Abstract:
BACKGROUND:NGM282, an engineered analogue of the gut hormone FGF19, improves hepatic steatosis and fibrosis biomarkers in patients with non-alcoholic steatohepatitis (NASH). However, NGM282 increases serum cholesterol levels by inhibiting CYP7A1, which encodes the rate-limiting enzyme in the conversion of cholesterol to bile acids. Herein, we investigate whether administration of a statin can manage the cholesterol increase seen in patients with NASH receiving treatment with NGM282. METHODS:In this phase II, open-label, multicenter study, patients with biopsy-confirmed NASH were treated with subcutaneous NGM282 once daily for 12 weeks. After 2 weeks, rosuvastatin was added in stepwise, biweekly incremental doses to a maximum of 40 mg daily. Both drugs were continued until the end of treatment at week 12. We evaluated plasma lipids, lipoprotein particles and liver fat content. RESULTS:In 66 patients who received NGM282 0.3 mg (n = 23), NGM282 1 mg (n = 21), or NGM282 3 mg (n = 22), circulating cholesterol increased from baseline at week 2. Initiation of rosuvastatin resulted in rapid decline in plasma levels of total cholesterol and low-density lipoprotein cholesterol. At week 12, reductions from baseline in total cholesterol levels of up to 18% (p <0.001), low-density lipoprotein cholesterol of up to 28% (p <0.001), triglycerides of up to 34% (p <0.001) and an increase in high-density lipoprotein cholesterol of up to 16% (p <0.001), with similar changes in lipoprotein particles, were observed in these patients. Robust decreases from baseline in 7alpha-hydroxy-4-cholesten-3-one (p <0.001) and liver fat content (p <0.001) were also observed. Rosuvastatin was safe and well-tolerated when co-administered with NGM282 in patients with NASH. CONCLUSIONS:In this multicenter study, NGM282-associated elevation of cholesterol was effectively managed with rosuvastatin. Co-administration of rosuvastatin with NGM282 may be a reasonable strategy to optimize the cardiovascular risk profile in patients with NASH. LAY SUMMARY:Non-alcoholic steatohepatitis (NASH) represents a large and growing public health concern with no approved therapy. NGM282, an engineered analogue of the gut hormone FGF19, reduces liver fat, liver injury and inflammation in patients with NASH. However, NGM282 increases cholesterol levels. Here we show that co-administration of a statin can manage the cholesterol increase seen in patients with NASH receiving treatment with NGM282, producing a favorable overall lipid profile.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Rinella ME,Trotter JF,Abdelmalek MF,Paredes AH,Connelly MA,Jaros MJ,Ling L,Rossi SJ,DePaoli AM,Harrison SAdoi
10.1016/j.jhep.2018.11.032subject
Has Abstractpub_date
2019-04-01 00:00:00pages
735-744issue
4eissn
0168-8278issn
1600-0641pii
S0168-8278(18)32615-1journal_volume
70pub_type
杂志文章,多中心研究abstract:BACKGROUND/AIMS:Inflammation in the liver is a complex interaction between parenchymal and non-parenchymal cells, and therefore can not be studied in vitro in pure cultures of these cells. METHODS:We investigated whether Kupffer cells in the liver slice are still responsive to an inflammatory stimulus of lipopolysacch...
journal_title:Journal of hepatology
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abstract:BACKGROUND/AIMS:The aim of the present study was to compare MELD score, Child-Turcotte-Pugh (CTP) score, modified Maddrey's Discriminant Function (DF) score, and the related variables in predicting in-hospital mortality of patients with alcoholic hepatitis. METHODS:A retrospective chart review and statistical analyses...
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pub_type: 杂志文章
doi:10.1016/j.jhep.2004.12.022
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abstract:BACKGROUND & AIMS:Genetic background may affect liver damage in patients with non-alcoholic fatty liver disease (NAFLD). The main outcomes of the study were to assess whether IL28B rs12979860 and rs8099917 polymorphisms, together with PNPLA3 rs738409 C>G polymorphism, are associated with lobular inflammation and fibros...
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abstract:BACKGROUND/AIMS:Angiogenesis plays a key role in development of portal hypertension (PHT) and represents a potential therapeutic target. We aimed to evaluate the molecular effects of sorafenib, a multiple tyrosine kinase inhibitor, on splanchnic hemodynamics in rats with partial portal vein ligation (PPVL). METHODS:Th...
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abstract:BACKGROUND & AIMS:Hepatitis B virus (HBV) has developed strategies to evade immune responses. However, the mechanisms involved remain unclear. The NLRP3 inflammasome plays crucial roles in antiviral host defense and its downstream factor IL-1β has been shown to inhibit HBV infection in vivo. This study aims to assess w...
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更新日期:2017-04-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2011.11.017
更新日期:2012-04-01 00:00:00
abstract:BACKGROUND/AIMS:To examine the T-cell repertoire which is involved in the immunopathogenesis of chronic hepatitis, we analyzed the T-cell receptor Vbeta gene usage in liver-infiltrating lymphocytes by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical technique. METHODS:Complementary DNA ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(97)80408-4
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更新日期:1994-09-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/s0168-8278(94)80146-0
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pub_type: 临床试验,杂志文章,随机对照试验
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abstract::Recently antibodies to hepatitis C virus were detected in sera of chronic active hepatitis patients, with anti-smooth muscle autoantibodies or with anti-liver/kidney microsomal type 1 autoantibodies. As the latter were used to differentiate autoimmune chronic active hepatitis from chronic non-A, non-B virus hepatitis,...
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pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1034/j.1600-0641.2000.033004640.x
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abstract::A diagnostic test has been developed to detect hepatitis B virus (HBV) DNA in human sera. This test involves a dot-blot technique in which non-radioactive nucleic acid labelled with 2-acetylaminofluorene (AAF) is used as probe. Two series of human sera from 228 blood donors and 113 HBsAg chronic carriers were tested b...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(87)80573-1
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abstract::Two to three percent of the world's population is chronically infected with hepatitis C virus (HCV) and thus at risk of developing liver cancer. Although precise mechanisms regulating HCV entry into hepatic cells are still unknown, several cell surface proteins have been identified as entry factors for this virus. Amo...
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pub_type: 评论,杂志文章
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pub_type: 杂志文章
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(91)90036-b
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2006.04.008
更新日期:2006-09-01 00:00:00
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更新日期:2015-09-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(88)80456-2
更新日期:1988-02-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(05)80665-8
更新日期:1992-11-01 00:00:00
abstract::Medical treatment of cirrhotic ascites is essentially supportive, dictated by the patient's discomfort, impaired cardiovascular or respiratory function and potential for infection. Treatment of 'simple' ascites (moderate fluid accumulation, serum albumin > 3.5 g/dl, serum creatinine < 1.5 mg/dl, no electrolyte disturb...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/s0168-8278(05)80447-7
更新日期:1993-01-01 00:00:00
abstract::Hepatocytes synthesise the majority of serum proteins. This production occurs in the endoplasmic reticulum (ER) and is adjusted by complex local and systemic regulatory mechanisms. Accordingly, serum levels of hepatocyte-made proteins constitute important biomarkers that reflect both systemic processes and the status ...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2018.04.018
更新日期:2018-08-01 00:00:00