Sodium-glucose cotransporter-2 inhibitors in heart failure. How durable is the decongestive effect?

This Editorial Comment refers to ‘Short- and mid-term effects of empagliflozin on sodium balance and fluid regulation in chronic heart failure’, by V. Bytyqi et al., https://doi.org/10.1002/ejhf.70078. Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have become a class I-recommended group of drugs for heart failure (HF) patients across the entire left ventricular ejection fraction (EF) spectrum.1,2 Although the effect of the drugs on hard clinical outcomes (a composite of mortality and HF hospitalizations) has been demonstrated, we still do not know the exact mechanism underlying the tremendous clinical success.3 As SGLT2 transporters are expressed in numerous cell types, including proximal renal tubule cells, and their inhibition leads to glucosuria, thus a diuretic effect should be considered as one of the potential physiological consequences.4 The early results of the EMPA-RESPONSE-AHF trial, which recruited 80 decompensated HF patients and randomized them to receive empagliflozin vs. placebo, showed higher cumulative urine output through day 4 [the difference of 3449 (95% CI 578–6321) mL, n = 28].5 This was followed by the mechanistic substudy, which aimed to provide information on electrolyte and glucose handling in patients exposed to SGLT2i. Empagliflozin led to a significant increase in the fractional excretion of glucose, accompanied by an increase in serum osmolarity without affecting fractional sodium excretion.6 In another mechanistic study, the initiation of empagliflozin monotherapy in patients with chronic HF and diabetes mellitus led to a significant increase in fractional excretion of sodium. After 14 days of treatment, the natriuretic effect of empagliflozin persisted, resulting in reductions in blood and plasma volumes.7 As mechanistic studies are inconclusive and do not clearly demonstrate whether the acute use of SGLT-2 inhibitors increases urinary sodium concentration, it should be emphasized that osmotic diuresis driven by glucosuria leads to an increase in total urine volume (Figure 1). Consequently, even if urinary sodium concentration does not rise after initiation of the treatment, the net amount of sodium excreted should still be higher.