Last updated: March 25, 2026
Retatrutide (LY3437943) produced an average 24.2% body weight loss at 48 weeks in the landmark Phase 2 trial published in the New England Journal of Medicine — the highest weight loss recorded for any anti-obesity drug in a clinical trial to date. It works by simultaneously activating three metabolic receptors: GLP-1, GIP, and glucagon.
Mechanism of Action
Retatrutide (LY3437943) simultaneously activates three metabolic receptors — a combination no approved drug achieves. Here's what each target does.
Controls appetite, slows gastric emptying, and enhances insulin secretion in response to meals. This is the same target as semaglutide (Ozempic/Wegovy) — a proven weight-loss mechanism in hundreds of thousands of patients.
Boosts insulin sensitivity and enhances fat metabolism. This is the same second target added by tirzepatide (Mounjaro/Zepbound), which is responsible for its superior efficacy over earlier GLP-1-only drugs.
The breakthrough third target. Activating glucagon receptors increases energy expenditure, promotes direct fat burning, and enhances hepatic (liver) metabolism. Only retatrutide hits this target — and it may explain the superior weight loss numbers.
Phase 2 Trial Data
Average percent body weight lost across all dose groups, measured at 24 and 48 weeks. Bars animate when you scroll to this section.
48-Week Outcomes
Percentage of participants achieving meaningful weight loss thresholds at 48 weeks. The higher the dose, the more consistent the results.
Competitive Landscape
Retatrutide vs the two leading approved GLP-1 medications. These are cross-trial estimates — see the note below.
Safety Profile
Reported adverse events for the 12mg dose group. Rates are consistent with the broader GLP-1 drug class — mostly GI-related and dose-dependent.
Starting at 2mg and slowly titrating up to higher doses significantly reduced GI side effects compared to starting directly at 4mg. Slow escalation is the standard protocol in clinical practice for all GLP-1-class drugs.
Most GI side effects were mild to moderate in severity and resolved over time. The discontinuation rate due to adverse events was low and consistent with other drugs in this class. No new serious safety signals were identified in the 48-week trial period.
All side effect percentages shown here are for the highest-dose group (12mg) where GI effects are most pronounced. Lower doses (4mg, 8mg) showed meaningfully lower rates of nausea and vomiting while still delivering strong efficacy.
Study Metadata
All data on this page is sourced from the Phase 2 NEJM publication. Full citation below.
Retatrutide (LY3437943) for Obesity — Full Study Record
Phase 3 Update — December 2025
The Phase 2 NEJM data was already historic. Then Phase 3 reported — and retatrutide may be setting records that won't be broken for a long time.
Placebo-adjusted weight loss hit 26.6%. The trial enrolled people with obesity plus knee osteoarthritis — a harder-to-treat population than the typical obesity trial. These may be the highest weight-loss numbers ever reported in a late-stage pharmaceutical trial for any indication.
The Phase 3 trial specifically enrolled patients with both obesity and knee osteoarthritis. In addition to exceptional weight loss, participants reported a 75% reduction in knee pain — a result driven both by reduced joint loading and direct anti-inflammatory effects.
This positions retatrutide as potentially relevant well beyond obesity — it could become a treatment of choice for the large overlap population with obesity-driven osteoarthritis.
A liver-focused substudy within the Phase 2 program examined retatrutide's effects on liver fat and cardiometabolic markers. The glucagon component is believed to drive direct hepatic fat oxidation — and the results reflect this.
Placebo comparison for liver fat: the placebo group saw a 0.3% increase in liver fat over the same period — making the contrast even more striking.
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Bottom Line
Separating confirmed Phase 2 findings from what still needs to be established in Phase 3 trials.
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Based on the retatrutide Phase 2 trial (NEJM 2023, NCT04881760, n=338) at the highest dose (12 mg/week). Lower doses produce proportionally smaller effects. Individual results vary significantly.
Retatrutide simultaneously activates GIP, GLP-1, and glucagon receptors — a triple mechanism that distinguishes it from semaglutide (GLP-1 only) and tirzepatide (GIP + GLP-1). GLP-1 activity suppresses appetite, GIP enhances the GLP-1 response, and glucagon receptor activation increases energy expenditure and thermogenesis. Phase 2 participants experienced strong early satiety signals within days. Nausea and GI discomfort are common early on due to accelerated dose escalation in the trial protocol.
The glucagon receptor component of retatrutide drives higher energy expenditure compared to GLP-1-only drugs — participants burn more calories even at rest. Phase 2 data shows early weight loss trajectories steeper than observed with semaglutide or tirzepatide at equivalent timepoints. Food intake reduction is profound, with many participants describing dramatic changes in hunger and portion size within the first month.
By week 12–24, retatrutide participants in the Phase 2 trial showed approximately 12–17% body weight loss (12 mg group), outpacing semaglutide at the same timepoints. Fasting insulin, triglycerides, and waist circumference all improve significantly. Lean mass preservation is a key differentiator — glucagon receptor agonism promotes fat oxidation while sparing muscle. GI side effects become less frequent as the dose stabilizes.
The Phase 2 trial showed 24.2% average body weight loss at 48 weeks in the highest-dose group (12 mg) — a result unprecedented in clinical trials for a pharmacological agent at that time. All dose groups showed statistically significant improvements in waist circumference, systolic blood pressure, fasting glucose, and lipid panels. Visceral (abdominal) fat — the metabolically dangerous type — showed particularly strong reductions. Phase 3 trials (TRIUMPH program) are ongoing to confirm these results in larger populations.
Disclaimer: This page is for educational and informational purposes only. It is not medical advice. Retatrutide is an investigational drug not yet approved by the FDA for any indication. Always consult with a qualified healthcare provider before starting any medication or treatment protocol. Data sourced from published peer-reviewed research (NEJM 2023, NCT04881760).