Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review.Abstract: Bile acid sequestrants The bile acid sequestrants are a group of medications used for binding certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut. (BAS BAS
1. Bachelor of Agricultural Science
2. Bachelor of Applied Science ) continue to command a position in the treatment of dyslipidemias 25 years after their introduction. Partial diversion of the enterohepatic circulation en·ter·o·he·pat·ic circulation
Circulation of substances such as bile salts, which are absorbed from the intestine and carried to the liver, where they are secreted into the bile and again enter the intestine. using BAS depletes the endogenous bile acid bile acid /bile ac·id/ (bil as´id) any of the steroid acids derived from cholesterol; classified as primary, those synthesized in the liver, e.g. pool by approximately 40%, thus stimulating an increase in bile acid synthesis from cholesterol, which lowers low-density lipoprotein cholesterol low-density lipoprotein cholesterol (lōˈ-denˑ·s (LDL-C LDL-C low-density-lipoprotein cholesterol ) by 15 to 26%. Three BAS are currently used for treating hypercholesterolemia Hypercholesterolemia Definition
Hypercholesterolemia refers to levels of cholesterol in the blood that are higher than normal.
Cholesterol circulates in the blood stream. It is an essential molecule for the human body. in the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. : the conventional sequestrants, cholestyramine cholestyramine /cho·le·sty·ra·mine/ (ko?le-sti´rah-men) see cholestyramine resin, under resin.
n. and colestipol, and the specifically engineered BAS, colesevelam hydrochloride colesevelam hydrochloride
Pharmacologic class: Bile acid sequestrant
Therapeutic class: Antihyperlipidemic
Pregnancy risk category B
Action(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 sequestration
In law, a writ authorizing a law-enforcement official to take into custody the property of a defendant in order to enforce a judgment or to preserve the property until a judgment is rendered. . 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 Statins
A class of drugs commonly used to lower LDL cholesterol levels.
Mentioned in: C-Reactive Protein , is becoming increasingly common due to complementary mechanisms of action. Low-dose statin stat·in
Any of a class of drugs that inhibit a key enzyme involved in the synthesis of cholesterol and promote receptor binding of LDL cholesterol, resulting in decreased levels of serum cholesterol. 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 niacin: see coenzyme; vitamin.
or nicotinic acid or vitamin B3
Water-soluble vitamin of the vitamin B complex, essential to growth and health in animals, including humans. , fibrates, and cholesterol absorption inhibitors Cholesterol absorption inhibitors are a class of compounds that prevents the uptake of cholesterol from the small intestine into the circulatory system. How They Work
There are two sources of cholesterol in the upper intestine: dietary (from food) and biliary (from bile). , may be useful in those patients who require intensive lipid-lowering, but are statin intolerant. BAS treatment can significantly reduce coronary artery disease coronary artery disease, condition that results when the coronary arteries are narrowed or occluded, most commonly by atherosclerotic deposits of fibrous and fatty tissue. (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 type 2 diabetes
See diabetes mellitus. .
Key Words: bile acid sequestrant, dyslipidemia, cholesterol, lipid-lowering, low density lipoprotein Low density lipoprotein (LDL)
A fraction of total serum lipids, the so called "bad" cholesterol.
Mentioned in: Hypercholesterolemia cholesterol (LDL-C), combination drug therapy, colesevelam HCl., cholestryamine, colestipol
Purpose and Rationale
The purpose of this review is to summarize how 25 years of controlled clinical trials controlled clinical trial,
n a research strategy that calls for two samples: an experimental sample of patients receiving a pharmaceutical, and a second sample of control patients receiving a placebo. of bile acid sequestrants (BAS) have established this drug class to safely and effectively treat hypercholesterolemia as part of both monotherapy and combination therapy, to reduce the risk of coronary artery disease (CAD), and to slow progression and induce regression of atherosclerosis atherosclerosis (ăth'ərōsklərō`sĭs): see arteriosclerosis.
or hardening of the arteries . As the only nonsystemic lipid-lowering agents, BAS also have a demonstrated safety record. In addition a newer, specifically engineered BAS may have greater potency, limited binding of comedications due to selective absorption, and lower incidence of gastrointestinal side effects Side effects
Effects of a proposed project on other parts of the firm. compared with older BAS. The practicing clinician should find that the data presented here support the use of BAS in patients with hypercholesterolemia.
