medwireNews: A post-hoc analysis of the CREDENCE trial suggests that canagliflozin could be beneficial in people with advanced diabetic kidney disease.
Study participants were enrolled to CREDENCE on the basis of having an estimated glomerular filtration rate (eGFR) of at least 30 mL/min per 1.73 m2 at the time of screening. But by the time of randomization, 174 (4%) of them had fallen below this threshold, to an average of 26 mL/min per 1.73 m2.
They were nevertheless allowed to continue in the trial, and baseline characteristics were well balanced between the 84 people randomly assigned to take canagliflozin and the 90 assigned to receive placebo.
During the 130-week follow-up period, patients taking canagliflozin had a significantly slower decline in kidney function than those taking placebo, with average annual rates of decline between week 3 and the last measurement being 1.30 versus 3.83 mL/min per 1.73 m2.
Of note, George Bakris (University of Chicago Medicine, Illinois, USA) and co-researchers found no sign of an acute, reversible decline in kidney function during the first few weeks of canagliflozin use, despite this being a known effect of sodium-glucose cotransporter (SGLT)2 inhibitors.
People with eGFR below 30 mL/min per 1.73 m2 were no more likely than those with better kidney function to discontinue study treatment, for any reason or for adverse effects. Their risk for kidney failure was reduced by a significant 33% with canagliflozin versus placebo, which was not significantly different to the 30% risk reduction gained by people with a higher eGFR.
Neither group had a significant change in their risk for acute kidney injury with canagliflozin versus placebo, or in their overall adverse event risk.
The findings are published in the Clinical Journal of the American Society of Nephrology, with a linked editorial from Sophia Zoungas (Monash University, Melbourne, Victoria, Australia) and Kevan Polkinghorne (Monash Health, Melbourne, Victoria, Australia), who describe the analysis as “compelling.”
However, they say: “An important omission was the number of euglycaemic ketoacidosis events,” noting that there was a 10-fold increased risk for this outcome with canagliflozin treatment 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,” they say.
Zoungas and Polkinghorne note that data from DAPA-CKD and the ongoing EMPA-Kidney trial will provide further efficacy and safety information for this population.
They conclude: “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.”
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Clin J Am Soc Nephrol 2020; doi:10.2215/CJN.10140620
Clin J Am Soc Nephrol 2020; doi:10.2215/CJN.16351020