Single cell transcriptomic analysis of SGLT2 expression supports an indirect or off-target role for the cardioprotective benefits of empagliflozin in heart failure

Abstract

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), such as empagliflozin, have shown remarkable benefits in reducing cardiovascular events and mortality in patients with heart failure irrespective of diabetes. Because of the magnitude of the benefits and broad application in both heart failure with reduced and preserved ejection fraction, there have been concerted efforts to identify a mechanism for the observed benefits. One hypothesis is that SGLT2i act directly on the heart. Given empagliflozin’s high specificity to SGLT2, we reasoned that SGLT2 expression would be a requirement for cells to respond to treatment via the expected drug target. Here, we present a comprehensive transcriptomic analysis of SLC5A2, which encodes SGLT2 at the single cell level in multiple datasets from healthy and HF donors, confirming its expression in a subset of kidney epithelial cells but minimal expression in other cell types. This was true irrespective of developmental stage, disease state, sequencing method or depth, and species. Therefore, it is likely that the cardioprotective benefits of SGLT2i cannot be explained by “canonical” interactions with SGLT2.