Does Empagliflozin Cause Hyponatremia?
No, empagliflozin does not cause hyponatremia—in fact, it increases serum sodium levels through osmotic diuresis and may be therapeutic for treating hyponatremia, particularly in syndrome of inappropriate antidiuresis (SIAD).
Mechanism of Action on Sodium Balance
- Empagliflozin promotes osmotic diuresis via urinary glucose excretion, which increases electrolyte-free water clearance and raises plasma sodium concentration 1, 2.
- The drug causes loss of 50-100 g of glucose per 24 hours in urine, resulting in water loss that concentrates serum sodium 3.
Clinical Evidence Supporting Sodium Elevation
Acute SIAD Treatment:
- In hospitalized patients with SIAD-induced hyponatremia (<130 mmol/L), empagliflozin increased median plasma sodium by 10 mmol/L versus 7 mmol/L with placebo (p=0.04) over 4 days 1.
- Patients with profound hyponatremia (<125 mmol/L) showed even greater response to empagliflozin 1.
Chronic SIAD Treatment:
- In outpatients with chronic SIAD, empagliflozin 25 mg daily increased serum sodium by 4.1 mmol/L (95% CI 1.7-6.5, p=0.004) compared to placebo over 4 weeks 2.
- This treatment also improved neurocognitive function (MoCA score increase of 1.16 points) 2.
Real-World Data:
- A retrospective analysis of 1,642 hospitalized patients with type 2 diabetes found no difference in hyponatremia prevalence between those on SGLT2 inhibitors (9.9%) versus controls (8.9%, p=0.554) 4.
- Median plasma sodium concentrations were identical (140 mmol/L) in both groups 4.
Critical Safety Consideration: Hypernatremia Risk
The actual concern with empagliflozin is hypernatremia, not hyponatremia, particularly in vulnerable populations:
- A case report documented severe hypernatremic dehydration (sodium 164 mmol/L) in a care-dependent stroke patient who could not autonomously replace water losses 5.
- The patient became unconscious from persistent glucosuria-induced volume depletion after 2 weeks of empagliflozin therapy 5.
High-Risk Populations Requiring Caution
Avoid or temporarily discontinue empagliflozin in patients who:
- Depend on others for fluid intake assistance 5.
- Have impaired sense of thirst 5.
- Cannot communicate thirst (e.g., post-stroke, dementia) 5.
- Are elderly or frail, as they have higher risk for volume depletion 6, 3.
Monitoring Recommendations
- The American College of Cardiology recommends close monitoring in patients with renal impairment, as empagliflozin has reduced glycemic efficacy when eGFR <45 mL/min/1.73m² 6.
- Elderly patients require careful monitoring for volume depletion and hypotension 6.
- Treatment should be discontinued when eGFR falls below 45 mL/s 3.
Clinical Bottom Line
Empagliflozin raises, not lowers, serum sodium through its osmotic diuretic effect. The drug shows promise as a treatment for hyponatremia in SIAD. However, clinicians must remain vigilant for the opposite problem—hypernatremic dehydration—especially in patients unable to maintain adequate fluid intake independently.