Abstract
BackgroundSodium–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.MethodsThis 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.ResultsAlmost 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.ConclusionThe 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
Highlights
Metformin has been used widely for a long period of time and is an established and fundamental glucose-lowering agent for the treatment of type 2 diabetes (T2D) [1,2,3]
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
Earlier cardiovascular outcome trials (CVOT) on sodium–glucose cotransporter 2 (SGLT2) inhibitors showed they markedly reduced the risk of hospitalization for heart failure (HF) (HHF) and mortality in patients with T2D and established atherosclerotic cardiovascular diseases (ASCVD) or at high-risk of cardiovascular events [8,9,10]
Summary
Metformin has been used widely for a long period of time and is an established and fundamental glucose-lowering agent for the treatment of type 2 diabetes (T2D) [1,2,3]. Earlier cardiovascular outcome trials (CVOT) on sodium–glucose cotransporter 2 (SGLT2) inhibitors showed they markedly reduced the risk of hospitalization for HF (HHF) and mortality in patients with T2D and established atherosclerotic cardiovascular diseases (ASCVD) or at high-risk of cardiovascular events [8,9,10] These striking findings led the European Society of Cardiology (ESC) in collaboration with the European Association for the Study of Diabetes (EASD) to develop guidelines for diabetes, pre-diabetes, and cardiovascular diseases. The latest American Diabetes Association (ADA) guidelines recommend the use of SGLT2 inhibitors in patients with T2D and HF, especially HFrEF, regardless of the patient’s diabetes status and prior use of metformin [13]. 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
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