Retatrutide

1. What It Does

Retatrutide (LY3437943) is an investigational peptide developed by Eli Lilly, designed as a unimolecular triagonist that simultaneously activates three metabolic hormone receptors:

• GLP-1 (Glucagon-Like Peptide-1) Receptor: Enhances insulin secretion, suppresses appetite, and slows gastric emptying.

• GIP (Glucose-Dependent Insulinotropic Polypeptide) Receptor: Amplifies insulin release in response to glucose intake and improves nutrient metabolism.

• Glucagon Receptor: Increases energy expenditure, promotes fat metabolism, and enhances hepatic glucose production while preventing hypoglycemia.

This novel molecular design approach allows a single peptide to target multiple pathways involved in energy homeostasis and metabolism. By simultaneously activating these receptors in a balanced manner, Retatrutide aims to provide a multifaceted approach to weight management and metabolic regulation that may exceed the efficacy of single or dual agonists.

2. Main Reported Benefits

• Significant Weight Loss: In a 48-week phase 2 clinical trial (TRIUMPH), participants receiving Retatrutide experienced up to a 24% reduction in body weight (mean weight loss of 17.5% at the 12 mg dose), outperforming other weight-loss medications like semaglutide (Wegovy, ~15%) and tirzepatide (Mounjaro/Zepbound, ~20%). At the highest dose (12 mg), 100% of participants lost at least 5% of their body weight, and 96% lost at least 10%.

• Improved Glycemic Control: Retatrutide has demonstrated clinically meaningful improvements in glycemic control, including reductions in HbA1c levels of up to 2.2 percentage points in individuals with type 2 diabetes.

• Enhanced Metabolic Health: The drug has been associated with reductions in liver fat (up to 70% decrease) and improvements in lipid profiles, contributing to overall metabolic health. This includes decreases in triglycerides, LDL cholesterol, and improvements in HDL cholesterol.

• Potential Cardiovascular Benefits: Early data suggest that Retatrutide may reduce cardiovascular risk factors through improvements in blood pressure, body weight, glycemic control, and lipid profiles, though further research is needed to confirm these effects.

3. Normal Applications

Retatrutide is currently in Phase 3 clinical trials and under investigation for the following applications:

• Obesity Management: Targeting individuals with obesity (BMI ≥30) or overweight conditions (BMI ≥27 with at least one weight-related comorbidity), aiming to achieve substantial and sustained weight loss.

• Type 2 Diabetes Treatment: As an adjunct therapy to diet and exercise to improve glycemic control in patients with type 2 diabetes, with the added benefit of significant weight reduction.

• Metabolic Syndrome and NAFLD/NASH: Potential use in managing metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) due to its effects on weight and liver fat reduction.

• Cardiovascular Risk Reduction: Being studied for potential cardiovascular risk reduction in patients with established cardiovascular disease or multiple cardiovascular risk factors.

4. Common Side Effects

Clinical trials have reported the following side effects associated with Retatrutide:

• Gastrointestinal Issues: Nausea (reported in up to 51% of participants), vomiting (up to 32%), diarrhea (up to 39%), and constipation are the most frequently reported side effects, often occurring during the initial stages of treatment and diminishing with continued use. These effects are dose-dependent and typically manageable with gradual dose escalation.

• Increased Heart Rate: Some participants experienced dose-dependent increases in heart rate (mean increase of 5-10 beats per minute), which peaked around 24 weeks and then declined.

• Cardiac Arrhythmias: Rare cases of cardiac arrhythmias, including supraventricular arrhythmias and prolonged QT syndrome, have been observed. Patients with pre-existing cardiovascular conditions require additional monitoring.

• Fatigue: Some participants reported increased tiredness, particularly during the dose escalation period.

It’s important to note that most side effects were mild to moderate in severity and tended to diminish over time as patients continued treatment.

5. Recommended Administration or Dosage

Retatrutide is administered via subcutaneous injection, with dosing regimens varying based on individual response and tolerability. In clinical trials, dosing strategies included:

• Initial Dose: Starting at 2 mg once weekly.

• Dose Escalation: Gradual increases every 4 weeks to reach target doses of 4 mg, 8 mg, or 12 mg, depending on patient response and side effect profile.

• Administration Site: Typically injected into the abdomen, thigh, or upper arm, with rotation of injection sites recommended.

Current Status and Timeline:

• Retatrutide is currently in Phase 3 clinical trials (as of April 2025)

• FDA approval could potentially come in late 2025 or 2026, pending successful trial completion

• Eli Lilly is investigating both obesity and diabetes indications separately

As Retatrutide is still under investigation, specific dosing recommendations for intramuscular administration in humans are not established. All administration should be conducted under the supervision of healthcare professionals within clinical trial settings.

Disclaimer: Retatrutide is an investigational drug currently undergoing clinical trials. It is not approved for general clinical use, and its safety and efficacy profiles are still being evaluated. Any consideration of its use should be confined to controlled clinical trials under the guidance of qualified healthcare professionals.