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.
Toxins produced by the intestinal bacteria may be an important cause for inflammation in patients with type 2 diabetes mellitus and chronic kidney disease. We propose that treatment with the diabetic medication, linagliptin and prebiotic inulin will decrease inflammation and slow the progression of chronic kidney disease as well as lower cardiovascular disease in patients with diabetic kidney disease.
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