Bile Acid Sequestrants in Microscopic Colitis: Clinical Outcomes and Utility of Bile Acid Testing.

BACKGROUND & AIMS: Bile acid sequestrants (BAS) may be a treatment in microscopic colitis (MC), but efficacy data are limited. We evaluated the effectiveness of BAS in MC and assessed the utility of bile acid testing to predict response. METHODS: Adults with MC treated with BAS (2010-2020) at Mayo Clinic were identified. Bile acid malabsorption was defined by elevated serum 7⍺-hydroxy-4-cholesten-3-one or by fecal testing using previously validated cutoffs. Response was defined at 12 ± 4 weeks after BAS initiation as: complete (resolution of diarrhea), partial (≥50% improvement in diarrhea), nonresponse (<50% improvement), and intolerance (discontinuation due to side effects). Logistic regression was used to identify predictors of response to BAS. RESULTS: We identified 282 patients (median age, 59 years [range, 20-87 years]; 88.3% women) with median follow-up of 4.5 years (range, 0.4-9.1 years). Patients were treated with the following BAS: 64.9% cholestyramine, 21.6% colesevelam, and 13.5% colestipol. Clinical outcomes were: 49.3% complete response, 16.3% partial response, 24.8% nonresponse, and 9.6% intolerance. There were no differences in outcomes between those on BAS alone or BAS combined with other medications (P = .98). The dose of BAS was not associated with response (P = .51). Bile acid testing was done in 31.9% of patients, and 56.7% were positive. No predictors of response to BAS were identified. After BAS discontinuation, 41.6% had recurrence at a median of 21 weeks (range, 1-172 weeks). CONCLUSION: In one of the largest cohorts evaluating BAS treatment in MC, nearly two-thirds had a partial or complete response. Additional research is needed to determine the role of BAS and bile acid malabsorption in MC.

Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer.

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies. METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L. RESULTS: 563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed. CONCLUSIONS: These complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective. GOV REGISTRATION NUMBER: NCT02400476.

The Role of Bile Acids in Chronic Diarrhea.

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.

Lipid-Lowering Agents and High HDL (High-Density Lipoprotein) Are Inversely Associated With Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Growing evidence from experimental animal models and clinical studies suggests the protective effect of statin use against rupture of intracranial aneurysms; however, results from large studies detailing the relationship between intracranial aneurysm rupture and total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), and lipid-lowering agent use are lacking. METHODS: The medical records of 4701 patients with 6411 intracranial aneurysms diagnosed at the Massachusetts General Hospital and the Brigham and Women's Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the effects of lipids (total cholesterol, LDL, and HDL) and lipid-lowering medications on intracranial aneurysm rupture risk. Propensity score weighting was used to account for differences in baseline characteristics of the cohorts. RESULTS: Lipid-lowering agent use was significantly inversely associated with rupture status (odds ratio, 0.58; 95% confidence interval, 0.47-0.71). In a subgroup analysis of complete cases that includes both lipid-lowering agent use and lipid values, higher HDL levels (odds ratio, 0.95; 95% confidence interval, 0.93-0.98) and lipid-lowering agent use (odds ratio, 0.41; 95% confidence interval, 0.23-0.73) were both significantly and inversely associated with rupture status, whereas total cholesterol and LDL levels were not significant. A monotonic exposure-response curve between HDL levels and risk of aneurysmal rupture was obtained. CONCLUSIONS: Higher HDL values and the use of lipid-lowering agents are significantly inversely associated with ruptured intracranial aneurysms.

75SeHCAT scan in bile acid malabsorption in chronic diarrhoea. / Gammagrafía con 75SeHCAT en la diarrea crónica por malabsorción de ácidos biliares.

