Bile Acid Sequestrant Cholestyramine Research Articles

Short-term treatment with cholestyramine increases long-acting anticoagulant rodenticide clearance from rabbits without affecting plasma vitamin K1 levels nor blood coagulation.

Administration of high dose vitamin K1 (VK1) overcomes coagulopathy and bleeding elicited by acute poisoning with long-acting anti-coagulant rodenticides (LAARs). However, long-term (months) treatment is required due to long LAAR biological half-lives that may lead to poor compliance and recurrent coagulopathy. The half-lives of LAARs are extended by slow metabolism, and similar to warfarin, are thought to undergo enterohepatic recirculation. We now show that treatment with the bile acid sequestrant cholestyramine (CSA) administered concomitantly with VK1 decreases plasma LAAR levels and increases LAAR fecal excretion. Daily CSA treatment for 14 days did not reduce plasma VK1 levels, nor increase prothrombin time. Collectively, these data show that CSA accelerates LAAR clearance from rabbits without adverse effects on VK1 anti-coagulation, and could provide an additional therapeutic option for treatment of LAAR poisoning.

Gastroparesis Worsens Indomethacin-Induced Gastric Antral Ulcers by Bile Reflux via Activation of 5-HT3 and Dopamine D2 Receptors in Mice.

We examined the contributions of gastric emptying and duodenogastric bile reflux in the formation of gastric antral ulcers induced by NSAIDs in mice. We used the murine re-fed indomethacin (IND) experimental ulcer model. Outcome measures included the appearance of gastric lesions 24h after IND treatment and the assessment of gastric contents and the concentration of bile acids 1.5h after re-feeding. The effects of atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, ondansetron, haloperidol, and dietary taurocholate and cholestyramine were also examined. IND (10mg/kg, s.c.) induced severe lesions only in the gastric antrum in the re-fed model. The antral lesion index and the amount of food intake during the 2-h refeeding period were positively correlated. Atropine and dopamine delayed gastric emptying, increased bile reflux, and worsened IND-induced antral lesions. SR57227 and apomorphine worsened antral lesions with increased bile reflux. These effects were prevented by the anti-emetic drugs ondansetron and haloperidol, respectively. The anti-emetic drugs markedly decreased the severity of antral lesions and the increase of bile reflux induced by atropine or dopamine without affecting delayed gastric emptying. Antral lesions induced by IND were increased by dietary taurocholate but decreased by the addition of the bile acid sequestrant cholestyramine. These results suggest that gastroparesis induced by atropine or dopamine worsens NSAID-induced gastric antral ulcers by increasing duodenogastric bile reflux via activation of 5-HT3 and dopamine D2 receptors.

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

Clostridioides difficile infection induces a rapid influx of bile acids into the gut during colonization of the host.

SUMMARYClostridioides difficile is the leading cause of nosocomial intestinal infections in the United States. Ingested C. difficile spores encounter host bile acids and other cues that are necessary for germinating into toxin-producing vegetative cells. While gut microbiota disruption (often by antibiotics) is a prerequisite for C. difficile infection (CDI), the mechanisms C. difficile employs for colonization remain unclear. Here, we pioneered the application of imaging mass spectrometry to study how enteric infection changes gut metabolites. We find that CDI induces an influx of bile acids into the gut within 24 h of the host ingesting spores. In response, the host reduces bile acid biosynthesis gene expression. These bile acids drive C. difficile outgrowth, as mice receiving the bile acid sequestrant cholestyramine display delayed colonization and reduced germination. Our findings indicate that C. difficile may facilitate germination upon infection and suggest that altering flux through bile acid pathways can modulate C. difficile outgrowth in CDI-prone patients.

