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Filip K. Knop - One of the best experts on this subject based on the ideXlab platform.
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Bile Acid Sequestrants for glycemic control in patients with type 2 diabetes: A systematic review with meta-analysis of randomized controlled trials
Journal of diabetes and its complications, 2017Co-Authors: Morten Hansen, David P. Sonne, Kristian Hallundbæk Mikkelsen, Lise Lotte Gluud, Tina Vilsbøll, Filip K. KnopAbstract:Abstract Aim To evaluate the effects of Bile Acid Sequestrants (BASs) versus placebo, no intervention or active comparators on glycemic control in type 2 diabetes. Methods Data were retrieved and a systematic review with meta-analyses was performed. We evaluated bias control and subgroup and sensitivity analyses were performed to evaluate heterogeneity and bias. Results We included 17 trials with a total of 2950 patients randomized to BASs (colesevelam or colestimide) versus placebo, no intervention, statins or sitagliptin. Random-effects meta-analysis showed that patients randomized to BASs had a lower hemoglobin A 1c at the end of treatment compared with the control group (mean difference−0.55%; 95% confidence interval−0.64 to −0.46). Analysis of trials with low risk of bias in all domains confirmed the findings. Data on adverse events were limited. There were no differences between trials stratified by the control group and no evidence of publication bias or small study effects. Conclusions Our analyses found that BAS treatment improves glycemic control. The size of the effect was clinically relevant and despite limited safety data, our findings support the inclusion of BASs in current diabetes management algorithms for type 2 diabetes.
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Bile Acid Sequestrants in type 2 diabetes: potential effects on GLP1 secretion.
European journal of endocrinology, 2014Co-Authors: David P. Sonne, Morten Hartvig Hansen, Filip K. KnopAbstract: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.
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Bile Acid Sequestrants: Glucose-Lowering Mechanisms and Efficacy in Type 2 Diabetes
Current Diabetes Reports, 2014Co-Authors: Morten Hansen, David P. Sonne, Filip K. KnopAbstract:Bile Acids are synthesized in the liver from cholesterol and have traditionally been recognized for their role in absorption of lipids and in cholesterol homeostasis. In recent years, however, Bile Acids have emerged as metabolic signaling molecules that are involved in the regulation of lipid and glucose metabolism, and possibly energy homeostasis, through activation of the Bile Acid receptors farnesoid X receptor (FXR) and TGR5. Bile Acid Sequestrants (BASs) constitute a class of drugs that bind Bile Acids in the intestine to form a nonabsorbable complex resulting in interruption of the enterohepatic circulation. This increases Bile Acid synthesis and consequently reduces serum low-density lipoprotein cholesterol. Also, BASs improve glycemic control in patients with type 2 diabetes. Despite a growing understanding of the impact of BASs on glucose metabolism, the mechanisms behind their glucose-lowering effect in patients with type 2 diabetes remain unclear. This article offers a review of the mechanisms behind the glucose-lowering effect of BASs, and the efficacy of BASs in the treatment of type 2 diabetes.
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Effect of Bile Acid Sequestrants on glycaemic control: protocol for a systematic review with meta-analysis of randomised controlled trials
BMJ open, 2012Co-Authors: Morten Hansen, David P. Sonne, Kristian Hallundbæk Mikkelsen, Lise Lotte Gluud, Tina Vilsbøll, Filip K. KnopAbstract:Introduction In addition to the lipid-lowering effect of Bile Acid Sequestrants (BASs), they also lower blood glucose and, therefore, could be beneficial in the treatment of patients with type 2 diabetes mellitus (T2DM). Three oral BASs are approved by the US Food and Drug Administration (FDA) for the treatment of hypercholesterolaemia: colestipol, cholestyramine and colesevelam. The BAS colestimide/colestilan is used in Japan. Colesevelam was recently approved by the FDA for the treatment of T2DM. We plan to provide a systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim to evaluate their potential as glucose-lowering agents in patients with T2DM. Methods and analysis In accordance with the preferred reporting items for systematic reviews and meta-analyses statement, a systematic review with meta-analysis of randomised clinical trials of BASs (vs placebo, oral antidiabetes drugs or insulin), reporting measures of glycaemic control in adult patients with T2DM, will be performed. Change in glycated haemoglobin constitutes the primary endpoint, and secondary endpoints include changes in fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, body weight and body mass index and adverse events. Electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE, along with manual searches in the reference lists of relevant papers. The analyses will be performed based on individual patient data and summarised data. The primary meta-analysis will be performed using random effects models owing to expected intertrial heterogeneity. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs. Ethics and dissemination The study will evaluate the potential of BASs as glucose-lowering agents and possibly contribute to the clinical management of patients with T2DM. Results The study will be disseminated by peer-review publication and conference presentation. Protocol registration PROSPERO CRD42012002552.
