Abstract：
BACKGROUND: Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity.
OBJECTIVE: This study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (Vo2).
METHODS: A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak Vo2 from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables.
RESULTS: The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak Vo2 fell in the placebo-treated patients by -0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak Vo2 fell by -0.01 mL/kg/min (P = 0.21); the difference in peak Vo2 between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak Vo2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10).
CONCLUSIONS: Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339).
OBJECTIVE: This study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (Vo2).
METHODS: A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak Vo2 from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables.
RESULTS: The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak Vo2 fell in the placebo-treated patients by -0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak Vo2 fell by -0.01 mL/kg/min (P = 0.21); the difference in peak Vo2 between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak Vo2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10).
CONCLUSIONS: Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339).
摘要：
背景：进展为有症状的心力衰竭是2型糖尿病的一种并发症；在这种情况下，心力衰竭发作通常先于运动能力下降。
目的：本研究旨在确定高选择性醛糖还原酶抑制剂AT-001可以稳定糖尿病心肌病（DbCM）个体的运动能力和降低的峰值摄氧量（Vo2）。
方法：共有691名符合纳入和排除标准的DbCM患者随机接受安慰剂或每日两次递增剂量的AT-001。纳入时的分层包括注册地区，心肺运动试验结果,和使用钠-葡萄糖协同转运蛋白2抑制剂或胰高血糖素样肽-1受体激动剂。主要终点是峰值Vo2从基线到15个月的成比例变化。亚组分析包括疾病严重程度和分层变量的测量。
结果：平均年龄为67.5±7.2岁，50.4%的参与者是女性。15个月前,安慰剂治疗患者的峰值Vo2下降-0.31mL/kg/min（与基线相比，P=0.005），而在接受高剂量AT-001的患者中,峰值Vo2下降了-0.01mL/kg/min(P=0.21);安慰剂和高剂量AT-001的峰值Vo2差异为0.30(P=0.19).在基线时未接受钠-葡萄糖协同转运蛋白2抑制剂或胰高血糖素样肽-1受体激动剂的患者的预设亚组分析中，安慰剂与高剂量AT-001在15个月时的峰值Vo2之间的差异为0.62mL/kg/min(P=0.04;交互作用P=0.10).
结论：在DbCM和运动能力受损的个体中，与安慰剂相比,使用AT-001治疗15个月后,运动能力没有显著改善.（AT-001在糖尿病心肌病患者中的安全性和有效性[ARISE-HF]；NCT04083339）。
目的：本研究旨在确定高选择性醛糖还原酶抑制剂AT-001可以稳定糖尿病心肌病（DbCM）个体的运动能力和降低的峰值摄氧量（Vo2）。
方法：共有691名符合纳入和排除标准的DbCM患者随机接受安慰剂或每日两次递增剂量的AT-001。纳入时的分层包括注册地区，心肺运动试验结果,和使用钠-葡萄糖协同转运蛋白2抑制剂或胰高血糖素样肽-1受体激动剂。主要终点是峰值Vo2从基线到15个月的成比例变化。亚组分析包括疾病严重程度和分层变量的测量。
结果：平均年龄为67.5±7.2岁，50.4%的参与者是女性。15个月前,安慰剂治疗患者的峰值Vo2下降-0.31mL/kg/min（与基线相比，P=0.005），而在接受高剂量AT-001的患者中,峰值Vo2下降了-0.01mL/kg/min(P=0.21);安慰剂和高剂量AT-001的峰值Vo2差异为0.30(P=0.19).在基线时未接受钠-葡萄糖协同转运蛋白2抑制剂或胰高血糖素样肽-1受体激动剂的患者的预设亚组分析中，安慰剂与高剂量AT-001在15个月时的峰值Vo2之间的差异为0.62mL/kg/min(P=0.04;交互作用P=0.10).
结论：在DbCM和运动能力受损的个体中，与安慰剂相比,使用AT-001治疗15个月后,运动能力没有显著改善.（AT-001在糖尿病心肌病患者中的安全性和有效性[ARISE-HF]；NCT04083339）。