Cholesterol and CAD
Maintaining cholesterol homeostasis homeostasis
Any self-regulating process by which a biological or mechanical system maintains stability while adjusting to changing conditions. Systems in dynamic equilibrium reach a balance in which internal change continuously compensates for external change in a feedback is critical because it plays a role in the synthesis of biologic membranes, steroid hormones, vitamin D vitamin D
Any of a group of fat-soluble alcohols important in calcium metabolism in animals to form strong bones and teeth and prevent rickets and osteoporosis. It is formed by ultraviolet radiation (sunlight) of sterols (see steroid) present in the skin. , and bile acids (BA). The cholesterol pool in a normal human is approximately 100 to 140 g; of this, about 10% is found in the circulation, with the remainder located predominantly in cell membranes. (1,2) Cholesterol balance is maintained by equilibrium between acquisition from de novo synthesis De novo synthesis refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to their being recycled after partial degradation. For example, de novo synthesis of nucleotides is an alternative to the salvage pathway. and dietary intake and loss by BA synthesis and fecal excretion. Preserving this balance avoids cholesterol accumulation in artery walls and the subsequent development of atherosclerosis.
Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipid-lowering therapy, as the link between LDL-C and CAD is well established. The target LDL-C goals are dependent upon a patient's level of CAD risk. For those patients with CAD or a CAD-risk equivalent, the National Cholesterol Education Program The National Cholesterol Education Program is a program managed by the National Heart, Lung and Blood Institute, a division of the National Institutes of Health. Its goal is to reduce increased cardiovascular disease rates due to hypercholesterolemia (elevated cholesterol (NCEP NCEP National Cholesterol Education Program ) recommends that LDL-C be lowered to <100 mg/dL in high-risk persons, but when risk is very high, a goal of <70 mg/dL is a reasonable option. (3) For moderately high-risk persons, an LDL-C goal of <130 mg/dL is recommended, but <100 mg/dL is a therapeutic option. NCEP guidelines encourage lifestyle and dietary modifications to reduce LDL-C, but acknowledge that pharmacological treatment will be necessary for many patients to lower LDL-C to recommended targets. (4)
BA Synthetic Pathway
BA are synthesized from hepatic cholesterol (Fig. 1) and stored in the gallbladder. During digestion, BA are secreted into the small intestine small intestine
Long, narrow, convoluted tube in which most digestion takes place. It extends 22–25 ft (6.7–7.6 m), from the stomach to the large intestine. , where they solubilize sol·u·bi·lize
To make substances such as fats soluble in water by the action of a detergent or similar agent. dietary fats and fat-soluble vitamins Fat-soluble vitamins
Fat-soluble vitamins can be dissolved in oil or in melted fat.
Mentioned in: sub> Deficiency to facilitate their absorption and transport. Enterohepatic circulation in a normal human (Fig. 2A) enables approximately 95% of BA to be reabsorbed in the distal ileum ileum: see intestine.
Final and longest segment of the small intestine. It is the site of absorption of vitamin B12 (see vitamin B complex) and reabsorption of about 90% of conjugated bile salts. and transported back to the liver; this efficient recycling of a small pool of BA (2-4 [g.sup.5]) occurs 5 to 10 times a day. (5-7) Because BA exist as anions at physiologic pH, they require active transporters to cross cell membranes. Several classes of these transporters have been described, including sodium-dependent transporters that mediate BA reabsorption reabsorption /re·ab·sorp·tion/ (re?ab-sorp´shun)
1. the act or process of absorbing again, as the absorption by the kidneys of substances (glucose, proteins, sodium, etc.) already secreted into the renal tubules.
2. from the distal ileum. (8) The 5% of intestinal BA that are not reabsorbed are excreted in feces, but subsequently replenished through de novo [Latin, Anew.] A second time; afresh. A trial or a hearing that is ordered by an appellate court that has reviewed the record of a hearing in a lower court and sent the matter back to the original court for a new trial, as if it had not been previously heard nor decided. BA synthesis. (5) The size of the BA pool is kept relatively constant through feedback inhibition feedback inhibition
Suppression of the activity of an enzyme by a product of the sequence of reactions in which the enzyme is participating. When the product accumulates in a cell beyond an optimal amount, it decreases its own production by inhibiting an enzyme involved in of BA synthesis, and thus interruption of the enterohepatic circulation of BA is able to promptly influence the metabolism of cholesterol. Tight regulation of the BA synthetic pathway is necessary to prevent the accumulation of BA in the body to hepatotoxic hep·a·to·tox·ic
Damaging or destructive to the liver.
