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Bile acid sequestrants (BASs) have often been used for bile acid diarrhea (BAD) but carry a high risk of adverse events. New generations of BASs show promising results; however, their efficacy remains unclear. This systematic review and meta‐analysis was conducted using PubMed, Cochrane, and Embase to assess randomized controlled trials (RCTs) published up to November 2023 to retrieve studies that measured the parameters before and after the administration of BASs. The outcomes assessed were cessation or improvement in diarrhea, fecal consistency, abdominal cramping, frequency of diarrhea, and adverse events. Risk ratios (RRs) and mean differences with 95% confidence intervals (CIs) were pooled using a random‐effects model. Statistical analyses were conducted using RStudio version 4.1.2. The protocol was prospectively registered with PROSPERO (CRD42023445444). Seven RCTs with a total of 311 patients were included, of which 168 (54%) were randomized to BASs. Among BAS‐treated patients, 101 (60.1%) received colesevelam, 40 (23.8%) received chenodeoxycholate, 18 (10.7%) received cholestyramine, and 9 (5.3%) received colestid. BASs were associated with a significant improvement in the cessation of diarrhea (RR 3.27; 95% CI 2.08 to 5.15; P ≤  .05) and liquid stool to normal fecal consistency (RR 2.69; 95% CI 1.56 to 4.65; P ≤  .05), as well as an increase in abdominal cramps (RR 5.27; 95% CI 1.21 to 22.93; P ≤  .05). There were no differences in urgency, adverse events, or nausea between groups. These findings indicate that BASs are effective in the treatment of BAD, as indicated by the improvement or cessation of diarrhea episodes. [ABSTRACT FROM AUTHOR]

BackgroundNeratinib 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.MethodsPatients 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.Results563 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.ConclusionsThese 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.ClinicaltrialsGov registration numberNCT02400476.

BackgroundCardiovascular 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.ObjectivesThe clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study.MethodsOf 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.ResultsUC 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).ConclusionsLong-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.

Objective: To systematically search the literature for trials evaluating luminal toxin-binding agents (LTBAs) for Clostridium difficile infection (CDI). Methods: A systematic search was conducted utilizing PubMed and International Pharmaceutical Abstracts with the following terms: anion-exchange resins, C difficile, cholestyramine, tolevamer, and colestipol. Articles were included if published in the English language and reported clinical outcomes of more than 5 adult humans with CDI treated with LTBAs. Results: Nearly all clinical trials evaluated LTBA as monotherapy for CDI and LTBAs are inferior to standard therapy. In contemporary practice, LTBAs are employed as adjunctive or sequential therapy for which there is a paucity of data. Some data suggest potential efficacy for recurrent CDI. Current guidelines for CDI assert LTBAs are contraindicated due to drug–drug interactions with vancomycin. However, the impact of this interaction on clinical outcomes has not been evaluated, and it is unknown whether higher doses of vancomycin or separating the administration of LTBAs from vancomycin would mitigate this interaction. Conclusion: LTBA monotherapy is inferior to vancomycin and metronidazole for CDI. Some data indicate possible benefit in reducing recurrent CDI, but outcomes with adjunctive and/or sequential LTBAs are unavailable. Further studies are needed to investigate the role of LTBAs for CDI. [ABSTRACT FROM AUTHOR]

Background Studies have documented the short-term vascular benefits of combination lipid therapy. Objective Our objective was to evaluate the long-term effects of combination lipid therapy on carotid intima-media thickness (CIMT) in patients with coronary artery disease. Methods We performed a case-control study in patients who had finished the Familial Atherosclerosis Treatment Study (FATS) and returned to usual care with statin therapy alone or had elected to participate in the 20-year FATS-Observational Study (FATS-OS) and received combination therapy with lovastatin (40 mg/day), niacin (2–3 g/day), and colestipol (20 gm/day) for 11 years, then continued with simvastatin (10–80 mg/day) or lovastatin (40–80 mg/day) plus niacin (2–4 g/day). After 17.8 ± 0.8 years with combination therapy and 19.0 ± 0.8 years with usual care, cholesterol levels and CIMT were collected in 43 FATS-OS patients and 26 usual care patients. Results Combination therapy group had a greater decrease in total cholesterol (−42 ± 14% vs −31 ± 17%, P = .008) and low-density lipoprotein cholesterol (LDL-C) (−57 ± 13% vs −38 ± 25%, P < .001) and greater increase in high-density lipoprotein cholesterol (HDL-C) (38 ± 43% vs 15 ± 23%, P = .02) as compared with usual care. CIMT (0.902 ± 0.164 vs 1.056 ± 0.169 mm, P < .001) on intensive therapy was significantly less compared with usual care. Multivariate regression analysis (coefficient, 95% CI) showed that combination therapy (−0.13; −0.21 to −0.04, P = .003) and on-therapy LDL-C (0.15; 0.02 to 0.28, P = .03) were significant independent predictors of CIMT. Conclusions Prolonged combination lipid therapy is associated with greater improvements in LDL-C and HDL-C levels and less atherosclerotic burden as compared with statin therapy alone. [ABSTRACT FROM AUTHOR]

