Preprint links unapproved retatrutide to weaker weight loss and heart symptoms

An analysis of de-identified electronic health records, posted as a preprint, found that people using unapproved retatrutide from online sellers or compounding pharmacies lost well under half the weight seen in the drug's clinical trials, while still showing a higher heart rate and more cardiovascular symptoms than matched users of approved medicines ^[1][2].

Retatrutide is an investigational triple-hormone-receptor agonist from Eli Lilly that acts on GIP, GLP-1 and glucagon receptors at once. The FDA has approved it for no use, and it remains in phase 3 testing ^[1][2].

What the records showed

Retatrutide is unapproved, so it leaves no pharmacy claim and no structured prescription entry; its trail exists mainly as free text in physician notes ^[1]. Researchers at nference, a health data company, used large language models on records from US academic medical centers and health systems ^[1][2]. They found 983 patients whose notes mentioned the drug; a clinician confirmed real use in 652 (66.3%), and a supply source was documented for 531 (54%) ^[1].

Of that 531, 378 (71.2%) reported getting the product somewhere other than a trial. Online or telehealth sellers accounted for 217 patients (57.4%), compounding pharmacies 111 (29.4%) and wellness clinics or medical spas 33 (8.7%) ^[2]. New use rose 1.8-fold every quarter between October 2023 and March 2026, with 228 new users in the first three months of 2026 ^[1][2].

The team assembled four matched groups: 89 trial participants, 243 direct-to-consumer users, 890 people beginning semaglutide (Ozempic, Wegovy, Rybelsus) and 890 beginning tirzepatide (Mounjaro, Zepbound). The arms averaged about 51 years old, about 63% women, a BMI of about 33 and prior incretin exposure of about 37.1% ^[1].

Over 6 to 12 months, the gray-market group lost 7.2% of body weight. Trial participants lost 15.5% (P=0.004), and matched tirzepatide users lost 7.7% ^[1][2]. Lilly has reported 28.3% average weight loss at 80 weeks in the 12 mg arm of TRIUMPH-1, where 45.3% of patients lost at least 30% ^[2]. That trial-cohort figure tracked closely with the 16.9% weighted-average loss across retatrutide and placebo arms at 80 weeks in TRIUMPH-1-4 ^[1].

Heart rate at three months climbed 4.3 beats per minute in the trial group and 2.5 bpm in the compounded group; neither matched comparison group showed a rise ^[1]. With both retatrutide groups pooled, new-onset tachycardia was 2.88 times as frequent as among matched tirzepatide users (95% CI 1.68-4.85) ^[2]. Cardiovascular symptoms carried a relative risk of 1.56 and neuropsychiatric symptoms 1.95, and major adverse coronary events were numerically higher than in matched tirzepatide users but not significantly so ^[1].

The study is observational, so it cannot show cause. Follow-up was short and uneven — a median of about three months in the retatrutide arms against six months for comparators — and start dates came from notes rather than dispensing records ^[1]. A manual check of 320 sampled extractions put exposure classification at 99.8% accurate and supply route at about 90% ^[1][2]. The preprint has not been peer reviewed ^[1].

Why it matters for patients

Physicians have no routine way to know about this use, since it appears in neither prescription nor insurance data; major EHR platforms have had no structured field for recording it ^[2]. Venky Soundararajan, nference's founder and chief scientific officer, said doctors should ask patients directly about unapproved peptides and that heart rate deserves monitoring when use is disclosed ^[1]. Priya Jaisinghani, an obesity specialist at NYU Langone Health who was not involved in the work, said that with unregulated products, patients cannot verify dose, purity or manufacturing quality ^[1].

There is no lawful way to buy retatrutide in the United States. In a March 31, 2025 letter to the National Association of Boards of Pharmacy, the FDA said retatrutide has no United States Pharmacopeia monograph and appears on neither the 503A nor the 503B bulk substances list, leaving no path for legal compounding ^[2]. The agency has also told consumers not to buy such products ^[2]. Lilly said patients have reported serious harms, including hospitalizations, after taking black-market retatrutide bought online ^[1].

Among patients whose records showed earlier use of an approved obesity drug, most had taken a Lilly product, and many stopped because of cost, disappointing results or side effects ^[2]. Some notes also describe co-formulations with other unapproved peptides such as cagrilintide, BPC-157, NAD+ and IGF-1 analogs, none of which has been evaluated in a clinical trial ^[1].

What happens next

Lilly plans to file for approval in the first quarter of 2027 ^[1][2]. The company has sued sellers and is pressing the FDA and other law enforcement agencies to act against illegal sales ^[1]. Researchers have not established how peptide purity affects weight loss or which cardiovascular outcomes follow investigational retatrutide use; the authors called for broader evaluation of unapproved peptide therapies ^[1].