causing liver damage. levels and to control the influence of BA on cholesterol metabolism. (6)
[FIGURE 1 OMITTED]
Cholesterol is converted to the two primary bile acids in hepatocytes, including cholic acid cholic acid /cho·lic ac·id/ (kol´ik) one of the primary bile acids in humans, usually occurring conjugated with glycine or taurine; it facilitates fat absorption and cholesterol excretion. (CA) and chenodeoxycholic acid chenodeoxycholic acid /che·no·de·oxy·cho·lic ac·id/ (ke?no-de-ok?se-kol´ik) a primary bile acid, usually conjugated with glycine or taurine; it facilitates fat absorption and cholesterol excretion. (CDCA CDCA Central District of California (US District Court)
CDCA California Desert Conservation Area
CDCA Chenodeoxycholic Acid
CDCA Center for Development in Central America
CDCA Canaan Dog Club of America ), via a cascade of 12 enzymatic reactions. (6,9) Under physiologic pH, BA are conjugated conjugated
estrogens, conjugated Warning - Hazardous drug!
C.E.S. to glycine glycine (glī`sēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Glycine is the only one of these amino acids that is not optically active, i.e. or taurine taurine /tau·rine/ (taw´ren) an oxidized sulfur-containing amine occurring conjugated in the bile, usually as cholyltaurine or chenodeoxycholyltaurine; it may also be a central nervous system neurotransmitter or neuromodulator. and exist in an anionic an·i·on
A negatively charged ion, especially the ion that migrates to an anode in electrolysis.
[From Greek, neuter present participle of anienai, to go up : ana-, ana- salt form. There are 2 pathways whereby BA are synthesized: the classic (or neutral) and the alternative (or acidic) pathway. BA are predominantly synthesized through the classic pathway, which produces CA and CDCA in roughly equal amounts: the initiating, and rate limiting In computer networks, rate limiting is used to control the rate of traffic sent or received on a network interface. Traffic that is less than or equal to the specified rate is sent, whereas traffic that exceeds the rate is dropped or delayed. , enzyme of this pathway is cholesterol 7[alpha]-hydroxylase (CYP CYP
In currencies, this is the abbreviation for the Cyprus Pound.
The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion. 7A1). After excretion into the bile, the primary bile acids CA and CDCA are partly 7[alpha]-dehydroxylated in the intestine by bacterial enzymes to create the secondary bile acids, deoxycholic acid deoxycholic acid /de·oxy·chol·ic ac·id/ (de-ok?se-ko´lik) a secondary bile acid formed from cholic acid in the intestine; it is a choleretic.
n. and lithocholic acid lithocholic acid
the product of bacterial metabolism of bile acids in the intestine. Insoluble and not reabsorbed. , respectively (Fig. 1). The alternative pathway alternative pathway
The activation of complement by direct contact with polysaccharides located on yeast cells, bacteria, or protozoa. It is a nonspecific immune response that does not rely on antibodies or T cells. for BA synthesis produces mainly CDCA and requires the enzyme oxysterol 7[alpha]-hydroxylase (CYP7B1) rather than CYP7A1. Genetic knockout studies of CYP7A1 and CYP7B1 in mice suggest that the classic pathway is more regulated than the alternative pathway. (10)
Several factors may affect BA synthesis. Typically, synthesis is enhanced via transcriptional upregulation of the CYP7A1 gene. (6) However, because HDL-C HDL-C high-density-lipoprotein cholesterol. is the preferred source of cholesterol for BA synthesis, (11-13) enhanced synthesis might also involve an upregulation of reverse cholesterol transport, perhaps via an increase in lecithin lecithin
Any of a class of phospholipids (also called phosphatidyl cholines) important in cell structure and metabolism. They are composed of phosphate, choline, glycerol (as the ester), and two fatty acids. Various fatty acids pairs distinguish the various lecithins. cholesterol acyltransferase (LCAT LCAT lecithin-cholesterol acyltransferase.
lecithin cholesterol acyltransferase
LCAT ) activity. (14) Ultimately, much of the regulation of the BA synthetic pathway occurs through transcription factors, including nuclear hormone receptors.
[FIGURE 2 OMITTED]
Nuclear Hormone Receptors and Their Role in BA and Cholesterol Homeostasis
Recent studies have indicated that BA regulate the transcription of genes involved in their synthesis and cholesterol homeostasis through effects on nuclear hormone receptors. Consequently, these receptors may represent novel therapeutic targets for hypercholesterolemia and provide insight into the BA pathway's role in other metabolic processes.