Perfluoroalkyl substance excretion: Effects of organic anion-inhibiting and resin-binding drugs in a community setting

BackgroundLonger serum half-lives of perfluoroalkyl substances (PFAS) in humans compared to other species has been attributed to differences in the activity of organic anion transporters (OAT). MethodsAmong 56,175 adult participants in the community-based C8 Health Project, 23 subjects were taking the uricosuric OAT-inhibitor probenecid, and 36 subjects were taking the bile acid sequestrant cholestyramine. In regression models of log transformed serum PFAS, medication effects were estimated in terms of mean ratios, adjusting for age, gender, BMI, estimated glomerular filtration rate (eGFR) and water-district of residence. ResultsProbenecid was associated with modest, but not statistically significant increases in serum PFAS concentrations. In contrast, cholestyramine significantly lowered serum PFAS concentrations, notably for perfluorooctane sulfonic acid (PFOS). ConclusionsThe effectiveness of cholestyramine in a community setting supports the importance of gastrointestinal physiology for PFAS excretion kinetics, especially for PFOS. We did not find clear evidence that probenecid, an inhibitor of OAT, affects PFAS clearance.

New therapeutic agents marketed in 2020: Part 2

New therapeutic agents marketed in 2020: Part 2

An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen.

A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile acid sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an 'anti-antibiotic' to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model of Enterococcus faecium gastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens.

Achieving delayed release of freeze-dried probiotic strains by extrusion, spheronization and fluid bed coating - evaluated using a three-step in vitro model.

Intake of probiotics is associated with many health benefits, which has generated an interest in formulating viable probiotic supplements. The present study had two aims. The first aim was to achieve gastrointestinal protection and delayed release of viable probiotics by pelletizing and coating freeze-dried probiotic strains, using riboflavin as a marker for release. The second aim was to set up a dynamic three-step in vitro model simulating the conditions in the human gastric, duodenum/jejunum and ileum compartments using physiologically relevant media to evaluate delayed release of the formulations. To simulate lowered bile acid concentrations in the ileum area of the gastrointestinal tract, a novel method using the bile acid sequestrant cholestyramine to lower bile acid concentrations in the small intestinal medium to physiologically relevant levels was attempted. Granulation, extrusion and spheronization was used to develop pellets containing viable probiotics using freeze-dried Lactobacullus reuteri as a model strain. Fluid bed coating the pellets with the pH-sensitive polymers Eudragit S100 or Eudragit FS30D resulted in targeted release in the ileum step of the three-step in vitro model based on release of the marker riboflavin.

Review article: bile acid diarrhoea - pathogenesis, diagnosis and management.

Bile acid diarrhoea results from imbalances in the homoeostasis of bile acids in the enterohepatic circulation. It can be a consequence of ileal disease/dysfunction, associated with other GI pathology or can be idiopathic. To summarise the different types of bile acid diarrhoea and discuss the currently available diagnostic methods and treatments. Bile acid diarrhoea is found in up to 40% of patients diagnosed as having functional diarrhoea/IBS-D, and in up to 80% of patients who have undergone ileal resection. It is likely under-diagnosed and under-treated. In idiopathic disease, errors in regulation feedback of fibroblast growth factor 19 contribute to the development of the condition. Clinical therapeutic trials for bile acid diarrhoea have been used to diagnose it, but the 75 SeHCAT test is the primary current method. It is sensitive, specific and widely available, though not in the USA. Other diagnostic methods (such as serum measurement of the bile acid intermediate 7α-hydroxy-4-cholesten-3-one, or C4) have less widespread availability and documentation, and some (such as faecal measurement of bile acids) are significantly more complex and costly. First-line treatment of bile acid diarrhoea is with the bile acid sequestrant cholestyramine, which can be difficult to administer and dose due to gastrointestinal side effects. These side effects are less prominent in newer agents such as colesevelam, which may provide higher efficacy, tolerability and compliance. Bile acid diarrhoea is common, and likely under-diagnosed. Bile acid diarrhoea should be considered relatively early in the differential diagnosis of chronic diarrhoea.

Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling.

Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease.

