Canagliflozin independently reduced plasma volume from conventional diuretics in patients with type 2 diabetes and chronic heart failure: a subanalysis of the CANDLE trial

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce the risk of heart failure progression and mortality rates. Moreover, osmotic diuresis induced by SGLT2 inhibition may result in an improved heart failure prognosis. Independent of conventional diuretics in patients with type 2 diabetes (T2D) and chronic heart failure, especially in patients with heart failure with preserved ejection fraction (HFpEF), it is unclear whether SGLT2i chronically reduces estimated plasma volume (ePV). As a subanalysis of the CANDLE trial, which assessed the effect of canagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP), we examined the change (%) in ePV over 24 weeks of treatment based on the baseline level associated with diuretic usage. In the CANDLE trial, nearly all patients were clinically stable (NYHA class I–II), with approximately 70% of participants presenting a baseline phenotype of HFpEF. A total of 99 (42.5%) patients were taking diuretics (mostly furosemide) at baseline, while 134 (57.5%) were not. Relative to glimepiride, canagliflozin significantly reduced ePV without worsening renal function in patients in both groups: −4.00% vs. 1.46% (p = 0.020) for the diuretic group and −6.14% vs. 1.28% (p < 0.001) for the nondiuretic group. Furthermore, canagliflozin significantly reduced serum uric acid without causing major electrolyte abnormalities in patients in both subgroups. The long-term beneficial effect of SGLT2i on intravascular congestion could be independent of conventional diuretic therapy without worsening renal function in patients with T2D and HF (HFpEF predominantly). In addition, the beneficial effects of canagliflozin are accompanied by improved hyperuricemia without causing major electrolyte abnormalities.