Effect Of Bile Acid Sequestrants Research Articles

Bile acid sequestrants in poor healing after endoscopic therapy of Barrett's esophagus.

Endoscopic therapy for neoplastic Barrett's esophagus (BE) has become the standard of care over the past two decades. In clinical practice, we regularly encounter patients who fail to achieve complete squamous epithelialization of the esophagus. Although the therapeutic strategies in the individual stages of BE, dysplasia, and esophageal adenocarcinoma are well studied and largely standardized, the problem of inadequate healing after endoscopic therapy is only marginally considered. This study aimed to shed light on the variables influencing inadequate wound healing after endoscopic therapy and the effect of bile acid sequestrants (BAS) on healing. Retrospective analysis of endoscopically treated neoplastic BE in a single referral center. In 12.1% out of 627 patients, insufficient healing was present 8 to 12 weeks after previous endoscopic therapy. The average follow-up duration was 38.8±18.4 months. Complete healing was achieved in 13 patients already after intensifying proton pump inhibitor therapy. Out of 48 patients under BAS, 29 patients (60.4%) showed complete healing. An additional eight patients (16.7%) improved, but only partial healing was achieved. Eleven (22.9%) patients showed no response to BAS augmented therapy. In cases of insufficient healing even under exhaustion of proton pump inhibitors, treatment with BAS can be an option as an ultimate healing attempt.

Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as "bad" cholesterol and high-density lipoprotein cholesterol (HDL-C) as "good" cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.

770-P: The Glucose-Lowering Effect of the Bile Acid Sequestrant Sevelamer Is Not Mediated by Glucagon-Like Peptide-1

Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycemic control in patients with type 2 diabetes (T2D). The mechanism behind the glucose-lowering effect of bile acid sequestrants is unknown but has been proposed to involve glucagon-like peptide 1 (GLP-1) secretion. Using the GLP-1 receptor antagonist exendin(9-39), we investigated the GLP-1-mediated contribution to the glucose-lowering effect of the bile acid sequestrant sevelamer in patients with T2D. In a randomized, double-blind, placebo-controlled, crossover study, patients (9 men/6 women) with T2D (median [interquartile range] age 68 [63-71] years, BMI 30.1 [26.6-33.0] kg/m2, HbA1c 48 [45-61] mmol/mol (6.5 [6.3-7.7]%), on metformin mono-therapy) underwent two 14-day treatment periods with either sevelamer or placebo in a randomized order. After each treatment period, patients participated in two experimental days, each involving a four-hour liquid meal test with concomitant infusion of exendin(9-39) or saline. Compared to placebo, sevelamer lowered both fasting plasma glucose concentrations ((mean ± SEM) 8.7 ± 0.3 vs. 10.2 ± 0.5 mmol/L, P <0.001) and postprandial plasma glucose excursions (baseline-subtracted area under the curve (bsAUC): 456.5 ± 40.3 vs. 620 ± 63.6 mmol/L × min, P <0.001). In both treatment periods, exendin(9-39) increased the glucose bsAUC compared to saline (P <0.001) with no absolute or relative difference between the two treatment periods (∆bsAUC: 365 ± 34.4 mmol/L × min [170 ± 27.6%] (sevelamer) vs. 428 ± 58.2 mmol/L × min [165 ± 40.2%] (placebo treatment), P = 0.17). In conclusion, using the GLP-1 receptor antagonist exendin(9-39), we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer; leaving the mechanism behind the glucose-lowering effect of sevelamer unresolved. Disclosure H. H. Nerild: Employee; Spouse/Partner; Novo Nordisk. A. Brønden: None. D. P. Sonne: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.

A Meta-Analysis Assessing Additional LDL-C Reduction from Addition of a Bile Acid Sequestrant to Statin Therapy

BackgroundStatins are the first-line therapy for reducing low-density lipoprotein cholesterol (LDL-C). However, there are secondary prevention patients who are either intolerant to maximal statin therapy or do not get adequate effects from a high-intensity statin. While data exist for the additional LDL-C-lowering effects of ezetimibe, there are no data on additional LDL-C lowering of bile acid sequestrants when combined with statin therapy. The purpose of this study was to quantify the LDL-C-lowering effects of bile acid sequestrants when added to statin therapy. MethodsDatabases (Medline via PubMed, Embase, and the Cochrane Library) were searched for randomized controlled trials comparing statin therapy to statin therapy with the addition of bile acid sequestrants. Nine studies were included in the meta-analysis. A meta-regression was performed to estimate the mean difference in LDL-C between the 2 groups. ResultsWithout controlling for other variables, data suggest that combining statin with bile acid sequestrant increases the percentage change in LDL-C by 16.2 points, on average, compared with statin use alone. ConclusionIn patients unable to tolerate an adequate statin dosage, bile acid sequestrants offer a viable alternative with additional LDL-C-lowering benefit.