Chronic diarrhoea is a common entity in daily clinical practice and it leads to a loss in these patients quality of life. It may be the main symptom of multiple ethiologies including bile acid malabsorption (BAM) which has a comparable prevalence to celiac disease. The BAM results from imbalances in the homeostasis of bile acids in the enterohepatic circulation. It can be a consequence of ileal disease or ileal dysfunction (BAM type i), it can be considered idiopathic or primary (BAM type ii) or associated with other gastrointestinal entities (BAM type iii). Among the different diagnostic methods available, 75SeHCAT study is the primary current method due to its sensitivity, specificity, safety and low cost. The main disadvantage is that it's not available in all countries, so other diagnostic methods have appeared, such as serum measurement of FGF19 and C4, however they are significantly more complex and costly. The first-line treatment of bile acid diarrhoea is bile acid sequestrant, such as cholestyramine, which can be difficult to administer due to its poor tolerability and gastrointestinal side effects. These are less prominent with newer agents such as colesevelam. In summary, the BAM is a common entity underdiagnosed and undertreated, so it is essential to establish a diagnosis algorithm of chronic diarrhoea in which the 75SeHCAT study would be first or second line in the differential diagnosis of these patients.

Mortality reduction in patients treated with long-term intensive lipid therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study-Observational Study.

BACKGROUND: Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia. OBJECTIVES: The clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study. METHODS: Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double therapy with simvastatin (40-80 mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model. RESULTS: UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26-0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15-0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27-1.14, P = .11). CONCLUSIONS: Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study-Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.

Long-term outcomes in patients diagnosed with bile-acid diarrhoea.

OBJECTIVE: Bile-acid diarrhoea (BAD) is a recognized cause of chronic diarrhoea; however, its detection remains suboptimal. Currently, there is a paucity of follow-up studies evaluating BAD. This work evaluates the natural history of BAD by examining individuals diagnosed with BAD [7 days of Se-homocholic acid taurine (SeHCAT) retention<10%] and determining the use of and response to bile-acid sequestrants (BAS). MATERIALS AND METHODS: Of the 515 patients, 40% (207/515) who underwent an SeHCAT test at Sheffield Teaching Hospitals (2001-2012) for chronic diarrhoea had BAD. Of the 207 (51%) patients, 107 were diagnosed between 2001 and 2009. In accordance with the guidelines, all of these patients were commenced on BAS. In March 2013, these individuals were reassessed either in the clinic or over the telephone as part of a local service evaluation project. Comparisons were made of both pretreatment and post-treatment variables using a Wilcoxon rank test. RESULTS: Of the 107 patients, 54% (58/107) were followed up, with a median time since diagnosis of 6 years. Among them, 38% were still using BAS at follow-up, with 28% using alternative antidiarrhoeals. The median stool frequency decreased from seven stools per day to three (P=0.0008) in those using BAS. The 34% of patients not receiving treatment had no change in their daily bowel frequency. The main reason for discontinuing treatment was poor tolerability of the BAS (colestyramine/colestipol). CONCLUSION: Our findings indicate that BAD is a chronic condition that best improves with BAS. Consideration should be given to therapeutic options that have a better tolerability profile.

Bile acid malabsorption in chronic diarrhea: pathophysiology and treatment.

BACKGROUND: Bile acid malabsorption (BAM) is a common but frequently under-recognized cause of chronic diarrhea, with an estimated prevalence of 4% to 5%. METHODS: The published literature for the period 1965 to 2012 was examined for articles regarding the pathophysiology and treatment of BAM to provide an overview of the management of BAM in gastroenterology practice. RESULTS: BAM is classified as type 1 (secondary to ileal dysfunction), type 2 (idiopathic) or type 3 (secondary to gastrointestinal disorders not associated with ileal dysfunction). The estimated prevalence of BAM is >90% in patients with resected Crohn disease (CD) and 11% to 52% of unresected CD patients (type 1); 33% in diarrhea-predominant irritable bowel syndrome (type 2); and is a frequent finding postcholecystectomy or postvagotomy (type 3). Investigations include BAM fecal bile acid assay, 23-seleno-25-homo-tauro-cholic acid (SeHCAT) testing and high-performance liquid chromatography of serum 7-α-OH-4-cholesten-3-one (C4), to determine the level of bile acid synthesis. A less time-consuming and expensive alternative in practice is an empirical trial of the bile acid sequestering agent cholestyramine. An estimated 70% to 96% of chronic diarrhea patients with BAM respond to short-course cholestyramine. Adverse effects include constipation, nausea, borborygmi, flatulence, bloating and abdominal pain. Other bile acid sequestering agents, such as colestipol and colesevelam, are currently being investigated for the treatment of BAM-associated diarrhea. CONCLUSIONS: BAM is a common cause of chronic diarrhea presenting in gastroenterology practice. In accordance with current guidelines, an empirical trial of a bile acid sequestering agent is warranted as part of the clinical workup to rule out BAM.

