Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Kentucky College of Medicine, University of Kentucky, Lexington, Kentucky, USA.
Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
Clin Transl Sci. 2021 Jan;14(1):11-19. doi: 10.1111/cts.12839. Epub 2020 Aug 25.
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P < 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-β agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.
非酒精性脂肪性肝病(NAFLD)是一种广泛存在且具有动态变化的疾病,可发生于各个年龄段,可导致肝硬化和肝细胞癌。目前,美国食品和药物管理局(FDA)尚未批准用于治疗 NAFLD 的药物;然而,这是一个活跃的研究领域。本文综述了用于治疗成人和儿童 NAFLD 的新兴药物疗法。研究中的药物疗法主要针对胆汁酸信号、胰岛素抵抗和肝脏内脂质处理。有三种药物已进入 III 期临床试验,其结果已经公布。在这些药物中,根据 REGENERATE 试验的中期分析,奥贝胆酸是唯一有前途的单一药物。奥贝胆酸显示,每天服用 25 毫克,18 个月后,非酒精性脂肪性肝炎(NASH)成人的纤维化减少(931 例患者中,纤维化减少 25%,安慰剂组为 12%,P<0.01)。正在进行的 III 期临床试验包括 REGENERATE 和 MAESTRO-NASH,研究甲状腺激素受体-β激动剂 MGL-3196。NASH 成人有前途的 II 期临床试验的结果也已经公布,这些试验研究了包括成纤维细胞生长因子(FGF)19 类似物 NGM282、GLP1 激动剂利拉鲁肽、FGF21 类似物 Pegbelfermin、钠葡萄糖协同转运蛋白 2 抑制剂恩格列净、酮己糖激酶抑制剂 PF-06835919、乙酰辅酶 A 羧化酶抑制剂 GS-0976 和趋化因子受体拮抗剂 Cenicriviroc 在内的药物。已完成和正在进行的临床试验强调,需要更细致地了解 NAFLD 亚组的表型,这可能需要采用个体化的药物治疗方法。