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TRIUMPH-4 (Retatrutide) - 28.7% Weight Loss Study design: 445 adults with obesity and knee osteoarthritis 68 weeks duration Published December 2025 Results at 12mg: Average weight loss: 28.7% (32.3 kg / 71.2 lbs) 20% responders: 73.4% 25% responders: 58.6% SURMOUNT-1 (Tirzepatide) - 22.5% Weight Loss Study design: 2,539 adults with obesity 72 weeks duration Published June 2022 Results at 15mg: Average weight loss: 22.5% (24 kg / 52 lbs) 20% responders: 57% 25% responders: 43% STEP 1 (Semaglutide) - 14.9% Weight Loss Study design: 1,961 adults with obesity 68 weeks duration Published March 2021 Results at 2.4mg: Average weight loss: 14.9% (15.3 kg / 33.7 lbs) 20% responders: 32% 25% responders: 12% Head-to-Head Comparison Key findings: Retatrutide vs Semaglutide: 93% more weight loss (28.7% vs 14.9%) Tirzepatide vs Semaglutide: 51% more weight loss (22.5% vs 14.9%) Retatrutide vs Tirzepatide: 28% more weight loss (28.7% vs 22.5%) Practical example for 100kg (220 lb) person: Semaglutide: 14.9 kg loss (33 lbs) 85.1 kg (188 lbs) Tirzepatide: 22.5 kg loss (50 lbs) 77.5 kg (171 lbs) Retatrutide: 28.7 kg loss (63 lbs) 71.3 kg (157 lbs) Mechanism of Action: Single vs Dual vs Triple Semaglutide: Single Agonist (GLP-1 Only) Targets one receptor: GLP-1: Reduces appetite, slows digestion, enhances insulin Brands: Ozempic (diabetes, 1mg weekly) Wegovy (weight loss, 2.4mg weekly) Effectiveness: 14.9% average weight loss Tirzepatide: Dual Agonist (GLP-1 + GIP) Targets two receptors: GLP-1: Appetite suppression GIP: Insulin sensitivity, metabolic improvement Brands: Mounjaro (diabetes, up to 15mg) Zepbound (weight loss, up to 15mg) Effectiveness: 22.5% average weight loss51% better than Semaglutide Retatrutide: Triple Agonist (GLP-1 + GIP + Glucagon) Targets three receptors: GLP-1: Appetite control GIP: Metabolic efficiency Glucagon: Energy expenditure, fat burning Status: Investigational (not yet FDA-approved) Effectiveness: 28.7% average weight loss93% better than Semaglutide Mechanism Comparison Table Why more targets = more weight loss: 1 target (Sema): Reduces calories in 15% weight loss 2 targets (Tirz): Reduces calories in + improves metabolism 22.5% weight loss 3 targets (Reta): Reduces calories in + improves metabolism + increases calories out 28.7% weight loss Safety and Side Effects Comparison Common Side Effects Key findings: Tirzepatide has the best tolerability profile: Lowest nausea (31% vs 43-44%) Lowest discontinuation among newer drugs (6.2%) Better GI side effects than either Retatrutide or Semaglutide Semaglutide has lowest discontinuation overall: Only 6.9% discontinued (best retention) Five years of real-world safety data Retatrutide has highest discontinuation: 18.2% discontinued (likely due to glucagon component) Limited safety data (investigational) Dosing Schedules Semaglutide (Wegovy): Week 1-4: 0.25mg Week 5-8: 0.5mg Week 9-12: 1mg Week 13-16: 1.7mg Week 17+: 2.4mg Tirzepatide (Zepbound): Week 1-4: 2.5mg Week 5-8: 5mg Week 9-12: 10mg Week 13+: 15mg Retatrutide (expected): Week 1-4: 2mg Week 5-8: 4mg Week 9-12: 6mg Week 13-16: 9mg Week 17+: 12mg (confirmed from TRIUMPH-4 Phase 3 protocol, Lilly press release December 2025) FDA Approval Status and Availability Semaglutide: First to Market (2021) FDA approval: 2017: Ozempic approved for diabetes June 2021: Wegovy approved for weight loss 5 years market experience Current availability: Available by prescription nationwide Cost: ~$1,349/month without insurance Tirzepatide: Newest Approved Option (2023) FDA approval: May 2022: Mounjaro approved for diabetes November 2023: Zepbound approved for weight loss 3 years market experience Current availability: Available by prescription nationwide Cost: ~$1,060/month without insurance Retatrutide: Investigational (2027-2028) Current status: Not FDA-approved (all four core Phase 3 trials now complete) Not available for prescription Access limited to clinical trial participants Expected timeline: Q1 2027: BLA filing expected (Biologics License Application, not NDA retatrutide is a biologic) ~2 months after filing: FDA accepts BLA, review clock starts Q3 2027 to Q1Q2 2028: Possible approval (priority review vs

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