Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure: a sub analysis of the CANDLE trial

Abstract

Background Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline. Methods Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function. Results The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89–1.08) in the canagliflozin group and 1.07 (95% CI 0.97–1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82–1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e′) showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e′ < 4.7 cm/s indicated there was an association with lower NT-proBNP levels in the canagliflozin group compared with that in the glimepiride group (ratio of change with canagliflozin/glimepiride (0.83, 95% CI 0.66–1.04). Conclusions In the subgroup with a lower LV diastolic function, canagliflozin showed a trend of reduced NT-pro BNP levels compared to that observed with glimepiride. This study suggests that the beneficial effects of canagliflozin treatment may be different in subgroups classified by the severity of LV diastolic dysfunction.

Diabetes mellitus status modifies the association between N-terminal B-type natriuretic peptide and all-cause mortality risk in ischemic heart failure: a prospective cohort study

“…The protective effects were attributed to several mechanisms, including the diuretic effect of SGLT2i, more efficient production of ATP, and mitochondrial function reestablishment [ 27 – 29 ]. The effect of SGLT2i on NT-proBNP was also recognized as another potential pathway to produce a beneficial impact [ 30 , 31 ] but remains controversial [ 32 ]. Our current results provide robust evidence that the association between NT-proBNP and mortality was more remarkable in HF patients with DM than without, suggesting that lowering NT-proBNP levels in patients with HF and DM would be a promising direction to gain benefit.…”

Heart failure in type 2 diabetes: current perspectives on screening, diagnosis and management

“…The reduction of CV-related events in people with T2D and CV risk can be attributed in parts to the lowered NT-proBNP concentration in the canagliflozin arm of the CANVAS trial [ 134 ]. Also, a trend towards lower NT-proBNP levels in the subgroup with a lower LV diastolic function was observed in the canagliflozin treated group compared to the glimepiride treated arm, as shown in a sub-analysis of the CANDLE trial [ 135 ]. In line with canagliflozin, dapagliflozin also lowered NT-proBNP levels significantly more than placebo in the DAPA-HF cohort [ 124 ].…”

Diabetes Mellitus Type 2, Prediabetes, and Chronic Heart Failure

“…The decreased NT-proBNP concentration in the canagliflozin arm of the CANVAS trial can be ascribed in part to the reduction in CV-related events in patients with T2D and CV risk [154]. In addition, a sub-analysis of the CANDLE study found a tendency toward decreased NT-proBNP levels in the subgroup with lower LV diastolic function in the canagliflozin treated arm compared to the glimepiride treated arm [155]. Dapagliflozin, like canagliflozin, reduced NT-proBNP levels considerably higher than placebo in the DAPA-HF group [145,149].…”