One nuclear hormone receptor, liver X receptor The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as PPAR, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. (LXR LXR Linux Cross Reference
LXR Luxor, Egypt - Luxor (Airport Code) ), binds another nuclear hormone receptor, retinoid X receptor retinoid X receptor One of 2 receptors for retinoids; RXR plays a key role in organ development, in particular of the skin. Cf Retinoic acid receptor. (RXR RXR Retinoid X Receptor
RXR Resource Exchange Register ); this complex binds oxysterols (early metabolites Metabolites
Substances produced by metabolism or by a metabolic process.
Mentioned in: Interactions of cholesterol), leading to enhanced transcription of CYP7A1. (9,15) The net result is that an increase in cholesterol levels promotes an increase in BA synthesis, suggesting that agonists of LXR might reduce serum cholesterol levels. However, activating LXR may increase triglyceride (TG) levels; thus any successful treatment would have to balance these two effects. One such LXR agonist agonist /ag·o·nist/ (ag´ah-nist)
1. one involved in a struggle or competition.
2. agonistic muscle.
3. , which inhibits atherosclerosis in mice but does not induce hypertriglyceridemia, has been described but has not been tested in humans. (16,17)
The farnesoid X receptor The farnesoid X receptor (FXR) is a nuclear hormone receptor with activity similar to that seen in other steroid receptors such as estrogen or progesterone but more similar in form to PPAR, LXR and RXR. (FXR FXR Fixer
FXR Flash X-Ray
FXR WinFax Pro Filename Extension Fax Received
FXR Harley-Davidson Super Glide motorcycle model ) also binds RXR, but when activated this complex has the opposite effect of LXR/RXR on CYP7A1 transcription. (6,9) Bile acids activate FXR/RXR, which stimulates the negative feedback loop. (18-20) BA-activated FXR also decreases transcription of apolipoprotein apolipoprotein /apo·lipo·pro·tein/ (ap?o-lip?o-pro´ten) any of the protein constituents of lipoproteins, grouped by function in four classes, A, B, C, and E.
n. (Apo) A-1. (21) BA sequestration may decrease FXR activity, thus increasing ApoA-1 levels. Furthermore, these data imply that an antagonist of FXR could increase high-density lipoprotein cholesterol high-density lipoprotein cholesterol See HDL-cholesterol. (HDL-C) via increasing ApoA-1. This theory is supported by data that a naturally occurring FXR antagonist, guggulsterone, can raise serum HDL-C levels in rats. (22)
Nuclear hormone receptors may be affected in patients treated with agents that sequester sequester v. to keep separate or apart. In so-called "high-profile" criminal prosecutions (involving major crimes, events, or persons given wide publicity) the jury is sometimes "sequestered" in a hotel without access to news media, the general public or their BA or otherwise interrupt enterohepatic circulation. It is tempting to speculate that depletion of the BA pool by these agents might decrease the activity of FXR/RXR, which in turn would allow for an increase in CYP7A1 transcription. However, the effects of such agents on FXR/RXR activity have not been studied directly.
Disrupting Enterohepatic Circulation
Interruption of enterohepatic circulation consists of partial diversion of bile, or a constituent of bile, to fecal excretion (Fig. 2B). Four different methods have been used to interrupt enterohepatic circulation, thereby lowering plasma cholesterol levels. Two of these methods are surgical: chronic partial ileal ileal /il·e·al/ (il´e-ahl) pertaining to the ileum.
Of or relating to the ileum.
pertaining to the ileum. bypass and short-duration partial drainage of hepatic bile to outside the body by a T-tube in the bile duct bile duct or biliary duct
Any of the excretory ducts in the liver that convey bile between the liver and the intestine, including the hepatic, cystic, and common bile ducts. Also called gall duct.
1. , and two are medical: BAS and cholesterol absorption inhibitors (CAI (1) (Computer-Assisted Instruction) Same as CBT.
(2) See CA.
CAI - Computer-Aided Instruction ). (1,5,23,24) Substantial reduction of serum cholesterol results from partial diversion of bile out of the body via a T-tube in the bile duct. An average daily loss of 1.5 g of cholic acid (CA) and 300 mg of cholesterol resulted in a decrease in serum total cholesterol (TC) of about 40% in 4 days, with this reduction maintained for up to 11 days of continued drainage. (23) CA was estimated to account for 71.5% of total BA loss. (24) This indicates the potential for similar effects to be obtained by medical interruption of enterohepatic circulation. The medical methods partially duplicate the effects of ileal bypass by diverting only one of the two steroid elements of bile, BA or cholesterol. Disruption of BA enterohepatic circulation by BAS to treat hypercholesterolemia is the focus of this review.
