British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
JAMA. 2020 Apr 14;323(14):1353-1368. doi: 10.1001/jama.2020.1906.
Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes.
To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes.
DESIGN, SETTING, AND PARTICIPANTS: Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019.
Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy.
The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%.
Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes.
In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status.
ClinicalTrials.gov Identifier: NCT03036124.
重要性：对于射血分数降低的心力衰竭（HFrEF）患者，需要额外的治疗方法。钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂可能是 HFrEF 患者的有效治疗方法，甚至对那些没有糖尿病的患者也是如此。
目的：评估达格列净在伴有或不伴有糖尿病的 HFrEF 患者中的疗效。
设计、地点和参与者：在 20 个国家的 410 个地点进行的 3 期随机试验的探索性分析。2017 年 2 月 15 日至 2018 年 8 月 17 日期间，新的心脏协会分类 II 至 IV 级、射血分数小于或等于 40% 和血浆 N 末端 pro B 型利钠肽升高的患者被纳入研究，最终随访时间为 2019 年 6 月 6 日。
干预措施：在推荐治疗的基础上，每日一次添加 10 毫克达格列净或安慰剂。
主要结果和措施：主要结局是心力衰竭恶化或心血管死亡的综合事件。该结果根据基线糖尿病状态进行分析，对于没有糖尿病的患者，则根据糖化血红蛋白水平小于 5.7%与大于或等于 5.7%进行分析。
结果：在 4744 名随机分组的患者中（平均年龄 66 岁；1109[23%]名女性；2605[55%]名无糖尿病），4742 名患者完成了试验。在没有糖尿病的患者中，达格列净组有 1298 名患者中的 171 名（13.2%）和安慰剂组有 1307 名患者中的 231 名（17.7%）发生主要结局（风险比，0.73[95%CI，0.60-0.88]）。在有糖尿病的患者中，达格列净组有 1075 名患者中的 215 名（20.0%）和安慰剂组有 1064 名患者中的 271 名（25.5%）发生主要结局（风险比，0.75[95%CI，0.63-0.90]）（P 值为 0.80）。在糖化血红蛋白水平小于 5.7%且没有糖尿病的患者中，达格列净组有 438 名患者中的 53 名（12.1%）和安慰剂组有 419 名患者中的 71 名（16.9%）发生主要结局（风险比，0.67[95%CI，0.47-0.96]）。在糖化血红蛋白水平至少为 5.7%的患者中，达格列净组有 860 名患者中的 118 名（13.7%）和安慰剂组有 888 名患者中的 160 名（18.0%）发生主要结局（风险比，0.74[95%CI，0.59-0.94]）（P 值为 0.72）。在没有糖尿病的患者中，达格列净组有 7.3%的患者和安慰剂组有 6.1%的患者报告了血容量不足的不良反应，而在有糖尿病的患者中，达格列净组有 7.8%的患者和安慰剂组有 7.8%的患者报告了肾脏不良事件。在没有糖尿病的患者中，达格列净组有 4.8%的患者和安慰剂组有 6.0%的患者报告了肾脏不良事件，而在有糖尿病的患者中，达格列净组有 8.5%的患者和安慰剂组有 8.7%的患者报告了肾脏不良事件。
结论和相关性：在这项 HFrEF 患者的随机试验的探索性分析中，与安慰剂相比，当添加到推荐治疗中时，达格列净显著降低了心力衰竭恶化或心血管死亡的风险，独立于糖尿病状态。
试验注册：ClinicalTrials.gov 标识符：NCT03036124。
