Canagliflozin reduces proteinuria by targeting hyperinsulinaemia in diabetes patients with heart failure: A post hoc analysis of the CANDLE trial

Aim To investigate factors associated with proteinuria regression in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin. Materials and Methods This study was a post hoc analysis of the CANDLE trial (UMIN000017669), which compared the effect of 24 weeks of treatment with canagliflozin or glimepiride for changes in N-terminal pro-brain natriuretic peptide in patients with T2DM and chronic heart failure (CHF). Factors associated with regression of proteinuria at 24 weeks were evaluated with multivariate logistic models. Results The rate of regression of proteinuria was higher (28/102, 27.5% vs. 12/112, 10.7%), and that of progression was lower (9/102, 8.8% vs. 26/112, 23.2%), in the canagliflozin versus the glimepiride group (P = .0001). There were no differences in the change in the estimated glomerular filtration rate category between groups. Insulin level, homeostatic model assessment of beta-cell function, homeostatic model assessment for insulin resistance and estimated plasma volume were decreased at 24 weeks in the regression subclass but not in the progression subclass, suggesting that regression of proteinuria is associated with the declines in these values in the canagliflozin group. Higher insulin level at baseline was solely associated with proteinuria regression in the multivariate logistic regression model (baseline insulin, as per a 1-mlU/L increase, odds ratio 1.24 [1.05-1.47], P = .011). Conclusions In patients with T2DM and CHF, regression of proteinuria with canagliflozin treatment was associated with the pretreatment insulin level. These results may provide clinicians with novel mechanistic insights into the beneficial effects of canagliflozin on renal outcomes and may warrant discussion for selecting preferred patient profiles, including pretreatment insulin levels.

Automated summary

The aim of this study was to investigate factors associated with proteinuria regression in patients with type 2 diabetes treated with canagliflozin. The results showed that the rate of proteinuria regression was higher and the rate of progression was lower in the canagliflozin group compared to the glimepiride group. In the regression subclass, insulin level, beta-cell function, insulin resistance, and estimated plasma volume were decreased at 24 weeks. Baseline insulin level was associated with proteinuria regression in the multivariate logistic regression model.