Use Of Bile Acid Sequestrants Research Articles

Efficacy of bile salt hydrolase synthesizing probiotic bacteria in the treatment of irritable bowel syndrome with diarrhea

Background. One of the mechanisms of the of irritable bowel syndrome with diarrhea (IBS-D) is bile acid malabsorption (BAM). In addition to the use of bile acid sequestrants, probiotic bacteria synthesizing bile salt hydrolase (BSH) are promising in the treatment of probable BAM. The purpose of the study was to compare the effectiveness of combined treatment (a probiotic based on strains of Lactobacillus, Streptococcus, Bifidobacterium, Saccharomyces boulardii and cholestyramine) with cholestyramine monotherapy in the treatment of IBS-D. Materials and methods. A 12-week randomized study included 108 patients with IBS-D divided into a control group (n = 51) receiving only cholestyra­mine and an experimental group (n = 57) receiving a combination of cholestyramine and the study probiotic. At baseline, the relative activity of BSH of the study probiotic capsules was determined. During the stages of the study, patients were examined using clinical scales. Results. The relative activity of BSH of the capsules with the studied probiotic was (2.07 ± 0.06) U/ml compared to (1.00 ± 0.04) U/ml of capsules with L.plantarum and (0.03 ± 0.01) U/ml — with L.plantarum without BSH genes. In the experimental group, the severity of bloating and visceral sensitivity index were lower after 8 and 12 weeks, and the value of the stool type according to the Bristol scale and its daily frequency — after 12 weeks compared to the control group, p < 0.05. According to the scale of IBS-adequate relief, the percentage of achieving a clinical effect was higher in the experimental group compared to the controls after 12 weeks, odds ratio was 1.31 (95% confidence interval 1.03–1.68), p = 0.038. Conclusions. Additional prescription of a probiotic with BSH synthesizing bacterial strains is more effective in improving clinical manifestations of IBS-D and achieving a therapeutic effect compared to cholestyramine monotherapy.

P402 A Pilot Study on the Effect of Colesevelam on the Microbiome in Primary Terminal Ileal Resected Crohn’s Disease

Abstract Background Surgery plays a pivotal role in ileal Crohn’s disease despite the risk of endoscopic recurrence following an ileocaecal resection greater than 65% within 12 months of surgery. More than 90% of Crohn’s patients have a concomitant diagnosis of bile acid diarrhoea following an ileal resection. This pilot study aimed to assess whether the use of bile acid sequestrants in post-operative Crohn’s patients with bile acid diarrhoea can alter the microbiome and prevent disease recurrence. Methods Post-operative Crohn’s patients with symptoms of diarrhoea underwent 75SeHCAT testing for bile acid diarrhoea. If positive (75SeHCAT < 15%), patients were treated with colesevelam and stool samples were collected at 4-weeks, 8-weeks and 6-12 months post-treatment. If negative (75SeHCAT > 15%), treatment was not given and were reviewed in clinic as per local guidelines. Patients underwent a 6-12 months post-operative colonoscopy where mucosal biopsies were taken. Disease activity was established using the endoscopic Rutgeert’s score, with disease remission defined as Rutgeerts score < i2 and disease recurrence ³ i2. Faecal and mucosal 16S ribosomal RNA gene analysis was undertaken to assess a/b-diversity and microbial composition. Results A total of 44 faecal samples and 44 mucosal biopsies were sequenced from 14 patients. 1/10 patients on colesevelam and 2/4 patients not on colesevelam demonstrated disease recurrence. There was no significant difference in a/b-diversity pre- and post-treatment. Pre-treatment, the three most abundant bacterial classes in all patients were Bacteroidia, Clostridia and Gammaproteobacteria (Figure 1). Following 6-12 months of treatment, out of the 9 patients on colesevelam, 5/9 (55.6%) had a reduction in Bacteroidia, 9/9 (100%) had an increase in Clostridia, and 7/9 (77.8%) had a reduction in Gammaproteobacteria. Of the two patients not given colesevelam, ½ (50%) showed a reduction in Bacteroidia, increase in Clostridia and a reduction in Gammaproteobacteria. Conclusion This small pilot study demonstrated that patients who were given colesevelam, a bile acid sequestrant, were more likely to be in disease remission at their 6-12 months colonoscopy review. Furthermore, treatment with colesevelam may have a role in altering the microbiome to help maintain remission states in post-operative Crohn’s disease. Larger mechanistic studies are now needed to confirm these findings and demonstrate statistical significance.

