making it one of the most potent obesity treatments ever studied. Retatrutide has gained significant attention among individuals seeking advanced metabolic support, those with obesity or type 2 diabetes, and biohackers exploring cutting-edge peptide therapies. Typical dosing protocols in clinical trials range from 1 mg to 12 mg administered once weekly via subcutaneous injection, with gradual dose escalation over 12 weeks to minimize side effects. Meaningful weight loss results typically emerge within 24 weeks, with continued improvements through 48 weeks and beyond.

What Is Retatrutide?

Retatrutide (LY3437943) is a single-peptide molecule conjugated to a fatty diacid moiety that functions as a triple agonist, targeting three distinct G-protein–coupled receptors: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon (GCG) receptors. This triple-receptor approach distinguishes retatrutide from existing therapies like semaglutide (single GLP-1 agonist) and tirzepatide (dual GIP/GLP-1 agonist).

What makes retatrutide unique is its receptor potency profile. Compared to endogenous ligands, retatrutide demonstrates approximately 8.9-fold greater potency at the human GIP receptor while being slightly less potent at GLP-1 and glucagon receptors (0.4 and 0.3 times, respectively). The pharmacokinetics support once-weekly dosing, with a half-life of approximately 6 days.

The primary human-use benefits observed in clinical research include:

• Substantial weight reduction (up to 24-29% of body weight)
• Improved glycemic control and HbA1c reduction
• Decreased waist circumference
• Improvements in blood pressure and lipid profiles
• Reversion of prediabetes to normoglycemia in 72% of participants

How It Works

GLP-1 Receptor Activation

The GLP-1 receptor agonism component of retatrutide promotes weight loss through multiple pathways. GLP-1 receptor activation suppresses appetite, enhances satiety, and delays gastric emptying. Additionally, GLP-1 stimulation enhances glucose-dependent insulin secretion, directly improving glycemic control while reducing glucagon release between meals.

GIP Receptor Activation

Glucose-dependent insulinotropic polypeptide (GIP) receptor activation complements GLP-1 effects by further enhancing insulin secretion in response to nutrient intake. The synergistic combination of GIP and GLP-1 agonism has demonstrated superior efficacy compared to GLP-1 alone, as evidenced by tirzepatide's performance versus semaglutide.

Glucagon Receptor Activation

The glucagon receptor component represents retatrutide's distinguishing feature. Glucagon receptor activation increases energy expenditure through thermogenic effects, promotes hepatic lipid oxidation, and may enhance substrate utilization. Research suggests glucagon agonism contributes to reductions in LDL cholesterol (approximately 20%) through effects on PCSK9 degradation.

Synergistic Triple-Receptor Effects

The simultaneous activation of all three receptors creates synergistic metabolic effects: appetite suppression, increased energy expenditure, improved glucose homeostasis, and enhanced fat oxidation occur concurrently. This multi-target approach addresses obesity through complementary mechanisms that single or dual agonists cannot achieve alone.

Dosage Protocols

Clinical trials have established dose-escalation protocols designed to optimize efficacy while minimizing gastrointestinal side effects. The phase 2 obesity trial utilized the following approach:

Starting doses: 2 mg or 4 mg weekly

Escalation schedule: Dose increases every 4 weeks for up to 12 weeks

Maintenance doses studied:

• 1 mg weekly (minimal escalation group)
• 4 mg weekly (moderate dose)
• 8 mg weekly (higher dose)
• 12 mg weekly (maximum studied dose)

Research indicates that initiating treatment with 2 mg rather than 4 mg partially mitigates gastrointestinal adverse events during the escalation phase. The 8 mg and 12 mg doses demonstrated the most substantial weight loss, with 100% of participants achieving at least 5% body weight reduction at 48 weeks.

For research peptide preparations, common reconstitution yields a concentration of 5 mg/mL when adding 2 mL of bacteriostatic water to a 10 mg vial.

How to Use / Administration

Retatrutide is administered via subcutaneous injection once weekly. In clinical trials, participants self-administered injections following standard subcutaneous injection protocols.

Injection sites: Common subcutaneous injection sites include the abdomen (avoiding the navel area), front of thighs, or upper arms. Rotation of injection sites is recommended to prevent lipodystrophy.

Timing: Retatrutide can be administered at any time of day, with or without meals. Consistency in weekly timing is recommended.

Injection technique: Standard subcutaneous injection protocols apply—clean the injection site with alcohol, pinch the skin, insert the needle at a 45-90 degree angle, inject slowly, and apply gentle pressure after withdrawal.