480 A Pre-Transplant Risk Factor Model Predicts Post-Transplant Cardiac Events in Patients With Liver Cirrhosis

role of bile acids in the progression of HE, mice were fed a diet enriched in the bile acid sequestrant cholestyramine, or the bile acids cholic acid (CA), deoxycholic acid (DCA) or ursodeoxycholic acid (UDCA) for 3 days prior to AOM injection. Subsequent assessment of neurological decline and liver damage was performed in these mice. The dose of bile acids given has previously been shown to not cause liver damage. Results: Total bile acids were increased in the brains of mice after AOM injection compared to controls. In parallel, fluorescently-derived bile acids were increased in the brains of AOM mice, suggesting that bile acids are entering from the periphery. Cholestyramine feeding reduced both the serum and brain bile acid levels and delayed the neurological decline associated with acute liver failure without any significant differences in liver damage. In contrast, feeding with CA and DCA worsened the AOM-induced neurological decline and significantly decreased the time taken to reach coma, with DCA having the greatest effect while UDCA feeding had no effect. Conclusions: These data indicate that circulating bile acids may be pathological in the brain during the course of HE, although precisely how they are dysregulating normal brain function is unknown. Strategies to minimize the total bile acid content in the serum may improve the outcome of patients with neurological symptoms associated with liver failure.

Antidyslipidemic effects of a farnesoid X receptor antagonist in primates

AimsWe investigated antidyslipidemic effects of a farnesoid X receptor antagonist compound-T3 in non-human primates as a novel treatment approach for dyslipidemia. Main methodsCynomolgus monkeys were fed a high-fat diet over 3weeks. Drugs were administered to the monkeys for a week, and their plasma and fecal lipid parameters were measured. Key findingsCompound-T3 dose-dependently decreased the plasma non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B levels in high-fat diet-fed cynomolgus monkeys. The plasma levels of 7α-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7α-hydroxylase activity, and total fecal bile acid levels increased, suggesting that the hypocholesterolemic effects would be dependent on the activation of cholesterol catabolism in the liver. Compound-T3 significantly increased the plasma levels of HDL cholesterol and apolipoprotein A-I. In this condition, the cholesterol absorption inhibitor ezetimibe significantly decreased the plasma non-HDL cholesterol levels and increased the fecal cholesterol levels without affecting plasma HDL cholesterol and triglyceride levels. Bile acid sequestrant cholestyramine tended to decrease plasma non-HDL cholesterol and increase fecal bile acid levels. The cholesteryl ester transfer protein inhibitor torcetrapib significantly increased plasma HDL cholesterol levels without affecting plasma non-HDL cholesterol and fecal cholesterol levels. SignificanceThe results of ezetimibe, cholestyramine, and torcetrapib treatments indicate that our high-fat diet fed monkey model would be a preferred animal model for studying non-statin type antidyslipidemic drugs. Compound-T3 significantly decreased non-HDL cholesterol levels and increased HDL cholesterol levels in the monkey model, suggesting that a farnesoid X receptor antagonist could be a therapeutic option in human dyslipidemia.

