Use of sodium–glucose cotransporter 2 (SGLT2) inhibitors for treatment of type 2 diabetes could potentially lead to hypoxic acute renal injury in the setting of dehydration and/or during use of nonsteroidal anti-inflammatory agents (NSAIDs) or radiocontrast studies, according to an Israeli research team.
Hence, those circumstances should be avoided while people are taking the SGLT2 inhibitor class of glucose-lowering agents, Samuel N Heyman, MD, of Hadassah Hebrew University Hospitals, Jerusalem, Israel, and colleagues advise in an observation piece, published online January 27 in Diabetes Care.
SGLT2 inhibitors, such as canagliflozin canagliflozin (Invokana, Janssen) and dapagliflozin (Farxiga/Forxiga, AstraZeneca), carry US Food and Drug Administration (FDA) label warningsabout acute kidney injury. At the same time, empagliflozin (Jardiance, Boehringer Ingelheim), also an SGLT2 inhibitor, has been associated with long-term renoprotection in the EMPA-REG Outcome Study. And 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.
Although one issue is acute renal injury and the other long-term renal protection, these observations have caused some confusion among physicians.
Urine Biomarkers Needed to Assess Occurrence of Renal Injury
Now, in their new publication, Dr Heyman and colleagues say "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 transglomerular pressure reduction, is a reversible inherent factor of long-term renal protection, SGLT2 inhibition could potentially lead to significant renal impairment under specific conditions."
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 SGLT2 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.
Available urine biomarkers that could potentially be used to detect tubular injury — such as neutrophil gelatinase–associated lipocalin or kidney injury molecule-1 — were not used in EMPA-REG, nor were they systematically studied in the reported acute-kidney-injury cases, Dr Heyman and colleagues point out.
"From this perspective, we believe that studies using urine biomarkers are required to assess the true occurrence of hypoxic tubular injury in patients on SGLT2 inhibitors with declining kidney function," they observe.
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."
And the possibility of SGLT-2 inhibitor–induced acute hypoxic kidney injury "should be thoroughly investigated and validated in humans," they add.
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.
The authors have no relevant financial relationships.