Kidney failure, CV events lower with canagliflozin than placebo, industry study finds

Canagliflozin was associated with lower rates of end-stage kidney disease and death from renal or cardiovascular causes than placebo, according to a recent industry-funded study of type 2 diabetes patients at high risk for kidney failure.

The trial, which was supported by Janssen, included 4,401 patients with type 2 diabetes, an estimated glomerular filtration rate (GFR) of 30 to below 90 mL/min/1.73 m², and albuminuria (ratio of albumin to creatinine between 300 and 5,000). All were treated with renin-angiotensin system blockade and they were randomized to 100 mg of canagliflozin, an oral sodium-glucose cotransporter-2 (SGLT2) inhibitor, or placebo daily. Results were published by the New England Journal of Medicine on April 14.

The trial was stopped early after a planned interim analysis, at which point patients had been followed for a median of 2.62 years. The canagliflozin group did significantly better on the study's primary outcome, a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 mL/min/1.73 m²), doubling of serum creatinine, or death from renal or cardiovascular causes. Event rates were 43.2 versus 61.2 per 1,000 patient-years (hazard ratio [HR], 0.70; 95% CI, 0.59 to 0.82; P=0.00001).

There were similar reductions in the risk of end-stage kidney disease (HR, 0.68; 95% CI, 0.54 to 0.86; P=0.002) and the composite renal outcome (end-stage kidney disease, doubling of creatinine, or death from renal causes) (HR, 0.66; 95% CI, 0.53 to 0.81; P<0.001) with the drug. The canagliflozin group also had a lower rate of cardiovascular death, myocardial infarction, or stroke (HR, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (HR, 0.61; 95% CI, 0.47 to 0.80; P<0.001). The groups had similar rates of amputation and fracture.

It's significant that these results were achieved among patients at high risk for kidney failure on a background of renin-angiotensin system blockade, the study authors said. They noted that between-group differences in glycemic control, weight, and blood pressure were modest, suggesting that the mechanism of benefit from SGLT2 inhibitors is likely independent of glucose levels. The similar rates of amputation and fracture are reassuring but do not explain why the earlier CANVAS trial found an increased risk of amputation with canagliflozin, the authors said. The early discontinuation of this trial was one of its limitations and may have limited the power of secondary outcomes, they added.

An accompanying editorial said that the trial was well done and that its importance “cannot be overstated.” It noted that the mechanisms of canagliflozin are probably both renal and systemic.