Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.

doi:10.1053/J.GASTRO.2013.05.042

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Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.

Journal Article•DOI•

Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease.

Sunder Mudaliar¹, Robert R. Henry¹, Arun J. Sanyal², Linda Morrow³, Hanns-Ulrich Marschall⁴, Mark Kipnes, Luciano Adorini⁵, Cathi Sciacca⁵, Paul Clopton¹, E. Castelloe⁵, Paul Dillon⁶, Mark Pruzanski⁵, David Shapiro⁵ - Show less +9 more•Institutions (6)

University of California, San Diego¹, Virginia Commonwealth University², AmeriCorps VISTA³, University of Gothenburg⁴, Intercept Pharmaceuticals⁵, Siemens⁶

01 Sep 2013-Gastroenterology (Elsevier)-Vol. 145, Iss: 3, pp 574-582

TL;DR: Administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease.

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About: This article is published in Gastroenterology.The article was published on 2013-09-01. It has received 794 citations till now. The article focuses on the topics: Insulin resistance & Nonalcoholic fatty liver disease.

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Journal Article•DOI•

EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease

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Giulio Marchesini, Christopher P. Day, Jean-François Dufour, Ali Canbay, Valerio Nobili, Vlad Ratziu, Herbert Tilg, Michael Roden, Amalia Gastaldelli, Hannele Yki-Järvinen, Fritz Schick, Roberto Vettor, Gema Frühbeck, Lisbeth Mathus-Vliegen - Show less +10 more

01 May 2016-Journal of Hepatology

TL;DR: The final purpose is to improve patient care and awareness of the importance of NAFLD, and to assist stakeholders in the decision-making process by providing evidence-based data, which also takes into consideration the burden of clinical management for the healthcare system.

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3,117 citations

Journal Article•DOI•

Mechanisms of NAFLD development and therapeutic strategies

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Scott L. Friedman¹, Brent A. Neuschwander-Tetri², Mary E. Rinella³, Arun J. Sanyal⁴•Institutions (4)

Icahn School of Medicine at Mount Sinai¹, Saint Louis University², Northwestern University³, Virginia Commonwealth University⁴

02 Jul 2018-Nature Medicine

TL;DR: Understanding of pathogenic mechanisms and clinical features of NAFLD is driving progress in therapeutic strategies now in clinical trials and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression are discussed.

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Abstract: There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.

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2,004 citations

Journal Article•DOI•

Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

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Brent A. Neuschwander-Tetri¹, Rohit Loomba², Arun J. Sanyal³, Joel E. Lavine⁴, Mark L. Van Natta⁵, Manal F. Abdelmalek⁶, Naga Chalasani⁷, Srinivasan Dasarathy⁸, Anna Mae Diehl⁶, Bilal Hameed⁹, Kris V. Kowdley¹⁰, Arthur J. McCullough¹¹, Norah A. Terrault⁹, Jeanne M. Clark⁵, James Tonascia⁵, Elizabeth M. Brunt¹², David E. Kleiner¹³, Edward Doo¹³ - Show less +14 more•Institutions (13)

Saint Louis University¹, University of California, San Diego², Virginia Commonwealth University³, Columbia University⁴, Johns Hopkins University⁵, Duke University⁶, Indiana University – Purdue University Indianapolis⁷, Case Western Reserve University⁸, University of California, San Francisco⁹, Virginia Mason Medical Center¹⁰, Cleveland Clinic¹¹, Washington University in St. Louis¹², National Institutes of Health¹³

14 Mar 2015-The Lancet

TL;DR: Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification.

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1,798 citations

Journal Article•DOI•

Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism.

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Annika Wahlström¹, Sama I. Sayin¹, Hanns-Ulrich Marschall¹, Fredrik Bäckhed², Fredrik Bäckhed¹ - Show less +1 more•Institutions (2)

University of Gothenburg¹, University of Copenhagen²

12 Jul 2016-Cell Metabolism

TL;DR: Host metabolism can be affected through microbial modifications of bile acids, which lead to altered signaling via bile acid receptors, but also by altered microbiota composition.

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1,495 citations

Cites background from "Efficacy and safety of the farnesoi..."

...Treatment with OCA for 6 weeks in patients with NAFLD and T2DMdose-dependently improved insulin sensitivity, estimated by euglycemic clamp, and reduced body weight, compared with placebo (Mudaliar et al., 2013)....
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Journal Article•DOI•

From NASH to HCC: current concepts and future challenges.

