SGLT2 Inhibitors Appear Beneficial In Advanced Kidney Disease, Too

A post-hoc subgroup analysis of the CREDENCE study found that treatment with canagliflozin slowed kidney-function decline in patients with advanced diabetic kidney disease and also reduced the risk of kidney failure and heart problems.

Based on the CREDENCE trial, the U.S. Food and Drug Administration approved the SGLT2 inhibitor for prevention of kidney failure among patients with type-2 diabetes with estimated glomerular filtration rate (eGFR) >30 mL/min per 1.73 m2.

A lingering question is whether the drug is similarly beneficial in patients with a lower eGFR.

To investigate, Dr. George Bakris of the University of Chicago Medicine and the CREDENCE trialists did a post-hoc efficacy and safety analysis of canagliflozin among the 174 trial participants who had eGFR <30 mL/min/1.73 m2 at randomization in comparison to those with eGFR at or above 30 mL/min/1.73 m2.

During the 130-week follow-up period, canagliflozin appeared to slow decline in kidney function in the subgroup with advanced kidney disease, compared with placebo, with a 66% difference (average eGFR decline of -1.30 vs. -3.83 mL/min/1.73 m2 per year), a significant difference.

The effects of canagliflozin on kidney, cardiovascular and mortality outcomes mirrored those seen in patients with less advanced kidney disease (eGFR >30).

"There was no imbalance in the rate of kidney-related adverse events or acute kidney injury (AKI) associated with canagliflozin between participants with eGFR <30 and ≥30 mL/min/1.73 m2," Dr. Bakris and colleagues report in the Clinical Journal of the American Society of Nephrology (CJASN).

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"Until recently, there were limited data regarding the use of SGLT2 inhibitors in patients with compromised kidney function, and there were few treatment options for this patient population who are at a high risk for developing kidney failure. This research suggests that canagliflozin is a safe treatment option for this patient population that can help to slow the progression of kidney disease," Dr. Bakris said in a news release.

In a linked editorial, Dr. Sophia Zoungas of Monash University and Dr. Kevan Polkinghorne of Monash Health, in Melbourne, Australia, say while the results of this post-hoc analysis are "compelling, an important omission was the number of euglycaemic ketoacidosis events."

They note that in the main CREDENCE trial there was a 10-fold increased risk for euglycemic ketoacidosis with canagliflozin in the overall trial population.

"Understanding the risk of this serious complication for this vulnerable patient population (already at risk of uremic acidosis), will be critical for safe prescribing. Further trials and real-world observational studies will hopefully address this concern," they write.

Data from the recently completed DAPA-CKD and the ongoing EMPA-Kidney trial will provide further efficacy and safety information on SGLT2 inhibitors in patients with advanced kidney disease, they note.

"Until then, it would seem reasonable for clinicians to commence SGLT2 inhibitors based on current indication (patients with type 2 diabetes and proteinuric kidney disease with eGFR>30), to monitor patients closely and to continue treatment based on individual tolerability, even when eGFR drops below 30 or until the commencement of chronic dialysis or receipt of a kidney transplant."

The CREDENCE study was sponsored by Janssen Research and Development, LLC, which co-developed canagliflozin with Mitsubishi Tanabe Pharma Corporation. All of the authors received research support and consulting fees from Janssen in relation to their roles on the steering committee of the CREDENCE trial.

—Reuters Staff

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