Arthu J Hartz - One of the best experts on this subject based on the ideXlab platform.
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evaluation of the effectiveness of lipid lowering therapy Bile Acid Sequestrants niacin psyllium and lovastatin for treating hypercholesterolemia in veterans
American Journal of Cardiology, 1993Co-Authors: Gordo Schectma, Ja Hia, Arthu J HartzAbstract:Veterans are frequently older, have more chronic illnesses, and take more medications than subjects volunteering for clinical trials. Because these factors may impair the effectiveness of lipid-lowering drug therapy, the effectiveness of drug therapy in veterans may differ from that measured in randomized controlled trials. In 297 patients with type Ha hyperlipidemia attending a large Veterans Administration Medical Center lipid clinic, adverse effects, compliance, lipid and lipoprotein responses to drug therapy were prospectively monitored. Bile Acid Sequestrants (4 packets/day) were associated with a high rate of adverse effects, and had the highest drug discontinuance rate (37%) and poorest compliance (73 ± 3% of the doses prescribed reported ingested) of all agents. Patients aged >60 years tolerated therapy with Bile Acid Sequestrants less well than did younger veterans (p < 0.01). Niacin (1.5 g/day) also had a high drug discontinuance rate (27%). Lovastatin (20 mg/day) had the lowest drug discontinuance rate (2%) and the highest compliance (90 ± 2%). Lovastatin also reduced low-density lipoprotein (LDL) cholesterol the most (−21.6 ± 2.0%), whereas niacin produced the largest increase in high-density lipoprotein (HDL) cholesterol (± 14.3 ± 2.2%); both niacin and lovastatin produced similar reductions in the LDLHDL ratio. However, psyllium (10.4 g/day) reduced LDL cholesterol by only 2%, and had no effect on the LDL/HDL ratio. Psyllium produced larger LDL cholesterol reductions in patients aged <60 years than in older patients (p < 0.01). Niacin and lovastatin are effective drugs for hypercholesterolemia management in the Veterans Administration Medical Center setting. However, in elderly veterans, Bile Acid Sequestrants were associated with a higher rate of adverse effects limiting compliance, and psyllium was ineffective.
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Evaluation of the effectiveness of lipid-lowering therapy (Bile Acid Sequestrants, niacin, psyllium and lovastatin) for treating hypercholesterolemia in veterans
The American journal of cardiology, 1993Co-Authors: Gordon Schectman, Jan Hiatt, Arthu J HartzAbstract:Veterans are frequently older, have more chronic illnesses, and take more medications than subjects volunteering for clinical trials. Because these factors may impair the effectiveness of lipid-lowering drug therapy, the effectiveness of drug therapy in veterans may differ from that measured in randomized controlled trials. In 297 patients with type IIa hyperlipidemia attending a large Veterans Administration Medical Center lipid clinic, adverse effects, compliance, lipid and lipoprotein responses to drug therapy were prospectively monitored. Bile Acid Sequestrants (4 packets/day) were associated with a high rate of adverse effects, and had the highest drug discontinuance rate (37%) and poorest compliance (73 +/- 3% of the doses prescribed reported ingested) of all agents. Patients aged > 60 years tolerated therapy with Bile Acid Sequestrants less well than did younger veterans (p < 0.01). Niacin (1.5 g/day) also had a high drug discontinuance rate (27%). Lovastatin (20 mg/day) had the lowest drug discontinuance rate (2%) and the highest compliance (90 +/- 2%). Lovastatin also reduced low-density lipoprotein (LDL) cholesterol the most (-21.6 +/- 2.0%), whereas niacin produced the largest increase in high-density lipoprotein (HDL) cholesterol (+/- 14.3 +/- 2.2%); both niacin and lovastatin produced similar reductions in the LDL/HDL ratio. However, psyllium (10.4 g/day) reduced LDL cholesterol by only 2%, and had no effect on the LDL/HDL ratio. Psyllium produced larger LDL cholesterol reductions in patients aged < 60 years than in older patients (p < 0.01). Niacin and lovastatin are effective drugs for hypercholesterolemia management in the Veterans Administration Medical Center setting.(ABSTRACT TRUNCATED AT 250 WORDS)
Bryce A Jones - One of the best experts on this subject based on the ideXlab platform.
