Whether higher doses of sodium-glucose co-transporter-2 (SGLT-2) inhibitors provide additional cardiorenal benefit remains uncertain despite pharmacokinetic evidence suggesting dose-dependent effects on surrogate markers. A post hoc analysis of the CANVAS randomized controlled trial published in Diabetes, Obesity and Metabolism evaluated renal and cardiovascular outcomes associated with canagliflozin 100 mg and 300 mg using participant-level data from 4,330 patients. 

The primary outcome was a composite of doubling of serum creatinine, renal failure, or death from renal causes. Secondary outcomes included composite cardiovascular events, hospitalization for heart failure, all-cause mortality, and progression or regression of albuminuria. Safety analyses included serious hyperkalemia and acute kidney injury.

Findings

• No significant difference was observed between canagliflozin 100 mg and 300 mg for the primary composite renal endpoint (hazard ratio [HR] 0.85; 95% CI 0.38-1.89; P=0.68).
• Compared with placebo, both canagliflozin doses were associated with lower risk of the primary renal endpoint: 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.
• No significant differences between doses were observed for cardiovascular outcomes, hospitalization for heart failure, all-cause mortality, or albuminuria progression and regression.
• Serious hyperkalemia and acute kidney injury rates were similar between treatment groups, with no additional safety concerns identified for either dose.

This post hoc CANVAS analysis did not identify evidence of dose-dependent differences in renal or cardiovascular outcomes between canagliflozin 100 mg and 300 mg. Both doses were associated with reduced kidney event risk versus placebo, supporting clinical benefit across dosing strategies.