Abstract: The ability of aluminium to inhibit the (Na+/K+)ATPase activity has been observed by several authors. During chronic dietary exposure to AlCl3, brain (Na+/K+)ATPase activity drops, even if no alterations of catalytic subunit protein expression and of energy charge potential are observed. The aluminium effect on (Na+/K+)ATPase activity seems to implicate the reduction of interacting protomers within the oligomeric ensemble of the membrane-bound (Na+/K+)ATPase. The activity of (Na+/K+)ATPase is altered by the microviscosity of lipid environment. We studied if aluminium inhibitory effect on (Na+/K+)ATPase is modified by alterations in synaptosomal membrane cholesterol content. Adult male Wistar rats were submitted to chronic dietary AlCl3 exposure (0.03g/day of AlCl3) and/or to colestipol, a hypolidaemic drug (0.31g/day) during 4months. The activity of (Na+/K+)ATPase was studied in brain cortex synaptosomes with different cholesterol contents. Additionally, we incubate synaptosomes with methyl-β-cyclodextrin for both enrichment and depletion of membrane cholesterol content, with or without 300μM AlCl3. This enzyme activity was significantly reduced by micromolar AlCl3 added in vitro and when aluminium was orally administered to rats. The oral administration of colestipol reduced the cholesterol content and concomitantly inhibited the (Na+/K+)ATPase. The aluminium inhibitory effect on synaptosomal (Na+/K+)ATPase was reduced by cholesterol depletion both in vitro and in vivo. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

In this article we discuss the available data on the effects of combined therapy of ezetimibe with agents affecting lipid metabolism other than statins. We consider studies evaluating the effects of combined therapy of ezetimibe with bile acid sequestrants, fenofibrate, niacin, n-3 fatty acids, plant sterols, orlistat, metformin, acarbose and glitazones. Combination of ezetimibe with bile acid sequestrants (especially colesevelam) was shown to have additional effects on lipid parameters in patients with hyperlipidemia. Combination of ezetimibe with fenofibrate may be a good approach to improve the overall lipid profile of patients with mixed hyperlipidemia. The addition of ezetimibe to niacin-based therapy can be useful for high-risk patients with dyslipidemia who are not achieving their assigned treatment goals. For patients who cannot tolerate statins there are useful combinations of ezetimibe with other drugs affecting lipid metabolism. These combinations improve many metabolic parameters, but more trials should be carried out to reach more robust conclusions about their effects on cardiovascular disease prevention. INSET: Key issues. [ABSTRACT FROM AUTHOR]

Bowel symptoms including diarrhoea can be produced when excess bile acids (BA) are present in the colon. This condition, known as bile acid or bile salt malabsorption, has been under recognized, as the best diagnostic method, the 75Se-homocholic acid taurine (SeHCAT) test, is not available in many countries and is not fully utilized in others. Reduced SeHCAT retention establishes that this is a complication of many other gastrointestinal diseases. Repeated studies show SeHCAT tests are abnormal in about 30% of patients otherwise diagnosed as diarrhoea-predominant irritable bowel syndrome or functional diarrhoea, with an estimated population prevalence of around 1%. Recent work suggests that the condition previously called idiopathic bile acid malabsorption (BAM) is not in fact due to a defect in absorption, but results from an overproduction of BA because of defective feedback inhibition of hepatic bile acid synthesis, a function of the ileal hormone fibroblast growth factor 19 (FGF19). The approach to treatment currently depends on binding excess BA, to reduce their secretory actions, using colestyramine, colestipol and, most recently, colesevelam. Colesevelam has a number of potential advantages that merit further investigation in trials directed at patients with bile acid diarrhoea. [ABSTRACT FROM PUBLISHER]