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Bile Acid sequestration reverses liver injury and prevents progression of nonalcoholic steatohepatitis in western diet fed mice
Journal of Biological Chemistry, 2020Co-Authors: Shogo Takahashi, Suman Ranjit, Andrew E Libby, David J Orlicky, Alexander Dvornikov, Xiaoxin X Wang, Komuraiah Myakala, Bryce A JonesAbstract:: Nonalcoholic fatty liver disease is a rapidly rising problem in the 21st century and is a leading cause of chronic liver disease that can lead to end-stage liver diseases, including cirrhosis and hepatocellular cancer. Despite this rising epidemic, no pharmacological treatment has yet been established to treat this disease. The rapidly increasing prevalence of nonalcoholic fatty liver disease and its aggressive form, nonalcoholic steatohepatitis (NASH), requires novel therapeutic approaches to prevent disease progression. Alterations in microbiome dynamics and dysbiosis play an important role in liver disease and may represent targetable pathways to treat liver disorders. Improving microbiome properties or restoring normal Bile Acid metabolism may prevent or slow the progression of liver diseases such as NASH. Importantly, aberrant systemic circulation of Bile Acids can greatly disrupt metabolic homeostasis. Bile Acid Sequestrants are orally administered polymers that bind Bile Acids in the intestine, forming nonabsorbable complexes. Bile Acid Sequestrants interrupt intestinal reabsorption of Bile Acids, decreasing their circulating levels. We determined that treatment with the Bile Acid sequestrant sevelamer reversed the liver injury and prevented the progression of NASH, including steatosis, inflammation, and fibrosis in a Western diet-induced NASH mouse model. Metabolomics and microbiome analysis revealed that this beneficial effect is associated with changes in the microbiota population and Bile Acid composition, including reversing microbiota complexity in cecum by increasing Lactobacillus and decreased Desulfovibrio The net effect of these changes was improvement in liver function and markers of liver injury and the positive effects of reversal of insulin resistance.
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Bile Acid sequestration reverses liver injury and prevents progression of nonalcoholic steatohepatitis in Western diet–fed mice
The Journal of biological chemistry, 2020Co-Authors: Shogo Takahashi, Suman Ranjit, Andrew E Libby, David J Orlicky, Alexander Dvornikov, Xiaoxin X Wang, Komuraiah Myakala, Yuhuan Luo, Cen Xie, Bryce A JonesAbstract:Nonalcoholic fatty liver disease is a rapidly rising problem in the 21st century and is a leading cause of chronic liver disease that can lead to end-stage liver diseases, including cirrhosis and hepatocellular cancer. Despite this rising epidemic, no pharmacological treatment has yet been established to treat this disease. The rapidly increasing prevalence of nonalcoholic fatty liver disease and its aggressive form, nonalcoholic steatohepatitis (NASH), requires novel therapeutic approaches to prevent disease progression. Alterations in microbiome dynamics and dysbiosis play an important role in liver disease and may represent targetable pathways to treat liver disorders. Improving microbiome properties or restoring normal Bile Acid metabolism may prevent or slow the progression of liver diseases such as NASH. Importantly, aberrant systemic circulation of Bile Acids can greatly disrupt metabolic homeostasis. Bile Acid Sequestrants are orally administered polymers that bind Bile Acids in the intestine, forming nonabsorbable complexes. Bile Acid Sequestrants interrupt intestinal reabsorption of Bile Acids, decreasing their circulating levels. We determined that treatment with the Bile Acid sequestrant sevelamer reversed the liver injury and prevented the progression of NASH, including steatosis, inflammation, and fibrosis in a Western diet-induced NASH mouse model. Metabolomics and microbiome analysis revealed that this beneficial effect is associated with changes in the microbiota population and Bile Acid composition, including reversing microbiota complexity in cecum by increasing Lactobacillus and decreased Desulfovibrio The net effect of these changes was improvement in liver function and markers of liver injury and the positive effects of reversal of insulin resistance.
Shogo Takahashi - One of the best experts on this subject based on the ideXlab platform.