S788 Long-Term Use of Bile Acid Sequestrants to Improve Diarrhea and Abdominal Pain in IBD Patients With Ileoanal Pouch Anastomosis: A Tertiary Referral Center Experience

Introduction: Bile acid (BA) sequestrants are commonly used in IBD following ileocecal resection to treat bile acid malabsorption and associated abdominal pain and diarrhea. There is less experience with use of BA binders in IBD patients following colectomy and ileoanal pouch reconstruction. IBD ileoanal pouch patients frequently experience bouts of diarrhea and abdominal pain and have limited treatment options. We sought to characterize our institutional experience with BA sequestrants to treat abdominal pain and diarrhea in a large cohort of IBD ileoanal pouch patients with a focus on longterm therapy and improvement in patient reported outcomes. Methods: We analyzed a prospective, natural history registry of consented IBD patients followed at a tertiary center (2009-2022). Patients with ileoanal pouch reconstruction following colectomy were identified and individuals with > 2 years of follow up formed the study cohort. BA sequestrants included cholestyramine, colestipol and colesevelam. Patient reported outcomes of diarrhea and abdominal pain, recorded at the time of clinic encounters were organized, and mean scores before and after bile acid binder therapy were compared. Results: There were 132 ileoanal pouch patients with longterm followup (mean age 51.8 + 13.9 years; 42% F; 58% M). BA sequestrants were initiated in 93 individuals and 63 patients (68%) continued therapy for >2 years, forming the multiyear therapy group. Patterns of BA sequestrant use included 48% receiving one, 41% trialing two and 11% using all three agents. The most commonly prescribed were colesevelam (48 patients), cholestyramine (33 patients) and colestipol (22 patients) and switching between BA sequestrants was commonly due to insurance coverage. The mean number of stools per day improved following initiation of BA sequestrants (p< 0.001). Abdominal pain scores also improved with longterm BA sequestrant therapy (p=0.017). Patterns of healthcare utilization improved with longterm BA sequestrant therapy with a reduction in annual patterns of emergency room visits (p=0.007) and hospitalizations (p< 0.001). (Figure) Conclusion: A majority of IBD ileoanal pouch patients benefitted from BA sequestrant treatment, reducing number of bowel movements and abdominal pain over a >2 year period, with a parallel reduction in healthcare utilization. Formal trials of BA sequestrants in the longterm management of chronic ileoanal pouch symptoms in the IBD patient population are warranted.Figure 1.: Results before and after bile acid sequestrants.

Bile acids regulate cysteine catabolism and glutathione regeneration to modulate hepatic sensitivity to oxidative injury.

Bile acids are signaling molecules that critically control hepatocellular function. Disrupted bile acid homeostasis may be implicated in the pathogenesis of chronic liver diseases. Glutathione is an important antioxidant that protects the liver against oxidative injury. Various forms of liver disease share the common characteristics of reduced cellular glutathione and elevated oxidative stress. This study reports a potentially novel physiological function of bile acids in regulating hepatic sulfur amino acid and glutathione metabolism. We found that bile acids strongly inhibited the cysteine dioxygenase type-1-mediated (CDO1-mediated) cysteine catabolic pathway via a farnesoid X receptor-dependent mechanism. Attenuating this bile acid repressive effect depleted the free cysteine pool and reduced the glutathione concentration in mouse liver. Upon acetaminophen challenge, cholestyramine-fed mice showed impaired hepatic glutathione regeneration capacity and markedly worsened liver injury, which was fully prevented by N-acetylcysteine administration. These effects were recapitulated in CDO1-overexpressing hepatocytes. Findings from this study support the importance of maintaining bile acid homeostasis under physiological and pathophysiological conditions, as altered hepatic bile acid signaling may negatively impact the antioxidant defense mechanism and sensitivity to oxidative injury. Furthermore, this finding provides a possible explanation for the reported mild hepatotoxicity associated with the clinical use of bile acid sequestrants in human patients.

