The 11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor INCB13739 Improves Hyperglycemia in Patients With Type 2 Diabetes Inadequately Controlled by Metformin Monotherapy
The 11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor INCB13739 Improves Hyperglycemia in Patients With Type 2 Diabetes Inadequately Controlled by Metformin Monotherapy
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DOI：
10.2337/dc09-2315
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发表时间：
2010-07-01
期刊：
影响因子：
16.2
通讯作者：
Huber, Reid
中科院分区：
文献类型：
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作者：
Rosenstock, Julio;Banarer, Salomon;Huber, Reid
目的11- β -羟基类固醇脱氢酶1型（11 β HSD1）将无活性的皮质醇转化为活性的皮质醇，从而增强细胞内糖皮质激素的作用。当11 β HSD1抑制剂1NCB13739加入正在进行的二甲双胍单药治疗时，对血糖控制不足（A1C 7-11%）的2型糖尿病患者的有效性和安全性进行了评估。研究设计和方法本双盲安慰剂对照平行研究随机选取302例接受二甲双胍单药治疗（平均1.5 g/天）的2型糖尿病患者（平均A1C为8.3%），接受5剂1NCB13739中的一剂或安慰剂，每天1次，持续12周。主要终点是研究结束时糖化血红蛋白的变化。其他终点包括空腹血糖、血脂、体重、不良事件和安全性的变化。12周后，与安慰剂相比，200 mg INCB13739可显著降低A1C（-0.6%）、空腹血糖（-24 mg/dl）和稳态模型评估胰岛素抵抗（HOMA-IR）（-24%）。高脂血症患者的总胆固醇、低密度脂蛋白胆固醇和甘油三酯均显著降低。在接受INCB13739治疗后，体重相对于安慰剂有所下降。观察到促肾上腺皮质激素的可逆剂量依赖性升高，通常在正常参考范围内。使用INCB13739后，男性的基础皮质醇稳态、睾酮和女性的游离雄激素指数没有变化。所有治疗组的不良事件相似。结论：在正在进行的二甲双胍治疗中添加INCB13739对单用二甲双胍控制血糖不足的2型糖尿病患者有效且耐受性良好。抑制11 β HSD1为控制2型糖尿病患者的血糖和心血管危险因素提供了一种新的潜在途径。
OBJECTIVE 11-beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) converts inactive cortisone into active cortisol, thereby amplifying intracellular glucocorticoid action. The efficacy and safety of the 11 beta HSD1 inhibitor 1NCB13739 were assessed when added to ongoing metformin monotherapy in patients with type 2 diabetes exhibiting inadequate glycemic control (A1C 7-11%).RESEARCH DESIGN AND METHODS This double-blind placebo-controlled paralleled study randomized 302 patients with type 2 diabetes (mean A1C 8.3%) on metformin monotherapy (mean 1.5 g/day) to receive one of five 1NCB13739 doses or placebo once daily for 12 weeks. The primary end point was the change in A1C at study end. Other end points included changes in fasting glucose, lipids, weight, adverse events, and safety.RESULTS After 12 weeks, 200 mg of INCB13739 resulted in significant reductions in A1C (-0.6%), fasting plasma glucose (-24 mg/dl), and homeostasis model assessment insulin resistance (HOMA-IR) (-24%) compared with placebo. Total cholesterol, LDL cholesterol, and triglycerides were all significantly decreased in hyperlipidemic patients. Body weight decreased relative to placebo after INCB13739 therapy. A reversible dose-dependent elevation in adrenocorticotrophic hormone, generally within the normal reference range, was observed. Basal cortisol homeostasis, testosterone in men, and free androgen index in women were unchanged by INCB13739. Adverse events were similar across all treatment groups.CONCLUSIONS INCB13739 added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. 11 beta HSD1 inhibition offers a new potential approach to control glucose and cardiovascular risk factors in type 2 diabetes.