scholarly journals Oral Lipid-Lowering Treatments Beyond Statins: Too Old and Outdated or Still Useful?

2021 ◽  
Vol 23 (12) ◽  
Author(s):  
Klaus G. Parhofer
Keyword(s):  
Bile Acid ◽  
Ldl Cholesterol ◽  
Treatment Algorithm ◽  
New Drugs ◽  
Lipid Lowering ◽  
Oral Drugs ◽  
Bile Acid Sequestrants ◽  
Risk Patients ◽  
Statin Drugs

Abstract Purpose of Review For many years, the lipid-lowering armamentarium consisted of statins and/or ezetimibe and/or bile acid sequestrants and/or fibrates. Now, with the availability of new drugs mostly injectables, the field has changed and the role of oral non-statin drugs (including bempedoic acid) must be reevaluated. Recent Findings Ezetimibe remains a very important combination partner for statins with continuously increasing treatment numbers. Bempedoic acid is another interesting combination partner for statin/ezetimibe or ezetimibe alone but lacks in contrast to ezetimibe evidence from outcome trials. The role of fibrates is less clear as they have shown disappointing results in outcome trials but may still be used in selected, high-risk patients with combined dyslipidemia. Bile acid sequestrants are now rarely used as there are stronger, better tolerable ways to lower LDL-cholesterol. Summary With the introduction of new injectable lipid-lowering drugs, some oral drugs such as ezetimibe and bempedoic acid still have an important spot in our treatment algorithm others such as fibrates have a less clear role while again others are now rarely used.

scholarly journals Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1104
Author(s):  
Cong Xie ◽  
Weikun Huang ◽  
Richard L. Young ◽  
Karen L. Jones ◽  
Michael Horowitz ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Peptide Yy ◽  
Glycogen Synthesis ◽  
Hormone Secretion ◽  
Gastrointestinal Hormones ◽  
Farnesoid X Receptor ◽  
Gastrointestinal Hormone ◽  
Bile Acid Sequestrants

Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge regarding bile acid physiology and metabolic health. Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulates the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome. These effects may contribute to the metabolic benefits of bile acid sequestrants, metformin, and bariatric surgery. This review focuses on the role of bile acids in energy intake and body weight, particularly their effects on gastrointestinal hormone secretion, the changes in obesity and T2D, and their potential relevance to the management of metabolic disorders.

scholarly journals Statin Intolerance in a Patient with Gilberts Syndrome and Hypercholesterolemia

2016 ◽  
Vol 3 (01) ◽  
pp. e8-e10 ◽  
Author(s):  
I. Jialal ◽  
D. Siegel
Keyword(s):  
Ldl Cholesterol ◽  
Unconjugated Bilirubin ◽  
Familial Combined Hyperlipidemia ◽  
Statin Intolerance ◽  
Gilbert’S Syndrome ◽  
Cholesterol Levels ◽  
Gilbert's Syndrome ◽  
Cytochrome 450 ◽  
Statin Drugs

Abstract Background: Statin intolerance especially myalgias can be a serious problem. Whilst it is well know that drugs that compete for Cytochrome 450 system can result in myalgias there is sparse data on the role of glucuronidation of statins contributing to statin intolerance We report on a 60 year old male with Hypercholesterolemia (HC) who was referred for management of his HC since he had statin intolerance manifesting as myalgias and was shown to have Gilbert’s Syndrome. Case Report: Investigation of this patient revealed he had Familial Combined Hyperlipidemia with a LDL-cholesterol of 189 mg/dl. He was also diagnosed with Gilbert’s Syndrome since he had elevated unconjugated bilirubin with no evidence of liver disease or hemolysis. The combination of Niacin, Cholestyramine and ezetimibe resulted in a successful decrease in his LDL-cholesterol to 114 mg/dl. Discussion: We believe that his Gilberts Syndrome resulted in an impairment in glucuronidation of statin drugs resulting in an increase in free drug levels and myalgias. We caution that clinicians should consider this possibility when confronted with a patient with both isolated elevations of unconjugated bilirubin and increase LDL-cholesterol levels before commencing statin therapy.