Background: Commercially available bile-acid sequestrants are not well tolerated by >80% of patients. Objective: The aim of the present study was to assess the effectiveness and tolerability of colesevelam hydrochloride in patients who developed bile-acid malabsorption after cancer therapy. Methods: The present study comprised 2 parts: a retrospective chart review of the electronic patient records and a patient questionnaire assessing outcome measures. All patients included in this study had a diagnosis of cancer and were being followed up in a cancer clinic at The Royal Marsden Hospital. In addition, all had symptoms of bile-acid malabsorption for >3 months and had been prescribed colesevelam in the gastroenterology clinic at the hospital. The electronic records of patients who were prescribed colesevelam between 2004 and 2007 were obtained from the hospital pharmacy. Those patients who were prescribed colesevelam and did not take any of the prescribed medication or did not return for a follow-up clinical review were excluded. To help further assess outcomes, a questionnaire was mailed to patients who were still residing in the United Kingdom, were not terminally ill, and were not lost to follow-up. The questionnaire comprised questions that assessed medication history (ie, whether patients were still taking colesevelam or not [and the reason for not taking colesevelam]), dosage, effectiveness for symptom relief, and adverse events. Results: In total, 45 patients (37 women and 8 men; median age, 58 years [range, 32–89 years]) who received treatment with colesevelam between 2004 and 2007 were included. Of these, 36 were sent a questionnaire and 30 responded. Identifiable causes of bile acid malabsorption in this sample population were pelvic radiotherapy (n = 29), small-bowel resection (12), upper gastrointestinal surgery (2), high-dose chemotherapy (1), and new-onset Crohn''s disease (1). Of these patients, 67% (30/45) had not previously responded to cholestyramine treatment, but following treatment with colesevelam, this group had a recorded improvement in: diarrhea, 83% (25/30); urgency of defecation, 74% (20/27); frequency of defecation, 72% (21/29); steatorrhea, 71% (12/17); abdominal pain, 68% (15/22); and fecal incontinence, 62% (13/21). Based on the medical chart review and the patient questionnaire, after colesevelam treatment, the following proportions of all 45 patients studied experienced improvement in symptoms: loose stool (diarrhea), 88% (medical chart) and 80% (questionnaire); frequency of defecation, 77% and 83%, respectively; steatorrhea, 76% and 80%; urgency of defecation, 76% and 80%; abdominal pain, 74% and 58%; and fecal incontinence, 69% and 74%. During the study period, 15 patients discontinued colesevelam: ineffectiveness, 5; adverse events, 5 (because ≥1 of the following: bloating, constipation, heartburn, abdominal pain, flatulence, or perianal soreness); and other reasons, 7 (too many tablets or tablets difficult to swallow [3]; symptoms resolved [2]; colesevelam replaced with another medication [1]; and lost to follow-up [1]). Sixty-seven percent (30/45) of patients continued using colesevelam for up to 4 years. Conclusion: In view of the data found in this retrospective chart review and patient questionnaire, prospective, double-blind, placebo-controlled trials of colesevelam for bile acid malabsorption are warranted. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Effects on serum lipoproteins were studied in ten patients with familial hypercholesterolaemia (FH) during consecutive eight-week treatment periods with fenofibrate 0.3 g/day, fenofibrate plus colestipol, 15 g/day, and fenofibrate 0.25 g/day plus colestipol. VLDL, LDL, HDL, HDL, and HDL were isolated by ultracentrifugation and precipitation. Lipids and apolipoproteins A-I and B were determined by enzymatic and immunonephelometric techniques, respectively. Administration of fenofibrate alone resulted in decreases in VLDL and LDL cholesterol (−48% and −18%) and in serum apolipoprotein B (−10%), but in increases in HDL, HDL, and HDL (+25%, +26%, and +24%), and in serum apolipoprotein A-I (+6%). Addition of colestipol produced a further reduction in LDL cholesterol (−31%) and in serum apolipoprotein B (−19%). The effects were maintained with less fenofibrate. In FH, an acceptable therapy combines the favourable effects of sufficient lowering of LDL and of a rise in HDL. [ABSTRACT FROM AUTHOR]

The hypocholesterolemic cation resins, cholestyramine and colestipol, have variable effects on the absorption parameters of a number of lipophillic, anion drugs. Because of the unpredictable nature of this interaction, we have assessed in human volunteers the effect of these resins on the rate and total absorption of phenytoin. Our results indicate that these resins do not affect the absorption parameters of phenytoin and that special care does not have to be exercised when these agents are co-administered. [ABSTRACT FROM AUTHOR]

The possibility of a pharmacokinetic interaction between two hypolipidemic drugs, colestipol, an ion exchange resin, and fenofibrate, a phenoxyacid derivative, was studied in 6 male volunteers. The investigation followed a four-step protocol during 18 days, and relied on determination of plasma and urinary levels of fenofibric acid, the active metabolite of fenofibrate. The kinetics of a single dose of fenofibrate 300 mg was established over 3 days. Thereafter, from Days 4 to 9 fenofibrate was given daily as 200 mg in the morning and 100 mg in the evening; the plasma fenofibric acid level reached about 10 µg/ml. From Days 9 to 15 the same dose of fenofibrate was administered together with colestipol 10 g in the morning and 5 g in the evening. Plasma fenofibric acid concentrations remained unchanged and the 24 h urinary excretion of fenofibric acid did not fall. On Day 15, a last single dose of fenofibrate 300 mg was given with colestipol 15 g. The pharmacokinetic pattern of fenofibric acid on Days 15 to 18 did not differ significantly from that found previously (Days 1 to 3). From these results, it is likely that there is no pharmacokinetic interaction between the two hypolipidemic drugs. [ABSTRACT FROM AUTHOR]