NEW IN THE TREATMENT OF TYPE 2 DIABETES

Diabetes mellitus (DM) is a major medical and social problem almost in all countries of the world. Currently, there are more and more various pharmacological agents that make management of the glycaemia in patients with type 2 diabetes extremely difficult. Therefore, when the physician is faced with the choice of glucose-lowering therapy, he should be clearly aware of all the options in contemporary treatment. 11 groups of hypoglycemic agents are used for the treatment of type 2 diabetes The biguanides. According to modern concepts, biguanides inhibit the oxidation of glucose by stimulating anaerobic glycolysis. Both in the consensus of ADA / EASD, and in the IDF recommendations metformin may be the drug of the choice for hypoglycemic therapy of diabetes type 2. Sulfonylurea derivatives: glibenclamide, glimepiride, gliquidone, Glipizide. They belong to a group of secretagogues, as their action is based on the ability to stimulate the secretion of insulin by s-cells of the pancreas. Prandial glucose regulators. Meglitinides (repaglinide and nateglinide) stimulate insulin secretion by s-cells. Due to the rapid normalization of stimulated insulin level after taking the drugs the risk of hypoglycaemia between meals is minimized. Insulin sensitayzers. Thiazolidinediones (rosiglitazone, pioglitazone) reduce insulin resistance of peripheral tissues by binding to receptors, activating peroxisome proliferation (PPARg) in the nuclear membrane. Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) competitively inhibits intestinal enzymes (α-glucosidase). It consequently slows carbohydrate absorption from foods and supply of glucose into the blood. Incretin mimetics. Analogues of glucagon-like peptide 1 (GLP-1) stimulate the biosynthesis and secretion of insulin, regulate food consumption, support s-cells in a healthy state, suppress glucagon secretion, depending on the glucose levels, affect the rate of gastric emptying, stimulat proliferation of s-cells. They include the following drugs: exenatide, exenatide-LAR, liraglutide, liksizenatid, albiglyutid, dulaglyutid. GLP-1 is splited by dipeptidyl peptidase type 4 (DPP-4), which formed the basis for the creation of inhibitors of the enzyme DPP-4 and thus the maintaince of GLP-1 effect. There are the following inhibitors of DPP-4: sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin. Inhibitors of sodium-glucose cotransporter 2 (SGLT2). Their mechanism of action is reduced to the suppression of glucose reabsorption in the kidney, followed by reduction of hyperglycemia. Representatives of the group are dapagliflozin and kanagliflozin. The other three groups of drugs: amylin mimetics (pramlintide), bile acid sequestrants (cholestyramine and colestipol) and dopamine-2 agonists (bromocriptine) are used only in addition to the treatment of diabetes. Conclusions. The choice of drug therapy is a difficult and complex task. The heterogeneity of patients with type 2 diabetes suggests, that for effective treatment of this chronic progressive disease may not be an optimal use of only one class of glucose-lowering drugs. When physicians select treatment strategy against type 2 diabetes, he should rely on the national and international clinical guidelines and research results, as well as on his own clinical experience, and be sure to take into account the individual characteristics of the patient.

RHDL administration increases reverse cholesterol transport in mice, but is not additive on top of ezetimibe or cholestyramine treatment

ObjectivePromoting reverse cholesterol transport (RCT) is a major atheroprotective property of HDL. The present study explored the effect of stimulating the first step of RCT (cholesterol efflux from macrophages) alone or in combination with stimulating the last step of RCT (fecal sterol excretion). Methods and resultsReconstituted HDL (rHDL) was injected into wild-type mice either with or without administration of the cholesterol absorption inhibitor ezetimibe or the bile acid sequestrant cholestyramine. Single dose administration of rHDL (100 mg apoA-I/kg) resulted in an early (4 h) increase in plasma free cholesterol levels (p < 0.001), without affecting hepatic cholesterol levels or fecal mass sterol excretion. rHDL injection also increased [3H]cholesterol appearance in plasma at an early time-point (4 h) after intraperitoneal administration of [3H]cholesterol-labeled mouse macrophage foam cells and fecal radioactivity excretion indicating completed RCT was increased by 26% (p < 0.05). Ezetimibe treatment inhibited intestinal cholesterol absorption by 74% (p < 0.01), but also the bile acid sequestrant cholestyramine decreased cholesterol absorption significantly (24%, p < 0.01). Consequently, ezetimibe increased RCT 2.1-fold (p < 0.001) primarily within fecal neutral sterols, while cholestyramine increased RCT by 3.6-fold (p < 0.001), primarily within bile acids (p < 0.001), but also within neutral sterols (p < 0.001). However, no additive effects of both intestinal sterol uptake inhibitors were observed on top of rHDL administration. ConclusionThese data demonstrate that increasing the first step of RCT by rHDL administration results in transient cholesterol mobilization from macrophages to plasma. This effect is not further enhanced by stimulating the last step of RCT, fecal sterol excretion.