BAS are positively charged Adj. 1. positively charged - having a positive charge; "protons are positive"
charged - of a particle or body or system; having a net amount of positive or negative electric charge; "charged particles"; "a charged battery" indigestible in·di·gest·i·ble
Difficult or impossible to digest: an indigestible meal.
in resins that bind to negatively charged Adj. 1. negatively charged - having a negative charge; "electrons are negative"
charged - of a particle or body or system; having a net amount of positive or negative electric charge; "charged particles"; "a charged battery" BA in the intestinal lumen and are then excreted with bound BA in the feces. BAS disrupt enterohepatic circulation of BA, depleting the endogenous BA pool by approximately 40%. (7) As BA are chronically depleted de·plete
tr.v. de·plet·ed, de·plet·ing, de·pletes
To decrease the fullness of; use up or empty out.
[Latin d , CYP7A1 and hepatic LDL receptors are upregulated, increasing BA synthesis and reducing plasma LDL-C concentrations. (7-25) BAS typically lower LDL-C by 15 to 26% at the maximum approved doses. (26-29) BAS can induce a slight increase (4-8%) in HDL-C levels. (30) ApoA-1, the major lipoprotein lipoprotein (lĭp'əprō`tēn), any organic compound that is composed of both protein and the various fatty substances classed as lipids, including fatty acids and steroids such as cholesterol. constituent of HDL (Hardware Description Language) A language used to describe the functions of an electronic circuit for documentation, simulation or logic synthesis (or all three). Although many proprietary HDLs have been developed, Verilog and VHDL are the major standards. , also increases with BAS treatment. (31) Small increases in TG may occur in patients taking BAS. (32-34)
The available BAS include the conventional sequestrants, cholestyramine and colestipol, and the specifically engineered BAS, colesevelam hydrochloride (HCl) (Table 1).
Cholestyramine is an anion exchange anion exchange
The process by which an anion in a liquid phase exchanges with another anion previously bound to a solid, positively charged phase. resin consisting of trimethylbenzylammonium groups in a long-chain polymer of styrene sty·rene
A colorless oily liquid from which polystyrenes, plastics, and synthetic rubber are produced. Also called vinylbenzene. and divinylbenzene, and colestipol is a long-chain polymer of diethylenetriamine and 1-chloro-2,3-epoxypropane. (35) These 2 agents are typically milled into powders for oral administration as a suspension with water or juice. (35) Colestipol is also formulated as a tablet, of which up to 16 may be administered daily. (33)
Cholestyramine and colestipol have a greater affinity for dihydroxy than for trihydroxy BA and therefore preferably bind to CDCA and deoxycholic acid. (7) Over time, this creates an imbalance in the BA pool, increasing the proportion of trihydroxy BA. (36) This may limit the efficacy of these BAS because, as the hydrophilic hydrophilic /hy·dro·phil·ic/ (-fil´ik) readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water.
adj. content of the BA pool increases, there are fewer BA for these agents to sequester.
Colesevelam HCl is a polyallylamine cross-linked with epichlorohydrin ep·i·chlo·ro·hy·drin
A colorless liquid, C3H5OCl, used as a solvent in making resins. and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide bromide, any of a group of compounds that contain bromine and a more electropositive element or radical. Bromides are formed by the reaction of bromine or a bromide with another substance; they are widely distributed in nature. . (37,38) Unlike the conventional BAS, the backbone of colesevelam HCl was specifically engineered to contain long hydrophobic hydrophobic /hy·dro·pho·bic/ (-fo´bik)
1. pertaining to hydrophobia (rabies).
2. not readily absorbing water, or being adversely affected by water.
3. side chains, which maximize hydrophobic interactions with BA, thus enhancing affinity, specificity and capacity compared with conventional BAS (Fig. 3). (37,39) Colesevelam HCl binds BA via both hydrophobic interactions and ionic bonding ionic bonding (ī·nˑ·ik b with primary amines, while quaternary quaternary /qua·ter·nary/ (kwah´ter-nar?e)
1. fourth in order.
2. containing four elements or groups.