Longterm treatment for 5 years of young patients with familial hypercholesterolemia was accompanied by monitoring of plasma levels of calcium, iron, sodium, parathyroid hormone and water- and fat soluble vitamins, since interference of the ion exchange resin with absorption of numerous substances as well as abnormal plasma levels of some of the above had been described in several studies. Treatment was effective in the group with good compliance (lowering of plasma cholesterol at the end of 5 years by 19% and, compared to the control group, by 23%). Adverse drug effects with respect to the above parameters were not found. Plasma levels of carotinoides and vitamin E were elevated in the patients according to elevated concentrations of lipoproteins which are carriers of these vitamins. [ABSTRACT FROM AUTHOR]

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BACKGROUND: Atorvastatin, a new HMG-CoA reductase inhibitor in clinical development has demonstrated an acceptable safety profile and marked cholesterol and triglyceride reduction at doses ranging from 10-80 mg/day. Since bile acid sequestering resins are often used in combination with HMGRIs to enhance cholesterol reduction, this trial was conducted to explore the use of atorvastatin alone and combined with colestipol in patients with primary hyperlipidemia. METHODS AND RESULTS: One hundred six patients with low-density lipoprotein (LDL) cholesterol >4.1 mM/L (160 mg/dL) and plasma triglycerides <3.9 mM/L (350 mg/dL) were randomized to treatment consisting of 20 g/day colestipol, 10 mg/day atorvastatin, or 10 mg/day atorvastatin plus 20 g/day colestipol for 12 weeks. Percent change from baseline in lipid variables were measured. The atorvastatin group showed a significant reduction in LDL cholesterol of 35% after 12 weeks. Combination therapy provided an additional 10% reduction in LDL cholesterol over that observed for atorvastatin alone. Twenty-one percent of all patients in the atorvastatin monotherapy group experienced associated adverse events compared with 60% in the combination therapy group. Ninety percent of atorvastatin monotherapy patients were compliant at every visit compared with 75% receiving combination therapy. CONCLUSIONS: Although the combination of atorvastatin plus colestipol was more effective in lowering LDL cholesterol than atorvastatin alone, atorvastatin 10 mg/day monotherapy provided a better safety profile and improved patient compliance, which may result in improved long-term cholesterol control. [ABSTRACT FROM AUTHOR]

In an effort to visualize whole body cholesteryl ester (CE) deposition using the nuclear medicine imaging technique of gamma camera scintigraphy, I-cholesteryl iopanoate (I-CI), a nonhydrolyzable CE analogue, was used as a marker for CE deposition in atherosclerotic New Zealand white rabbits. Groups of animals were fed either a cholesterol-enriched diet (2%, w/w) or the same diet supplemented with the hypolipidemic drugs colestipol (1%, w/w) and/or clofibrate (0.3%, w/w). Injections of I-CI were administered biweekly. At the end of 15 weeks, animals were scintigraphically scanned and sacrificed for tissue analysis. The results demonstrated that while drug treatment had no significant effect on plasma lipid levels, it substantially lessened atherosclerotic involvement in the thoracic-abdominal aorta. These differences in aortic lipid accumulation were reflected in the whole-body scans which showed a reduction in tissue accumulation of I-CI in the drug-treated groups. Gamma camera scintigraphy thus represents a rapid means of visualizing tissue CE accumulation which could facilitate the evaluation of lipid-lowering drug efficacy and possible antiatherosclerotic effect. [ABSTRACT FROM AUTHOR]

The effects of orange flavoured colestipol granules, 10 g/day, in 37 boys and 29 girls aged 10-16 years with familial hypercholesterolaemia were examined first in an eight week double blind, placebo controlled protocol, then in open treatment for 44-52 weeks. All patients were on a low fat diet. Low density lipoprotein cholesterol levels were reduced by 19.5% by colestipol v 1.0% by placebo. Levels of serum folate, vitamin E, and carotenoids were reduced in the colestipol group, but not the vitamin E/cholesterol and carotenoid/cholesterol ratios or serum concentrations of vitamins A and D. After one year of colestipol, two thirds of the participants remained in the study, of whom half took > or = 80% of the prescribed dose. Those who took > or = 80% of the dose had a greater decrease in serum 25-hydroxyvitamin D levels than those who took < 80%. No adverse effects on weight gain or linear growth velocity were observed. Although low dose colestipol effectively reduces low density lipoprotein cholesterol levels, only a minority of adolescents adhered to the new formulation for one year. Folate and possibly vitamin D supplementation is recommended. [ABSTRACT FROM AUTHOR]