Executive Summary: Retatrutide Clinical Profile

Key Findings

Retatrutide (LY3437943), Eli Lilly's investigational triple incretin receptor agonist, demonstrates unprecedented efficacy for obesity management with weight loss approaching bariatric surgery levels (24.2% at highest dose). Phase 2 clinical trials show remarkable metabolic benefits with a manageable but significant side effect profile. Phase 3 trials are ongoing with results expected throughout 2025.

Mechanism & Differentiation

• Triple-receptor targeting: Simultaneously activates GLP-1, GIP, and glucagon receptors
• Unique value proposition: Combines appetite suppression (GLP-1) with enhanced insulin function (GIP) and increased energy expenditure (glucagon)
• Pharmacokinetics: 120-hour half-life enabling once-weekly subcutaneous administration
• Superiority margin: Approximately 3-4% greater weight loss than tirzepatide (dual agonist) and 9-10% greater than semaglutide (GLP-1 agonist)

Efficacy Profile (48-week data)

• Weight reduction: Dose-dependent response from 8.7% (1 mg) to 24.2% (12 mg)
• High-threshold responders: 83% achieved ≥15% weight loss; 26% achieved ≥30% weight loss at 12 mg
• Glycemic benefits: 72% of prediabetic subjects normalized glucose; 2.02% HbA1c reduction in diabetic cohort
• Liver effects: 82.4% reduction in liver fat content at 12 mg; 86% normalized liver fat (<5%)
• Cardiometabolic improvements: BP reduction (-8.4/-4.2 mmHg); triglycerides (-27.6%); LDL (-13.8%)

Safety & Tolerability

• Gastrointestinal events: Dose-dependent incidence of nausea (58.2%), vomiting (45.5%), diarrhea (36.4%) at 12 mg
• Discontinuation rate: 14.5% at 12 mg versus 3.6% for placebo
• Cardiovascular effects: Increased heart rate (8-10 BPM) despite blood pressure reduction
• Safety signals: Low incidence of transient liver enzyme elevations (1%), gallbladder events (1.8%)
• Serious adverse events: Similar between retatrutide (4-6%) and placebo (4%)