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

低剂量吡格列酮筛查和早期干预在 T2DM 和 NASH 患者初级保健中的作用

• 批准号: 10160896
• 负责人: Kenneth Cusi
• 金额: $ 59.57万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-08 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160896
• 关键词: Adipose tissue; Awareness; Biopsy; Cardiovascular Diseases; Cirrhosis; Clinic; Clinic Visits; Clinical; Complication; Complications of Diabetes Mellitus; Consensus; Cross-Sectional Studies; Devices; Diabetic macrovascular disease; Diagnosis; Disease; Dose; Early Diagnosis; Early Intervention; Early treatment; Edema; Epidemic; Event; Fatty Liver; Fibrosis; Generic Drugs; Gold; Health; Hepatic; Hepatology; Histology; Insulin Resistance; Internships; Intervention; Knowledge; Lead; Liver; Liver Fibrosis; Liver diseases; Lower Extremity; Malignant neoplasm of liver; Malignant neoplasm of urinary bladder; Measures; Metabolic; Microvascular Dysfunction; Monitor; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Pioglitazone; Placebos; Prevalence; Primary Care Physician; Primary Health Care; Prospective Studies; Public Health; Resolution; Resources; Risk; Role; Safety; Severities; Testing; Time; Tissues; Translating; Ultrasonography; Weight Gain; adiponectin; arm; bone loss; diabetic; experience; improved; interest; lipid metabolism; liver biopsy; liver inflammation; macrovascular disease; mortality; non-alcoholic fatty liver disease; non-diabetic; nonalcoholic steatohepatitis; novel; novel strategies; patient screening; primary care setting; primary endpoint; primary outcome; receptor; response; screening; side effect

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.

项目摘要/摘要 已知非酒精性脂肪性肝炎（NASH）常发生于2型糖尿病（T2 DM）。肝病专家 我从他们的临床经验以及许多横断面研究中了解到这一点，其中T2 DM是 常见于肝硬化或肝癌患者。然而，这些知识并没有渗透到初级保健中， 医生（PCP）或转化为T2 DM患者的系统筛查。大多数PCP只是保持 他们基本上不知道与NASH相关的健康风险，并且对该流行病的信息有限 因此，在初级保健环境中，NASH的发病率很高，没有找到筛查或治疗的理由。新的研究导致 肝病学家一致认为中度纤维化（≥F2）患者的疾病路径导致 肝硬化或肝癌，更多的心血管疾病和死亡率增加。不幸的是，大多数NASH患者 直到现在才被诊断出来，为时已晚。有证据表明，非专利药如吡格列酮（PIO）会导致 在约60%的患者中，NASH的解决是一个挽救生命和资源的机会。但大多数 肝病学家由于不希望的副作用（体重增加，较低的 四肢水肿、骨质流失、膀胱癌？）。然而，由于即使是低剂量的PIO（15 mg/天）也会增加 脂联素~2倍，改善脂肪组织胰岛素抵抗，很可能有类似的效果， 在肝“脂毒性”和肝组织学上实现，剂量具有最小的副作用。但这 在NASH患者的剂量反应研究中，这一假设从未得到过检验。 我们建议为T2 DM和NASH患者开发一种新的策略，将重点从晚期糖尿病转移到晚期NASH。 诊断和转诊到肝病科，到PCP诊所进行早期诊断和干预。首先，建立 在PCP背景下（目标1），我们将评估中晚期纤维化（≥F2）问题的严重程度 通过CAP/VCTE（Fibroscan）筛查NAFLD/肝纤维化。患有NASH纤维化的人将获得治疗 低剂量PIO（15 mg/天）或安慰剂（目标2;还将使用30 mg/天的中剂量， 比较安全性和有效性，但关注的是15 mg/天剂量）。我们将避免45毫克/天的高剂量 我们的研究小组将其用于概念验证研究，但与长期安全性问题和有限的临床 验收在目标3中，将对所有T2 DM和NAFLD患者（未参与目标2）进行约4年的随访 确定NAFLD对糖尿病并发症的影响（与无NAFLD的糖尿病患者相比）。最近 横断面研究表明，NAFLD具有更大的微血管和大血管糖尿病风险， 并发症然而，这从未被前瞻性地研究过。 总之，上述高度互补的研究将提供关于该流行病的第一个令人信服的证据 PCP诊所内的NASH纤维化;测试NASH纤维化可以在T2 DM中早期识别并治疗 安全地通过PCP与低剂量PIO，以及NAFLD对糖尿病并发症的影响。