INDICATIONS FOR USE

Retatrutide is an investigational multi-agonist peptide currently in advanced clinical trials for obesity management, metabolic disease, and insulin resistance. Although not yet FDA approved, it has demonstrated unprecedented levels of weight reduction and metabolic improvement in human studies. Early evidence suggests potential future applications in type 2 diabetes mellitus and cardiometabolic risk reduction.

EVIDENCE RATING

✦✦ : Strong human clinical trial data with robust efficacy signals, but not yet FDA approved.

ROUTE OF ADMINISTRATION

• Subcutaneous injection

COMMON INITIAL DOSING REGIMENS

• Standard clinical trial dosing: 1 mg weekly for 4 weeks, then increase to 4 mg weekly for 4 weeks, then titrate to 8 mg, 12 mg, or 16 mg weekly depending on tolerability and clinical response.

• NOTE: These dose levels reflect clinical trial protocols, not individualized practice. Retatrutide is highly potent, and many patients experience significant effects at doses far lower than those used in trials. We strongly believe that smaller, more frequent dosing (micro-titration) improves tolerability and overall outcomes. Each regimen is personalized based on patient sensitivity, gastrointestinal tolerance, and rate of weight reduction.

MECHANISM OF ACTION

• Retatrutide is a triple agonist that simultaneously activates the receptors for GLP-1, GIP, and glucagon. This combined activity results in a unique metabolic profile:

• GLP-1 and GIP agonism enhances insulin secretion, reduces glucagon levels during hyperglycemia, slows gastric emptying, and suppresses appetite through central satiety pathways.

• Glucagon receptor agonism increases resting energy expenditure and promotes enhanced fat oxidation. When combined with incretin activity, glucagon signaling may help preserve or improve lean mass while accelerating fat loss.

• The synergy of activating all three pathways has been associated with greater weight reduction than any single or dual agonist therapy to date.

COMMON SIDE EFFECTS

• Gastrointestinal: Nausea, vomiting, diarrhea, constipation, and abdominal bloating. These effects are dose-dependent and most prominent during rapid dose escalation.

• Metabolic: Transient increases in heart rate have been reported, along with mild elevations in liver enzymes at higher doses. Hypoglycemia is uncommon unless combined with insulin or sulfonylureas.

• Injection Site: Mild erythema, swelling, or tenderness at the injection site.

• Severe Effects: Rare events include pancreatitis and gallbladder disease. In trials, transient increases in hepatic markers and resting heart rate have been observed; monitoring is advised during dose escalation.

CONTRAINDICATIONS

• Absolute: Personal or family history of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia syndrome type 2 (MEN 2), or hypersensitivity to retatrutide or its peptide excipients.

• Relative: Significant gastrointestinal motility disorders, a history of pancreatitis, moderate to severe hepatic impairment, or active gallbladder disease. Caution is advised in patients with underlying cardiac arrhythmias due to small but consistent increases in resting heart rate observed in trials.

NOTES ON EFFICACY / COMPOUNDING

• Retatrutide has produced the greatest weight-loss outcomes ever recorded in clinical trials. In phase 2 data, patients receiving the highest tolerated dose lost approximately 24% of their body weight at 48 weeks, with projected weight loss at 72 weeks exceeding 30% in many individuals. These results surpass all existing GLP-1–based therapies, including semaglutide and tirzepatide.