Accelerating Use of Unapproved Retatrutide Is Associated with Weaker Weight Loss and Increased Cardiovascular Symptoms

Retatrutide use outside of clinical trials is associated with less than half the weight loss seen in trials and significant cardiovascular symptom burden.

Summary and findings

This study measured the weight loss and cardiovascular symptoms associated with retatrutide use in a real-world setting. In 652 patients confirmed to have exposure to retatrutide, the observed weight loss was 7.2% at 6-12 months for those using compounded retatrutide, compared to 15.5% in trial participants. The study highlights the differences in outcomes between trial and non-trial settings.

Abstract

Retatrutide, an investigational GIP/GLP-1/glucagon receptor agonist delivered up to 28.3% mean weight reduction in the Phase 3 TRIUMPH programs, but it has not yet received FDA approval. Using a federated U.S. EHR network of 29 million patients, we identified rapidly increasing use of non-trial products purported to contain retatrutide. LLM-aided adjudication of de-identified EHRs shows 983 patients whose clinical notes mention retatrutide, with confirmed exposure in 652 patients (66.3%), and documented supply route tracing in 531 patients (54%). Of these 531 users, 378 (71.2%) obtained purported retatrutide outside of trial participation, mostly through online or telehealth vendors (57.4%) and compounding pharmacies (29.4%). Retatrutide usage grew 1.8-fold per quarter from October 2023 through March 2026, reaching 137 new users from October–December 2025, and 228 new users from January-March 2026. Next, we conducted an analysis anchored on the retatrutide/placebo trial participants (n=89), who were nearest-neighbor matched 1:3:10:10 with compounded retatrutide (n=243), semaglutide (n=890), and tirzepatide (n=890) initiators, with matching covariates of age, race, sex, baseline BMI, diabetes status, prior incretin therapy exposure, and time since the most recent exposure. The observed weight loss among retatrutide trial participants in this routine care setting was 15.5% at 6–12 months, closely approaching the observed 16.9% mean weight loss across the retatrutide and placebo arms at 80 weeks after treatment initiation in TRIUMPH-1-4 (weighted average). Users of compounded retatrutide lost 7.2% body weight at 6-12 months, considerably less than the 15.5% observed in the retatrutide trial cohort (P=0.004) and comparable to the weight-loss achieved among matched tirzepatide users (7.7%; P=0.79). A significant increase in heart-rate was observed at 3 months for both the retatrutide trial cohort (+4.3 beats per minute [bpm], P=0.028) and the compounded retatrutide cohort (+2.5 bpm, P=0.011), which was not observed in the matched semaglutide or tirzepatide cohorts (P>0.9). The retatrutide trial cohort showed numerically higher, but not statistically significant, rates of 3-point MACE versus matched tirzepatide users (RR 1.77, 95% CI 0.19–7.94; P=0.34) and semaglutide users (RR 1.02, 95% CI 0.12–4.17; P=1.00), with similar findings for expanded MACE versus tirzepatide (RR 2.03, 95% CI 0.38–7.09; P=0.21) and semaglutide (RR 1.25, 95% CI 0.24–4.07; P=0.73). Furthermore, new-onset symptom burden was significantly elevated for the pooled retatrutide cohort (trial and compounded users combined) compared to both semaglutide and tirzepatide comparators, including higher-risk of cardiovascular symptoms (RR 1.56 [1.26-1.92], q<0.001) and neuropsychiatric symptoms (RR 1.95 [1.61-2.36], q<0.001). Taken together, accelerating gray-market retatrutide use is associated with less than half the trial-level weight loss while retaining retatrutide’s characteristic heart-rate rise and elevated cardiovascular symptom burden, underscoring the need for heightened clinical awareness and real-time real-world evidence to identify emerging risks before regulatory approval.

Elsewhere in the Retatrutide (LY3437943) corpus