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Bile Acid sequestration reverses liver injury and prevents progression of nonalcoholic steatohepatitis in western diet fed mice
Journal of Biological Chemistry, 2020Co-Authors: Shogo Takahashi, Suman Ranjit, Andrew E Libby, David J Orlicky, Alexander Dvornikov, Xiaoxin X Wang, Komuraiah Myakala, Bryce A JonesAbstract:: Nonalcoholic fatty liver disease is a rapidly rising problem in the 21st century and is a leading cause of chronic liver disease that can lead to end-stage liver diseases, including cirrhosis and hepatocellular cancer. Despite this rising epidemic, no pharmacological treatment has yet been established to treat this disease. The rapidly increasing prevalence of nonalcoholic fatty liver disease and its aggressive form, nonalcoholic steatohepatitis (NASH), requires novel therapeutic approaches to prevent disease progression. Alterations in microbiome dynamics and dysbiosis play an important role in liver disease and may represent targetable pathways to treat liver disorders. Improving microbiome properties or restoring normal Bile Acid metabolism may prevent or slow the progression of liver diseases such as NASH. Importantly, aberrant systemic circulation of Bile Acids can greatly disrupt metabolic homeostasis. Bile Acid Sequestrants are orally administered polymers that bind Bile Acids in the intestine, forming nonabsorbable complexes. Bile Acid Sequestrants interrupt intestinal reabsorption of Bile Acids, decreasing their circulating levels. We determined that treatment with the Bile Acid sequestrant sevelamer reversed the liver injury and prevented the progression of NASH, including steatosis, inflammation, and fibrosis in a Western diet-induced NASH mouse model. Metabolomics and microbiome analysis revealed that this beneficial effect is associated with changes in the microbiota population and Bile Acid composition, including reversing microbiota complexity in cecum by increasing Lactobacillus and decreased Desulfovibrio The net effect of these changes was improvement in liver function and markers of liver injury and the positive effects of reversal of insulin resistance.
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Bile Acid sequestration reverses liver injury and prevents progression of nonalcoholic steatohepatitis in Western diet–fed mice
The Journal of biological chemistry, 2020Co-Authors: Shogo Takahashi, Suman Ranjit, Andrew E Libby, David J Orlicky, Alexander Dvornikov, Xiaoxin X Wang, Komuraiah Myakala, Yuhuan Luo, Cen Xie, Bryce A JonesAbstract:Nonalcoholic fatty liver disease is a rapidly rising problem in the 21st century and is a leading cause of chronic liver disease that can lead to end-stage liver diseases, including cirrhosis and hepatocellular cancer. Despite this rising epidemic, no pharmacological treatment has yet been established to treat this disease. The rapidly increasing prevalence of nonalcoholic fatty liver disease and its aggressive form, nonalcoholic steatohepatitis (NASH), requires novel therapeutic approaches to prevent disease progression. Alterations in microbiome dynamics and dysbiosis play an important role in liver disease and may represent targetable pathways to treat liver disorders. Improving microbiome properties or restoring normal Bile Acid metabolism may prevent or slow the progression of liver diseases such as NASH. Importantly, aberrant systemic circulation of Bile Acids can greatly disrupt metabolic homeostasis. Bile Acid Sequestrants are orally administered polymers that bind Bile Acids in the intestine, forming nonabsorbable complexes. Bile Acid Sequestrants interrupt intestinal reabsorption of Bile Acids, decreasing their circulating levels. We determined that treatment with the Bile Acid sequestrant sevelamer reversed the liver injury and prevented the progression of NASH, including steatosis, inflammation, and fibrosis in a Western diet-induced NASH mouse model. Metabolomics and microbiome analysis revealed that this beneficial effect is associated with changes in the microbiota population and Bile Acid composition, including reversing microbiota complexity in cecum by increasing Lactobacillus and decreased Desulfovibrio The net effect of these changes was improvement in liver function and markers of liver injury and the positive effects of reversal of insulin resistance.
Bart Staels - One of the best experts on this subject based on the ideXlab platform.
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Bile Acid Sequestrants: glucose-lowering mechanisms.