Bile acid sequestrants for glycemic control in patients with type 2 diabetes: A systematic review with meta-analysis of randomized controlled trials

AimTo evaluate the effects of bile acid sequestrants (BASs) versus placebo, no intervention or active comparators on glycemic control in type 2 diabetes. MethodsData 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. ResultsWe 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 A1c 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. ConclusionsOur 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.

Effect of Bile Acid Sequestrants on the Risk of Cardiovascular Events: A Mendelian Randomization Analysis.

Statins lower low-density lipoprotein cholesterol (LDL-C) and risk of coronary artery disease (CAD), but they may be ineffective or not tolerated. Bile acid sequestrants (BAS) reduce LDL-C, yet their clinical efficacy on CAD remains controversial. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of cholestyramine and colesevelam. We then used Mendelian randomization to estimate the effect of BAS on reducing the risk of CAD. First, we quantified the effect of rs4299376 (ABCG5/ABCG8), which affects the intestinal cholesterol absorption pathway targeted by BAS and then we used these estimates to predict the effect of BAS on CAD. Nineteen randomized controlled trials with a total of 7021 study participants were included. Cholestyramine 24 g/d was associated with a reduction in LDL-C of 23.5 mg/dL (95% confidence interval [CI] -26.8,-20.2; N=3806) and a trend toward reduced risk of CAD (odds ratio 0.81, 95% CI 0.70-1.02; P=0.07; N=3806), whereas colesevelam 3.75 g/d was associated with a reduction in LDL-C of 22.7 mg/dL (95% CI -28.3, -17.2; N=759). Based on the findings that rs4299376 was associated with a 2.75 mg/dL decrease in LDL-C and a 5% decrease in risk of CAD outcomes, we estimated that cholestyramine was associated with an odds ratio for CAD of 0.63 (95% CI 0.52-0.77; P=6.3×10(-6)) and colesevelam with an odds ratio of 0.64 (95% CI 0.52-0.79, P=4.3×10(-5)), which were not statistically different from BAS clinical trials (P>0.05). The cholesterol lowering effect of BAS may translate into a clinically relevant reduction in CAD.

The Effect of Bile Acid Sequestrants on Progression of Coronary Arterial Calcification

The author's practice, Boulder Internal Medicine, owns an EBT.

SeHCAT [tauroselcholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile acid pool loss: a systematic review and cost-effectiveness analysis

SeHCAT [tauroselcholic (selenium-75) acid] for the investigation of bile acid malabsorption and measurement of bile acid pool loss: a systematic review and cost-effectiveness analysis

Effect of bile acid sequestrants on glycaemic control: protocol for a systematic review with meta-analysis of randomised controlled trials

IntroductionIn 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...

Potential New Approaches to Modifying Intestinal GLP-1 Secretion in Patients with Type 2 Diabetes Mellitus : Focus on Bile Acid Sequestrants.

Type 2 diabetes mellitus is associated with a progressive decline in insulinproducing pancreatic β-cells, an increase in hepatic glucose production, and a decrease in insulin sensitivity. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) stimulate glucose-induced insulin secretion; however, in patients with type 2 diabetes, the incretin system is impaired by loss of the insulinotropic effects of GIP as well as a possible reduction in secretion of GLP-1. Agents that modify GLP-1 secretion may have a role in the management of type 2 diabetes. The currently available incretin-based therapies, GLP-1 receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 (DPP-4) inhibitors (CD26 antigen inhibitors) [incretin enhancers], are safe and effective in the treatment of type 2 diabetes. However, they may be unable to halt the progression of type 2 diabetes, perhaps because they do not increase secretion of endogenous GLP-1. Therapies that directly target intestinal L cells to stimulate secretion of endogenous GLP-1 could possibly prove more effective than treatment with GLP-1 receptor agonists and DPP-4 inhibitors. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes include G-protein-coupled receptor (GPCR) agonists, α-glucosidase inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, metformin, bile acid mimetics and bile acid sequestrants. Both the GPCR agonist AR231453 and the novel bile acid mimetic INT-777 have been shown to stimulate GLP-1 release, leading to increased insulin secretion and improved glucose tolerance in mice. Similarly, a study in insulin-resistant rats demonstrated that the bile acid sequestrant colesevelam increased GLP-1 secretion and improved glucose levels and insulin resistance. In addition, the bile acid sequestrant colestimide (colestilan) has been shown to increase GLP-1 secretion and decrease glucose levels in patients with type 2 diabetes; these results suggest that the glucose-lowering effects of bile acid sequestrants may be partly due to their ability to increase endogenous GLP-1 levels. Evidence suggests that GPCR agonists, α-glucosidase inhibitors, PPAR agonists, metformin, bile acid mimetics and bile acid sequestrants may represent a new approach to management of type 2 diabetes via modification of endogenous GLP-1 secretion.

