From the Department of Paediatrics (M.L.M., D.B.D.) and the Wellcome Trust-Medical Research Council Institute of Metabolic Science (D.B.D.), University of Cambridge, and the Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital (S.B., S.D.), Cambridge, the National Centre for Cardiovascular Prevention and Outcomes, University College London (S.T.C., J.D.), and the WellChild Laboratory, Evelina London Children's Hospital, St. Thomas' Hospital (R.N.D.), London, the Institute of Cellular Medicine (Diabetes), Faculty of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne (S.M.M.), and the Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford (H.A.W.N.) - all in the United Kingdom; the Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto (D.D., F.H.M.); and the Institute of Endocrinology and Diabetes, Children's Hospital at Westmead and University of Sydney, Sydney (K.C.D.), and the Telethon Kids Institute, University of Western Australia, Perth (T.W.J.) - both in Australia.
N Engl J Med. 2017 Nov 2;377(18):1733-1745. doi: 10.1056/NEJMoa1703518.
Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long-term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin-converting-enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents.
We screened 4407 adolescents with type 1 diabetes between the ages of 10 and 16 years of age and identified 1287 with values in the upper third of the albumin-to-creatinine ratios; 443 were randomly assigned in a placebo-controlled trial of an ACE inhibitor and a statin with the use of a 2-by-2 factorial design minimizing differences in baseline characteristics such as age, sex, and duration of diabetes. The primary outcome for both interventions was the change in albumin excretion, assessed according to the albumin-to-creatinine ratio calculated from three early-morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve. Key secondary outcomes included the development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk (carotid intima-media thickness and levels of high-sensitivity C-reactive protein and asymmetric dimethylarginine).
The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low-density lipoprotein, and non-high-density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima-media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy. Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups.
The use of an ACE inhibitor and a statin did not change the albumin-to-creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476 .).
在 1 型糖尿病青少年中，青春期期间白蛋白排泄量的快速增加先于微量白蛋白尿和大量白蛋白尿的发生，而微量白蛋白尿和大量白蛋白尿是长期发生肾脏和心血管疾病的风险因素。我们假设，白蛋白排泄量较高的青少年可能受益于血管紧张素转换酶（ACE）抑制剂和他汀类药物，这两种药物尚未在青少年中得到充分评估。
我们筛选了年龄在 10 至 16 岁之间的 4407 名 1 型糖尿病青少年，发现其中 1287 名青少年的白蛋白/肌酐比值处于较高的三分之一；其中 443 名青少年被随机分配到 ACE 抑制剂和他汀类药物的安慰剂对照试验中，采用 2×2 析因设计，尽量减少年龄、性别和糖尿病病程等基线特征的差异。两种干预措施的主要结局均为白蛋白排泄量的变化，通过计算每 6 个月采集的 3 份晨尿样本中的白蛋白/肌酐比值来评估，该比值表示为曲线下面积。主要次要结局包括微量白蛋白尿的发生、视网膜病变的进展、肾小球滤过率的变化、血脂水平以及心血管风险的测量（颈动脉内膜中层厚度以及高敏 C 反应蛋白和不对称二甲基精氨酸的水平）。
ACE 抑制剂治疗、他汀类药物治疗或两者联合治疗均未影响主要结局。与安慰剂相比，ACE 抑制剂的使用与较低的微量白蛋白尿发生率相关；在主要结局和统计分析计划的阴性结果背景下，这种较低的发生率并不被认为具有统计学意义（风险比，0.57；95%置信区间，0.35 至 0.94）。他汀类药物的使用显著降低了总胆固醇、低密度脂蛋白胆固醇和非高密度脂蛋白胆固醇、甘油三酯以及载脂蛋白 B 与载脂蛋白 A1 的比值，而这两种药物均对颈动脉内膜中层厚度、其他心血管标志物、肾小球滤过率或视网膜病变的进展没有显著影响。药物治疗方案的总体依从率为 75%，各组的严重不良事件相似。
ACE 抑制剂和他汀类药物的使用并未随时间改变白蛋白/肌酐比值。（由青少年糖尿病研究基金会等资助；AdDIT ClinicalTrials.gov 编号，NCT01581476）。
