医学
多元醇途径
心力衰竭
醛糖还原酶
耐受性
糖尿病性心肌病
心脏病学
内科学
糖尿病
安慰剂
心肌病
心脏病
临床终点
随机对照试验
内分泌学
不利影响
病理
替代医学
作者
James L. Januzzi,Javed Butler,Stefano Del Prato,Justin A. Ezekowitz,Nasrien E. Ibrahim,Carolyn S.P. Lam,Gregory D. Lewis,Thomas H. Marwick,Julio Rosenstock,W.H. Wilson Tang,Faı̈ez Zannad,Francesca Lawson,Riccardo Perfetti,James L. Januzzi
标识
DOI:10.1016/j.ahj.2022.11.003
摘要
Diabetic cardiomyopathy (DbCM) is a specific form of heart muscle disease that may result in substantial morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Hyperactivation of the polyol pathway is one of the primary mechanisms in the pathogenesis of diabetic complications, including development of DbCM. There is an unmet need for therapies targeting the underlying metabolic abnormalities that drive this form of Stage B heart failure (HF). Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway, and AR inhibition has been shown to reduce diabetic complications, including DbCM in animal models and in patients with DbCM. Previous AR inhibitors (ARIs) were limited by poor specificity resulting in unacceptable tolerability and safety profile. AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs. ARISE-HF (NCT04083339) is an ongoing Phase 3 randomized, placebo-controlled, double blind, global clinical study to investigate the efficacy of AT-001 (1000 mg twice daily [BID] and 1500 mg BID) in 675 T2DM patients with DbCM at high risk of progression to overt HF. ARISE-HF assesses the ability of AT-001 to improve or prevent decline in exercise capacity as measured by functional capacity (changes in peak oxygen uptake [peak VO2]) over 15 (and possibly 27) months of treatment. Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiacbiomarkers. The ARISE-HF Trial is fully enrolled. This report describes the rationale and study design of ARISE-HF.
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