Renal Effects of SGLT2 Inhibitors: An Update

Josselin Nespoux; Volker Vallon


Curr Opin Nephrol Hypertens. 2020;29(2):190-198. 

In This Article

SGLT2 Inhibition may Improve Kidney Metabolism and Autophagy

The greatest transport burden in the diabetic kidney is on the early proximal tubule.[13,44] By inhibiting SGLT2, the transport burden is more equally distributed among the tubular segments. Moreover, by lowering GFR, the total tubular transport burden is reduced. These effects of SGLT2 inhibition may also help to preserve mitochondrial function and tubular cell metabolism, which is expected to preserve tubular function and GFR in the long-term. Preliminary studies in T1DM Akita mice and patients with T2DM, showed that diabetes increased the urinary ratio of lactate to pyruvate, which may reflect a metabolic shift from mitochondrial oxidation to more glycolysis, and that this was reversed by an SGLT2 inhibitor.[48] A study in patients with T2DM and albuminuria found that dapagliflozin treatment increased urinary metabolites previously linked to mitochondrial metabolism compared with placebo, thus suggesting that dapagliflozin improves mitochondrial function in diabetes.[49] Studies in Akita mice showed that empagliflozin reduced the renal accumulation of p62, providing first evidence that SGLT2 inhibition may improve autophagy in the diabetic kidney.[50] Lee et al. showed that empagliflozin treatment improved mitochondrial fragmentation and enhanced renal proximal tubule cell autophagic activity under high glucose conditions and in STZ-treated mice, potentially involving the AMPK and mTOR pathway, thereby leading to lesser apoptosis and tubulointerstitial fibrosis.[51] Similarly, the SGLT2 inhibitor ipragliflozin reversed the tubular and mitochondrial damage caused by high-fat diet in mice, independent of blood glucose levels.[52] Thus, SGLT2 inhibitors may exert renoprotection and preserve kidney integrity by improving tubular energetics, mitochondria integrity and function, as well as autophagy (Figure 2).