Azizi Michel, Ménard Joël, Peyrard Séverine, Lièvre Michel, Marre Michel, Chatellier Gilles
Centre d'Investigations Cliniques, Hôpital Européen Georges Pompidou, 20-40 rue Leblanc, 75908 Paris cedex 15, France.
Diabetes Care. 2006 Jun;29(6):1331-6. doi: 10.2337/dc06-0255.
The purpose of this study was to assess patients' and physicians' compliance with ACE inhibitor treatment, by measuring an endogenous biomarker of ACE inhibition, urinary N-acetyl-Ser-Asp-Lys-Pro (AcSDKP), in the Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) trial, which compared ramipril (1.25 mg o.d.) with placebo in 4,912 patients with type 2 diabetes and microalbuminuria/proteinuria.
The urine AcSDKP-to-creatinine ratio was measured blind to treatment in all participants who completed follow-up and provided spot urine samples (n = 1,871).
The median urinary AcSDKP-to-creatinine ratio was six times higher for ramipril than for placebo. Urinary AcSDKP-to-creatinine ratios displayed a bimodal distribution in both groups, with a very large intergroup overlap. Based on cluster analysis, we defined truly adherent ramipril patients as those with a ratio > or =4 nmol/mmol and truly adherent placebo patients as those with a ratio < 4 nmol/mmol. After excluding patients withdrawing prematurely from the study or known to have used a nonstudy ACE inhibitor, 27.3% of the 597 ramipril patients had ratios <4, indicating poor compliance, and 9.7% of the 621 placebo patients had ratios > or =4, indicating intake of a nonstudy ACE inhibitor. Correcting for compliance by using AcSDKP-guided analysis affected surrogate outcome results (decrease in systolic blood pressure and urinary albumin excretion) only slightly.
The systematic use of spot urinary AcSDKP determination facilitated the detection of defects in compliance with ACE inhibitor treatment in both patients and physicians. Urinary AcSDKP measurement could be a useful biomarker for assessing compliance with ACE inhibition in the routine care of diabetic patients.
本研究旨在通过测量非胰岛素依赖型糖尿病、高血压、微量白蛋白尿、蛋白尿、心血管事件与雷米普利（DIABHYCAR）试验中血管紧张素转换酶（ACE）抑制的内源性生物标志物——尿N-乙酰丝天冬赖脯氨酸（AcSDKP），来评估患者和医生对ACE抑制剂治疗的依从性。该试验在4912例2型糖尿病合并微量白蛋白尿/蛋白尿患者中，将雷米普利（每日1.25毫克）与安慰剂进行了比较。
对所有完成随访并提供随机尿样的参与者（n = 1871），在不知道治疗情况的前提下测量尿AcSDKP与肌酐的比值。
雷米普利组尿AcSDKP与肌酐比值的中位数比安慰剂组高6倍。两组的尿AcSDKP与肌酐比值均呈双峰分布，组间重叠很大。基于聚类分析，我们将真正依从雷米普利治疗的患者定义为比值≥4 nmol/mmol的患者，将真正依从安慰剂治疗的患者定义为比值<4 nmol/mmol的患者。在排除过早退出研究或已知使用非研究ACE抑制剂的患者后，597例雷米普利患者中有27.3%的比值<4，表明依从性差；621例安慰剂患者中有9.7%的比值≥ 4，表明服用了非研究ACE抑制剂。使用AcSDKP指导分析校正依从性后，对替代结局结果（收缩压降低和尿白蛋白排泄减少）的影响很小。
系统地测定随机尿样中的AcSDKP有助于发现患者和医生在ACE抑制剂治疗依从性方面的缺陷。在糖尿病患者的常规护理中，测量尿AcSDKP可能是评估ACE抑制依从性的有用生物标志物。
