Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis

Siddiqui, Mohammad Shadab; Natta, Mark L. Van; Connelly, Margery A.; Vuppalanchi, Raj; Neuschwander‐Tetri, Brent A.; Tonascia, James; Guy, Cynthia D.; Loomba, Rohit; Dasarathy, Srinivasan; Wattacheril, Julia; Chalasani, Naga; Sanyal, Arun J.

doi:10.1016/j.jhep.2019.10.006

Cited by 102 publications

(82 citation statements)

References 37 publications

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“…However, administration of synthetic FXR agonists to atherogenic mice prevented plaque formation in three studies, presumably by lipid-lowering and anti-inflammatory effects [ 149 , 150 , 151 ]. Although the FXR agonist obeticholic acid (OCA) lowered hepatic fat in human subjects with non-alcoholic steatohepatitis (NASH), it had paradoxical effects on cholesterol levels, increasing LDL and decreasing high-density lipoprotein (HDL) cholesterol [ 152 ].…”

Section: Gut Microbiota In Atherosclerosismentioning

confidence: 99%

Gut Microbiota in Hypertension and Atherosclerosis: A Review

et al. 2020

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Gut microbiota and its metabolites such as short chain fatty acids (SCFA), lipopolysaccharides (LPS), and trimethylamine-N-oxide (TMAO) impact cardiovascular health. In this review, we discuss how gut microbiota and gut metabolites can affect hypertension and atherosclerosis. Hypertensive patients were shown to have lower alpha diversity, lower abundance of SCFA-producing microbiota, and higher abundance of gram-negative bacteria, which are a source of LPS. Animal studies point towards a direct role for SCFAs in blood pressure regulation and show that LPS has pro-inflammatory effects. Translocation of LPS into the systemic circulation is a consequence of increased gut permeability. Atherosclerosis, a multifactorial disease, is influenced by the gut microbiota through multiple pathways. Many studies have focused on the pro-atherogenic role of TMAO, however, it is not clear if this is a causal factor. In addition, gut microbiota play a key role in bile acid metabolism and some interventions targeting bile acid receptors tend to decrease atherosclerosis. Concluding, gut microbiota affect hypertension and atherosclerosis through many pathways, providing a wide range of potential therapeutic targets. Challenges ahead include translation of findings and mechanisms to humans and development of therapeutic interventions that target cardiovascular risk by modulation of gut microbes and metabolites.

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Section: Gut Microbiota In Atherosclerosismentioning

confidence: 99%

Gut Microbiota in Hypertension and Atherosclerosis: A Review

et al. 2020

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“…All of the lipoprotein changes reverted to baseline 12 weeks after OCA discontinuation. 134 A study in healthy volunteers also revealed an increase in LDL-C, confirming OCA's direct effects on LDL-C, presumably via increased intrahepatic cholesterol content and decreased LDL receptor cell surface expression ( Figure 3). 135 In this study, HDL particles decreased largely due to a reduction in medium and small HDL, and total LDL particles increased along with an increase in large LDL and LDL-C. 135 In order to evaluate whether OCA has long-term detrimental effects on CVD, it would be important to determine if concurrent statin treatment can reduce LDL-C in OCA-treated subjects.…”

Section: Farnesoid X Receptor Agonists and Fibroblast Growth Factormentioning

confidence: 59%

“…In both studies, OCA vs placebo treatment led to 16%-24% increases in LDL-C. 132,133 To gain a better understanding of OCA's effects, nuclear magnetic resonance analysis of lipoprotein particle concentrations was obtained before and after OCA treatment. 134 OCA treatment elicited increases in large-buoyant and small-dense LDL particles. The increases trended higher at 12 weeks than 72 weeks, which may be attributed to increased use of statins in patients whose LDL-C levels were increased by OCA, and tended to be much higher for large than small LDL.…”

