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Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects
Quick Takes
- In a randomized trial of 20 stable HF patients with type 2 diabetes, SGLT-2 inhibitor use was associated with direct natriuresis with a synergistic response in combination with a loop.
- SGLT-2 inhibitor use was not associated with potassium wasting or neurohormonal activation.
- Effect of SGLT-2 inhibitor was sustained without tachyphylaxis over 14 days and the natriuretic effect did not vary between individuals with an eGFR <60 vs. >60 ml/min/m2.
Study Questions:
What are the acute and intermediate effects of sodium-glucose co-transporter-2 (SGLT-2) inhibitors on natriuresis, volume status, and neurohormonal activation in heart failure (HF) patients?
Methods:
This was a randomized, blinded, placebo-controlled trial of 20 patients with stable HF and type 2 diabetes. Patients received 10 mg of empagliflozin or placebo for 14 days followed by a 2-week washout period and crossover to 14 days of treatment with an alternate agent. Endpoints of interest were natriuretic effect of empagliflozin both as monotherapy and in combination with loop diuretics and change in neurohormones within 14 days of therapy.
Results:
Enrolled individuals were predominantly male and obese with a mean age of 60 years and median glycated hemoglobin (HbA1c) of 7.1%. Overall, nine patients had HF with reduced ejection fraction. Mean daily loop diuretic dose was high, suggesting diuretic resistance. Empagliflozin administration was associated with a 27-fold increase in urinary glucose and sodium excretion, which peaked at 3 hours and lasted 6 hours. Repeat doses yielded the same glycosuric response at days 1 and 14, but the natriuretic response was more sustained at day 14. With loop diuretic, there was a synergistic effect on natriuresis without attenuation at day 14. Compared to placebo, the urine output, net fluid balance, and total sodium output were higher with empagliflozin. The natriuretic effect was direct and not due to osmotic diuresis. The natriuretic response was not different in patients with an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 as compared to those with eGFR >60 ml/min/1.73 m2.
Serum potassium levels were not different between empagliflozin and placebo. While empagliflozin was associated with a reduction in blood volume, there was no detectable activation of the renin-angiotensin-aldosterone system (RAAS). Change in plasma norepinephrine was better with empagliflozin compared to placebo. Changes in eGFR did not differ between the two groups. Empagliflozin was well tolerated with no significant difference in blood pressure and no instances of genitourinary infections, symptomatic hypoglycemia, or diabetic ketoacidosis.
Conclusions:
In a randomized controlled trial of 20 patients with stable HF and type 2 diabetes, empagliflozin had a natriuretic effect as monotherapy and a synergistic effect when combined with a loop diuretic. Renal dysfunction did not limit the natriuretic effect of empagliflozin and potassium loss did not occur with its use. There was no significant RAAS or sympathetic nervous system activation with empagliflozin.
Perspective:
Loop or thiazide diuretics form the cornerstone of HF management due to symptomatic benefits. However, the associated natriuresis leads to neurohormonal activation and frequently causes renal dysfunction and potassium wasting. Empagliflozin use was associated with direct natriuresis without potassium wasting, renal injury, or neurohormonal activation. This effect of SGLT-2 inhibitors is likely secondary to increased sodium delivery to the macula densa while loop diuretics antagonize this. In addition, empagliflozin was well tolerated compared to placebo with no change in blood pressure.
Limitations of this study include its small size and mechanistic design. Only patients with stable HF and type 2 diabetes were studied and results cannot be inferred to patients without diabetes or with decompensated HF.
Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure
Keywords: Blood Pressure, Diabetes Mellitus, Type 2, Diuretics, Glomerular Filtration Rate, Heart Failure, Natriuresis, Natriuretic Agents, Obesity, Potassium, Primary Prevention, Renal Insufficiency, Renin-Angiotensin System, Sodium Chloride Symporter Inhibitors, Sodium Potassium Chloride Symporter Inhibitors
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