Clinical inquiry. Postcholecystectomy diarrhea: what relieves it?

A trial of a bile acid binder such as cholestyramine or colestipol may benefit patients with postcholecystectomy diarrhea.

The 'forgotten' bile acid sequestrants: is now a good time to remember?

Over 30 years ago, bile acid sequestrants (BAS) were among the first drugs approved to lower cholesterol levels. For over 10 years, BAS have been known to reduce glucose levels. Most importantly, BAS have been shown in outcomes studies to reduce cardiovascular events. Because they are true nonsystemic agents, BAS are generally safe and not associated with serious systemic adverse experiences. Despite their proven atherosclerotic coronary heart disease (CHD) benefits, and irrespective of their favorable effects on major CHD risk factors (hypercholesterolemia and hyperglycemia), BAS are not among the more frequently used drug treatments for hypercholesterolemia, even in patients with type 2 diabetes mellitus. Recent "high-profile" findings of investigational and approved lipid-altering and antidiabetes drug therapies illustrate that drug-induced improvements in lipid and glucose levels do not always reduce CHD risk. It may therefore be time to reconsider the clinical use of BAS. This review focuses on the recent lessons learned, and the potential mechanisms involved in efficacy and safety issues raised with torcetrapib and rosiglitazone with analogies related to the use of BAS therapy. Known and proposed mechanisms of how BAS may improve lipid and glucose levels are discussed, which are effects that may help explain how BAS reduce CHD risk. Improved tolerability of newer BAS (eg, colesevelam hydrochloride) and a "new" appreciation of the historic benefits of these "old" therapeutic agents may lead to an increased treatment role for these drugs, particularly in hypercholesterolemic patients with type 2 diabetes mellitus.

Bile acid sequestrants and the treatment of type 2 diabetes mellitus.

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.

Safety considerations with gastrointestinally active lipid-lowering drugs.

Gastrointestinally active agents such as cholesterol absorption inhibitors (CAIs) (eg, ezetimibe) and bile acid sequestrants (BAS) (the resins cholestyramine and colestipol, or colesevelam, a nonabsorbable polymer) offer important options for lipid-lowering therapy. Ezetimibe is a novel CAI that inhibits the absorption of dietary and biliary cholesterol without affecting the absorption of triglycerides or fat-soluble vitamins. In clinical trials, there has been no evidence of increased rates of myopathy or rhabdomyolysis associated with ezetimibe, whether in use as monotherapy or in a combination with statin therapy, although there exist case reports of possible ezetimibe-associated myopathy. Ezetimibe alone does not appear to increase liver transaminase levels significantly, but the coadministration of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) with ezetimibe marginally increases this risk. However, reported increases in liver enzymes have not been associated with clinically meaningful symptoms and often return to baseline levels after the discontinuation of therapy or with continued treatment. To date, no cases of liver failure, liver transplantation, or death have been reported. BAS have been used clinically since the 1960s for lowering low-density lipoprotein cholesterol. Because they are not absorbed from the gastrointestinal tract into the blood, these agents do not contact most body organs and are therefore systemically safe. However, case reports and pharmacokinetic data disclose 3 kinds of adverse effects: (1) the decreased absorption of concomitant medications and sometimes of certain vitamins; (2) the physicochemical alteration of intestinal contents leading to constipation and, very rarely, intestinal obstruction; and (3) modest increases in plasma triglyceride levels due to the alteration of hepatic lipid metabolism. The newest BAS, colesevelam, has greater specificity for bile acids compared with the older agents cholestyramine and colestipol, eliminating most drug interactions and reducing the tendency for constipation. Overall, CAIs and BAS have excellent systemic safety profiles when used alone or in combination with other lipid-lowering drugs.

