Glucagon-like Peptide-1 Receptor-based Therapeutics for Metabolic Liver Disease.

IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Endocrine reviews Pub Date : 2023-01-12 DOI:10.1210/endrev/bnac018
Julian M Yabut, Daniel J Drucker
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引用次数: 21

Abstract

Glucagon-like peptide-1 (GLP-1) controls islet hormone secretion, gut motility, and body weight, supporting development of GLP-1 receptor agonists (GLP-1RA) for the treatment of type 2 diabetes (T2D) and obesity. GLP-1RA exhibit a favorable safety profile and reduce the incidence of major adverse cardiovascular events in people with T2D. Considerable preclinical data, supported by the results of clinical trials, link therapy with GLP-RA to reduction of hepatic inflammation, steatosis, and fibrosis. Mechanistically, the actions of GLP-1 on the liver are primarily indirect, as hepatocytes, Kupffer cells, and stellate cells do not express the canonical GLP-1R. GLP-1RA reduce appetite and body weight, decrease postprandial lipoprotein secretion, and attenuate systemic and tissue inflammation, actions that may contribute to attenuation of metabolic-associated fatty liver disease (MAFLD). Here we discuss evolving concepts of GLP-1 action that improve liver health and highlight evidence that links sustained GLP-1R activation in distinct cell types to control of hepatic glucose and lipid metabolism, and reduction of experimental and clinical nonalcoholic steatohepatitis (NASH). The therapeutic potential of GLP-1RA alone, or in combination with peptide agonists, or new small molecule therapeutics is discussed in the context of potential efficacy and safety. Ongoing trials in people with obesity will further clarify the safety of GLP-1RA, and pivotal studies underway in people with NASH will define whether GLP-1-based medicines represent effective and safe therapies for people with MAFLD.

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基于胰高血糖素样肽-1受体的代谢性肝病治疗
胰高血糖素样肽-1 (GLP-1)控制胰岛激素分泌、肠道蠕动和体重,支持GLP-1受体激动剂(GLP-1RA)的开发,用于治疗2型糖尿病(T2D)和肥胖。GLP-1RA具有良好的安全性,可降低T2D患者主要不良心血管事件的发生率。临床试验结果支持了大量临床前数据,将GLP-RA治疗与肝脏炎症、脂肪变性和纤维化的减少联系起来。从机制上讲,GLP-1对肝脏的作用主要是间接的,因为肝细胞、库普弗细胞和星状细胞不表达典型的GLP-1R。GLP-1RA可降低食欲和体重,减少餐后脂蛋白分泌,减轻全身和组织炎症,这些作用可能有助于减轻代谢性脂肪性肝病(MAFLD)。在这里,我们讨论了改善肝脏健康的GLP-1作用的不断发展的概念,并强调了GLP-1R在不同细胞类型中持续激活与控制肝脏糖脂代谢以及减少实验和临床非酒精性脂肪性肝炎(NASH)相关的证据。GLP-1RA单独或与肽激动剂或新小分子疗法联合的治疗潜力在潜在疗效和安全性的背景下进行了讨论。正在进行的针对肥胖患者的试验将进一步阐明GLP-1RA的安全性,而针对NASH患者的关键研究将确定基于glp -1的药物对MAFLD患者是否有效和安全。
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来源期刊
Endocrine reviews
Endocrine reviews 医学-内分泌学与代谢
CiteScore
42.00
自引率
1.00%
发文量
29
期刊介绍: Endocrine Reviews, published bimonthly, features concise timely reviews updating key mechanistic and clinical concepts, alongside comprehensive, authoritative articles covering both experimental and clinical endocrinology themes. The journal considers topics informing clinical practice based on emerging and established evidence from clinical research. It also reviews advances in endocrine science stemming from studies in cell biology, immunology, pharmacology, genetics, molecular biology, neuroscience, reproductive medicine, and pediatric endocrinology.
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