The SGLT2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure: results from a placebo-controlled randomised trial

Abstract

Introduction Sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardiovascular protective properties in addition to the metabolic effects and represent a cornerstone of treating patients with chronic heart failure (CHF). We hypothesised that empagliflozin reduces tissue sodium content in patients with CHF. Methods In a double-blind, randomised (2:1), placebo-controlled, parallel-group, clinical trial, 74 patients with NYHA class II–III CHF and an ejection fraction of 49% or less received empagliflozin 10 mg once daily or placebo for 3 months. In each patient, tissue sodium content of the lower leg was assessed non-invasively by sodium-MRI (23Na-MRI) at baseline, after 1 and 3 months of treatment. Results After 1 and 3 months treatment with empagliflozin (n = 48), a significant decrease in skin sodium content was observed (1 month: 22.8 ± 6.1 vs. 21.6 ± 6.0 AU, p = 0.039; 3 months: 22.9 ± 6.1 vs. 21.6 ± 6.1 AU, p = 0.013), while there was no change in muscle sodium and muscle water content. In direct comparison, the change in skin sodium content between baseline and 3 months was − 1.3 ± 3.5 AU in the empagliflozin group versus 0.6 ± 3.5 AU in the placebo group (p for between-group difference = 0.022). No significant difference regarding change in muscle sodium and in muscle water content was observed after 3 months treatment between the two groups. Conclusion This trial showed a significant decrease in skin sodium content after 1 and 3 months of treatment with empagliflozin. The decrease in skin sodium content may reflect a decrease in subclinical micro-oedema or/and in non-osmotic bound tissue sodium, both reported to impair left ventricular function. Trial registration number NCT03128528 (http://www.clinicaltrials.gov). Trial registration date 25th April 2017.

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

“…From our comprehensive review, we identified 27 studies that evaluated the effects of SGLT2 inhibitors on urinary sodium and water excretion in healthy volunteers or patients with type 2 diabetes, heart failure, or chronic kidney disease, for periods ranging from 3 days to 3 months (Table 1). 12,32,37,39,40,42,44,46,58,61,[63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] Typically, dietary sodium and use of diuretics were not controlled; sodium balance was not achieved; and some studies analyzed spot (rather than 24-hour) urine collections. 12,46,67,81 Trials that were double-blind and placebo-controlled are less subject to these confounding factors.…”

“…83 Heart Failure With and Without Recent Acute Decompensation In patients with chronic heart failure receiving low doses of loop diuretics, the response to SGLT2 inhibition was characterized primarily by an increase in electrolyte-free water clearance. Four double-blind, placebo-controlled trials reported on the effects of SGLT2 inhibitors in patients who were treated with and responsive to furosemide equivalent doses <40 to 80 mg/d; 12,42,79,80 2 of the 4 trials evaluated patients with acutely decompensated heart failure. In all 4 trials, SGLT2 inhibition produced an immediate and persistent increase in urinary volume, which was not accompanied by significant changes in urinary sodium excretion and was attributed to an osmotic diuresis produced by glycosuria.…”

“…113,114 In large-scale heart failure trials, SGLT2 inhibition for 3 months produces only modest changes in natriuretic peptides and left ventricular filling pressures (even in patients with volume overload), with little correlation between changes in natriuretic pep-tides and metrics of decongestion. 105,[115][116][117] Even in acutely decompensated heart failure, changes in NT-proBNP are not apparent 79 or are modest and not sustained. 118…”

“…On the basis of a comprehensive review, we identified 13 studies that evaluated the effects of SGLT2 inhibitors on extracellular water (Table 3). 44,46,67,72,73,79,99,103,108,[124][125][126][127][128] These reports performed measurements using diverse methods, typically without a control group, making it difficult to reliably discern a treatment effect. In 5 trials that were double blind and placebo controlled, SGLT2 inhibition modestly decreased extracellular fluid in patients with diabetes or heart failure after 1 to 2 weeks, but with little effect after 1 to 3 months.…”

The ongoing need to improve long‐term patient survival of pediatric solid organ recipients

“…We must do more to improve the survival and quality of life of our patients, 14 which is worse than that of pediatric cancer survivors 15 . We have learned about the potential cardiovascular benefits of sodium‐glucose cotransporter 2 inhibitors (SGLT2i), 16 as these medications have been associated with the reduction of skin sodium in sodium MRI studies 17 . SGLT2i are also nephroprotective 16 and reduce hypertension 18 .…”