SGLT2 inhibition ‘could overcome diuretic resistance’
medwireNews: A small randomized crossover trial indicates that treatment with empagliflozin in people with type 2 diabetes and heart failure (HF) already using a loop diuretic results in increased urine output without sodium loss.
The success of sodium-glucose cotransporter (SGLT)2 inhibitors for HF outcomes in recent trials may increase the number of people being prescribed these medications in addition to a diuretic, say Chim Lang (University of Dundee, UK) and study co-authors.
They therefore aimed to study the effects of the combination, in particular whether it resulted in natriuresis.
“At this time, sequential nephron blockade with thiazide-like diuretics used in combination with loop diuretics is often used to overcome diuretic resistance in acute decompensated [congestive] HF,” they explain in Circulation.
“However this strategy does not always work and is associated with the hazards of hypokalaemia, hyponatraemia, hypotension and renal failure.”
The team recruited 23 people with type 2 diabetes and HF with reduced ejection fraction. They were aged an average of 69.8 years, in New York Heart Association functional class II–III, and 74% were male. They took empagliflozin 25 mg/day for 6 weeks and placebo for 6 weeks in a randomly assigned order with a 2-week washout period in between. Both participants and investigators were blinded to the treatment order.
Empagliflozin resulted in an average 535 mL increase in 24-hour urine output by day 3, relative to placebo, which was maintained at week 6. It also caused a nonsignificant average 272 mL increase in electrolyte-free water clearance at day 3, which became statistically significant at week 6, at 312 mL versus placebo.
There was no change in average 24-hour urinary sodium excretion, measured either as mmol/L (–7.44 vs placebo) or mmol/day (33.55 vs placebo) at either timepoint. There was a nonsignificant increase in average fractional excretion of sodium at day 3 (0.30% vs placebo), but this had disappeared by week 6.
This shows “that diuresis without significant natriuresis is quickly achieved by day 3” of treatment with empagliflozin, say the researchers.
“Potentially, this highlights the SGLT2 inhibitor as an alternative to the thiazide-like diuretics in those who have may have evidence of fluid retention resistance to loop diuretics alone.”
Five trial participants required a 50% reduction of their loop diuretic dose during the empagliflozin phase of the trial, which then had to be reinstated due to clinical signs of increased congestion. Two participants needed an increase of their previous diuretic dose after empagliflozin discontinuation and two whose doses had not changed were admitted to hospital with decompensated HF after empagliflozin discontinuation.
The researchers also note that a post-hoc analysis of DAPA-HF found the highest risk for adverse events related to volume depletion in participants who were taking both dapagliflozin and a diuretic.
“These findings underscore the need for vigilance regarding volume status and judicious adjustment of loop diuretic doses when initiating a SGLT2 inhibitor in HF patients,” they conclude.
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