Renoprotective Effect of SGLT2 Inhibitors Mediated Largely by Hematocrit

Increases in the proportion of red blood cells mediates the reduction in renal risks associated with SGLT2 inhibitor therapy in patients with type 2 diabetes and cardiovascular disease, a study found.

Improvements in renal outcomes among patients treated with sodium-dependent glucose cotransporter-2 (SGLT2) inhibitors are due mainly to an increase in the proportion of red blood cells, according to data presented at the 58th European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 2021 virtual congress.

In a post-hoc analysis of patients with cardiovascular disease and type 2 diabetes in the EMPA-REG OUTCOME trial, empagliflozin was associated with a 46% reduction in the risk of the study’s composite renal end point from baseline to week 12 compared with placebo in an unadjusted analysis, lead investigator Christoph Wanner, MD, of the University Hospital of Würzburg, Germany, reported in an oral presentation. After adjusting for hematocrit value, empagliflozin was associated with a 31% decreased risk of the composite end point. From these data, investigators calculated that hematocrit accounted for 40.7% of empagliflozin’s renoprotective effect. Other variables associated with treatment benefit were hemoglobin A1c, systolic blood pressure, and free fatty acids. These factors combined with hematocrit mediated 79% of the treatment benefit.

In a time-dependent Cox regression analysis, empagliflozin treatment was associated with a 44% decreased risk of the composite endpoint compared with placebo, with hematocrit explaining 99.5% of this treatment benefit, Dr Wanner reported.

“Volume/hematopoiesis markers, such as hematocrit or hemoglobin, were strong mediators of the empagliflozin treatment benefit on the composite kidney outcome in EMPA-REG OUTCOME participants with type 2 diabetes and cardiovascular disease,” Dr Wanner told congress attendees. “When considering changes over the full observation period, hematocrit mediated almost all the empagliflozin treatment effect.”

The composite end point consisted of a first sustained estimated glomerular filtration rate (eGFR) decline of 40% or more from baseline, initiation of continuous kidney replacement therapy, or death from kidney disease, compared with placebo.


Wanner C, Nangaku M, Kraus BJ, et al. Mediators of the empagliflozin treatment effect on kidney outcomes in the EMPA-REG OUTCOME trial. Presented at the 58th ERA-EDTA 2021 virtual congress held June 5-8, 2021. Abstract MO1061.

This article originally appeared on Renal and Urology News