Comparison of Insomnia Risk between Spironolactone and Esaxerenone in Individuals with Hypertension

Spironolactone (SPL) is a steroidal mineralocorticoid receptor antagonist (MRA) that binds non-specifically to sex hormone receptors. Given the role of sex hormones in sleep regulation, SPL may pose a theoretical risk of insomnia through off-target activity. Recently introduced, esaxerenone (ESAX) is a non-steroidal MRA with high mineralocorticoid receptor selectivity, attracting attention for its potentially favorable safety profile.

This study was conducted to compare the risk of insomnia between SPL and ESAX. Individuals with a history of hypertension who newly initiated either agent were enrolled from the DeSC database. Inverse probability of treatment weighting was used to assess differences in insomnia incidence between treatment groups.

We analyzed 5,091 individuals without a history of insomnia: 1,910 received SPL and 3,181 received ESAX. The median age was 72 (interquartile range [IQR], 67-79) years, 55% of participants were male, and the median estimated glomerular filtration rate was 66.3 (IQR, 56.1-76.2) mL/min/1.73 m². Over a median follow-up of 512 (IQR, 240-848) days, 356 insomnia events were observed. Weighted Cox regression analysis indicated a significantly higher risk of incident insomnia among SPL users than ESAX users (hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.32-2.10). In sex-stratified analyses, the HRs were 1.79 (95% CI, 1.30-2.47) for men and 1.59 (95% CI, 1.15-2.20) for women.

Using a nationwide claims database, we demonstrated that, compared with ESAX, SPL use was associated with a greater likelihood of developing insomnia.