Effect of Canagliflozin on Estimated Fluid Volumes in Patients with Heart Failure and type 2 Diabetes: A Post-hoc Analysis of the CANDLE Trial

Background: In patients with chronic heart failure (CHF) and type 2 diabetes (T2D), inhibition of the sodium-glucose cotransporter-2 (SGLT2) improves cardiorenal outcomes, but the effects of the SGLT2 inhibitor canagliflozin on body fluid volume and renal function remain to be clarified. Methods: This was a post-hoc analysis of 233 patients with CHF and T2D in the CANDLE Trial (UMIN000017669), an investigator-initiated, multi-center, randomized open-label trial that compared the effect of canagliflozin (100 mg, n=113) with glimepiride (starting dose: 0.5 mg, n=120) on changes in N-terminal pro-brain natriuretic peptide. The time courses of estimated plasma volume (ePV, calculated with the Straus formula), estimated extracellular volume (eEV, determined by the body surface area), and estimated glomerular filtration rate (eGFR, calculated with the modified Cockcroft formula) were compared between the canagliflozin and glimepiride groups at weeks 4, 12, and 24. Results: Reductions in ePV and eEV were observed only in the canagliflozin group until week 12 (change from baseline at week 12, ePV; -7.63%; 95% confidence interval [CI], -10.71 to -4.55%, p<0.001, eEV; -123.15 mL; 95% CI, -190.38 to -55.92 mL, p<0.001). Whilst ePV stopped falling after week 12, eEV continued to fall until week 24 ([change from baseline at week 24] – [change from baseline at week 12], ePV; 1.01%; 95%CI, -2.30 to 4.32%, p=0549, eEV; -125.15 mL; 95% CI, -184.35 to -65.95 mL, p<0.001). An initial significant reduction in eGFR was observed in the canagliflozin group (change from baseline at week 4, -4.18 mL/min/1.73 m 2 ; 95% CI, -5.99 to -2.37 mL/min/1.73 m 2 , p<0.001), but after 4 weeks, eGFR stopped falling, and the difference between groups became insignificant (change from baseline at week 24, -1.27 mL/min/1.73 m 2 ; 95% CI, -3.05 to 0.51 mL/min/1.73 m 2 , p=0.162, [change from baseline at week 24] – [change from baseline at week 12], 0.89 mL/min/1.73 m 2 ; 95% CI, -0.74 to 2.51 mL/min/1.73 m 2 , p=0.284). Conclusions: Canagliflozin reduced ePV and eEV gradually, whilst glimepiride did not. Maintenance of a modest reduction in ePV by canagliflozin suggests appropriate intravascular volume reduction contributing to cardiorenal benefits in patients with CHF and T2D.