Results Timelines

Clinical trial data provides clear expectations for results timelines:

Week 24 (6 months):

• 12 mg dose: -17.5% body weight
• 8 mg dose: -17.3% body weight
• 4 mg dose: -12.9% body weight

Week 48 (12 months):

• 12 mg dose: -24.2% body weight
• 8 mg dose: -22.8% body weight
• 4 mg dose: -17.1% body weight

Notably, weight loss curves had not plateaued at 48 weeks, suggesting continued benefits with longer treatment duration. Phase 3 trial data at 68 weeks demonstrated up to 28.7% weight loss with the 12 mg dose.

Achievement thresholds at 48 weeks (12 mg dose):

• ≥5% weight loss: 100% of participants
• ≥10% weight loss: 93% of participants
• ≥15% weight loss: 83% of participants
• ≥20% weight loss: 63% of participants
• ≥25% weight loss: 48% of participants
• ≥30% weight loss: 26% of participants

Research Evidence

The clinical evidence base for retatrutide continues to expand through multiple trials:

Phase 2 Obesity Trial (NEJM, 2023): This randomized, double-blind, placebo-controlled trial enrolled 338 adults with obesity. The 12 mg dose produced 24.2% weight loss at 48 weeks, with 100% of participants achieving ≥5% weight reduction.

Phase 2 Type 2 Diabetes Trial (Lancet, 2023): In adults with type 2 diabetes, retatrutide demonstrated clinically meaningful improvements in glycemic control alongside robust weight reductions.

Phase 3 Obesity Trial (2025): Recent phase 3 data showed participants taking retatrutide 12 mg lost an average of 28.7% body weight at 68 weeks, with 23.7% achieving ≥35% weight loss.

Body Composition Analysis (Lancet Diabetes & Endocrinology, 2025): In adults with type 2 diabetes, retatrutide significantly improved total body fat mass reduction compared to placebo and dulaglutide.

Meta-Analysis (2024): A systematic review confirmed retatrutide demonstrated significant improvements in body weight and metabolic outcomes with an appropriate safety profile.

Stacking

Currently, there is limited published research on combining retatrutide with other peptides or compounds. Given its comprehensive triple-receptor mechanism, retatrutide functions as a standalone therapy addressing multiple metabolic pathways simultaneously.

Theoretical considerations for researchers:

• With other GLP-1 agonists: Not recommended due to overlapping mechanisms and increased risk of gastrointestinal adverse events
• With metformin: Clinical trials included participants on stable metformin therapy; combination appeared well-tolerated
• With lifestyle interventions: All clinical trials incorporated dietary counseling and physical activity guidance, which should be considered complementary rather than optional

Reconstitution, Storage & Prep

Lyophilized (powder) form storage:

• Store at -20°C for long-term preservation
• Protect from light
• Stable at 2-8°C (refrigerator) for shorter periods

Reconstitution protocol:

1. Allow the vial to reach room temperature
2. Draw bacteriostatic water using a sterile syringe (typically 2 mL for a 10 mg vial)
3. Inject the diluent slowly down the vial wall to avoid foaming
4. Gently swirl or roll the vial until powder fully dissolves—do not shake vigorously
5. Inspect for complete dissolution and absence of particulates

Reconstituted solution storage:

• Store at 2-8°C (refrigerator)
• Use within 28-30 days of reconstitution
• Protect from light
• Do not freeze reconstituted solution

Side Effects

The safety profile of retatrutide is consistent with other incretin-based therapies, with gastrointestinal events being most common:

Common side effects (dose-dependent):

• Nausea (14-45% depending on dose)
• Diarrhea (9-20%)
• Vomiting (3-26%)
• Constipation (7-16%)
• Decreased appetite (13-31%)
• Fatigue (4-12%)

Less common effects:

• Injection site reactions
• Mild increases in heart rate (dose-dependent, peaking at 24 weeks then declining)
• Cutaneous hyperesthesia (altered skin sensation)
• Transient increases in lipase levels

Serious but rare:

• Acute pancreatitis (1 case in phase 2 trial)
• Hypersensitivity reactions
• Biliary disorders (cholelithiasis, cholecystitis)

Gastrointestinal side effects typically occur during dose escalation, are predominantly mild to moderate, and can be partially mitigated by using lower starting doses (2 mg vs. 4 mg).

Legal Status / FDA

Retatrutide is not currently approved by the FDA or any regulatory agency worldwide. It remains an investigational medication undergoing clinical development by Eli Lilly.

Current development status:

• Multiple Phase 3 trials ongoing
• Phase 3 trial results expected throughout 2025-2026
• NDA submission projected for late 2025 to Q1 2026 (analyst projections)
• Potential FDA approval: Late 2026 to 2027

Research-grade retatrutide is available through peptide suppliers for research purposes. However, these products are not intended for human use and are sold strictly for laboratory research.