Anti-dementia and anti-hyperlipidemic medication use at end of life in elderly lung cancer patients: Analysis of SEER-Medicare data.

10027 Background: Despite risk for polypharmacy, elderly cancer patients may receive drugs whose time to benefit likely exceeds life expectancy. This study aims to describe use of drugs considered potentially unnecessary, namely anti-hyperlipidemics and anti-dementia drugs, and to identify factors associated with their use in Stage 3 or 4 non-small cell lung cancer (NSCLC) patients approaching end of life. Methods: We identified all patients older than 65 diagnosed with primary Stage 3 or 4 NSCLC between 2006 and 2011 in the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Information on drug prescriptions was extracted from Medicare Part D files. First-time hospice enrollment or death date was used as the final endpoint in analysis. The primary outcome was use of drugs of interest at 4 months before NSCLC diagnosis, 6 months and 3 months before death or hospice. Associations with demographic or other factors were tested using the Pearson χ2 test. Results: Of all 7983 patients, 45.1% were taking statins before diagnosis, while 40.7% and 30.9% were still taking statins at 6 and 3 months before death or hospice. Use of bile acid sequestrants, fibric acid derivatives, and cholesterol absorption inhibitors were found to decrease toward death or hospice. In contrast, anti-dementia drug use did not decrease, with 3.4% before diagnosis and 4.2% and 3.5% at 6 and 3 months before death or hospice. Approximately 30% of anti-dementia medications were newly prescribed at 6 and 3 months before study endpoint. Having a higher number of prescriptions at 3 months before death or hospice was associated with higher rates of drug use both before and after cancer diagnosis. Having a higher Charlson comorbidity index correlated with greater anti-dementia drug use before diagnosis. Demographic, socioeconomic, and treatment factors were not found to be correlated with drug use. Conclusions: A high prevalence of statin use persists while a notable proportion of anti-dementia drugs are newly prescribed toward death or hospice. Our findings suggest an opportunity for clinicians to re-evaluate risks and benefits of potentially unnecessary medications in elderly patients nearing end of life.

Bile Acid diarrhea: prevalence, pathogenesis, and therapy.

Bile acid diarrhea (BAD) is usually seen in patients with ileal Crohn’s disease or ileal resection. However, 25% to 50% of patients with functional diarrhea or diarrhea-predominant irritable bowel syndrome (IBS-D) also have evidence of BAD. It is estimated that 1% of the population may have BAD. The causes of BAD include a deficiency in fibroblast growth factor 19 (FGF-19), a hormone produced in enterocytes that regulates hepatic bile acid (BA) synthesis. Other potential causes include genetic variations that affect the proteins involved in BA enterohepatic circulation and synthesis or in the TGR5 receptor that mediates the actions of BA in colonic secretion and motility. BAs enhance mucosal permeability, induce water and electrolyte secretion, and accelerate colonic transit partly by stimulating propulsive high-amplitude colonic contractions. There is an increased proportion of primary BAs in the stool of patients with IBS-D, and some changes in the fecal microbiome have been described. There are several methods of diagnosing BAD, such as 75selenium homotaurocholic acid test retention, serum C4, FGF-19, and fecal BA measurement; presently, therapeutic trials with BA sequestrants are most commonly used for diagnosis. Management involves the use of BA sequestrants including cholestyramine, colestipol, and colesevelam. FXR agonists such as obeticholic acid constitute a promising new approach to treating BAD.

Beyond intestinal soap--bile acids in metabolic control.

