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肥胖-炎症-“胰岛素抵抗-2型糖尿病(T2D)和心血管疾病”的潜在致病联系。我们的基础科学发现表明，炎症联系是由转录主开关NF-KB的激活所介导的。根据我们将基本发现转化为临床的目标，我们已经确定抗炎水杨酸盐是一种潜在的新型药物，通过抑制IKK？/NF-？B途径来治疗这些疾病。对T2D患者进行的为期2至4周的单地点临床试验的初步结果显示，大剂量的阿司匹林(7克/天)或水杨酸盐(3.0至4.5克/天)对许多代谢参数有显著和非常显著的影响，包括降低空腹和餐后血糖、总胆固醇、甘油三酯、游离脂肪酸和肝脏葡萄糖的产生，以及改善胰岛素刺激的葡萄糖处置。这项申请旨在通过“原则证明”阶段来确定是否总体上抑制IKK/核因子-βB，特别是水杨酸盐疗法可能为治疗糖尿病患者提供新的途径。我们建议进行一项双盲、安慰剂对照试验，以评估沙柳酸盐的疗效，这是一种安全的FDA批准的药物，最初剂量为3.0g/d，耐受性增加到4.0g/d。有记录但控制不佳的T2D(7.0%；HbA1c&lt；9.5%)的患者目前正在接受饮食和运动结合SFU或二甲双胍的治疗，将继续他们目前的治疗。在为期4周的单一面膜安慰剂磨合期之后，受试者将被随机接受为期26周的试验期，分别接受安慰剂和沙柳酸盐口服。建议的主要终点是HbA1c的改进。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、胆固醇和甘油三酯水平、游离脂肪酸、血压以及循环标志物和潜在的炎症介质。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。这些研究首次提出，直接针对炎症，在这种情况下，通过用水杨酸盐(水杨酸盐)特异性抑制IKK/NF-？B轴，是否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.