Very Long O-antigen Chains Enhance Fitness during Salmonella-induced Colitis by Increasing Bile Resistance

Intestinal inflammation changes the luminal habitat for microbes through mechanisms that have not been fully resolved. We noticed that the FepE regulator of very long O-antigen chain assembly in the enteric pathogen Salmonella enterica serotype Typhimurium (S. Typhimurium) conferred a luminal fitness advantage in the mouse colitis model. However, a fepE mutant was not defective for survival in tissue, resistance to complement or resistance to polymyxin B. We performed metabolite profiling to identify changes in the luminal habitat that accompany S. Typhimurium-induced colitis. This analysis suggested that S. Typhimurium-induced colitis increased the luminal concentrations of total bile acids. A mutation in fepE significantly reduced the minimal inhibitory concentration (MIC) of S. Typhimurium for bile acids in vitro. Oral administration of the bile acid sequestrant cholestyramine resin lowered the concentrations of total bile acids in colon contents during S. Typhimurium infection and significantly reduced the luminal fitness advantage conferred by the fepE gene in the mouse colitis model. Collectively, these data suggested that very long O-antigen chains function in bile acid resistance of S. Typhimurium, a property conferring a fitness advantage during luminal growth in the inflamed intestine.

Bile Acid-Induced Virulence Gene Expression of Vibrio parahaemolyticus Reveals a Novel Therapeutic Potential for Bile Acid Sequestrants

Vibrio parahaemolyticus, a bacterial pathogen, causes human gastroenteritis. A type III secretion system (T3SS2) encoded in pathogenicity island (Vp-PAI) is the main contributor to enterotoxicity and expression of Vp-PAI encoded genes is regulated by two transcriptional regulators, VtrA and VtrB. However, a host-derived inducer for the Vp-PAI genes has not been identified. Here, we demonstrate that bile induces production of T3SS2-related proteins under osmotic conditions equivalent to those in the intestinal lumen. We also show that bile induces vtrA-mediated vtrB transcription. Transcriptome analysis of bile-responsive genes revealed that bile strongly induces expression of Vp-PAI genes in a vtrA-dependent manner. The inducing activity of bile was diminished by treatment with bile acid sequestrant cholestyramine. Finally, we demonstrate an in vivo protective effect of cholestyramine on enterotoxicity and show that similar protection is observed in infection with a different type of V. parahaemolyticus or with non-O1/non-O139 V. cholerae strains of vibrios carrying the same kind of T3SS. In summary, these results provide an insight into how bacteria, through the ingenious action of Vp-PAI genes, can take advantage of an otherwise hostile host environment. The results also reveal a new therapeutic potential for widely used bile acid sequestrants in enteric bacterial infections.

Regulation of Bile Acid Synthesis by Fat-soluble Vitamins A and D

Bile acids are required for proper absorption of dietary lipids, including fat-soluble vitamins. Here, we show that the dietary vitamins A and D inhibit bile acid synthesis by repressing hepatic expression of the rate-limiting enzyme CYP7A1. Receptors for vitamin A and D induced expression of Fgf15, an intestine-derived hormone that acts on liver to inhibit Cyp7a1. These effects were mediated through distinct cis-acting response elements in the promoter and intron of Fgf15. Interestingly, transactivation of both response elements appears to be required to maintain basal Fgf15 expression levels in vivo. Furthermore, whereas induction of Fgf15 by vitamin D is mediated through its receptor, the induction of Fgf15 by vitamin A is mediated through the retinoid X receptor/farnesoid X receptor heterodimer and is independent of bile acids, suggesting that this heterodimer functions as a distinct dietary vitamin A sensor. Notably, vitamin A treatment reversed the effects of the bile acid sequestrant cholestyramine on Fgf15, Shp, and Cyp7a1 expression, suggesting a potential therapeutic benefit of vitamin A under conditions of bile acid malabsorption. These results reveal an unexpected link between the intake of fat-soluble vitamins A and D and bile acid metabolism, which may have evolved as a means for these dietary vitamins to regulate their own absorption.

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.