Over the past decade, it has become apparent that bile acids are involved in a host of activities beyond their classic functions in bile formation and fat absorption. The identification of the farnesoid X receptor (FXR) as a nuclear receptor directly activated by bile acids and the discovery that bile acids are also ligands for the membrane-bound, G-protein coupled bile acid receptor 1 (also known as TGR5) have opened new avenues of research. Both FXR and TGR5 regulate various elements of glucose, lipid and energy metabolism. Consequently, a picture has emerged of bile acids acting as modulators of (postprandial) metabolism. Therefore, strategies that interfere with either bile acid metabolism or signalling cascades mediated by bile acids may represent novel therapeutic approaches for metabolic diseases. Synthetic modulators of FXR have been designed and tested, primarily in animal models. Furthermore, the use of bile acid sequestrants to reduce plasma cholesterol levels has unexpected benefits. For example, treatment of patients with type 2 diabetes mellitus (T2DM) with sequestrants causes substantial reductions in plasma levels of glucose and HbA1c. This Review aims to provide an overview of the molecular mechanisms by which bile acids modulate glucose and energy metabolism, particularly focusing on the glucose-lowering actions of bile acid sequestrants in insulin resistant states and T2DM.

Real-world utilization patterns and outcomes of colesevelam hcl in the ge electronic medical record

BackgroundIn randomized controlled trials (RCTs), colesevelam HCI, added to other anti-diabetic therapy, reduced hemoglobin A1C by approximately 0.3% to 0.4% over 16- to 26-weeks compared with an increase of approximately 0.1% to 0.2% for placebo, for a placebo-adjusted treatment effect of approximately 0.5%. Evidence on real-world effectiveness is unknown. This retrospective cohort study examined A1C changes following colesevelam HCL initiation in patients with diabetes, regardless of concomitant anti-diabetic medication use.Methods2000–2011 GE Centricity electronic medical records data were used to identify patients with type 2 diabetes mellitus (T2DM) aged 18 or older initiating colesevelam HCL. The sample was further restricted to uncontrolled patients with database activity ≥ 395 days before and after colesevelam HCL initiation, A1C > 7% during 90 days prior to starting colesevelam HCL, without prior use of bile acid sequestrants, and with at least one A1C result between 42 to 210 days after initiation. Three overlapping time intervals were created for A1C measurement, including 16-weeks, 26-weeks, and 52-weeks following therapy initiation. The last observed A1C lab measurement during each interval was used to define change from baseline. Mean change in A1C was examined using paired t-tests. Sensitivity analyses considered only patients who remained on colesevelam HCL through each respective measurement period, as well as the effect of concomitant diabetes medications.ResultsOf 1,709,393 patients in the GE database with T2DM, 1,747 met inclusion criteria. The cohort was 58% female, 38% age ≥ 65, and the majority was white. For the 16-week endpoint (N = 1,385), A1C dropped from a mean of 8.22% to 7.75% (mean change −0.47%; P < 0.0001). For the 26- and 52-week endpoints (N = 1,747), A1C dropped from a mean of 8.25% to 7.81% (mean change −0.44%; P < 0.0001) and 8.25% to 7.79% (mean change −0.46%; P < 0.0001), respectively. Sensitivity analyses showed that A1C reductions were of similar direction and magnitude for patients who remained on treatment, and for the subgroups of patients stratified by receipt of concomitant T2DM treatments.ConclusionsThe 0.44% to 0.47% A1C reduction observed in this study was similar to the reduction observed in RCTs, supporting the real-world effectiveness of colesevelam HCL in reducing A1C.

Use and indications of cholestyramine and bile acid sequestrants

Cholestyramine is a bile acid sequestrant, like colestipol and colesevelam. These molecules are positively charged non-digestible resins that bind to bile acids in the intestine to form an insoluble complex, which is excreted in the feces. They are used mainly for the treatment of primary hypercholesterolemia and hypercholesterolemia associated with mild hypertriglyceridemia, in patients not responding to dietary treatment as well as a second line-treatment for pruritus associated with cholestatic disease, in patients with incomplete biliary obstruction. Several data indicate that modulation of bile acid homeostasis has a good clinical effect in managing diabetes mellitus and the diarrhea from bile acid malabsorption. In this review, we present the "in label" use and indication for these compounds, revisiting the other clinical applications that may benefit from the use of bile acid sequestrants in the near future.

