Role of Screening and Early Intervention in Primary Care with Low-Dose Pioglitazone for Patients with T2DM and NASH

项目摘要/摘要 非酒精性脂肪性肝炎(NASH)常见于2型糖尿病(T2 DM)。肝病专家 从他们的临床经验以及许多横断面研究中了解这一点，其中T2 DM是 在肝硬变或肝细胞癌患者中常见。然而，这种知识并没有渗透到初级保健中。 医生(PCP)或转化为对T2 DM患者的系统筛查。大多数PCP只是简单地保留 大部分人不知道与NASH相关的健康风险，对这种流行病的信息有限 在初级保健环境中的NASH，因此没有找到筛查或治疗的理由。新的研究导致了 肝病专家一致认为，中度纤维化(≥F2)患者的疾病路径会导致 到肝硬变或肝癌，更多的心血管疾病和更高的死亡率。不幸的是，大多数NASH患者 今天才被诊断出来，直到为时已晚。有证据表明，吡格列酮(PIO)等仿制药会导致 NASH的解决在约60%的患者中，这是一个错过了拯救生命和资源的机会。然而，大多数 由于不良的副作用(体重增加、体重降低)，肝病专家对开PIO感到不舒服 四肢浮肿、骨质流失、膀胱癌？)然而，由于即使是低剂量的PIO(15毫克/天)也会增加 脂联素~2倍并改善脂肪组织的胰岛素抵抗，很可能有类似的作用 对肝脏的“脂肪毒性”和肝脏组织学有显著影响，且剂量副作用最小。不过，这个 这一假说以前从未在NASH患者的剂量反应研究中得到验证。 我们建议为T2 DM和NASH患者开发一种新的策略，将重点从晚期转移到 诊断和转诊到肝科，到初级保健诊所进行早期诊断和干预。第一，确立 PCP环境(目标1)中晚期纤维化(≥F2)问题的严重程度我们将 CAP/VCTE(纤维扫描)筛查NAFLD/肝纤维化。那些患有NASH纤维化的人将得到治疗 使用低剂量的PIO(15毫克/天)或安慰剂(目标2；30毫克/天的中剂量也将用于 比较安全性和有效性，但人们感兴趣的是每天15毫克的剂量)。我们将避免每天高达45毫克的剂量 被我们的团队用于概念验证研究，但与长期安全问题和有限的临床相关 接受。在目标3中，所有患有2型糖尿病和非酒精性脂肪肝的患者(没有参加目标2)将被跟踪~4年 目的：确定非酒精性脂肪肝对糖尿病并发症的影响(与非非酒精性脂肪肝的糖尿病患者相比)。近期 横断面研究表明，NAFLD具有更高的微血管和大血管糖尿病风险 并发症。然而，这从来没有被前瞻性地研究过。 总之，上述互补性很强的研究将提供有关该流行病的第一个令人信服的证据。 PCP诊所内NASH-纤维化的研究；测试NASH-纤维化可以在T2 DM早期发现并进行治疗 使用小剂量PIO的PCPS的安全性以及NAFLD对糖尿病并发症的影响。

Project Abstract/Summary Nonalcoholic steatohepatitis (NASH) is known to occur often in type 2 diabetes mellitus (T2DM). Hepatologists know this firsthand from their clinical experience as well as from many cross-sectional studies, where T2DM is common among patients with cirrhosis or HCC. However, this knowledge has not trickled down to primary care physicians (PCPs) or translated into a systematic screening of patients with T2DM. Most PCPs simply remain largely unaware about the health risks associated with NASH and have limited information about the epidemic of NASH in the primary care setting, therefore, not finding a reason why to screen or treat. New studies have led to a consensus among hepatologists that patients with moderate fibrosis (≥F2) are on a disease path that leads to cirrhosis or HCC, more cardiovascular disease and increased mortality. Unfortunately, most NASH patients today are not diagnosed until it is too late. With evidence that a generic drug such as pioglitazone (PIO) leads to resolution of NASH in ~60% of patients, this is a missed opportunity to save lives and resources. However, most hepatologists are uncomfortable with prescribing PIO due to undesirable side effects (weight gain, lower extremity edema, bone loss, bladder cancer?). However, since even low doses of PIO (15 mg/day) increases adiponectin ~2-fold and improves adipose tissue insulin resistance, it is likely that a similar effect may be achieved on hepatic “lipotoxicity” and liver histology with doses that have minimal side effects. However, this hypothesis has never been tested before in a dose-response study in pts with NASH. We propose to develop a novel strategy for patients with T2DM and NASH shifting the focus from a late diagnosis and referral to hepatology, to an early diagnosis and intervention in the PCP clinics. First, to establish the magnitude of the problem of moderate-to-advanced fibrosis (≥F2) within the PCP setting (Aim 1) we will screen for NAFLD/liver fibrosis by CAP/VCTE (Fibroscan). Those with NASH-fibrosis will be offered treatment with low-dose PIO (15 mg/day) or placebo (Aim 2; an intermediate-dose of 30 mg/day will be also used to compare safety and efficacy, but interest is on the 15 mg/day dose). We will avoid the high 45 mg/day doses used by our group for proof-of-concept studies but associated with long-term safety concerns and limited clinical acceptance. In Aim 3, all patients with T2DM and NAFLD (not participating in Aim 2) will be followed for ~4 years to establish the impact of NAFLD on diabetic complications (compared to diabetics without NAFLD). Recent cross-sectional studies suggest that NAFLD carries a greater risk of micro- and macrovascular diabetic complications. However, this has never been prospectively studied. In summary, the above highly complementary studies will offer the first compelling evidence of the epidemic of NASH-fibrosis within PCP clinics; test that NASH-fibrosis can be identified early-on in T2DM and treated safely by PCPs with low-dose PIO, and the impact of NAFLD on diabetic complications.