medwireNews: The sodium-glucose cotransporter (SGLT)2 inhibitor empagliflozin reduces estimated extracellular volume and plasma volume in patients who have heart failure with reduced ejection fraction, shows a randomized trial.
“A substantial reduction in fluid volumes might be an important mechanism underlying the clinical benefits of SGLT2 inhibitors,” suggest Morten Schou (Herlev and Gentofte University Hospital, Denmark) and co-researchers.
Their findings come from a preplanned subanalysis of a trial in which 120 patients with heart failure and reduced ejection fraction were randomly assigned to receive empagliflozin or placebo for 12 weeks. Most participants were in New York Heart Association class II, and 88% had type 2 diabetes.
During treatment, estimated extracellular volume fell from an average of 16.4 to 16.3 L in the empagliflozin group but rose from 16.9 to 17.0 L in the placebo group, giving a significant adjusted average difference of 0.12 L between the two groups.
Estimated plasma volume also fell in the empagliflozin group, compared with a slight rise in the placebo group, to give a significant adjusted average difference of 7.3% favoring empagliflozin treatment.
“The reductions in extracellular volume and plasma volume were not notably different, suggesting that reductions in plasma volume, rather than interstitial fluid, might be the main contributor to the reduction in extracellular volume,” write the researchers in The Lancet Diabetes & Endocrinology.
“However, whether the magnitude of change in extracellular volume and plasma volume can account for the clinical benefits of SGLT2 inhibitors reported in clinical outcome trials cannot be deduced from our results.”
And the team stresses that “uncertainty remains” as to how accurately changes in the surrogate measures used “reflect changes in the actual extracellular and plasma volume.”
Directly measured glomerular filtration rate (GFR) fell from an average of 77.8 to 71.2 mL/min in the empagliflozin group, versus almost no change (83.7 to 83.8 mL/min) in the placebo group, to give a significant adjusted difference of 7.5 mL/min between the groups.
The reduction in GFR with empagliflozin is consistent with the temporary reduction in estimated GFR reported in large clinical trials, which is not thought to impact outcomes.
Schou and team suggest that this acute decline “might reflect a reduction in intraglomerular pressure, as reported in patients with diabetes without heart failure, and is thus likely to be nephroprotective over time, as has been confirmed by clinical outcome trials.”
They add: “The effect of empagliflozin treatment on measured GFR is considerable, and renal protection and improved volume regulation might be important mechanisms of SGLT2 inhibitors.”
However, the researchers stress that their results “clearly show” that this initial fall in GFR is underestimated when GFR is estimated rather than measured directly, “which should be considered when initiating empagliflozin treatment in clinical practice.”
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