A pilot study of fenofibrate to prevent kidney function loss in type 1 diabetes

摘要 尽管过去20年在血糖和血压控制方面有所改善，而且引入了 肾保护药物，如肾素-血管紧张素系统阻滞剂(RASB)，总的发病率 1型糖尿病(T1D)的肾脏疾病(ESKD)仍居高不下。寻求新的治疗方法来预防 糖尿病肾病(DKD)和/或延缓其在T1D进展为ESKD，我们已经建立了一个独特的 高质量学术中心联盟，我们将其命名为Perl(预防早期肾功能 糖尿病中的损失)强调对T1D的DKD病程相对较早的干预，当 肾脏损害更有可能被减缓或停止。现场和ACCORD试验的结果表明 PPAR-α激动剂非诺贝特的肾脏保护作用，增加了使用该药的兴奋可能性 用于预防T1D患者肾小球滤过率下降的廉价仿制药。然而，这些数据是获得的 通过对临床特征最适合心血管疾病研究的T2D人群进行事后分析。因此， 需要一项专门设计的临床试验来评估对肾小球滤过率下降的影响，以确定DKD 非诺贝特在T1D的适应症。作为第一步，作为对FOA PAS-20-160临床用小型R01的响应 针对NIDDK任务范围内的疾病的试验“，我们设计了一项先导性研究，包括40项 患有T1D和早期至中度DKD的参与者，ESKD的风险很高，他们将在两个 Perl站点，按1：1的随机比例与非诺贝特或安慰剂治疗18个月。穿过 在这项先导性研究中，我们将：1.明确非诺贝特对肾功能急性影响的性质。它 目前尚不清楚非诺贝特治疗开始时观察到的EGFR减少是否是 非诺贝特引起的肌酐产生和/或肾小管处理的伪影，或相应的 到GFR的实际减少。我们将解决这一争议，这对关键的 试验设计，通过血浆碘己醇消失直接测量GFR-Perl 网站是有经验的。2.生成关于非诺贝特对GFR下降的长期影响的进一步数据 T1D和DKD患者是GFR快速下降和ESKD的高危人群。积极的一面 非诺贝特在现场和ACCORD中的效果被观察到没有被选为 如果不进行治疗，DKD和WHO的平均GFR下降仅略高于因年龄增长而导致的生理性下降。 要为肾脏结果的关键试验提供令人信服的理由，产生初步数据至关重要 该药在DKD患者中的有效性和安全性 正在向ESKD迈进。3.确定非诺贝特对高血压风险增加的生物标志物的影响 肾小球滤过率快速下降。非诺贝特对这些生物标志物中的一个或多个的有益作用将证实任何 在AIM 2中确定的非诺贝特益处的趋势。有了这项试验的结果，我们将做好最佳准备 向NIDDK申请支持一项关键试验，以建立非诺贝特在T1D的肾脏适应症。

SUMMARY Despite improvements in the past 20 years in glycemic and blood pressure control, and the introduction of “reno-protective” drugs such as renin-angiotensin system blockers (RASB), the overall incidence of end- stage kidney disease (ESKD) in type 1 diabetes (T1D) remains high. To seek new treatments to prevent diabetic kidney disease (DKD) and/or slow its progression to ESKD in T1D, we have established a unique consortium of high-quality academic centers, which we have named PERL (Preventing Early Renal Function Loss in Diabetes) to emphasize the focus on intervening relatively early in the course of DKD in T1D, when renal damage can more likely be slowed or stopped. Findings from the FIELD and ACCORD trials suggest a reno-protective effect of the PPAR-alpha agonist fenofibrate, raising the exciting possibility of using this inexpensive generic drug to prevent GFR decline in persons with T1D. These data, however, were obtained through post-hoc analyses of T2D populations with clinical characteristics optimized for CVD studies. Thus, a clinical trial specifically designed to evaluate effects on GFR decline is required to firmly establish a DKD indication for fenofibrate in T1D. As a first step, and in response to FOA PAS-20-160 “Small R01s for clinical trials targeting diseases within the mission of NIDDK”, we have designed a pilot study including 40 participants with T1D and early-to-moderate DKD, at high risk of ESKD, who will be enrolled at two of the PERL sites and randomized in a 1:1 ratio to treatment with fenofibrate or placebo for 18 months. Through this pilot study we will: 1. Define the nature of the acute effect of fenofibrate on kidney function. It remains unclear whether the eGFR reduction observed at the beginning of fenofibrate treatment is an artifact of fenofibrate-induced changes in creatinine production and/or renal tubular handling, or corresponds to an actual reduction in GFR. We will resolve this controversy, which has crucial implications for the pivotal trial design, by directly measuring GFR by plasma iohexol disappearance – a methodology in which PERL sites are experienced. 2. Generate further data on the long-term effects of fenofibrate on GFR decline in persons with T1D and DKD who are at high risk of rapid GFR decline and ESKD. The positive effects of fenofibrate in FIELD and ACCORD were observed in individuals who were not selected for having DKD and who, if untreated, had a mean GFR decline barely above the physiological decline due to aging. To make a compelling case for a pivotal trial for kidney outcomes, it is crucial to generate preliminary data on the effectiveness and safety of this drug in persons selected for having DKD and being rapidly progressing towards ESKD. 3. Determine the effects of fenofibrate on biomarkers of increased risk of fast GFR decline. A salutary effect of fenofibrate on one or more of these biomarkers will corroborate any trend of a fenofibrate benefit identified in Aim 2. With the results of this pilot, we will be optimally prepared to apply to NIDDK for support of a pivotal trial to establish a kidney indication for fenofibrate in T1D.