Mechanisms of kidney protection by gliflozins

Presented at ERA-EDTA during the virtual meeting by Christopher Wanner (Würzburg, Germany)

Introduction and methods

Results of the EMPA-REG OUTCOME trial demonstrated a reduced rate of CV events by the SGLT2 inhibitor empagliflozin in type 2 diabetes patients. In addition, benefit for kidney function was observed by empagliflozin treatment in diabetes patients with diabetic nephropathy. Other SGLT2i trials have confirmed this finding of kidney benefit in type 2 diabetes patients with diabetic nephropathy. Moreover, the DAPA-CKD trial showed that in patients with CKD (non-diabetic) the composite renal endpoint was reduced by the SGLT2 inhibitor dapagliflozin.

Mechanism of kidney benefit by SGLT2 inhibitors are largely unknown. Therefore, a post-hoc analysis was performed using data from the EMPA-REG OUTCOME trial. The two doses groups were pooled (empagliflozin 10 and 25 mg/d) and the effect of 17 factors from different physiological areas on the risk reduction of the composite renal endpoint by empagliflozin compared to placebo was examined. Effects were determined on a time-dependent basis and also at week 12.

Main results

• In a time-dependent analysis, empagliflozin reduced the renal endpoint compared to placebo (unadjusted HR 0.56).
• After adjusting for hematocrit over time, HR for the effect by empagliflozin was 1.0, suggesting that hematocrit was a strong mediator.
• Adjusting for serum uric acid concentration and albuminuria resulted in risk reductions of 33.2% and 31%, respectively.
• At week 12, renal endpoint was reduced by empagliflozin compared to placebo (unadjusted HR was 0.54). Adjusting for hematocrit, the HR was 0.69. Adjusting for HbA1c, blood pressure and fatty acid levels resulted in risk reductions of 28.3%, 16.8% and 16.5%, respectively.

Conclusions

This post-hoc analysis of EMPA-REG OUTCOME suggest that hematocrit is the most important mediator of the benefit that is observed with the SGLT2 inhibitor on renal function.

Prof. Wanner said: “These correlations now need to be investigated further – for example, to determine whether a role is played here by hemoconcentration due to increased urinary excretion induced by gliflozin, or by enhanced erythrocyte production.”

Source: press release ERA-EDTA, June 6, 2021