Patients who use gray-market retatrutide seemed to achieve roughly half the expected weight-loss benefit relative to Eli Lilly’s clinical trials of the drug, while still experiencing high rates of cardiovascular effects, researchers reported in a preprint study.

At this time, retatrutide isn’t approved by the FDA and is in phase 3 clinical trials. The company has announced plans to submit for drug approval in first quarter 2027. However, demand for the triple-agonist has surged.

This demand largely driven by social media, in peptide forums and in press reports has created a gray market, said Venky Soundararajan, PhD, founder and chief scientific officer, nference, Cambridge, Massachusetts.

“Anecdotes can tell you people are buying the drug; they cannot tell you how many, whether they are actually taking it, or what happens to them clinically,” he told Medscape Medical News. “We wanted to know whether the clinical record could answer those questions for a drug with no prescription trail.”

Their findings were “both surprising and concerning,” he said, “calling for more systemic and holistic evaluation of unapproved peptide therapies.”

Lilly also continues to state its concern about the unregulated version. “The FDA has made clear that sales of unapproved retatrutide to consumers are illegal, yet black-market sellers openly sell what they claim to be retatrutide as a weight-loss ‘hack’ when in reality they are selling illegal drugs,” a company spokesperson told Medscape Medical News. “Patients have reported serious harms after taking black-market retatrutide they purchased online, including hospitalizations.”

‘Real-Time, Real-World Evidence’

Unlike most retrospective observational studies, which start from a prescription or pharmacy claim, the researchers used large language models and de-identified electronic health records (EHRs) from US academic medical centers and health systems to capture the complete clinical note history of patients taking retatrutide.

“Retatrutide isn’t an approved product, so it has no national drug code, no pharmacy claim, and no structured prescription record anywhere in the health system,” Soundararajan explained. “Evidence about who is taking it exists only in the physician narrative in the form of free text in clinical notes.”

Using the nference AI platform, the researchers retrieved the full clinical-note history for every patient whose record mentioned the drug and adjudicated three outcomes: whether the patient actually took the drug; where they obtained the drug; and when they started taking the drug. A clinician manually re-reviewed 320 randomly sampled extractions against the source notes. Exposure classification was 99.8% accurate and supply route was roughly 90% accurate.

Patients who received the direct-to-consumer drugs were matched to semaglutide and tirzepatide initiators on seven baseline characteristics — age, sex, race, BMI, type 2 diabetes, prior semaglutide or tirzepatide exposure, and days since the most recent prior exposure.

The researchers then constructed four analytic cohorts by matching each retatrutide population (trial and direct-to-consumer patients) against those who initiated either semaglutide or tirzepatide in 2025. Matched arms were balanced by age (about 51 years), sex (about 63% women), BMI (about 33), and documented prior incretin exposure (about 37.1%). This yielded 89 trial patients, 243 direct-to-consumer patients, 890 semaglutide patients, and 890 tirzepatide patients.

Analyses showed a rapidly increasing use of nontrial products purported to contain retatrutide, with a 1.8-fold increase per quarter from October 2023 through March 2026.

Adjudication of the de-identified EHRs showed 983 patients whose clinical notes mentioned retatrutide, with confirmed exposure in 652 patients (66.3%), and documented supply route tracing in 531 (54%).

Of the 531 users with documented supply route tracing, 378 (71.2%) obtained purported retatrutide outside of clinical trial participation, mostly through online or telehealth vendors (57.4%) and compounding pharmacies (29.4%).

The researchers then conducted an analysis of the 89 retatrutide/placebo clinical trial participants who were matched with those starting compounded retatrutide (243 direct-to-consumer patients), semaglutide (890), and tirzepatide (890).

Weight loss among the 89 retatrutide trial participants 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).

In contrast, compounded retatrutide users lost 7.2% body weight at 6-12 months, less than the 15.5% observed in the retatrutide trial cohort and comparable to the weight-loss achieved among matched tirzepatide users (7.7%).

