Do SGLT2 Inhibitors Cause Kidney Damage?

Professor Samuel N. Heyman, MD, Division of Medicine, Hadassah Hebrew University Hospitals, Jerusalem, and colleagues recently published a hypothesis suggesting that the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors may lead to acute kidney injury (AKI) under certain conditions. These findings were based on clinical observations and previous research (Diabetes Care. Published online ahead of print January 27, 2017 doi: 10.2337/dc16-2200).
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Some of the conditions highlighted in the paper include dehydration as a result of osmotic diuresis and natriuresis and intensification of renal parenchymal hypoxia and hypoxic kidney injury.

This second possibility indicates that “physiological hypoxia in the renal medulla is further intensified in the diabetic kidney and that SGLT inhibition further intensifies medullary hypoxia,” Dr. Heyman told Pharmacy Learning Network. “This might be especially important under conditions known to particularly intensify medullary hypoxia, namely nonsteroidal anti-inflammatory drugs (NSAIDs) and radiocontrast agents (eg, iothalamate, ioversol, iodixanol, iohexol), since such insults, combined with SGLT2 inhibitors, may in concert lead to medullary hypoxic injury, manifested as AKI.”

SGLT2 inhibitors are used concurrently with diet and exercise to lower blood sugar in patients with type 2 diabetes. They are also sometimes taken with other medications. Canagliflozin, dapagliflozin, and empagliflozin are some commonly used SGLT2 inhibitors.

Dr. Heyman emphasized the following observations leading to the hypothesis of potential medullary hypoxic injury causing SGLT2 inhibitor-mediated AKI:

• Diabetes leads to profound renal medullary hypoxia.
• Medullary hypoxia in the diabetic kidney evokes hypoxic stress response and predisposes to hypoxic tubular injury.
• SGLT inhibition intensifies medullary hypoxia.
• Increased erythropoietin and reticulocytosis in patients taking SGLT2 inhibitors indicates that renal oxygenation drops.

“Until these hypotheses are tested (in animal studies and in patients on SGLT2 inhibitors and declining estimated glomerular filtration rate by using urine biomarkers), clinicians should avoid the concomitant use of SGLT2 inhibitors with NSAIDs and stop SGLT2 inhibitors prior to studies using radiocontrast agents in order to avoid the possible development of hypoxic acute tubular necrosis,” Dr. Heyman said. 

The authors note in the paper that studies using urine biomarkers are necessary to ascertain the true occurrence of hypoxic tubular injury in those taking SGLT2 inhibitors who have declining kidney function, as they were not evaluated in previous research (ie, the EMPA-REG OUTCOM study) or in the reported cases of AKI linked to use of SGLT2 inhibitors.

Further, the authors stress the importance of maintaining one’s hydration status to lower the risk of volume depletion in high-risk patients with diabetes who are taking SGLT2 inhibitors.

Finally, Dr. Heyman suggests that caution should be exercised in individuals with conditions that “may produce a too profound alteration of glomerular hemodynamics in response to SGLT2 inhibitors,” such as diuretic-induced volume depletion or renin–angiotensin–aldosterone system blockade.

The paper was published in Diabetes Care.--Meredith Edwards White