Agomelatine and the potential inverse risk of metabolic disorders: a nationwide cohort study with an active comparator design in Taiwan

Agomelatine, a melatonergic antidepressant, acts as a dual MT1/MT2 receptor agonist and a 5-HT2C receptor antagonist, effectively resynchronizing circadian rhythms while exerting antidepressant and anxiolytic properties. It is considered safe and may have anti-inflammatory, antioxidant, and blood pressure-lowering properties. However, its effects on hypertension, diabetes, and hyperlipidemia remain unclear. This study aimed to assess the association between agomelatine use and the impact on these metabolic conditions. Using Taiwan’s National Health Insurance data, this nationwide cohort study compared 25,923 agomelatine users with 83,535 fluoxetine users. Outcomes included new-onset hypertension, diabetes, and hyperlipidemia over a 5-year follow-up. An active-comparator design with propensity score weighting balanced baseline characteristics. Cox proportional hazards models provided hazard ratios (HRs) and 95% confidence intervals (CIs). All analyses were conducted using SAS. In the propensity score-weighted cohort over a 5-year follow-up, agomelatine users exhibited a significantly lower risk of hypertension compared to fluoxetine users (adjusted HR 0.802; 95% CI, 0.770–0.836). Consistent with this cardiovascular benefit, agomelatine use was also associated with reduced risks of incident diabetes mellitus (adjusted HR 0.875; 95% CI, 0.827–0.927) and hyperlipidemia (adjusted HR 0.938; 95% CI, 0.906–0.972) throughout the study period. Subgroup analyses showed generally consistent inverse associations for hypertension across various demographic and clinical strata. This nationwide cohort study demonstrates associations between agomelatine use and lower risks of hypertension, diabetes mellitus, and hyperlipidemia. These findings provide population-based evidence that may inform future research, although further studies are warranted to confirm these observations.