Ott Christian, Kistner Iris, Keller Mirjam, Friedrich Stefanie, Willam Carsten, Bramlage Peter, Schmieder Roland E
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Ulmenweg 18, 91054, Erlangen, Germany.
Institute for Pharmacology and Preventive Medicine, Mahlow, Germany.
Diabetologia. 2016 Dec;59(12):2579-2587. doi: 10.1007/s00125-016-4083-4. Epub 2016 Sep 1.
AIMS/HYPOTHESIS: Endothelial dysfunction predicts cardiovascular damage and renal involvement. Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in the early stage of type 2 diabetes. The aim of the study was to assess the effect of linagliptin on the endothelial function of the renal vasculature.
In this randomised, double-blind, parallel-group, investigator-initiated trial, 62 patients with type 2 diabetes were randomly assigned (by computer-generated random code) to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks. The primary objective was to assess endothelial function of the renal vasculature, by constant-infusion input-clearance and urinary albumin/creatinine ratio (UACR), both before and after blockade of NOS with N -monomethyl-L-arginine (L-NMMA).
Treatment with linagliptin for 4 weeks reduced fasting, postprandial blood glucose and HbA, although not significantly; no change occurred with placebo. Renal plasma flow (RPF) did not change after linagliptin or placebo. After 4 weeks the absolute change in RPF due to L-NMMA was smaller in the linagliptin group than in the placebo group (-46.8 ± 34 vs -65.1 ± 36 ml/min, p = 0.045), indicating a lower basal NO activity after treatment with linagliptin. Consistently, the response of UACR to L-NMMA increased in the placebo group (p = 0.059) but not in the linagliptin group (p = 0.276), pointing to an upregulation of NO activity in the placebo group. No clinically meaningful safety concerns were evident.
CONCLUSIONS/INTERPRETATION: Our data suggest that treatment with the dipeptidyl peptidase-4 inhibitor linagliptin for 4 weeks prevented the impairment of renal endothelial function due to hyperglycaemia in type 2 diabetes.
ClinicalTrials.gov NCT01835678 FUNDING: : This study was funded by Boehringer Ingelheim.
目的/假设：内皮功能障碍可预测心血管损害和肾脏受累情况。动物实验和人体研究表明，在2型糖尿病早期，一氧化氮（NO）活性及内皮型一氧化氮合酶（NOS）表达增加。本研究旨在评估利格列汀对肾血管内皮功能的影响。
在这项由研究者发起的随机、双盲、平行组试验中，62例2型糖尿病患者通过计算机生成的随机编码被随机分配，分别接受5mg利格列汀（n = 30）或安慰剂（n = 32）治疗4周。主要目的是在使用N-单甲基-L-精氨酸（L-NMMA）阻断NOS前后，通过持续输注输入清除率和尿白蛋白/肌酐比值（UACR）评估肾血管的内皮功能。
利格列汀治疗4周可降低空腹血糖、餐后血糖和糖化血红蛋白（HbA），但差异无统计学意义；安慰剂组则无变化。利格列汀或安慰剂治疗后肾血浆流量（RPF）均未改变。4周后，利格列汀组因L-NMMA导致的RPF绝对变化小于安慰剂组（-46.8±34 vs -65.1±36 ml/min，p = 0.045）,表明利格列汀治疗后基础NO活性较低。同样，安慰剂组UACR对L-NMMA的反应增加（p = 0.059），而利格列汀组无增加（p = 0.276），这表明安慰剂组NO活性上调。未发现明显的具有临床意义的安全问题。
结论/解读：我们的数据表明，使用二肽基肽酶-4抑制剂利格列汀治疗4周可预防2型糖尿病患者因高血糖导致的肾内皮功能损害。
ClinicalTrials.gov NCT01835678
本研究由勃林格殷格翰公司资助。
