Anti-inflammatory Therapy in Diabetic CKD

描述（由申请人提供）：糖尿病是美国终末期肾病（ESRD）的最常见原因。在2型糖尿病（T2 DM）患者中，持续性炎症是慢性肾病（CKD）进展为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特性。人体肠道内有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。富含菊粉的益生元低聚果糖（β-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并减轻炎症。在一项2 × 2析因临床试验中，我们将随机分配120例T2 DM-CKD患者，每日接受利格列汀/β-菊粉/安慰剂治疗，持续12个月。首先，我们将证明招募、随机化和保留研究参与者以记录至少90%参与者的终点的可行性。其次，我们将确定利格列汀和β-菊糖在减少全身炎症方面的功效。我们将研究治疗后血浆内毒素水平和选定的炎症标志物的变化。将使用定量真实的时间PCR测定肠道微生物植物群的变化。第三，我们建议评价利格列汀和β-菊粉治疗对选定的探索性临床终点的影响。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评价肾功能下降率。还将定量蛋白尿的变化。将使用最先进的相位敏感双反转恢复磁共振波谱（MR）成像研究动脉粥样硬化的进展/消退。我们将使用高度创新的MR成像技术来确定左心室质量和功能。这项新的试点研究将证明这一概念，建立可行性，并产生初步数据，以证明全面临床试验的启动。

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.