This study aimed to evaluate the incidence and risk of hyponatremia associated with desmopressin use in male patients with lower urinary tract symptoms (LUTS), using a nationwide population-based database in South Korea. Although desmopressin is frequently used to treat nocturia, concerns remain regarding its safety profile, particularly in older adults and those with comorbid conditions. We sought to clarify whether desmopressin therapy is independently associated with an increased risk of hyponatremia compared to other LUTS-related medications.

This retrospective cohort study used data from the National Health Insurance Service of South Korea. Male patients diagnosed with benign prostatic hyperplasia (BPH) and treated with desmopressin between 2011 and 2012 were included. Patients were followed until December 2020. Individuals with advanced renal impairment, syndrome of inappropriate antidiuretic hormone secretion (SIADH), hepatic disease, malignancies, or prior hyponatremia were excluded. Three treatment cohorts were identified: desmopressin monotherapy, alpha-blockers alone, and alpha-blockers combined with antimuscarinics. Hyponatremia was defined as two or more outpatient visits or one hospitalization with a relevant diagnostic code. Propensity score matching and Cox proportional hazards regression models were used to estimate hazard ratios (HRs). Kaplan–Meier analysis evaluated the cumulative probability of hyponatremia.

Among 33,533 patients, the overall incidence of hyponatremia was 6.0% in the desmopressin group, 4.5% in the alpha-blocker group, and 5.0% in the combination therapy group. After matching, desmopressin use was associated with a higher HR for hyponatremia (HR 1.273, 95% CI 0.988–1.640), though this did not reach statistical significance (p = 0.062). Multivariate analysis identified advanced age (HR 1.652), chronic heart failure (HR 2.532), peripheral vascular disease (HR 2.251), and renal disease (HR 2.383) as significant risk factors for hyponatremia. Kaplan–Meier curves showed no significant difference in hyponatremia-free survival between treatment groups over a five-year follow-up period (log-rank p = 0.181).

Although desmopressin demonstrated a numerical trend toward increased risk, it was not statistically significant. The most important predictors of hyponatremia were underlying comorbidities that affect fluid regulation. These findings emphasize the need for careful patient selection, particularly in elderly patients or those with cardiovascular or renal comorbidities.

Desmopressin remains a viable treatment option for nocturia in male patients with LUTS when used appropriately. With proper baseline assessment and regular monitoring of serum sodium levels, the risk of hyponatremia can be minimized. These findings support the continued use of desmopressin in clinical practice, provided that clinicians apply individualized risk assessment and implement safety protocols for high-risk patients.