1. Consisting of four; in fours. amine amine (əmēn`, ăm`ēn): see under amino group.
Any of a class of nitrogen-containing organic compounds derived, either in principle or in practice, from ammonia (NH3). side chains stabilize the structure. (37) Thus, a larger number of BA can bind to, and remain bound by, the colesevelam HCl polymer, allowing for an increase in fecal excretion of BA per dose. Colesevelam HCl binds to both dihydroxy and trihydroxy BA (30,36) and binds CA with greater affinity than cholestyramine or colestipol in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment.
In an artificial environment outside a living organism. . (39) Thus, colesevelam HCl should not result in an imbalance in the BA profile, nor should it be subject to the reduced efficacy seen over time with cholestyramine and colestipol.
Safety and Tolerability of BAS
To determine the safety of BAS therapy, a review of the published literature and the prescribing information for each BAS was conducted. In February 2005, the PubMed database was searched using the terms BA sequestrants, BA resins, BA binding, cholestyramine, colestipol, and colesevelam, in conjunction with the terms safety, adverse events, adverse effects, and side effects. In addition, these terms were used to search Reactions Weekly, which includes published case reports, incidence, and clinical studies discussing adverse events (January 2000-February 2005).
The large molecular size of BAS preparations prevents them from being absorbed by the intestinal mucosa, which leads to fewer systemic adverse effects. (7,35,40) The major adverse effects reported with conventional BAS are gastrointestinal, including constipation and flatulence flatulence /flat·u·lence/ (flat´u-lens) excessive formation of gases in the stomach or intestine.
flat·u·lence or flat·u·len·cy
The presence of excessive gas in the digestive tract. . For example, in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), 39% of cholestyramine-treated patients reported moderate-to-severe constipation, versus 10% of placebo-treated patients. (26) In addition, titration titration (tītrā`shən), gradual addition of an acidic solution to a basic solution or vice versa (see acids and bases); titrations are used to determine the concentration of acids or bases in solution. of cholestyramine to higher doses (>8 g/d) to enhance lipid-lowering may further increase adverse effects and decrease compliance. (41,42) Adverse effects, as well as complicated dosing schedules and poor palatability, result in discontinuation dis·con·tin·u·a·tion
A cessation; a discontinuance.
Noun 1. discontinuation - the act of discontinuing or breaking off; an interruption (temporary or permanent)
discontinuance rates of 40 to 60% for patients taking conventional BAS. (26,43,44)
Because of its enhanced BA binding, colesevelam HCl can be administered at lower doses than cholestyramine and colestipol, thus reducing adverse effects. (28,29,37) However, constipation and dyspepsia dyspepsia: see indigestion. are reported in more patients taking colesevelam HCl versus placebo (11% versus 7% and 8% versus 3% for constipation and dyspepsia, respectively). (32) Although the lower incidence of gastrointestinal adverse effects for colesevelam HCl may increase patient compliance and adherence to therapy as compared with cholestyramine and colestipol, this has not been studied directly.
[FIGURE 3 OMITTED]
Effects on intestinal mucosa and tumorigenesis tumorigenesis /tu·mor·i·gen·e·sis/ (-jen´e-sis) oncogenesis.
Formation or production of tumors.
Cholestyramine and colestipol treatment caused disruptive changes in colonic morphology in rats, (45) and cholestyramine increased the number of colon tumors in rats also receiving carcinogen carcinogen: see cancer.
Agent that can cause cancer. Exposure to one or more carcinogens, including certain chemicals, radiation, and certain viruses, can initiate cancer under conditions not completely understood. . (46) However, clinical experience indicates that even if similar changes occur in humans, they do not lead to increases in tumorigenesis with long-term use of these BAS. (33,34) Cholestyramine treatment did not cause an excess of gastrointestinal tumors during the 10-year duration of the LRC-CPPT trial (26) or in the 6 years of follow-up. (47) Colesevelam HCl did not increase tumorigenesis in mice at doses up to 3 g/kg/d (approximately 50 times the maximum recommended daily dose for humans); however, in rats, an increase in the incidence of pancreatic acinar cell acinar cell
A secreting cell lining an acinus, especially one of the cells of the pancreas that furnish pancreatic juice. Also called acinous cell. adenoma adenoma: see neoplasm. was seen at doses approximately 20 times the maximum recommended daily dose for humans with no differences in colon tumorigenesis observed. (32)
Drug interactions and effects on bioavailability bioavailability /bio·avail·a·bil·i·ty/ (bi?o-ah-val?ah-bil´i-te) the degree to which a drug or other substance becomes available to the target tissue after administration.
