Endocrine Abstracts

Background: Hyponatremia (Na+≤134 mmol/L), the most common electrolyte derangement, is caused by inappropriate vasopressin-mediated water resorption in the kidney. Treating symptomatic hyponatremia is difficult and risky; as difficult as maintaining normal sodium levels. We tested if tolvaptan, an oral vasopressin V2 receptor antagonist, improves hyponatremia and self-reported health outcomes.

Methods: Two multicenter, randomized, double-blind, placebo-controlled trials evaluated tolvaptan in asymptomatic, non-hypovolemic hyponatremia patients. Upon obtaining local Ethics Committee approval and patients’ consent, oral placebo (n=223) or tolvaptan (n=225) was given for 30 days. The first single daily dose (15 mg) was monitored in-hospital with optional fluid restriction. Patients were discharged and fluid intake and study drug (30 or 60 mg) were titrated as clinically indicated. Co-primary endpoints were the average daily area under the curve of serum sodium concentration change from baseline to day 4 and 30. Overall SF-12 Physical (PCS) and Mental Component Summary (MCS) score changes from baseline to day 30 were secondary endpoints. A hyponatremia disease-specific survey (HDS) was also tested.

Results: Serum sodium increased more with tolvaptan than placebo over the first 4 days (P<0.001) and the entire 30-days (P<0.001). On stopping tolvaptan therapy, sodium concentrations fell to placebo levels. The day 30 PCS was unchanged, however the MCS was significantly improved in the tolvaptan group (P=0.02). MCS improvements correlated positively with rise in serum sodium (r=0.2, P=0.001). Tolvaptan differed from placebo in the HDS survey in the moderately severe hyponatremia subjects (<130 mmol/L) in mental concentration, calculation and memory (P<0.05 or better). Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination.

Conclusions: Tolvaptan, an oral V2 receptor antagonist, effectively increased and maintained serum sodium concentrations in hyponatremic patients. These changes were associated with improved perception of mental/cognitive health.