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Caution: NSAIDs with SGLT-2 Inhibitors May Cause Renal Injuries

New research finds issue in the context of dehydration, and/or during use of nonsteroidal anti-inflammatory agents (NSAIDs) or radiocontrast studies.  

This possible combination should be avoided while people are taking the SGLT-2 inhibitor class of glucose-lowering agents, according to Samuel N Heyman, MD, of Hadassah Hebrew University Hospitals, Jerusalem, Israel, and colleagues.

Two SGLT-2 inhibitors, canagliflozin and dapagliflozin, carry U.S. Food and Drug Administration (FDA) label warnings about acute kidney injury, but, paradoxically, another SGLT-2 inhibitor, empagliflozin, has been associated with long-term renoprotection in the EMPA-REG Outcome Study. Canagliflozin is being specifically tested in a diabetic kidney-disease population in the large multicenter randomized Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial.

There might be a few explanations for this troubling news other than mere chance and publication bias. They note that “while an initial reduction in glomerular filtration rate, related to trans-glomerular pressure reduction, is a reversible inherent factor of long-term renal protection, SGLT-2 inhibition could potentially lead to significant renal impairment under specific conditions.”

They found that the sodium glucose cotransporter 2 (SGLT-2) inhibitor empagliflozin provided renal protection over four years of follow-up in patients with type 2 diabetes. Furthermore, the incidence of overt acute kidney injury (AKI) showed a trend in favor of the treatment group, especially beyond 18 months of randomization. However, a recent U.S. Food and Drug Administration Drug Safety Communication reports 101 cases of AKI in patients treated with SGLT-2 inhibitors, some of whom required hospitalization and dialysis.

Dehydration resulting from osmotic diuresis and natriuresis is one such condition that is mentioned in the FDA label warning and could particularly affect frail patients on diuretics, they note. In addition, both animal and human data suggest that diabetes itself raises the risk of renal parenchymal hypoxia and hypoxic injury. And the authors’ previous study suggests that both hypoxia and the expression of hypoxia-inducible factors are intensified in the diabetic kidney (Biomed Res Int. 2013; 2013:123589), while experimental diabetes predisposes to medullary hypoxic tubular injury.

Thus, Dr. Heyman and colleagues argue, the introduction of SGLT-2 inhibitors for diabetes treatment could further aggravate the hypoxia at the corticomedullary junction, which in turn could be worsened even further in the setting of concomitant agents that also predispose to medullary hypoxic injury, including NSAIDs or radiocontrast agents.

Tubular injury can currently be detected by urine biomarkers, such as neutrophil gelatinase associated lipocalin or kidney injury molecule-1, preceding or even in the absence of overt renal functional impairment. Such biomarkers were not evaluated in the BI 10773 (Empagflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), nor were they systematically studied in the reported cases of SGLT-2 inhibition associated AKI. From this perspective, it is believed that studies using urine biomarkers are required to assess the true occurrence of hypoxic tubular injury in patients on SGLT-2 inhibitors with declining kidney function.  Thus, it is prudent to suggest that special care be taken regarding maintenance of the hydration status to reduce the risk of volume depletion in high-risk patients with diabetes on SGLT-2 inhibitors. Furthermore, the possibility of SGLT-2 induced hypoxic AKI should be thoroughly investigated and validated in humans.  Meanwhile, with this possibility in mind, the researchers propose avoidance of the concomitant administration of agents that lead to iatrogenic hypoxic medullary injury: avoidance of NSAIDs in patients on SGLT-2 inhibitors and cessation of SGLT-2 inhibitors prior to radiocontrast studies.

In the meantime, “it is prudent to suggest that special care be taken regarding maintenance of the hydration status to reduce the risk of volume depletion in high-risk patients with diabetes on SGLT-2 inhibitors,” researchers said. And, they concluded, the possibility of SGLT-2 inhibitor–induced acute hypoxic kidney injury “should be thoroughly investigated and validated in humans.”

Until then, “we propose avoidance of the concomitant administration of agents that lead to iatrogenic hypoxic medullary injury: avoidance of NSAIDs in patients on SGLT-2 inhibitors and cessation of SGLT-2 inhibitors prior to radiocontrast studies,” they reiterate.

Practice Pearls:

  • Researchers recommend avoidance of NSAIDs in patients on SGLT-2 inhibitors and cessation of SGLT-2 inhibitors prior to radiocontrast studies.
  • Special care needs to be taken regarding maintenance of the hydration status to reduce the risk of volume depletion in high-risk patients with diabetes on SGLT-2 inhibitors.
  • It is important to warn your patients to avoid NSAIDs when taking SGLT-2 inhibitors.

Diabetes Care. Published online January 27, 2017. Article