Clinical evidence and mechanistic basis for vildagliptin's action when added to metformin
Clinical evidence and mechanistic basis for vildagliptin's action when added to metformin
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DOI：
10.1111/j.1463-1326.2010.01321.x
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发表时间：
2011-03-01
影响因子：
5.8
通讯作者：
Bosi, E.
中科院分区：
文献类型：
--
作者：
Ahren, B.;Foley, J. E.;Bosi, E.
已经开发了几种新的口服抗糖尿病药物，称为“格列汀类”或“酶二肽基肽酶-IV（DPP-4）通道物”，用于治疗2型糖尿病，格列汀类的关键临床用途是与二甲双胍联合使用。不同格列汀与DPP-4催化位点相互作用的动力学存在重要差异，这可能导致不同的药代动力学、药效学和给药方案。因此，需要对单个格列汀进行表征，在此我们讨论了广泛研究的DPP-4抑制剂vildaglavin，其结合特性可确保在血浆中存在可检测药物水平的情况下抑制酶。由于维达鲁肽最常用的剂量为50 mg，每日一次或两次，与二甲双胍联合使用，因此本文重点介绍这些剂量方案。所有临床试验采用vildageline（50 mg，每日一次或两次）作为二甲双胍的辅助治疗（通过MEDLINE检索使用关键词vildageline和二甲双胍确定或已知的作者将在新闻中）进行审查，这是目前对vildageline作用机制的了解。在稳定剂量的二甲双胍基础上加用维达利，可使HbA 1c和空腹血糖呈剂量相关性降低。50 mg每日两次观察到的额外疗效[Δ HbA 1c类似于-1.1%（-12.1 mmol/mol）]相对于50 mg每日一次[Δ HbA 1c类似于-0.7%（-7.7 mmol/mol）]归因于晚上剂量的维达鲁肽的过夜效应，DPP-4抑制延长，完整和促胰岛素形式的胰高血糖素样肽-1（GLP-1）空腹水平升高。维达利的治疗作用主要由GLP-1介导，二甲双胍可增强维达利提高完整GLP-1血浆水平的作用。维达利是体重中性的，并且具有非常低的低血糖潜力，这可以通过其增强α细胞和β细胞对葡萄糖的敏感性的显著能力来解释。因此，当以每日两次给药方案加入二甲双胍时，维达鲁肽提供了具有临床意义的结局，利用其紧密结合和缓慢解离的特性，导致持续的过夜效应。
Several new oral antidiabetic agents, known as 'gliptins' or 'enzyme dipeptidyl peptidase-IV (DPP-4) inhibitors', have been developed for the treatment of type 2 diabetes and a key clinical use of the gliptins is in combination with metformin. There are important differences in the kinetics of the interaction of different gliptins with the catalytic site of DPP-4, which may lead to varying pharmacokinetics, pharmacodynamics and dosing regimens. Therefore, individual gliptins need to be characterized and here we discuss the extensively studied DPP-4 inhibitor vildagliptin, which has binding characteristics that ensure inhibition of the enzyme beyond the presence of detectable drug levels in plasma. As vildagliptin has been used most often at doses of 50 mg once or twice daily, in combination with metformin, this review focuses on these dose regimens. All clinical trials employing vildagliptin (50 mg once or twice daily) as an add-on therapy to metformin (identified by MEDLINE search using keywords vildagliptin and metformin or known by authors to be in press) are reviewed, as is current knowledge of the mechanism of action of vildagliptin. Vildagliptin added to a stable dose of metformin elicits a dose-related decrease in both HbA1c and fasting plasma glucose. The additional efficacy seen with 50 mg twice daily [delta HbA1c similar to- 1.1% (-12.1 mmol/mol)] relative to 50 mg once daily [delta HbA1c similar to- 0.7% (-7.7 mmol/mol)] is attributable to an overnight effect of the evening dose of vildagliptin, with prolonged DPP-4 inhibition and elevated fasting levels of the intact and insulinotropic form of glucagon-like peptide-1 (GLP-1). Vildagliptin's therapeutic actions are primarily mediated by GLP-1 and metformin enhances vildagliptin's effect to raise plasma levels of intact GLP-1. Vildagliptin is weight-neutral and has a very low hypoglycaemic potential, explained by its remarkable ability to enhance both alpha-cell and beta-cell sensitivity to glucose. Therefore, vildagliptin offers a clinically important outcome when added to metformin with a twice daily dose regimen, taking advantage of its tight binding and slow dissociation characteristics that lead to a sustained overnight effect.