The Effect of Canagliflozin Dose on Renal and Cardiovascular Outcomes in Type 2 Diabetes and High Cardiovascular Risk

Pharmacokinetic data suggest a potential dose-dependent effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors on surrogate markers of efficacy, but the impact of SGLT-2 inhibitor dose on renal and cardiovascular outcomes remains uncertain.

In this post hoc analysis, we evaluated the efficacy and safety of two canagliflozin doses (100 and 300 mg) on hard clinical endpoints using participant-level data from the CANVAS randomised controlled trial (4330 patients). The primary outcome was a composite of doubling of serum creatinine, renal failure, or death due to renal cause. Secondary outcomes included a composite cardiovascular endpoint; hospitalisation for heart failure; all-cause mortality; and progression or regression of albuminuria. Safety outcomes included serious hyperkalaemia and acute kidney injury. Cox proportional hazards models were used.

There was no significant difference in the composite renal endpoint between the two doses: hazard ratio (HR) 0.85; 95% confidence interval (CI) 0.38-1.89 (p = 0.68). Both doses, however, were associated with significant reductions in the incidence of the primary renal endpoint compared with placebo: HR 0.49 (95% CI 0.25-0.95; p = 0.03) for 100 mg and HR 0.41 (95% CI 0.20-0.83; p = 0.01) for 300 mg. There was no difference between the two doses of the drug in any of the secondary endpoints. Importantly, no added safety concerns were identified with either dose.

In this post hoc analysis of the CANVAS trial, we did not observe evidence of a dose-dependent effect of canagliflozin on renal or cardiovascular outcomes. Both doses reduced the risk of kidney events versus placebo, suggesting clinical benefit at any dose.