Sports / WADA

Retatrutide is not explicitly named on the World Anti-Doping Agency (WADA) Prohibited List as of 2026. However, athletes should exercise extreme caution:

• GLP-1 receptor agonists (including semaglutide) have been on WADA's monitoring list since 2024
• Retatrutide could potentially fall under prohibited categories related to metabolic modulators or peptide hormones
• WADA reserves the right to prohibit substances that enhance performance or pose health risks
• Athletes subject to anti-doping testing should consult with their sports organization before using any investigational compound

Conclusion

Retatrutide represents a significant advancement in peptide-based metabolic therapy, offering a novel triple-receptor mechanism that addresses obesity and metabolic dysfunction through complementary pathways. Clinical trial data demonstrating up to 28.7% weight loss positions retatrutide as potentially the most effective pharmacological obesity treatment studied to date. While awaiting regulatory approval, the compound has generated substantial interest among researchers and individuals seeking advanced metabolic support. As with any investigational compound, thorough understanding of dosing protocols, administration techniques, potential side effects, and legal considerations is essential for informed decision-making.

FAQ

What makes retatrutide different from semaglutide or tirzepatide?
Retatrutide activates three receptors (GLP-1, GIP, and glucagon) compared to semaglutide's single GLP-1 target and tirzepatide's dual GLP-1/GIP mechanism. The addition of glucagon receptor agonism may enhance energy expenditure and fat oxidation, contributing to greater weight loss.

How much weight can I expect to lose with retatrutide?
Phase 2 trials showed 24.2% weight loss at 48 weeks with the 12 mg dose, while phase 3 data demonstrated 28.7% at 68 weeks. Individual results vary based on dose, duration, and adherence to lifestyle modifications.

How long does it take to see results?
Meaningful weight loss typically becomes apparent within 12-24 weeks. At 24 weeks, participants on the 12 mg dose had lost an average of 17.5% body weight, with continued improvements through 48 weeks and beyond.

What are the most common side effects?
Gastrointestinal effects including nausea, diarrhea, vomiting, and constipation are most common. These typically occur during dose escalation, are mild to moderate, and often improve with continued use.

Is retatrutide FDA approved?
No. Retatrutide remains investigational and is not approved by the FDA or any regulatory agency. Phase 3 trials are ongoing, with potential approval projected for 2026-2027.

How is retatrutide administered?
Retatrutide is administered as a once-weekly subcutaneous injection. Clinical trials used dose escalation starting at 2-4 mg weekly, increasing every 4 weeks to maintenance doses of 4-12 mg.

Can retatrutide be used for type 2 diabetes?
Clinical trials have demonstrated significant improvements in glycemic control in participants with type 2 diabetes, including HbA1c reductions and reversion of prediabetes to normoglycemia. However, it is not yet approved for any indication.

How should reconstituted retatrutide be stored?
Reconstituted retatrutide should be refrigerated at 2-8°C, protected from light, and used within 28-30 days. Do not freeze reconstituted solution.

References

1. Jastreboff AM, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389:514-526. https://www.nejm.org/doi/full/10.1056/NEJMoa2301972
2. Rosenstock J, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial. Lancet. 2023;402(10401):529-544. https://pubmed.ncbi.nlm.nih.gov/37385280/
3. Eli Lilly. What to know about retatrutide. https://www.lilly.com/news/stories/what-to-know-about-retatrutide
4. Lilly's triple G agonist boasts 28.7% weight loss in Phase III trial. Clinical Trials Arena. 2025. https://www.clinicaltrialsarena.com/news/lilly-retatrutide-data-phase-iii-trial/
5. Lilly's obesity triple pulls off 29% weight loss in trial. Pharmaphorum. 2025. https://pharmaphorum.com/news/lillys-obesity-triple-pulls-29-weight-loss-trial
6. Effects of retatrutide on body composition in people with type 2 diabetes. Lancet Diabetes Endocrinol. 2025. https://www.thelancet.com/journals/landia/article/PIIS2213-8587%2825%2900092-0/abstract
7. Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist. PMC. 2024. https://pmc.ncbi.nlm.nih.gov/articles/PMC12026077/
8. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatohepatitis. Nature Medicine. 2024. https://www.nature.com/articles/s41591-024-03018-2
9. The power of three: Retatrutide's role in modern obesity management. European Journal of Pharmacology. 2024. https://www.sciencedirect.com/science/article/abs/pii/S0014299924007854
10. Retatrutide for Weight Loss: Availability, Dosage, and More. GoodRx. 2025. https://www.goodrx.com/conditions/weight-loss/retatrutide-weight-loss
11. WADA Prohibited List 2026. World Anti-Doping Agency. https://www.wada-ama.org/en/prohibited-list
12. Retatrutide Injection: Package Insert / Prescribing Information. Drugs.com. https://www.drugs.com/pro/retatrutide-injection.html