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Quentin M. Anstee¹, Quentin M. Anstee², Helen L. Reeves³, Helen L. Reeves², Elena Kotsiliti⁴, Olivier Govaere¹, Mathias Heikenwalder⁴ - Show less +3 more•Institutions (4)

Newcastle University¹, Newcastle upon Tyne Hospitals NHS Foundation Trust², Freeman Hospital³, German Cancer Research Center⁴

01 Jul 2019-Nature Reviews Gastroenterology & Hepatology

TL;DR: This Review discusses NAFLD-associated HCC, including its epidemiology, key features that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities, and the challenges and future directions of research.

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Abstract: Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC.

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761 citations

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References

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Diagnosis and Classification of Diabetes Mellitus

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Vittorio Basevi

06 Feb 2011-Diabetes Care

TL;DR: The chronic hyperglycemia of diabetes is associated with long-term damage, dys-function, and failure of differentorgans, especially the eyes, kidneys, nerves, heart, and blood vessels.

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13,077 citations

Journal Article•DOI•

Glucose clamp technique: a method for quantifying insulin secretion and resistance.

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Ralph A. DeFronzo¹, Jordan D. Tobin¹, Reubin Andres¹•Institutions (1)

Yale University¹

01 Sep 1979-American Journal of Physiology-endocrinology and Metabolism

TL;DR: Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique] are described.

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Abstract: Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.

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7,271 citations

"Efficacy and safety of the farnesoi..." refers background or methods in this paper

...C IN IC A L IV ER confirmatory of beneficial effects of OCA on both hepatic and peripheral insulin sensitivity.(35,41) Treatment with OCA also induced a significant decrease in g-glutamyltransferase levels, a marker of fatty liver disease that is associated with prediabetes and diabetes in the general population,(42) and a known risk factor for development of diabetes in patients with NAFLD....
[...]
...The patients received a primed constant intravenous infusion of regular human insulin (Humulin, U 100; Eli Lilly, Indianapolis, IN) during the 2-step euglycemic clamp procedure as previously described.(35) In the first step of the clamp, a lowdose submaximal insulin infusion rate (60 mU m(2) body surface area/min) was used for 180 minutes; in the second step, a high-dose insulin infusion rate (120 mU m(2) body surface area/ min) was used for an additional 120 minutes to maximally suppress endogenous glucose production and maximally stimulate peripheral glucose uptake....
[...]

Journal Article•DOI•

Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis

[...]

Takeshi Inagaki¹, Mihwa Choi¹, Antonio Moschetta¹, Li Peng¹, Carolyn L. Cummins¹, Jeffrey G. McDonald¹, Guizhen Luo², Stacey A. Jones², Bryan Goodwin², James A. Richardson¹, Robert D. Gerard¹, Joyce J. Repa¹, David J. Mangelsdorf¹, Steven A. Kliewer¹ - Show less +10 more•Institutions (2)

University of Texas Southwestern Medical Center¹, GlaxoSmithKline²

01 Oct 2005-Cell Metabolism

TL;DR: It is demonstrated that fibroblast growth factor 15 signals from intestine to liver to repress the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1), which catalyzes the first and rate-limiting step in the classical bile acid synthetic pathway.