Novel pathways for glycaemic control in type 2 diabetes: focus on bile acid modulation

Type 2 diabetes is a common disorder with high risk of macrovascular and microvascular complications. These complications are largely driven by hyperglycaemia, dyslipidaemia and hypertension, for which aggressive treatment is thus warranted. Achieving and maintaining control of all three risk factors is especially difficult, however, and new therapeutic approaches could be useful. Bile acids have a well-established and important role in cholesterol homeostasis. Normally, their levels are maintained primarily by ileal reabsorption and enterohepatic recycling. Bile acid sequestrants bind bile acids in the intestine, reduce this recycling and deplete the bile acid pool, thereby stimulating use of hepatic cholesterol for bile acid synthesis, which leads to accelerated removal of LDL from the plasma and a decrease in LDL-cholesterol levels. Interestingly, recent evidence suggests that bile acid sequestrants can lower glucose levels to a clinically meaningful degree. This review presents this evidence and the possible mechanisms by which these glucose-lowering effects occur and discusses the apparently unique ability of bile acid sequestrants among lipid-lowering agents to significantly improve two cardiovascular risk factors, hyperglycaemia and dyslipidaemia. There is renewed interest in the use of bile acid sequestrants in individuals with type 2 diabetes, most of whom would benefit from additional reductions in both LDL-cholesterol and glycaemia.

The 2007 Heart-UK Survey of Lipid Clinics and Clinical Practice in the UK

An electronic survey of lipid clinics and clinical practice was sent to 120 UK clinics and 67 replied. Clinics were provided by chemical pathology in 31%, general medicine in 21% and diabetes services in 17%. The average clinic size was 638 patients and saw 168 new patients/year. 70% of referrals originated from primary care, 8% from cardiology and 7% from diabetes. 90% of patients had previously tried statins and 40% ezetimibe. 22% of patients had familial hypercholesterolaemia (FH) but only 9% of clinics had access to genetic nurse services. The Joint British Societies-2 Guideline was used in 50% and the National Service Framework in 25%. Targets used were total cholesterol (TC) <5 or 4 mmol/L; LDL-C <3 or 2 mmol/L; HDL-C >1 mmol/L in men, >1 or 1.2 mmol/L in women; triglycerides <1.7 or <2 mmol/L in primary prevention. In secondary prevention TC <4 and LDL-C <2 was preferred. 56% preferred to use the JBS-2 secondary prevention targets for FH. Patients were managed with statins alone in 45%, statin-ezetimibe 20% and statin-fibrate in 15%. 14% were considered statin intolerant and 10% unresponsive. There was wide variation in target attainment with statins. Compliance was considered a major issue by 80% and affected the use of bile acid sequestrants, niacin and statins. Children with FH were seen with parents in 73% of services with about 20 children/clinic. 32 patients were receiving apheresis. 84% of clinics did not use apheresis services. 34% of clinics audited target attainment using a mixture of notes and databases. Only 27% of clinics discharged FH patients to primary care.

Ezetimibe: Rationale and role in the management of hypercholesterolemia

Elevated low-density lipoprotein (LDL) cholesterol plays an important role in the development of atherosclerosis. In part, plasma LDL levels are dependent on cholesterol absorption in the intestine and the rate of intrinsic cholesterol synthesis. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors has often proven to be successful in reducing plasma LDL levels. However, a significant number of patients do not reach their target LDL levels despite statin therapy. As is reviewed, drugs that inhibit cholesterol absorption are a useful adjunct to lipid-lowering therapy by statins. This review discusses the mechanisms involved in intestinal absorption of cholesterol and its transport as potential targets of newer agents that affect cholesterol absorption. The use of bile acid sequestrants and esters of plant stanols, as well as other intestinally active agents for reducing plasma LDL levels, has been limited by side effects and difficulties in patient compliance. In contrast, the new selective cholesterol transporter inhibitor ezetimibe has been demonstrated to reduce plasma LDL alone or in combination with statins without significant adverse effects. In spite of the robust lipid-lowering data with ezetimibe, questions about clinical outcomes, safety, and efficacy in various combinations remain.

