Targeting Inflammation in Type 2 Diabetes: Clinical Trial Using Salsalate

描述（由申请人提供）： 流行病学、生理学和药理学证据支持一种潜在的致病联系，依次导致肥胖-炎症-胰岛素抵抗-> 2型糖尿病（T2 D）和心血管疾病。我们的基础科学研究结果表明，炎症联系是由转录主开关NF-κ B的激活介导的。根据我们的目标，将基本的研究结果转化为临床，我们已经确定了抗炎水杨酸盐作为一种潜在的新的一类药物，用于治疗这些疾病，通过抑制IKK？/NF-？B途径。在T2 D患者中进行的为期2- 4周的单中心临床试验的初步结果显示，高剂量阿司匹林（7 g/天）或双水杨酸（3.0至4.5克/天）对许多代谢参数具有显著和高度显著的影响，包括空腹和餐后葡萄糖、总胆固醇、甘油三酯，游离脂肪酸和肝葡萄糖产生以及胰岛素刺激的葡萄糖处置的改善。本申请旨在通过“原理证明”阶段来确定IKK？/NF-？一般的B抑制剂和特别的双水杨酯疗法可能为治疗糖尿病患者提供新的途径。我们提出了一项双盲、安慰剂对照试验，用于评估双水杨酯的疗效，双水杨酯是一种安全的FDA批准的药物，最初剂量为3.0 g/天，耐受剂量逐渐增加至4.0 g/天。有记录但控制不佳的T2 D患者（7.0%<HbA 1c < 9.5%），目前正在接受饮食和运动联合SFU或二甲双胍治疗，将继续接受目前的治疗。在为期4周的单面罩安慰剂导入期后，受试者将随机接受安慰剂与双水杨酸酯口服治疗，为期26周。拟定的主要终点是HbA 1c改善。还将监测胰岛素抵抗和代谢综合征的其他指标，包括血糖、胰岛素和C肽水平、胆固醇和甘油三酯组、游离脂肪酸、血压和循环标志物以及潜在的炎症介质。虽然被认为是非常低的，但潜在副作用的风险将被仔细监测。这些研究第一次问是否直接针对炎症，在这种情况下，通过特异性抑制IKK/NF-？B轴与双水杨酸（水杨酸盐），为治疗糖尿病和代谢综合征患者提供了新的途径。

DESCRIPTION (provided by applicant): Epidemiological, physiological and pharmacological evidence support a potential pathogenic link leading sequentially from obesity-inflammation-"insulin resistance->type 2 diabetes (T2D) and cardiovascular disease. Our basic science findings indicate that the inflammatory link is mediated by activation of the transcriptional master switch, NF-KB. Following our goals to translate basic findings to the clinic, we have identified anti-inflammatory salicylates as a potential new class of drugs for the treatment of these disorders through inhibition of the IKK¿/NF-?B pathway. Preliminary results from 2- to 4-week long, single-site clinical trials in T2D patients showed that high-doses of either aspirin (7 g/day) or salsalate (3.0 to 4.5 g/day) have pronounced and highly significant effects on many metabolic parameters, including reductions in fasting and postprandial glucose, total cholesterol, triglycerides, free fatty acids and hepatic glucose production and improvements in insulin-stimulated glucose disposal. This application aims to progress past the 'proof-of-principle' stage to determine whether IKK¿/NF-?B inhibition in general and salsalate therapy in particular might provide new avenues for treating patients with diabetes. We propose a double-masked, placebo-controlled trial for assessing the efficacy of salsalate, a safe and FDA-approved drug, initially dosed at 3.0 g/day and escalating as tolerated to 4.0 g/day. Patients with documented but poorly controlled T2D (7.0%< HbA1c < 9.5%), currently being treated with diet and exercise in combination with either SFU or metformin, will be continued on their current therapy. Following a 4-week single-mask placebo run-in period, subjects will be randomized to receive placebo vs. salsalate orally for a 26-week trial period. The proposed primary endpoint is an improvement in HbA1c. Other measures of insulin resistance and the metabolic syndrome will also be monitored, including blood glucose, insulin and C-peptide levels, cholesterol and triglyceride panels, free fatty acids, blood pressure, and circulating markers and potential mediators of inflammation. While thought to be very low, the risk of potential side effects will be carefully monitored. These studies ask for the first time whether directly targeting inflammation, in this case by specifically inhibiting the IKK/NF-?B axis with salsalate (salicylate), provides new avenues for treating patients with diabetes and the metabolic syndrome.