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). Participants with type 2 diabetes (HbA(1c) 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n = 30) or placebo (n = 30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. Compared with placebo, colesevelam improved HbA(1c) (mean change from baseline of 0.3 [SD 1.1]% for placebo [n = 28] and -0.3 [1.1]% for colesevelam [n = 26]), glucose concentrations, fasting plasma glucose clearance and glycolytic disposal of oral glucose. Colesevelam did not affect gluconeogenesis or appearance rate (absorption) of oral glucose. Fasting endogenous glucose production and glycogenolysis significantly increased with placebo but were unchanged with colesevelam (treatment effect did not reach statistical significance). Compared with placebo, colesevelam increased total GLP-1 and GIP concentrations and improved HOMA-beta cell function while insulin, glucagon and HOMA-insulin resistance were unchanged. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents. ClinicalTrials.gov NCT00596427 The study was funded by Daiichi Sankyo.

Bile Acid Sequestrants: Glucose-Lowering Mechanisms

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.

Review of Studies on the Effect of Bile Acid Sequestrants in Patients with Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) and prediabetes (or patients at risk for diabetes) have been increasing in epidemic proportions. Dyslipidemia and hypertension are cardiovascular risk factors frequently associated with diabetes and prediabetes. Bile acid sequestrants (BAS) were initially approved for the treatment of elevated low-density lipoprotein cholesterol (LDL-C), but they were subsequently found to have a glucose-lowering effect as well. Colesevelam hydrochloride (HCl), a BAS, has been approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM based on several studies that used it as an addition to sulfonylurea-based, metformin-based, and insulin-based therapies. Colesevelam HCl has not been approved for use for glycemic control in type 1 diabetes or for treating diabetic ketoacidosis and has not been studied in T2DM as monotherapy or in combination with dipeptidyl peptidase 4 inhibitors, or extensively with thiazolidinediones. A recent study has examined the combination of colesevelam HCl and metformin as an initial therapy for treatment-naïve patients with T2DM. Another recent study, which looked at colesevelam for the treatment of dyslipidemia of prediabetes, raised the possibility of the use of colesevelam therapy for both dyslipidemia and hyperglycemia of T2DM. This article reviews and summarizes the recent clinical studies regarding colesevelam as therapy for both diabetes and dyslipidemia. This dual mechanism of action is an attractive feature for the treatment of diabetes.

Reducing Cardiovascular Complications of Type 2 Diabetes by Targeting Multiple Risk Factors

Insulin resistance syndrome is characterized by hyperglycemia, atherogenic dyslipidemia, hypertension, and abdominal obesity. Hyperglycemia is the major risk factor for microvascular complications in type 2 diabetes. However, 70% to 80% of patients with type 2 diabetes will die of macrovascular disease. Atherogenic dyslipidemia-characterized by elevated triglyceride levels, low high-density lipoprotein cholesterol (HDL-c) levels, and a preponderance of small, dense, low-density lipoprotein (LDL) particles-is the major cause of atherosclerosis in individuals with type 2 diabetes. Therefore, treatment of type 2 diabetes must address hyperglycemia to prevent microvascular disease (retinopathy, neuropathy, and nephropathy) and atherogenic dyslipidemia to prevent macrovascular complications. Emerging evidence indicates lipid and glucose homeostasis are interrelated via bile acid-activated nuclear hormone receptor signaling pathways. Agents that act on these pathways could simultaneously address hyperglycemia and dyslipidemia in patients with type 2 diabetes. Recent studies have shown that bile acid sequestrants, including cholestyramine, colestimide, and colesevelam HCl, significantly improve glycemic control and reduce LDL cholesterol levels in patients with type 2 diabetes. This paper will review the effects of bile acid sequestrants on both glucose and lipid metabolism in patients with type 2 diabetes.

