Cardiovascular Diabetology Research Group, Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
Cardiovasc Diabetol. 2018 May 17;17(1):71. doi: 10.1186/s12933-018-0716-x.
Early glucose lowering intervention in subjects with type 2 diabetes mellitus was demonstrated to be beneficial in terms of micro- and macrovascular risk reduction. However, most of currently ongoing cardiovascular outcome trials are performed in subjects with manifest atherosclerosis and long-standing diabetes. Therefore, the aim of this study is to investigate the effects of the dipeptidylpeptidase-4 inhibitor linagliptin in subjects with coronary artery disease (CAD) but early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements.
In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2 h glucose > 200 mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy and an HbA1c < 75 mmol/mol) and established CAD. Participants were randomized to receive either linagliptin (5 mg) once daily orally or placebo for 12 weeks. The primary outcome was the change in flow mediated dilatation (FMD). The secondary objective was to investigate the effect of linagliptin treatment on arginine bioavailability ratios [Global arginine bioavailability ratio (GABR) and arginine to ornithine ratio (AOR)]. Arginine, ornithine and citrulline were measured in serum samples with a conventional usual amino acid analysis technique, involving separation of amino acids by ion exchange chromatography followed by postcolumn continuous reaction with ninhydrin. GABR was calculated by L-arginine divided by the sum of (L-ornithine plus L-citrulline). The AOR was calculated by dividing L-arginine by L-ornithine levels. Group comparisons were calculated by using a two-sample t-test with Satterthwaite adjustment for unequal variances.
We investigated 43 patients (21% female) with a mean age of 63.3 ± 8.2 years. FMD at baseline was 3.5 ± 3.1% in the linagliptin group vs. 4.0 ± 2.9% in the placebo group. The change in mean FMD in the linagliptin group was not significantly different compared to the change in the placebo group (0.43 ± 4.84% vs. - 0.45 ± 3.01%; p = 0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR; p = 0.608 and AOR; p = 0.549).
Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or the arginine bioavailability ratios. Trial registration ClinicalTrials.gov, NCT02350478 ( https://clinicaltrials.gov/ct2/show/NCT02350478 ).
在 2 型糖尿病患者中早期降低血糖的干预措施已被证明在减少微血管和大血管风险方面是有益的。然而，目前正在进行的大多数心血管结局试验都是在有明显动脉粥样硬化和长期糖尿病的患者中进行的。因此，本研究的目的是研究二肽基肽酶-4 抑制剂利拉利汀在伴有冠状动脉疾病（CAD）但早期 2 型糖尿病（T2DM）的患者中的作用，以评估一系列心血管替代测量指标。
这是一项随机、安慰剂对照、双盲、单中心研究，纳入了早期糖尿病（餐后糖尿病（2 小时血糖>200mg/dl）或仅接受饮食治疗或稳定剂量二甲双胍单药治疗且糖化血红蛋白<75mmol/mol）和已确诊的 CAD 患者。参与者被随机分配接受利拉利汀（5mg）或安慰剂每日口服一次，疗程为 12 周。主要结局是血流介导的扩张（FMD）的变化。次要目标是研究利拉利汀治疗对精氨酸生物利用度比值[整体精氨酸生物利用度比值（GABR）和精氨酸与鸟氨酸比值（AOR）]的影响。使用常规常规氨基酸分析技术测量血清样本中的精氨酸、鸟氨酸和瓜氨酸，该技术涉及离子交换色谱分离氨基酸，然后与水合茚三酮连续后反应。GABR 是由 L-精氨酸除以（L-鸟氨酸加 L-瓜氨酸）的总和计算得出。AOR 是由 L-精氨酸除以 L-鸟氨酸水平计算得出。使用具有不等方差 Satterthwaite 调整的两样本 t 检验计算组间比较。
我们调查了 43 名（21%为女性）患者，平均年龄为 63.3±8.2 岁。利拉利汀组的基线 FMD 为 3.5±3.1%，安慰剂组为 4.0±2.9%。利拉利汀组的平均 FMD 变化与安慰剂组的变化无显著差异（0.43±4.84%对-0.45±3.01%；p=0.486）。精氨酸生物利用度比值（GABR；p=0.608 和 AOR；p=0.549）未见明显改善。
在伴有 CAD 和早期 T2DM 的患者中，利拉利汀治疗并未改善内皮功能或精氨酸生物利用度比值。试验注册ClinicalTrials.gov，NCT02350478（https://clinicaltrials.gov/ct2/show/NCT02350478）。