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1,577 citations

"Efficacy and safety of the farnesoi..." refers background in this paper

...A BA-induced mechanism promoting insulin sensitivity relies on FXR-mediated production of fibroblast growth factor (FGF) 19 (and its mouse orthologue FGF15), an enterokine released by the ileal enterocyte that activates the cognate receptor FGFR4 in the liver to suppress CYP7A1/CYP8B1 expression, thus leading to reduced production of BAs.21,22 Treatment with FGF19 improves indices of dyslipidemia, hepatic steatosis, hyperinsulinemia, hyperleptinemia, and insulin sensitivity while reducing body weight and adiposity in mice fed a high-fat diet and ob/ob mice.23 In addition, treatment with FGF19 decreases hepatic triglyceride and free fatty acid levels as well as serum alanine aminotransferase (ALT) levels in FXR-deficient mice, ameliorating dysregulated hepatic lipogenesis due to absent FXR signaling.24 Treatment with FGF19 also restores glycogen loss in insulin-deficient diabetic animals, activating an insulin-independent endocrine pathway.25 Obeticholic acid (OCA; INT-747), a 6a-ethyl derivative of chenodeoxycholic acid, is a first-in-class selective FXR agonist with anticholestatic and hepatoprotective properties.26 OCA shows 100-fold greater FXR agonistic activity than chenodeoxycholic acid, the natural FXR agonist in humans.27 OCA does not activate other nuclear receptors,28 and its activities appear to be mediated only by FXR.29–31 A range of preclinical studies have shown that OCA increases insulin sensitivity and regulates glucose homeostasis, modulates lipid metabolism, and exerts antiinflammatory and antifibrotic effects in the liver, kidney, and intestine, the principal FXR-expressing organs.32 In light of the increasing preclinical evidence for the therapeutic potential of FXR agonists in the regulation of glucose and lipidmetabolism,OCAwas tested in a proof-ofconcept study in patients with type 2 diabetes mellitus and NAFLD and is reported here....
[...]
...A BA-induced mechanism promoting insulin sensitivity relies on FXR-mediated production of fibroblast growth factor (FGF) 19 (and its mouse orthologue FGF15), an enterokine released by the ileal enterocyte that activates the cognate receptor FGFR4 in the liver to suppress CYP7A1/CYP8B1 expression, thus leading to reduced production of BAs.(21,22) Treatment with FGF19 improves indices of dyslipidemia, hepatic steatosis, hyperinsulinemia, hyperleptinemia, and insulin sensitivity while reducing body weight and adiposity in mice fed a high-fat diet and ob/ob mice....
[...]

Journal Article•DOI•

Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.

[...]

Sama I. Sayin¹, Annika Wahlström¹, Jenny Felin¹, Sirkku Jäntti², Hanns-Ulrich Marschall¹, Krister Bamberg³, Bo Angelin⁴, Tuulia Hyötyläinen², Matej Orešič², Fredrik Bäckhed⁵, Fredrik Bäckhed¹ - Show less +7 more•Institutions (5)

University of Gothenburg¹, VTT Technical Research Centre of Finland², AstraZeneca³, Karolinska University Hospital⁴, University of Copenhagen⁵

05 Feb 2013-Cell Metabolism

TL;DR: It is suggested that the gut microbiota not only regulates secondary bile acids metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum.

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1,576 citations

"Efficacy and safety of the farnesoi..." refers background in this paper

...The gut microbiota has recently been shown to influence the size and composition of the bile acid pool throughout the enterohepatic system via FXR-dependent mechanisms.(49) Intriguingly, OCA can increase ileal FGF15 and suppress hepatic CYP7A1 expression in germ-free mice, showing its capacity to reverse their reduced FXR signaling and further supporting a potential cross talk between OCA and the gut microbiota....
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Journal Article•DOI•

Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation

[...]

Philippe Lefebvre¹, Bertrand Cariou, Fleur Lien, Folkert Kuipers, Bart Staels - Show less +1 more•Institutions (1)

French Institute of Health and Medical Research¹

01 Jan 2009-Physiological Reviews

TL;DR: Results suggest that modulation of FXR activity and BA metabolism may open new attractive pharmacological approaches for the treatment of the metabolic syndrome and type 2 diabetes.

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Abstract: The incidence of the metabolic syndrome has taken epidemic proportions in the past decades, contributing to an increased risk of cardiovascular disease and diabetes. The metabolic syndrome can be d...

...read moreread less

1,376 citations

"Efficacy and safety of the farnesoi..." refers background in this paper

...Importantly, in this study, OCA induced a marked doserelated increase in plasma levels of FGF19, a primary FXRresponsive transcriptional product.(11) It is noteworthy that FGF19 is not up-regulated by ursodeoxycholic acid,(44) a BA with no FXR agonistic activity(26) that is used to treat primary biliary cirrhosis and has also been tested in patients with NASH at dosages ranging up to 30 mg ∙ kg 1 ∙ day (1), with inconclusive results across several studies....
[...]
...It regulates a wide variety of target genes critically involved in the control of BA synthesis and transport, lipid metabolism, and glucose homeostasis.(11) In particular, FXR controls glucose metabolism through regulation of gluconeogenesis and glycogenolysis in the liver, as well as regulation of peripheral insulin sensitivity in striated muscle and adipose tissue, suggesting potential beneficial effects of FXR agonists in patients with diabetes and NAFLD....
[...]