Fluvastatin in familial hypercholesterolemia: A cohort analysis of the response to combination treatment

A recent randomized, double-blind, double-dummy trial revealed differences in the response of patients with heterozygous familial hypercholesterolemia to combination therapy with the new, wholly synthetic 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor fluvastatin, 20 mg/day and then 40 mg/day, plus the fibric acid analogue bezafibrate, 400 mg/day, vs combination therapy wtth fluvastatin, 40 mg/day, plus the bile acid sequestrant (resin) cholestyramine, 8 g/day. The main purpose of the present cohort analysis was to determine whether these differences in lipid response were related to imbalances in the patients' prior responses to up to 42 weeks of fluvastatin monotherapy, 20 mg/day, 40 mg/day, and, in some patients, 60 mg/day, in 2 earlier studies. For the present analysis, we identified 18 patients in the fluvastatin plus bezafibrate group (cohort 1) and 16 patients in the fluvastatin plus cholestyramine group (cohort 2) for whom complete dose-response data were available for the full 56-week duration of all 3 studies. Subsets of 7 patients in cohort 1 and 8 patients in cohort 2 had received the 60 mg/day fluvastatin dose during a previous monotherapy study. In cohort 1, low density lipoprotein cholesterol (LDL-C) decreased by 19% with 20 mg/day fluvastatin, by 27% with 40 mg/day fluvastatin, by 31% with 20 mg/day fluvastatin plus bezafibrate, and by 35% with 40 mg/day fluvastatin plus bezafibrate, and the LDL-C/high density lipoprotein cholesterol (HDL-C) ratio had fallen by 46% at the end of combination therapy. In cohort 2, LDL-C declined by 19% with 20 mg/day fluvastatin, by 23% with 40 mg/day fluvastatin, and by 31% with fluvastatin plus cholestyramine, and the LDL-C HDL-C ratio was lowered by 38% at the combination therapy endpoint. Thus, the LDL-C response was similar in both cohorts, except for the enhancement of the effect on the LDL-C HDL-C ratio seen with the combination of fluvastatin plus bezafibrate, compared with the combination of fluvastatin plus cholestyramine. That is, the addition of either bezafibrate or cholestyramine lowered LDL-C levels by an additional 9–10% relative to the decreases achieved with 40 mg/day fluvastatin alone. According to the findings of the cohort analysis, some of the differences in efficacy observed between the 2 combination regimens were related to prior response to monotherapy, which, in turn, may have reflected patient gender and/or compliance with therapy. No clinically meaningful abnormalities in aspartate aminotransferase, alanine aminotransferase, or creatine kinase levels were noted with either combination regimen, which suggests that the regimens were equally safe. Although both combinations were effective, fluvastatin plus bezafibrate appeared to be superior, since it lowered triglyceride levels by 24%, in contrast to the 8% increase seen with fluvastatin plus cholestyramine. We conclude that the combination of fluvastatin with bezafibrate is a good alternative for the treatment of severe familial hypercholesterolomia when a fluvastatin-resin combination is poorly tolerated and/or does not achieve goal lipid levels. However, careful monitoring is recommended in light of reports of the development of myopathy and rhabdomyolysis with the use of fibrates alone or in combination with other fungally derived HMG-CoA reductase inhibitors.

Cost-effectiveness of drug therapy for hypercholesterolaemia: a review of the literature.

In this article we review published studies of the cost-effectiveness of drug therapy for hypercholesterolaemia to take stock of the principal findings that have been reported to date. We identified 9 studies that met all criteria for inclusion in our review, including 3 of bile-acid sequestrants (cholestyramine, colestipol), 2 of HMG-CoA reductase inhibitor (lovastatin), and 4 that considered both an HMG-CoA reductase inhibitor (simvastatin) and a bile-acid sequestrant (cholestyramine). While these studies were largely consistent in methodological approach, some differences were noted in the costs attributed to drug therapy. The cost-effectiveness of therapy with bile-acid sequestrants was found to range from $100 000 to $209 000 per year of life saved (1991 $US) for middle-aged men (42 to 55 years of age) with moderately high cholesterol levels (280 to 290 mg/dl) and otherwise average coronary risk characteristics. Corresponding cost-effectiveness ratios that have been reported for lovastatin range from $64 000 to $82 000, while those for simvastatin range from $45 000 to $65 000. Studies to date therefore suggest that therapy with HMG-CoA reductase inhibitors (i.e. lovastatin and simvastatin) is substantially more cost-effective than treatment with bile-acid sequestrants.