Section: Farnesoid X Receptor Agonists and Fibroblast Growth Factormentioning

confidence: 88%

“…OCA treatment elicited a reduction in large VLDL and an increase in small VLDL without any change in total VLDL concentration. 134 Thus, the net effect of FXR agonism is a shift to what some lipidologists believe is a less atherogenic lipoprotein profile. OCA vs placebo treatment also led to 2.6%-4.5% reductions in HDL-C. Total HDL particles were similarly reduced including both large and medium HDL particle concentrations, most likely due to increased clearance.…”

Section: Farnesoid X Receptor Agonists and Fibroblast Growth Factormentioning

confidence: 99%

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Review article: the impact of liver‐directed therapies on the atherogenic risk profile in non‐alcoholic steatohepatitis

Connelly

Rivera

Guyton

et al. 2020

Aliment Pharmacol Ther

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Summary Background Patients with non‐alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, are at higher risk of cardiovascular disease (CVD) and associated mortality. Therefore, it is important to understand how new therapies for non‐alcoholic steatohepatitis (NASH) may impact CVD risk factors in these patients. Aims To summarise the effects of drug therapies on lipid and lipoprotein levels in patients with NASH and provide insight into the potential mechanisms for the observed changes. Methods PubMed searches of the literature were performed and results were compiled. Results Recent clinical trials have highlighted the safety and efficacy of drug candidates for the treatment of NASH. Several agents have shown improvements in the histological features of NASH and liver function. Pioglitazone, a drug that is currently available for type 2 diabetes and may be useful for NASH, exhibits beneficial effects on lipids. However, agents such as farnesoid X receptor agonists, which are in development for NASH, may adversely affect circulating lipids and lipoproteins. Conclusions NASH is a multi‐system disease with a disproportionate CVD burden. Current and future drugs for NASH have had variable impact on the atherogenic risk profile. Potential co‐administration of a statin may help mitigate the negative impact of some of these therapies on lipid and lipoprotein levels.

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“…Elevated non-HDL cholesterol levels were linked to increased mortality even after adjusting for other cardiovascular risk factors. 26 The issue of alterations in the lipid profile in this study is addressed in a subsequent paper published only 2 weeks later in another journal. 27 This study was based on the 196 patients in the FLINT study.…”

Section: Drug Tre Atment Of Nafldmentioning

confidence: 97%

Obeticholic acid for treatment of NAFLD—A drug in search of a disease

2020

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Introduction: Non-alcoholic fatty liver disease (NAFLD) is the hepatic component of the metabolic syndrome. Although the only proven treatments are weight loss, diet, exercise and consumption of coffee, many medications are being investigated for treatment of NAFLD. Aim:To present different aspects of NAFLD as part of the metabolic syndrome and to review some aspects of obeticholic acid (OCA) therapy. Methods:We comment on the REGENERATE trial of OCA for treating NAFLD.Results: This trial (1968 patients with F2-3 fibrosis or F1 fibrosis and ≥ 1 comorbidity) has several limitations. The incidence of pruritus in the OCA group is 22% in the 25 mg dose, 17% in the 10 mg dose and 14% in the placebo group. Pruritus was not rigidly defined and in a trial of elafibranor for NAFLD, only 1% had pruritus in the placebo group. OCA causes hyperlipidaemia; the placebo group had a decrease in cholesterol of 3 mg/dL in the first month vs an increase of 17.8 mg/dL in the 10 mg dose and 23.8 mg/dL in the 25 mg dose group. Since 56% of the patients had diabetes mellitus and 69% had hypertension, this is likely to be detrimental. The interim analysis showed a 'significant histological improvement' but there is no data regarding clinical end-points. The issue of changes in lipids was addressed in a separate publication 2 weeks later. Conclusion:The current trials of treatment for NAFLD need to have robust treatment in the placebo groups and address clinical outcomes. At present, it appears to be drugs in search of a disease.

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Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis

Cited by 102 publications

References 37 publications

Gut Microbiota in Hypertension and Atherosclerosis: A Review

Gut Microbiota in Hypertension and Atherosclerosis: A Review

Review article: the impact of liver‐directed therapies on the atherogenic risk profile in non‐alcoholic steatohepatitis

Obeticholic acid for treatment of NAFLD—A drug in search of a disease

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