TriNetX Cohort Shows 90% Higher Heart Failure Incidence After One-Year Melatonin Exposure in Insomnia Patients

Researchers extracted de-identified records from the TriNetX Global Research Network and matched adults with chronic insomnia who had continuous melatonin documentation for one year or longer against similar patients lacking any melatonin record. They excluded prior heart failure and concurrent sleep-medication users, then tracked incident heart failure, hospitalization, and all-cause mortality over five years. The primary analysis yielded an approximately 90% relative increase; a sensitivity analysis restricted to two prescriptions separated by at least 90 days produced an 82% elevation, strengthening the exposure definition.

The finding arrives amid widespread over-the-counter melatonin use whose purity and dose are unregulated in the United States. Earlier smaller studies and meta-analyses had reported neutral or modestly favorable cardiovascular signals in short-term settings, yet none examined multi-year exposure in an insomnia population already at elevated baseline cardiac risk. The present design cannot separate melatonin effects from residual confounding by unmeasured insomnia severity or co-morbidities.

Confirmation would require a prospective cohort or randomized trial that verifies adherence through pharmacy fills and captures echocardiographic or biomarker endpoints. Such data could alter prescribing conversations for the millions of nightly users and prompt regulatory scrutiny of labeling claims that currently emphasize safety without long-term cardiovascular evidence.