Endocrinology · Medical Literature
Hyponatremia correction is associated with increased brain-derived neurotrophic factor levels: A pilot secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial.
Abstract
Chronic hyponatremia is associated with cognitive deficits, yet the underlying mechanisms remain elusive. A cerebral growth factor which is crucial for cognition and memory is brain-derived neurotrophic factor (BDNF), but its role in hyponatremia has never been investigated. We here examined the influence of hyponatremia correction on serum BDNF levels. This study represents a secondary post hoc analysis of a prospective randomized, double-blind, crossover, placebo-controlled trial. Nine patients with syndrome of inappropriate antidiuresis (SIAD) completed 4 weeks treatments with empagliflozin 25 mg/day versus placebo. Serum sodium, BDNF levels, and Montreal Cognitive Assessment (MoCA) were assessed at baseline and after treatment cycles. Median baseline sodium was 131 mmol/L [130-133], which increased to 134 mmol/L ([131-136], p = .04) after empagliflozin treatment and remained stable after placebo phase (130 mmol/L [126-132], p = .9). Sodium increase was significantly associated with BDNF increase, also after adjusting for treatment arm, sex, age, baseline sodium, and antidepressant treatment (per 1 mmol/L sodium increase: estimate = 0.70 ng/mL, p = .048). This association was stronger upon empagliflozin treatment as shown by the interaction analysis (p = .03). In a subgroup of patients reaching normonatremia after empagliflozin treatment, BDNF increase was slightly higher compared to patients with persistent hyponatremia. MoCA scores did not differ between empagliflozin and placebo phase. Sodium increase was significantly associated with an increase in neurocognitive biomarker BDNF. Further research is needed to clarify BDNF's role in cognitive impairment in hyponatremia and its response to different treatment approaches. Trial registration: ClinicalTrials.gov (NCT03202667).
Clinical relevance
Chronic hyponatremia — most commonly due to SIAD — is a prevalent electrolyte disorder associated with measurable cognitive deficits, yet the neurobiological mechanisms linking low serum sodium to neurocognitive dysfunction remain poorly understood. This pilot study is the first to investigate BDNF, a key mediator of synaptic plasticity, neurogenesis, and cognitive function, as a potential mechanistic link between hyponatremia and cognitive impairment. Given the rising use of SGLT2 inhibitors as a treatment strategy for SIAD, understanding their neurobiological effects beyond sodium correction is of immediate clinical and therapeutic relevance.
Key findings
1. Median serum sodium increased significantly from 131 mmol/L [IQR 130–133] to 134 mmol/L [IQR 131–136] following 4 weeks of empagliflozin 25 mg/day (p = .04), while placebo produced no significant change (130 mmol/L [IQR 126–132], p = .9). 2. Each 1 mmol/L increase in serum sodium was independently associated with a 0.70 ng/mL increase in serum BDNF (estimate = 0.70 ng/mL, p = .048), after adjusting for treatment arm, sex, age, baseline sodium, and antidepressant use. 3. The association between sodium correction and BDNF rise was significantly stronger in the empagliflozin arm compared to placebo, as demonstrated by interaction analysis (p = .03), suggesting a possible drug-specific or correction-magnitude-dependent effect on BDNF. 4. In the subgroup of patients who achieved normonatremia following empagliflozin treatment, BDNF increases were numerically greater than in those with persistent hyponatremia, though formal statistical comparisons are limited by the small subgroup size. 5. Montreal Cognitive Assessment (MoCA) scores did not differ significantly between the empagliflozin and placebo phases, indicating that 4 weeks of partial sodium correction may be insufficient to produce detectable improvements in global cognitive screening measures. 6. The study is limited by a very small sample size (n = 9 completers in a crossover design), pilot/post hoc secondary analysis status, and lack of correction for multiple comparisons, requiring cautious interpretation of all findings.
Practice implications
Clinicians managing patients with chronic SIAD should be aware that even modest sodium correction (median rise of 3 mmol/L) with empagliflozin 25 mg/day may upregulate BDNF, a biomarker of neuroplasticity, potentially offering a neurobiological rationale for targeting eunatremia beyond symptom relief alone. While MoCA did not demonstrate short-term cognitive benefit, the dissociation between BDNF response and cognitive scores suggests that longer treatment durations and larger trials with sensitive neuropsychological endpoints are needed before BDNF or cognition can be used as treatment targets. Until confirmatory evidence is available, BDNF should not guide clinical decision-making, but this pilot data supports prioritizing complete sodium normalization — rather than partial correction — as a therapeutic goal in SIAD.