Sodium-Glucose Cotransporter 2 Inhibitors

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have emerged as the most impactful advance in clinical nephrology since the wide-spread adoption of angiotensinogen-converting enzyme inhibitors. An investigative spotlight now focuses on this drug class, in large part due to their profound cardiorenal protective effects. More than 13,000 manuscripts related to SGLT2is have been published since these agents were approved for clinical use in 2012. Preservation of kidney function and reduction in cardiovascular morbidity and mortality are seen in a variety of patient populations taking SGLT2is. Remarkably, cardiorenal protection is afforded to patients with or without diabetes, suggesting the mechanisms involved include more than glycemic control.

A clinically important phenomenon associated with SGLT2i treatment is the promotion of urinary Mg²⁺ conservation.¹ Improved Mg²⁺ intake is associated with a lower risk of heart failure.² Higher circulating Mg²⁺ levels are associated with a lower risk of cardiovascular and all-cause mortality in patients with CKD.³ SGLT2is improve circulating Mg²⁺ in settings as disparate as congenital Mg²⁺ wasting, diabetes mellitus, calcineurin inhibition, and cisplatin. These observations suggest that Mg²⁺ conservation may contribute to improved cardiovascular outcomes in patients receiving SGLT2is.

Mg²⁺ wasting is a well-known adverse effect of platinum-based therapies. This occurs, at least in part, due to cellular toxicity and associated disruption of solute transport in the thick ascending limb (TAL)—the major site of tubular Mg²⁺ reabsorption. In the TAL, a lumen-positive transepithelial potential (V_TE), generated by the coupled activity of renal outer medullary K⁺ channels (electrogenic) and the Na-K-Cl cotransporter (NKCC2; electroneutral), drives paracellular Mg²⁺ transport through the tight junctional claudin-16/9 complex. Reduction in NKCC2 activity by cisplatin likely reduces V_TE, decreasing Mg²⁺ reabsorption in that segment.

In this issue of JASN, Jesus et al. provide evidence that cisplatin-induced Mg²⁺ wasting can be reversed in rats by administering the SGLT2i, empagliflozin.⁴ They demonstrate reduced fractional excretion of Mg²⁺ (FEMg²⁺) with SGLT2i compared with cisplatin alone, indicating enhanced tubular reabsorption. In rats treated with cisplatin, empagliflozin reduces atrophy of the TAL and distal convoluted tubule segments, restoring the diuretic response to furosemide or hydrochlorothiazide. Consistent with improved tubular health and function, empagliflozin-treated animals exhibit restored abundance of active, phosphorylated NKCC2; active, phosphorylated NaCl cotransporter; the Mg²⁺-selective, transient receptor potential channel M6 (TRPM6); and claudin-16. Empagliflozin enhances phosphorylated NaCl cotransporter in rats not receiving cisplatin, but does not alter phosphorylated NKCC2, claudin-16, or TRPM6 abundance in uninjured animals, suggesting that at least some of the protective effects of empagliflozin may be specific to cisplatin-induced injury.

This work sheds new light on the physiology of Mg²⁺ conservation with SGLT2i treatment in the context of cisplatin treatment. Still, the molecular mechanisms driving these protective effects remain unresolved. The segmental location of Mg²⁺ reabsorption was not determined from these experiments, as changes in transporter expression do not necessarily indicate changes in Mg²⁺ flux. For example, in a rat model of metabolic syndrome, dapagliflozin reduced FEMg²⁺ and improved blood Mg²⁺ without any apparent change in TRPM6 or claudin-16 abundance.⁵ Although the method of transporter abundance measurement in that study (immunohistochemistry intensity) was not definitive, the findings highlight the concept that Mg²⁺ transport may be influenced independently of transporter abundance. FEMg²⁺ reflects the composite of transport throughout the nephron, and the impact of empagliflozin on Mg²⁺ flux in individual segments is still unknown. SGLT2 is an electrogenic transporter. Inhibition of Na⁺–glucose cotransport in the proximal tubule shifts the luminal V_TE in the positive direction.⁶ SGLT2i treatment also redistributes Na⁺ reabsorption from the proximal tubule to more distal nephron segments. This may increase electrolyte cycling through NKCC2 and renal outer medullary K⁺ and shift the luminal V_TE in the TAL in the positive direction. Either of these effects would enhance the driving force for Mg²⁺ reabsorption in that respective segment. The predominating tubular segment and mechanism by which SGLT2 inhibitors enhance tubular Mg²⁺ reabsorption thus remains unclear.

The manuscript by Jesus et al. also provides provocative findings related to cisplatin-associated AKI. Twenty to 40% of patients treated with cisplatin experience AKI. Jesus et al. find that empagliflozin protects GFR and BUN levels. These results echo those of Abdelrahman et al., who showed similar protection in mice treated with another SGLT2i, canagliflozin.⁷ Canagliflozin attenuated the inflammatory and oxidative damage caused by cisplatin, significantly improving biochemical and histological evidence of tissue damage. The proposed mechanism of kidney protection was secondary to reduced accumulation of cisplatin in the proximal tubular epithelial cells. The effects of empagliflozin on platinum accumulation, inflammation, or oxidative factors were not examined in the study by Jesus et al. It also remains unclear whether kidney protection was causally related to the Mg²⁺ status of the animals. Mg²⁺ loading reduces accumulation of platinum in kidney tissue⁸ and reduces the risk of cisplatin-induced AKI.⁹ Regardless of the cause, findings that SGLT2i protects against AKI are important and deserving of further exploration.

Little is known regarding the influence of SGLT2 inhibition on the efficacy of platinum-based chemotherapy regimens. Whether SGLT2i influences cisplatin's chemotherapeutic efficacy remains to be seen. Cisplatin clearance likely changes with the fall in GFR observed with SGLT2i treatment. A more general concern regarding combined SGLT2i/chemotherapeutic treatment is the potential for the higher risk of infection because of heavy glycosuria in the context of chemotherapy-associated leukopenia. Further effects related to carbohydrate calorie-wasting caused by SGLT2 inhibition may also be of concern in patients with cancer, where nutritional status is a challenge.

Despite these practical concerns, Jesus et al. provide exciting new evidence addressing the ability of SGLT2 inhibitors to promote urinary Mg²⁺ conservation and broaden the potential settings in which SGLT2 inhibition may help preserve kidney function. As such, the stream of surprises provided by these agents remains as sweet as the urine they produce.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F297.

Author Contributions

Conceptualization: Evan C. Ray.

Writing – original draft: Andrew J. Nickerson, Evan C. Ray.

Writing – review & editing: Andrew J. Nickerson, Evan C. Ray.

Funding

E.C. Ray: Division of Diabetes, Endocrinology, and Metabolic Diseases (R01DK139177).