Abstract Body (Do not enter title and authors here): Background:
Chronic insomnia affects up to one-third of adults, and over-the-counter melatonin is increasingly promoted as a “cardiometabolic-friendly” sleep aid. Robust data on its long-term cardiovascular safety are lacking.

Methods:
We queried the TriNetX Global Research Network for adults ≥ 18 years with an insomnia diagnosis (ICD-10 F51.0). The exposed cohort required ≥ 1 melatonin prescription and ≥ 365 exposure-days; controls had no melatonin exposure. Patients with prior heart failure (HF) or other prescription hypnotics were excluded. Propensity-score matching (1:1, caliper 0.1) balanced 65, 414 melatonin users with 65, 414 controls on demographics, 15 comorbidities, concomitant cardiometabolic drugs, laboratories, vitals, and health-care utilization (all post-match standardized mean differences < 0.02). Outcomes were assessed 5 years after the index date. The primary endpoint was incident HF (ICD-10 I50.). Secondary endpoints were HF hospitalization and all-cause mortality. Hazard ratios (HR) were obtained from stratified Cox models.

Results:
During 5-year follow-up, incident HF occurred in 3,021 melatonin users (4.6%) versus 1, 797 controls (2.7%), corresponding to an HR of 1.89 (95% CI 1.78–2.00) and an absolute risk difference of 1.9% (p < 0.001). HF-related hospitalization occurred in 12, 411 users (19.0%) and 4, 309 controls (6.6%)—HR 3.44 (95% CI 3.32–3.56). All-cause mortality was higher in melatonin users (5, 118 [7.8%] vs 2, 820 [4.3%]; HR 2.09, 95% CI 1.99–2.18). Results were consistent in sensitivity analyses requiring ≥ 2 melatonin fills ≥ 90 days apart (HR for HF 1.82).

Conclusions:
In a large, multinational real-world cohort rigorously matched on >40 baseline variables, long-term melatonin supplementation in insomnia was associated with an 89% higher hazard of incident heart failure, a three-fold increase in HF-related hospitalizations, and a doubling of all-cause mortality over 5 years. These findings challenge the perception of melatonin as a benign chronic therapy and underscore the need for randomized trials to clarify its cardiovascular safety profile.