Metabolic syndrome and related disorders, 2010Co-Authors: Janne Prawitt, Bart StaelsAbstract:Bile Acids are not only intestinal detergents, but also act as signaling molecules to control Bile Acid and metabolic homeostasis. By binding to the nuclear receptor farnesoid X receptor (FXR) or the membrane receptor TGR5, Bile Acids regulate lipid, glucose, and energy metabolism. The removal of Bile Acids from the enterohepatic cycle by orally administered Sequestrants, nonabsorbable resins that complex Bile Acids in the intestinal lumen, is an effective treatment to reduce plasma cholesterol concentrations in dyslipidemia. In diabetic patients, Sequestrants further lower hyperglycemia, and are thus useful in glycemic control. Here, we review the signaling pathways involved in the glucose-regulatory function of Bile Acids and our current understanding of the mechanisms behind the glucose-lowering effect of Bile Acid Sequestrants.
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Bile Acid Sequestrants for lipid and glucose control.
Current diabetes reports, 2010Co-Authors: Bart Staels, Yehuda Handelsman, Vivian FonsecaAbstract:Bile Acids are generated in the liver and are traditionally recognized for their regulatory role in multiple metabolic processes including Bile Acid homeostasis, nutrient absorption, and cholesterol homeostasis. Recently, Bile Acids emerged as signaling molecules that, as ligands for the Bile Acid receptors farnesoid X receptor (FXR) and TGR5, activate and integrate multiple complex signaling pathways involved in lipid and glucose metabolism. Bile Acid Sequestrants are pharmacologic molecules that bind to Bile Acids in the intestine resulting in the interruption of Bile Acid homeostasis and, consequently, reduction in low-density lipoprotein cholesterol levels in hypercholesterolemia. Bile Acid Sequestrants also reduce glucose levels and improve glycemic control in persons with type 2 diabetes mellitus (T2DM). This article examines the mechanisms by which Bile Acid-mediated activation of FXR and TGR5 signaling pathways regulate lipid and glucose metabolism and the potential implications for Bile Acid sequestrant-mediated regulation of lipid and glucose levels in T2DM.
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A review of Bile Acid Sequestrants: potential mechanism(s) for glucose-lowering effects in type 2 diabetes mellitus.
Postgraduate medicine, 2009Co-Authors: Bart StaelsAbstract:AbstractClinical evidence has demonstrated that Bile Acid Sequestrants reduce glucose levels in patients with type 2 diabetes mellitus (T2DM). This effect has been confi rmed in multiple double-blind, placebo-controlled clinical studies with the Bile Acid sequestrant colesevelam hydrochloride (HCl). Colesevelam HCl was approved by the US Food and Drug Administration in January 2008 as an adjunctive therapy for patients with T2DM to improve glycemic control. However, the mechanism of action for the glucose-lowering effect of Bile Acid Sequestrants is unclear. Bile Acid Sequestrants are nonsystemic pharmacological agents that bind Bile Acids in the gastrointestinal tract, thereby diverting Bile Acids from the enterohepatic circulation. This, in turn, upregulates Bile Acid synthesis (via cholesterol 7-alpha-hydroxylase), which utilizes cholesterol, resulting in reduced low-density lipoprotein cholesterol levels. Recent research has revealed that Bile Acids are tightly controlled signaling molecules that have...
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Bile Acid Sequestrants and the Treatment of Type 2 Diabetes Mellitus
Drugs, 2007Co-Authors: Bart Staels, Folkert KuipersAbstract:Bile Acids promote Bile formation and facilitate dietary lipid absorption. Animal and human studies showing disturbed Bile Acid metabolism in diabetes mellitus suggest a link between Bile Acids and glucose control. Bile Acids are activating ligands of the farnesoid X receptor (FXR), a nuclear receptor with an established role in Bile Acid and lipid metabolism. Evidence suggests a role for FXR also in maintenance of glucose homeostasis. Animal and human studies employing Bile Acid Sequestrants (Bile Acid binding agents), which interrupt the enterohepatic circulation of Bile Acids and effectively reduce plasma cholesterol, support a link between Bile Acid and glucose metabolism. In lipid-lowering trials, Bile Acid Sequestrants, such as colesevelam hydrochloride, colestyramine (cholestyramine) and colestilan (colestimide), have also been shown to lower plasma glucose and glycosylated haemoglobin levels, suggesting the utility of these agents as a potential therapy for type 2 diabetes. In this article, we review the relationship between Bile Acid metabolism and glucose homeostasis, and present data demonstrating the utility of Bile Acid Sequestrants in the management of diabetes.