Effect of canagliflozin on N-terminal pro-brain natriuretic peptide in patients with type 2 diabetes and chronic heart failure according to baseline use of glucose-lowering agents

Abstract

Background Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of a deterioration in heart failure (HF) and mortality in patients with a broad range of cardiovascular risks. Recent guidelines recommend considering the use of SGLT2 inhibitors in patients with type 2 diabetes (T2D) and HF, irrespective of their glycemic control status and background use of other glucose-lowering agents including metformin. However, only a small number of studies have investigated whether the effects of SGLT2 inhibitor in these patients differ by the concomitant use of other glucose-lowering agents. Methods This was a post-hoc analysis of the CANDLE trial (UMIN000017669), an investigator-initiated, multicenter, open-label, randomized, controlled trial. The primary aim of the analysis was to assess the effect of 24 weeks of treatment with canagliflozin, relative to glimepiride, on N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in patients with T2D and clinically stable chronic HF. In the present analysis, the effect of canagliflozin on NT-proBNP concentration was assessed in the patients according to their baseline use of other glucose-lowering agents. Results Almost all patients in the CANDLE trial presented as clinically stable (New York Heart Association class I to II), with about 70% of participants having HF with a preserved ejection fraction phenotype (defined as a left ventricular ejection fraction ≥ 50%) at baseline. Of the 233 patients randomized to either canagliflozin (100 mg daily) or glimepiride (starting dose 0.5 mg daily), 85 (36.5%) had not been taking any glucose-lowering agents at baseline (naïve). Of the 148 patients who had been taking at least one glucose-lowering agent at baseline (non-naïve), 44 (29.7%) and 127 (85.8%) had received metformin or a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, respectively. The group ratio (canagliflozin vs. glimepiride) of proportional changes in the geometric means of NT-proBNP concentration was 0.95 (95% confidence interval [CI] 0.76 to 1.18, p = 0.618) for the naïve subgroup, 0.92 (95% CI 0.79 to1.07, p = 0.288) for the non-naïve subgroup, 0.90 (95% CI 0.68 to 1.20, p = 0.473) for the metformin-user subgroup, and 0.91 (95% CI 0.77 to 1.08, p = 0.271) for the DPP-4 inhibitor-user subgroup. No heterogeneity in the effect of canagliflozin, relative to glimepiride, on NT-proBNP concentration was observed in the non-naïve subgroups compared to that in the naïve subgroup. Conclusion The impact of canagliflozin treatment on NT-proBNP concentration appears to be independent of the background use of diabetes therapy in the patient population examined. Trial registration University Medical Information Network Clinical Trial Registry, number 000017669. Registered on May 25, 2015

Effects of sodium-glucose cotransporter-2 inhibitors on nutritional status in heart failure with reduced ejection fraction

“…Also, these parameters were significantly correlated with each other. Similarly, lower NT-pro-BNP levels were found after SGLT-2 inhibitor treatment in other studies involving patients with HF 15 , 16 . In some studies, improvement in exercise capacity, quality of life, and NYHA class were observed in patients with symptomatic HF after SGLT-2 inhibitor treatment 16 , 17 .…”

Comparing the Effects of Canagliflozin vs. Glimepiride by Body Mass Index in Patients with Type 2 Diabetes and Chronic Heart Failure: A Subanalysis of the CANDLE Trial

“…The median NT-proBNP levels in each treatment group are shown in Table 1 . Detailed information on background medications for T2D and chronic HF have been previously shown elsewhere [ 9 , 13 ].…”

“…The median NT-proBNP levels in each treatment group are shown in Table 1. Detailed information on background medications for T2D and chronic HF have been previously shown elsewhere [9,13]. Table 1 shows the baseline demographics and clinical characteristics for the full analysis set, stratified by baseline BMI.…”

Association between serum insulin levels and heart failure-related parameters in patients with type 2 diabetes and heart failure treated with canagliflozin: a post-hoc analysis of the randomized CANDLE trial

“…To investigate the influence of baseline serum insulin levels on treatment effects for those parameters at week 24, data were analyzed using linear regression models for NT-proBNP and linear mixed models for other parameters in subgroups according to baseline serum insulin level. The ratio (canagliflozin vs. glimepiride) of the proportional change from baseline to week 24 in NT-proBNP was estimated based on a natural logarithmic scale [ 28 ]. A p - value for the interaction between the study treatments and baseline serum insulin category on the NYHA class was calculated using an ordinal logistic regression model analysis.…”