Because BAS are not metabolized, there are no incidences of systemic drug-drug interactions. However, BAS are positively charged and therefore may nonspecifically bind to coadministered drugs, particularly those that are acidic, and thus reduce the bioavailability of these drugs.
BAS, in reducing the intestinal content of BA, may impair the solubilization and absorption of fat-soluble substances, including fat-soluble vitamins. (35) Therefore, it is recommended that these vitamins be supplemented in patients receiving long-term BAS therapy. Decreases in vitamin absorption may occur to a lesser extent in patients treated with colesevelam HCl compared with the conventional BAS, as one study found that colesevelam HCl did not significantly change serum levels of vitamins A and E. (29)
Cholestyramine can affect the bioavailability of coad-ministered drugs; valproic acid valproic acid /val·pro·ic ac·id/ (-ik) an anticonvulsant used particularly for the control of absence seizures.
An anticonvulsive drug used to treat seizure disorders. , warfarin warfarin (wôr`fərĭn), anticoagulant used to treat blood clots. In large doses it causes bleeding. Warfarin, mixed with bait, is used in rodent control.
Anticoagulant drug, marketed as Coumadin. , cardiac glycosides cardiac glycosides,
n.pl steroidal phytochemicals that have a history of use as cardiac medicines, including digitalis and lily of the valley. Not recommended for use without physician guidance. Also called
cardioactive glycosides. (eg, digoxin digoxin: see digitalis. ), quinidine quinidine (kwĭn`ĭdēn'), heart muscle relaxant used to maintain regular heart rhythm patterns. It is an alkaloid chemically similar to quinine and, like quinine, occurs naturally in some species of cinchona trees. , glipizide, thiazide diuretics, propranolol propranolol /pro·pran·o·lol/ (-pran´o-lol) a ß, used as the hydrochloride salt in the treatment and prophylaxis of certain cardiac disorders, the treatment of tremors and of inoperable pheochromocytoma, and the prophylaxis of migraine. , phenobarbital phenobarbital /phe·no·bar·bi·tal/ (fe?no-bahr´bi-tal) a long-acting barbiturate, used as the base or sodium salt as a sedative, hypnotic, and anticonvulsant.
n. , penicillin G penicillin G
The most commonly used penicillin compound, used primarily in the form of its stable salts. Also called benzylpenicillin. , estrogens Estrogens
Hormones produced by the ovaries, the female sex glands.
Mentioned in: Acne, Polycystic Ovary Syndrome
n. , progestins Progestins
A female hormone, like progesterone, that acts on the inner lining of the uterus.
Mentioned in: Anabolic Steroid Use, Endometrial Cancer , and phenylbutazone phenylbutazone /phen·yl·bu·ta·zone/ (-bu´tah-zon) a nonsteroidal antiinflammatory drug used in the short-term treatment of severe rheumatoid disorders unresponsive to less toxic agents. have been reported. (34,48-50) Similarly, interactions of colestipol with gemfibrozil, propranolol, furosemide furosemide /fu·ro·sem·ide/ (fu-ro´se-mid) a loop diuretic used in the treatment of edema and hypertension.
A white to yellow crystalline powder used as a diuretic. , tetracycline tetracycline (tĕ'trəsī`klēn), any of a group of antibiotics produced by bacteria of the genus Streptomyces. They are effective against a wide range of Gram positive and Gram negative bacteria, interfering with protein , and penicillin G have been reported. (33) Colestipol has also been reported to interfere with absorption of thiazide diuretics, but to a lesser extent than cholestyramine. (51) Absorption of digoxin is not affected by colestipol. (52) Fewer interactions of colestipol with some coad-ministered drugs, as compared with cholestyramine, may occur because cholestyramine is more highly charged.