A significant increase in heart rate was observed at 3 months for both the retatrutide trial cohort (+4.3 beats per minute [bpm]) and the compounded retatrutide cohort (+2.5 bpm), which was not seen in the matched semaglutide or tirzepatide cohorts.

The retatrutide trial cohort also showed numerically higher, but not statistically significant, rates of three-point major adverse coronary events (MACEs) vs matched tirzepatide users (relative risk [RR], 1.77) and semaglutide users (RR, 1.02), with similar findings for expanded MACE vs tirzepatide (RR, 2.03) and semaglutide (RR, 1.25).

The new-onset symptom burden was significantly higher for the pooled retatrutide cohort (trial and compounded users combined) than both semaglutide and tirzepatide comparators, including a higher risk for cardiovascular symptoms (RR, 1.56) and neuropsychiatric symptoms (RR, 1.95).

“Taken together, accelerating gray-market retatrutide use was 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,” the authors concluded.

Limitations included the observational nature of the study, which precludes proof of cause; short and uneven follow-up (median roughly 3 months in the retatrutide arms vs 6 months in comparators); and index dates derived from notes rather than dispensing records.

‘Ask Patients About Use’

“Clinicians should ask patients directly about unapproved peptide use,” Soundararajan advised. “Where use is disclosed, heart rate warrants monitoring…Expectations should also be set realistically for patients, since gray-market purported retatrutide did not deliver clinical trial-level weight loss in our observational study.”

Some gray-market products are documented in clinical notes not just as retatrutide but also as co-formulations with other unapproved peptides, such as cagrilintide, BPC-157, NAD+, and IGF-1 analogues. None of these have been evaluated in a clinical trial.

Furthermore, he added, “patients entering incretin trials may already carry gray-market exposure histories that standard screening won’t capture.”

Priya Jaisinghani, MD, an obesity specialist at NYU Langone Health, New York City, who was not involved in the study, told Medscape Medical News that despite important limitations, “the study provides an important signal that patients are obtaining unapproved retatrutide through unregulated channels, where the product, dose, purity, manufacturing quality, safety, and efficacy cannot be reliably verified.”

Like Soundararajan, she said, “Clinicians should proactively ask patients about the use of unapproved drugs or peptides, recognizing that this is occurring in the community, and encourage patients to report any adverse events or concerning reactions.”

“At the same time,” she added, “it is important to distinguish these unregulated products from Lilly’s expanded-access efforts for certain patients living with severe, refractory obesity while retatrutide remains investigational. Ultimately, this study highlights that patients are already accessing investigational therapies outside the evidence-based medical system and we need to take that seriously. Patients deserve access to safe, evidence-based treatments.”

‘Not Real Medicine’: Lilly

Eli Lilly has filed multiple lawsuits against companies selling illegal retatrutide. They are also urging the FDA and additional law enforcement agencies to take action against the “illegal” sales of retatrutide.

In recognition of the demand, Lilly announced an expanded access program for certain qualifying patients. “We believe that everyone who needs medicine deserves real medicine, and this study is further evidence that what is being sold on the black market is not medicine — it is entirely unverified, unapproved, and not worth the risk,” the company spokesperson said.

“Social media, e-commerce platforms, and other businesses must stop enabling and fueling this illegal market and must take proactive steps to cut off the infrastructure enabling this illegal trade.”

The authors reported being employees of nference, inc., which conducts research collaborations with various biopharmaceutical companies whose therapeutic products are included in this study. None of these companies, nor any other nference collaborator, funded, supported, or had any role in the independent study design, data acquisition, analysis, interpretation, manuscript preparation, or the decision to submit this work for publication. All analyses were conducted by the authors using de-identified EHR data. The authors declared having no additional competing interests. Jaisinghani disclosed consulting for Eli Lilly, Novo Nordisk, Madrigal, and Corcept.

Marilynn Larkin, MA, is an award-winning medical writer and editor based in New York City whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.