SGLT2 Inhibitors and Kidney Protection: Mechanisms Beyond Tubuloglomerular Feedback

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk for kidney failure and are a key component of guideline-directed therapy for CKD. While SGLT2 inhibitors' ability to activate tubuloglomerular feedback and reduce hyperfiltration-mediated kidney injury is considered to be the central mechanism for kidney protection, recent data from experimental studies raise questions on the primacy of this mechanism. This review examines SGLT2 inhibitors' role in tubuloglomerular feedback and summarizes emerging evidence on following of SGLT2 inhibitors' other putative mechanisms for kidney protection: optimization of kidney's energy substrate utilization and delivery, regulation of autophagy and maintenance of cellular homeostasis, attenuation of sympathetic hyperactivity, and improvement in vascular health and microvascular function. It is imperative to examine the effect of SGLT2 inhibition on these different physiologic processes to help our understanding of mechanisms underpinning kidney protection with this important class of drugs.