Larger eGFR Declines Could Improve Effectiveness of Canagliflozin

A drop in estimated glomerular filtration rate (eGFR) could still provide robust renal outcomes for end-stage kidney disease (ESKD) patients treated with canagliflozin, according to new research.

A team, led by Megumi Oshima, Department of Renal and Metabolic, The George Institute for Global Health, University of New South Wales Sydney, assessed whether eGFR declines less than 57% could detect canagliflozin’s effects on renal outcomes.

Historically, clinical trials evaluating the effects of a new therapy with creatinine-based renal end points use doubling of serum creatinine—equivalent to a 57% eGFR reduction—requiring large sample size.

In the post hoc study, the investigators compared the effects of canagliflozin with a placebo on composite renal outcomes using sustained 57%, 50%, 40%, or 30% eGFR reductions in conjunction with end-stage kidney disease and renal death.

Because canagliflozin causes an acute reversible hemodynamic decline in eGFR, the investigators made estimates using all eGFR values, as well as estimates that exclude early measures of eGFR influenced by the acute hemodynamic effect.

The investigators examined the data of 10,142 patients, 93 (0.9%), 161 (1.6%), 352 (3.5%), and 800 (7.9%) participants recorded renal outcomes on the basis of 57%, 50%, 40%, or 30% eGFR reduction, respectively, during a mean follow-up period of 188 weeks.

When compared with a 57% eGFR reduction (RR, 0.51; 95% CI, 0.34-0.77), the investigators identified the effect sizes were progressively attenuated when using 50% (RR, 0.61; 95% CI, 0.45-0.83), 40% (RR, 0.70; 95% CI, 0.57-0.86), or 30% (RR, 0.81; 95% CI, 0.71-0.93) eGFR reductions.

In an analysis where the researchers controlled for the acute hemodynamic fall in eGFR, they found effect sizes were comparable, regardless of whether a 57%, 50%, 40%, or 30% eGFR reduction was used. Estimated sample sizes for studies on the basis of lesser eGFR reduction s were much reduced by controlling for this early hemodynamic effect.

“Declines in eGFR <57% may provide robust estimates of canagliflozin’s effects on renal outcomes if the analysis controls for the drug’s acute hemodynamic effect,” the authors wrote.

Already a proven treatment for cardiovascular disease, canagliflozin could help patients suffering from kidney disease, after positive results from the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) study.

During American Society of Nephrology (ASN) Kidney Week in Washington, D.C., Janssen Pharmaceutical Companies of Johnson & Johnson announced the results of the phase III study, showing the consistent renal and cardiovascular benefit in treating patients with moderate to severe renal deficiency with canagliflozin, the only diabetes medicine indicated to slow down the progression of diabetic nephropathy.

The medication also reduces the risk of hospitalization for heart failure in patients with type 2 diabetes and diabetic nephropathy.

In the CREDENCE study, the investigators found patients with various levels of kidney function or estimated glomerular filtration rates (eGFR) benefit with a reduced risk of renal and cardiovascular events.

The study, “Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program,” was published online in the Journal of the American Society of Nephrology.