Three Generations of Bile Acid Sequestrants

1998 ◽  
Vol 550 ◽  
Author(s):  
W. Harry Mandeville ◽  
William Braunlin ◽  
Pradeep Dhal ◽  
Amy Guo ◽  
Chad Huval ◽  
...  
Keyword(s):  
Bile Acid ◽  
Ldl Cholesterol ◽  
Third Generation ◽  
Cholesterol Reduction ◽  
Bile Acid Sequestrants ◽  
Binding Isotherms ◽  
Bile Acid Binding ◽  
Binding Mechanisms ◽  
Site Binding ◽  
Binding Structure

AbstractCholestyramine, the first bile acid sequestrant to be marketed, has been in use for over 20 years. Despite its low potency, requiring 16-24 g of polymer to achieve 20% LDL cholesterol reduction in hypercholesterolemic individuals, only one other sequestrant, colestipol, has come to market in the ensuing period. GelTex Pharmaceuticals has been involved for over six years in the discovery and development of new, more potent polymeric sequestrants. Two binding mechanisms are presented — one that operates via an aggregate binding structure and one that is effective via a defined site binding structure. These two binding mechanisms are compared and contrasted through bile acid binding isotherms. The best of these new sequestrants bind bile acids through a combination of hydrophobicity and ion exchange. Optimization and balancing of each of these interactions led us to more potent materials. The first of these, colesevelam hydrochloride is expected to be three to four times more potent than cholestyramine. A third generation product is still in research at GelTex. With another twofold increase in potency possible, single tablet therapy may become a reality.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion

2014 ◽  
Vol 171 (2) ◽  
pp. R47-R65 ◽  
Author(s):  
David P Sonne ◽  
Morten Hansen ◽  
Filip K Knop
Keyword(s):  
Type 2 Diabetes ◽  
Bile Acid ◽  
Bile Acids ◽  
G Protein ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Bile Acid Sequestrants ◽  
G Protein Coupled

Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently – despite elusive mechanisms of action – bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5.

scholarly journals Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles

2021 ◽  
Vol 11 (1) ◽  
pp. 4
Author(s):  
Boyan Zhang ◽  
Folkert Kuipers ◽  
Jan Freark de de Boer ◽  
Jan Albert Kuivenhoven
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Metabolism ◽  
Ldl Cholesterol ◽  
Farnesoid X Receptor ◽  
New Drugs ◽  
Bile Acid Metabolism ◽  
Atherosclerotic Cardiovascular Disease ◽  
Faecal Excretion ◽  
Alcoholic Fatty Liver

New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process.

Abstract 18396: Low Rate of LDL-Goal-Attainment in 57,855 High-Risk-Patients in Europe, Canada, South-Africa, Middle East and China - Results of DYSIS

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Anselm K Gitt ◽  
Dominik Lautsch ◽  
Martin Horack ◽  
Baishali Ambegaonkar ◽  
Jean Ferrieres ◽  
...  
Keyword(s):  
Clinical Practice ◽  
High Risk ◽  
Secondary Prevention ◽  
Goal Attainment ◽  
Ldl Cholesterol ◽  
Statin Treatment ◽  
Lipid Lowering ◽  
High Risk Patients ◽  
Risk Patients ◽  
Very High

Background: Statin treatment is routinely used for secondary prevention world-wide. Little is known about the prevalence of persistent lipid abnormalities under chronic statin treatment for secondary prevention and possible differences in LDL-Cholesterol (LDL-C) goal attainment in clinical practice between countries in different parts of the world. Methods: Between 2008 and 2012, consecutive statin-treated outpatients were enrolled in 26 countries worldwide, (DYSIS = Dyslipidemia International Study; list of countries in table) to assess LDL-C goal attainment for secondary prevention. European Society of Cardiology recommendations were used to classify patient risk, and to define LDL-cholesterol treatment goals. Data were collected under real life conditions in physicians’ offices and hospital outpatient wards. Results: Serum lipid values of 57,885 consecutive statin-treated outpatients were studied in the context of their cardiovascular risk factors, and the potency and composition of their lipid-lowering treatment. In the very-high risk patients only 21.7% did reach the currently recommended LDL-Chol target <70mg/dl with large differences between the countries varying from 9.2% to 44.3%. In the high-risk population the LDL-Chol target <100mg/dl was achieved in 38.0% oft he patients, varying between 16.6% and 66.7% between countries Conclusion: Despite chronic statin treatment, only 21.7% of the very-high-risk patients reached the current recommended LDL-Chol target <70mg/dl in this large multinational cross-sectional trial, highlighting the persistent large gap between guideline recommendations and clinical practice. Further treatment escalations are necessary to reduce the risk of subsequent cardiovascular events.

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