Retatrutide (LY3437943)
LY3437943
Retatrutide (LY3437943) is an investigational triple agonist for the GIP, GLP-1, and glucagon receptors developed by Eli Lilly. Phase 2 trials showed up to 24.2% mean weight loss at 48 weeks (DOI: 10.1056/NEJMoa2301972) and Phase 3 topline results reported up to 28.7% at 68 weeks, positioning it as a potentially next-generation treatment for obesity and related metabolic conditions. Not FDA-approved as of March 2026.
Last updated: 2026-03-12
Safety Summary
Most adverse effects are gastrointestinal, dose-dependent, and concentrated during initial dose-titration; they generally improve with continued use. Discontinuation rates due to AEs in Phase 3 TRIUMPH-4: 12.2% (9 mg), 18.2% (12 mg), 4.0% (placebo). Dysesthesia is a novel signal at higher doses requiring ongoing monitoring -- more frequent in Phase 3 data (~20.9% at 12 mg) than initially suggested by Phase 2 data. Heart rate increases typically peak around 24 weeks then decline. No excess major adverse cardiac events in Phase 2. Rodent C-cell thyroid tumors observed in class-wide nonclinical studies (GLP-1/GIP agonists) -- limited human relevance but a recognized nonclinical signal. Post-discontinuation weight regain is anticipated based on GLP-1RA class data but not yet directly documented for retatrutide, DOI:10.1056/NEJMoa2301972.
Known Side Effects
Very common -- up to ~45.8% at higher doses
Common -- up to ~33.3% at higher doses
Common -- up to ~16.7% at higher doses
Common, dose-dependent
Common -- modest dose-dependent increase of ~5-10 bpm, peaking around 24 weeks
Reported at ~20.9% incidence in the 12 mg group at longer follow-up (Phase 3 TRIUMPH-4)
Infrequent
Occasional, transient
Rare
Reported in community/early phase, dose-related
Reported during escalation
Who Should NOT Use This
GLP-1 receptor agonist class contraindication based on rodent C-cell tumor findings
Clinical trials excluded pregnant/breastfeeding women. Labeling advises avoidance; contraception recommended for women of childbearing potential.
Potential risk of pancreatitis with this class of drugs.
Retatrutide delays gastric emptying, which could exacerbate pre-existing severe GI conditions.
Pharmacodynamic additive effects increase hypoglycemia risk. Dose reduction and close monitoring required.
Baseline hypoglycemia conditions warrant avoidance or careful evaluation.
Retatrutide slows gastric emptying and can alter oral drug absorption. Affected drugs include oral contraceptives, levothyroxine, some oral anticoagulants.
Not well characterized in trials. Trials showed renal improvements but monitoring advised.
Safety and efficacy not established in pediatric populations.
Talk to Your Doctor
Before considering Retatrutide (LY3437943), discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-10]
Evidence Assessment
Retatrutide has completed Phase 2 trials with peer-reviewed publications in high-impact journals (NEJM, Lancet, Nature Medicine) and has Phase 3 TRIUMPH program results reported (TRIUMPH-4 topline results Dec 2025 showing 28.7% weight loss at 68 weeks). Multiple Phase 3 trials are active/completed across indications. Not yet FDA-approved. Evidence tier 2 is appropriate for late-stage Phase 3 with substantial human data but pre-approval, DOI:10.1056/NEJMoa2301972.
1Triple--Hormone-Receptor Agonist Retatrutide for Obesity -- A Phase 2 TrialNCT04881760PMID 37366313
Jastreboff AM, Kaplan LM, FrÃas JP, et al. - New England Journal of Medicine (2023) - Phase 2, randomized, double-blind, placebo-controlled - 338
Dose-dependent weight loss: 48-week results -- 1 mg: -8.7%, 4 mg: -17.1%, 8 mg: -22.8%, 12 mg: -24.2% (placebo: -2.1%). GI AEs common but mostly mild-moderate.
Limitations: Industry-sponsored (Eli Lilly), Phase 2 sample size, limited diversity, 95% CIs not reported in text.
2Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trialNCT04867785PMID 37385280
Rosenstock J, Urva S, Coskun T, et al. - The Lancet (2023) - Phase 2, randomized, double-blind, placebo and active-controlled - 281
At 24 weeks, mean HbA1c change: -2.02% with 12 mg vs -0.01% with placebo. Weight loss up to 16.94% at 36 weeks in T2DM population.
Limitations: Industry-sponsored, US-only, relatively short duration.
3Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial
Hartman ML, Sanyal AJ, Loomba R, et al. - Nature Medicine (2024) - Phase 2a, randomized, double-blind, placebo-controlled - 98
Mean relative change in liver fat at 24 weeks: 12 mg: -82.4% (placebo: +0.3%). Liver fat normalization (<5%): 12 mg: 86% (placebo: 0%).
Limitations: Short duration (24 weeks), surrogate marker primary endpoint, industry-sponsored.
4TRIUMPH-4: Retatrutide Phase 3 trial in obesity with knee osteoarthritisNCT05931367
Eli Lilly and Company - Sponsor press release (Dec 11, 2025) (2025) - Phase 3, randomized, double-blind, placebo-controlled - 445
68-week weight loss: 9 mg: -26.4%, 12 mg: -28.7%, placebo: -2.1%. WOMAC pain: 9 mg: -75.8%, 12 mg: -74.3%, placebo: -40.3%. Dysesthesia more frequent in active arms.
Limitations: Topline press release -- not yet peer-reviewed. 95% CIs not provided.
5Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide
Li et al. - Cell Discovery (2024) - Structural/functional pharmacology
Confirmed triple agonism via cryo-EM. Comparative functional potency: ~8.9Ã- vs GIP at GIPR, ~0.3Ã- vs glucagon at GCGR, ~0.4Ã- vs GLP-1 at GLP-1R.
Limitations: In vitro structural/functional study -- not clinical outcomes data.
6LY3437943: From discovery to clinical proof of concept
- Cell Metabolism (2022) - Clinical and translational report -- discovery to Phase 1
Discovery and preclinical characterization through to clinical proof of concept.
Limitations: Early-phase discovery/PoC data.
7Efficacy and safety of retatrutide: a systematic review and meta-analysis of RCTs
- PMC (systematic review) (2025) - Systematic review and meta-analysis
Pooled analysis confirming dose-dependent weight loss, sustained efficacy, clinically meaningful BP and lipid improvements, predominantly mild-moderate GI AEs.
Limitations: Limited to published trial data at time of review.
8Comparative Efficacy and Safety of Glucagon Receptor Agonists: A Network Meta-Analysis of RCTsPMID 41787737
Abulehia A et al. - Endocrinology, Diabetes & Metabolism (2026) - Network meta-analysis of 14 RCTs
Retatrutide demonstrated greatest weight reduction vs placebo (MD -13.44 kg; 95% CI [-18.38, -8.51]) among glucagon receptor agonists. Largest HbA1c effect.
Limitations: Network meta-analysis (indirect comparisons). Lower tolerability noted for retatrutide.
9Retatrutide--A Game Changer in Obesity Pharmacotherapy
Katsi et al. - Biomolecules (PMC) (2025) - Narrative review
Comprehensive review covering mechanism, clinical efficacy, PK (half-life ~6 days, Tmax ~24-48h), and safety profile.
Limitations: Review article -- synthesizes existing data.
10Effect of retatrutide on kidney parameters
- PMC (2025) - Clinical sub-study / analysis
Reduced UACR, modest eGFR increases with no nephrotoxicity signal.
Limitations: Specific to renal endpoints; severe renal impairment not well characterized.