Genetically determined apo B levels and peak LDL density predict angiographic response to intensive lipid-lowering therapy.

OBJECTIVE: Lipid-lowering therapy (LL-Rx) reduces coronary artery disease (CAD) but the response varies amongst individuals. We investigated the contribution of three genetic forms of dyslipidaemia characterized by elevated plasma apo B, familial hypercholesterolaemia (FH), familial combined hyperlipidaemia (FCHL), and elevated Lp(a), to the angiographic response with LL-Rx. METHODS AND RESULTS: Fifty-one men, with premature CAD and elevated plasma apo B, were selected in whom a genetic diagnosis was based on lipid phenotypes in relatives. Subjects received conventional (diet +/- colestipol) or intensive LL-Rx (niacin or lovastatin plus colestipol). Clinical parameters and CAD severity were measured before and after 2 years of treatment. Twenty-seven patients had FCHL, 12 FH and 12 elevated Lp(a). Regression of coronary stenosis was dependent on the effect of therapy (P < 0.001), genetic form of dyslipidaemia (P = 0.004) and the interaction between the two variables (P = 0.02). Significant regression of coronary stenosis occurred only in FCHL and Lp(a) (P = 0.03, vs. control groups); CAD progression was only slowed in FH. CONCLUSIONS: Three genetic forms of dyslipidaemia were associated with different angiographic outcomes during intensive LL-Rx. Different forms of dyslipidaemia therefore may require different lipid-lowering strategy. Patients with FH and buoyant LDL require more aggressive reduction of LDL cholesterol whilst those with either FCHL or elevated Lp(a) with dense LDL need LDL cholesterol reduction as well as therapies aimed at reduction of the small, dense LDL particles.

Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review.

Bile acid sequestrants (BAS) continue to command a position in the treatment of dyslipidemias 25 years after their introduction. Partial diversion of the enterohepatic circulation using BAS depletes the endogenous bile acid pool by approximately 40%, thus stimulating an increase in bile acid synthesis from cholesterol, which lowers low-density lipoprotein cholesterol (LDL-C) by 15 to 26%. Three BAS are currently used for treating hypercholesterolemia in the United States: the conventional sequestrants, cholestyramine and colestipol, and the specifically engineered BAS, colesevelam hydrochloride (HCl). Compared with conventional BAS, colesevelam HCl has enhanced specificity, greater affinity, and higher capacity for binding bile acids, due to its polymer structure engineered for bile acid sequestration. BAS are not absorbed by the intestine and thus have no systemic drug-drug interactions, but may interfere with the absorption of some drugs. Although BAS monotherapy effectively lowers LDL-C, combination therapy, especially with BAS and statins, is becoming increasingly common due to complementary mechanisms of action. Low-dose statin plus BAS combinations lead to greater or similar LDL-C reductions compared with high-dose statin monotherapy and may have a better safety profile. Combinations of BAS with nonstatin lipid-lowering agents, including niacin, fibrates, and cholesterol absorption inhibitors, may be useful in those patients who require intensive lipid-lowering, but are statin intolerant. BAS treatment can significantly reduce coronary artery disease (CAD) progression and the risk of CAD-associated outcomes. It is also becoming clear that BAS and other therapies that manipulate the bile acid synthetic pathway may have clinically useful therapeutic effects on other metabolic disorders including type 2 diabetes.