Management of Hyperlipidemia in the Pediatric Population.

Heterozygous familial hypercholesterolemia (FH) affects one in every 500 persons and is the most common cause of markedly elevated cholesterol levels in children. Other causes of primary hyperlipidemia include familial combined hyperlipidemia, which is also common (approximately 1%) but not usually manifest until after puberty, and very rare genetic disorders that may lead to severe hypertriglyceridemia and chylomicronemia syndrome. In children with heterozygous FH, the short-term risk of clinical events is low; therefore, management starts with stratification of risk, followed by dietary modification, and in high-risk cases, pharmacologic treatment initiated after puberty. Male gender, a family history of premature coronary heart disease, and level of low-density lipoprotein (LDL) cholesterol above 4.9 mmol/L are important determinants of risk. Trials have shown that statins effectively lower LDL cholesterol levels; in one study, statins restored endothelial function, with no clinically adverse effects. The effects of statins for longer than 2 years have not been studied. The use of bile acid sequestrants (resins) is limited by compliance and side effects. Children with homozygous FH require expert management with LDL apheresis, high doses of effective statins, and cardiologic follow-up. Ezetimibe, the first in a new class of cholesterol absorption inhibitors, may provide additional efficacy in homozygous FH.

Perspectives: Benefits of a new, nonsystemic lipid-lowering agent: the clinician's perspective.

Though attractive because of their nonsystemicaction, use of the bile acid sequestrants cholestyra-mine and colestipol is limited in part by their poortolerability. Specifically, gastrointestinal side effects,including constipation, indigestion, cramping, bloat-ing, and flatulence, have restricted the use of bileacid sequestrants.

Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.

To describe recent temporal patterns of cholesterol-lowering medication use and the characteristics that may have influenced the initiation of cholesterol-lowering therapy among those aged 65 years or older. A cohort of 5201 adults 65 years or older were examined annually between June 1989 and May 1996. We added 687 African American adults to the cohort in 1992-1993. We measured blood lipid levels at baseline and for the original cohort in the third year of follow-up. We assessed the use of cholesterol-lowering drugs at each visit. The prevalence of cholesterol-lowering drug use in 1989-1990 was 4.5% among the men and 5.9% among the women; these figures increased over the next 6 years to 8.1% and 10.0%, respectively, in 1995-1996. There was a 4-fold increase in the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during the 6 years of follow-up, from 1.9% of all participants in 1989-1990 to 7.5% in 1995-1996. The use of bile acid sequestrants, nicotinic acid, and probucol declined from initial levels of less than 1% each. Among the participants who were untreated in 1989-1990, but eligible for cholesterol-lowering therapy after a trial of dietary therapy according to the 1993 guidelines of the National Cholesterol Education Panel, less than 20% initiated drug therapy in the 6 years of follow-up, even among subjects with a history of coronary heart disease. Among participants untreated at baseline but eligible for either cholesterol-lowering therapy or dietary therapy, initiation of cholesterol-lowering drug therapy was directly associated with total cholesterol levels, hypertension, and a history of coronary heart disease, and was inversely related to age, high-density lipoprotein cholesterol levels, and difficulties with activities of daily living. Other characteristics that form the basis of the 1993 National Cholesterol Education Panel guidelines-diabetes, smoking, family history of premature coronary heart disease, and total number of risk factors-were not associated with the initiation of cholesterol-lowering drug therapy. Given the clinical trial evidence for benefit, those aged 65 to 75 years and with prior coronary heart disease appeared undertreated with cholesterol-lowering drug therapy.

CPPT post-trial follow-up - use of bile-acid sequestrants justified

CPPT post-trial follow-up - use of bile-acid sequestrants justified