Anti-inflammatory Therapy in Diabetic CKD

描述(申请人提供)：糖尿病是美国终末期肾病(ESRD)最常见的原因。在2型糖尿病(T2 DM)患者中，持续性炎症是慢性肾脏病(CKD)进展为终末期肾病(ESRD)和相关心血管疾病的基础。利格列汀是一种口服降糖药，具有抗炎、抗蛋白尿和心肾保护作用。人类肠道中含有1014种细菌，肠道微生物失衡与炎症、胰岛素抵抗和动脉粥样硬化有关。益生素低聚果糖强化菊粉(p-菊粉)已被证明可以恢复肠道微生物平衡，从而减少内毒素的产生和减轻炎症。在一项二乘二析因临床试验中，我们将随机选择120名T2 DM-CKD患者，在12个月内每天服用利格列汀/p-菊粉/安慰剂。首先，我们将演示招募、随机和保留研究参与者的可行性，以记录至少90%的参与者的终点。其次，我们将确定利格列汀和p-菊粉在减轻全身炎症方面的疗效。我们将研究治疗过程中血浆内毒素水平和选定的炎症标志物的变化。肠道微生物区系的变化将使用实时定量聚合酶链式反应来确定。第三，我们建议评估利格列汀和p-菊粉对选定的探索性临床终点的治疗效果。我们将使用估计的肾小球滤过率和血浆胱抑素水平的斜率来评估肾功能下降率。蛋白尿的变化也将被量化。动脉粥样硬化的进展/消退将使用最先进的相敏双反转恢复磁共振波谱(MR)成像进行研究。我们将使用一种高度创新的磁共振成像技术来确定左心室质量和功能。这项新颖的先导性研究将证明这一概念，确立可行性，并产生初步数据，以证明启动全面临床试验的合理性。

DESCRIPTION (provided by applicant): Diabetes is the most common cause of end-stage renal disease (ESRD) in the US. In patients with type 2 diabetes mellitus (T2DM), persistent inflammation underpins the progression of chronic kidney disease (CKD) to ESRD and the associated cardiovascular disease. Linagliptin is an oral anti-hyperglycemic agent that has anti-inflammatory, anti-proteinuric, and cardio-renal protective properties. The human gut harbors 1014 bacteria, and gut microbial imbalance has been linked to inflammation, insulin resistance, and atheroscleroisis. Prebiotic oligofructose enriched inulin (p-inulin) has been shown to restore gut microbial balance, thereby reducing endotoxin generation and attenuating inflammation. In a two-by-two factorial clinical trial we will randomize 120 T2DM-CKD patients to receive linagliptin/p-inulin/placebo daily for 12 months. First, we will demonstrate the feasibility of recruitment, randomization, and retention of study participants to record endpoints in at least 90 percent of participants. Secondly, we will establish the efficacy of linagliptin and p-inulin in reducing systemic inflammation. We will study the change in plasma levels of endotoxin and selected markers of inflammation with treatment. Alterations in gut microbial flora will be determined using quantitative real time-PCR. Thirdly, we propose to evaluate the effect of treatment with linagliptin and p-inulin on selected exploratory clinical end- points. We will evaluate the rate of decline of kidney function using the slope of estimated glomerular filtration rate and plasma cystatin level. The change in proteinuria will also be quantitated. Progression/regression of atherosclerosis will be studied using state of art phase-sensitive dual inversion recovery magnetic resonance spectroscopy (MR) imaging. We will determine left ventricular mass and function using a highly innovative MR imaging technique. This novel pilot study will prove the concept, establish feasibility, and generate preliminary data to justify the launching of a full-clinical trial.