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. 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. 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. 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

中文翻译：

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根据降糖药的基线使用情况，卡格列净对 2 型糖尿病合并慢性心力衰竭患者 N 端脑利钠肽前体的影响

钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂可降低具有广泛心血管风险的患者心力衰竭 (HF) 恶化和死亡率的风险。最近的指南建议考虑在患有 2 型糖尿病 (T2D) 和 HF 的患者中使用 SGLT2 抑制剂，无论他们的血糖控制状态和其他降糖药物（包括二甲双胍）的背景使用情况如何。然而，只有少数研究调查了 SGLT2 抑制剂对这些患者的影响是否因同时使用其他降糖药物而不同。这是对 CANDLE 试验 (UMIN000017669) 的事后分析，该试验是一项由研究者发起的、多中心、开放标签、随机对照试验。分析的主要目的是评估卡格列净治疗 24 周的效果，相对于格列美脲，对 T2D 和临床稳定的慢性 HF 患者 N 端脑利钠肽前体 (NT-proBNP) 浓度的影响。在本分析中，根据患者使用其他降糖药物的基线情况，评估了卡格列净对 NT-proBNP 浓度的影响。CANDLE 试验中几乎所有患者都表现出临床稳定（纽约心脏协会 I 级至 II 级），约 70% 的参与者在基线时具有保留射血分数表型（定义为左心室射血分数 ≥ 50%）的 HF . 在随机接受卡格列净（每天 100 毫克）或格列美脲（起始剂量每天 0.5 毫克）的 233 名患者中，85 名（36.5%）在基线时未服用任何降糖药物（未接受过治疗）。在基线时（非初治）至少服用一种降糖药的 148 名患者中，44 名（29.7%）和 127 名（85.8%）接受了二甲双胍或二肽基二肽酶 4（DPP-4）抑制剂，分别。对于初始亚组，NT-proBNP 浓度几何平均值的比例变化的组比（卡格列净与格列美脲）为 0.95（95% 置信区间 [CI] 0.76 至 1.18，p = 0.618），0.92（95% CI 0.79）到 1.07，p = 0.288）对于非初始亚组，0.90（95% CI 0.68 到 1.20，p = 0.473）对于二甲双胍使用者亚组，0.91（95% CI 0.77 到 1.08，p = 0.271） DPP-4 抑制剂用户亚组。与初始亚组相比，在非初始亚组中观察到卡格列净相对于格列美脲对 NT-proBNP 浓度的影响没有异质性。卡格列净治疗对 NT-proBNP 浓度的影响似乎与检查的患者人群中糖尿病治疗的背景使用无关。试验注册 大学医学信息网临床试验注册，编号000017669。2015年5月25日注册