Treatment of hyperlipidemia in renal transplant recipients.

Treatment of hyperlipidemia in renal transplant recipients.

SK&F 97426-A a more potent bile acid sequestrant and hypocholesterolaemic agent than cholestyramine in the hamster

SK&F 97426-A is a novel bile acid sequestrant which was selected for comparison with cholestyramine in vivo because of its superior in vitro bile acid binding properties. The effects of the two sequestrants on faecal bile acid excretion, plasma total cholesterol, VLDL + LDL and HDL cholesterol and triglyceride concentrations and on liver enzymes involved in the synthesis and metabolism of cholesterol were investigated in normocholesterolaemic hamsters. Four studies were conducted to determine the relative potencies of the two resins using a range of doses of the sequestrants over treatment periods of up to 2 weeks. Curves fitted to the resulting data allowed common maximum responses and separate ED 50s to be calculated for each sequestrant. The maximum response of both sequestrants was to increase bile acid excretion by 352% and lower plasma total cholesterol by 37–58%. LDL + VLDL and HDL cholesterol were reduced by 56–75% and 25–41%, respectively. SK&F 97426-A was 3 times more potent than cholestyramine at increasing the excretion of bile acids in the faeces and 2.1–3.4-fold and 2.3–3.2-fold more potent at lowering total plasma cholesterol and LDL plus VLDL cholesterol, respectively. In some of the experiments SK&F 97426-A was also more potent than cholestyramine at lowering HDL cholesterol. Plasma triglycerides were also lowered by both sequestrants by up to 31 % after 1 week but the relative potency could not be determined. These HDL cholesterol and total triglyceride lowering effects of bile acid sequestrants in the hamster are known not to occur in people treated with cholestyramine. There were minimal differences between hamsters treated for 1 or 2 weeks in the relative potencies or ED 50s calculated for the total plasma cholesterol, LDL + VLDL and HDL cholesterol. Both sequestrants may have been slightly more efficacious on these parameters after 2 weeks of treatment. Liver weights were reduced by about 15% by both sequestrants at 2% (w/w) in the diet for 1 week. The activities of the liver HMG-CoA reductase and cholesterol 7a-hydroxylase were increased as expected, whilst the activity of the acyl-CoA:cholesterol acyltransferase was reduced by both sequestrants at this dose. SK&F 97426-A was, therefore, 2–3-fold more potent as a bile acid sequestrant and hypocholesterolaemic agent than cholestyramine when tested in the hamster.

Increased turnover of very low density lipoprotein triglyceride during treatment with cholestyramine in familial hypercholesterolaemia

Kinetics of very low density lipoprotein (VLDL) triglyceride were determined in seven patients with heterozygous familial hypercholesterolaemia, using a 3H-glycerol technique. The study was repeated after 5-7 weeks of therapy with the bile acid-binding resin, cholestyramine. The rate of synthesis of VLDL triglyceride was increased by 85% (P less than 0.05) during resin therapy. Simultaneously, the fractional catabolic rate of VLDL was increased by 40% (P less than 0.02), so that only a moderate increase in plasma concentration was observed. Repeated measurements of VLDL size by electron microscopy (before, 1 week, and 5-7 weeks after initiation of therapy) indicated that a transient increase in VLDL size occurred in response to cholestyramine. The results are consistent with a stimulatory effect of bile acid sequestrants on VLDL triglyceride production and indicate that, in most subjects, a compensatory increase in VLDL triglyceride removal occurs.

The hepatobiliary axis and lipoprotein metabolism: effects of bile acid sequestrants and ileal bypass surgery

Cholesterol excretion from the body is achieved almost exclusively via the hepatobiliary axis. Disruption of the integrity of this pathway by interruption of the enterohepatic circulation produces profound changes in cholesterol metabolism that affect every body tissue. This is particularly evident in the liver and gut which are the major sources of this sterol in the plasma. Elevated plasma cholesterol levels have been implicated in the pathogenesis of atherosclerosis and, in consequence, strenuous efforts have been made to find appropriate hypocholesterolemic therapy to reduce this risk. Medical or surgical interruption of the enterohepatic circulation is, to date, the most successful means of lowering plasma cholesterol, and in this review we examine the ramifications of such therapy on lipid and lipoprotein metabolism in the liver, gut, and plasma.