Colesevelam HCl, unlike cholestyramine, did not decrease the absorption of valproic acid or the common cardiovascular agents warfarin, digoxin, and quinidine. (53) In addition, colesevelam HCl did not affect the bioavailability of metoprolol metoprolol /met·o·pro·lol/ (met?ah-pro´lol) a cardioselective ß used in the form of the succinate and tartrate salts in the treatment of hypertension, chronic angina pectoris, and myocardial infarction. . (53) Coadministration of colesevelam HCl with sustained-release (SR) verapamil verapamil /ve·rap·a·mil/ (ve-rap´ah-mil) a calcium channel blocker that dilates coronary arteries and decreases myocardial oxygen demand, used as the hydrochloride salt in the treatment of angina pectoris and of hypertension and the reduced the [C.sub.max] and AU[C.sub.(0-[infinity])] of SR verapamil by 31% and 11%, respectively. (53) However, the clinical significance of this finding is unclear because even in the absence of colesevelam HCl, significant inter-individual variability in SR verapamil pharmacokinetic properties is observed. (53)
Colesevelam HCl's apparent lack of effect on the bioavailability of coadministered agents is an important consideration when using combination therapies. Colesevelam HCl does not adversely affect the pharmacokinetics of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase reductase /re·duc·tase/ (-tas) a term used in the names of some of the oxidoreductases, usually specifically those catalyzing reactions important solely for reduction of a metabolite. inhibitor lovastatin lovastatin /lo·va·stat·in/ (lo´vah-stat?in) an antihyperlipidemic agent that acts by inhibiting cholesterol synthesis, used in the treatment of hypercholesterolemia and other forms of dyslipidemia and to lower the risks associated with , which is frequently administered in combination with colesevelam HCl to additively lower LDL-C. (54) In addition, colesevelam HCl, when administered either concomitantly or 4 hours following fenofibrate, had no significant effect on the bioavailability of fenofibrate. Furthermore, when the two drugs were coadministered, colesevelam HCl did not significantly affect the total drug exposure as measured by the AU[C.sub.(0-t)] and AU[C.sub.(0-[infinity])] of fenofibric acid. (55) Interactions of colesevelam HCl with other drugs have not been studied.
Contraindications and precautions
BAS are contraindicated in patients with bowel obstruction Bowel obstruction
A blockage in the intestine which prevents the normal flow of waste down the length of the intestine.
Mentioned in: Anal Atresia, Diverticulosis and Diverticulitis
bowel obstruction . Because BAS may modestly increase TG levels and have not been studied in patients with significantly elevated TG levels (>300 mg/dL), they should not be used in these patients or in those with familial abetalipoproteinemia or genetic hypobetalipoproteinemia.
BAS should only be used in pregnant women if clearly needed; cholestyramine and colestipol carry a pregnancy category C Pregnancy category C
No adequate human or animal studies; or adverse fetal effects in animal studies, but no available human data.
Mentioned in: Antianxiety Drugs rating, and colesevelam HCl carries a more favorable pregnancy category B Pregnancy category B
Animal studies indicate no fetal risk, but no human studies; or adverse effects in animals, but not in well-controlled human studies.
Mentioned in: Antianxiety Drugs rating. Colesevelam HCl administered at approximately 30 times the approved dose did not show any significant adverse reproductive or fertility effects in rats. (56) In addition, colesevelam HCl did not lead to developmental toxicity in rats or rabbits or in pre- or postnatal postnatal /post·na·tal/ (-na´t'l) occurring after birth, with reference to the newborn.
Of or occurring after birth, especially in the period immediately after birth. toxicity in rats. (57)
Efficacy of BAS Therapy
Controlled clinical trials have evaluated the efficacy of BAS for both lipid alterations and atherosclerotic regression.
Monotherapy with BAS: lipid effects
BAS monotherapy has been used to treat hypercholesterolemia since the 1960s. (58-60) All BAS are indicated as first-line therapy for primary hypercholesterolemia and lower LDL-C by 15 to 26%. (26-29) with maximum effects observed within 2 weeks. (35) Following discontinuation of BAS treatment, cholesterol levels typically return to pretreatment pretreatment,
n the protocols required before beginning therapy, usually of a diagnostic nature; before treatment.
n See predetermination. levels within a month, without a transitory rebound to higher levels. (35) Studies employing BAS monotherapy are summarized in Table 2.
Two trials of the effects of cholestyramine therapy conducted in the 1970s, the LRC-CPPT study (26,61) and the National Heart, Lung, and Blood Institute National Heart, Lung, and Blood Institute,
n.pr established in 1948, this division of the National Institutes of Health is responsible for research and education on cardiovascular, pulmonary, systemic diseases, and sleep disorders. (NHLBI NHLBI,
n.pr See National Heart, Lung, and Blood Institute. ) Type II Coronary Intervention Study, (27,62) demonstrated that BAS significantly lowered TC and LDL-C.
LRC-CPPT was a double-blind, placebo-controlled trial of the effects of cholestyramine on the prevention of CAD in 3,806 men with primary hypercholesterolemia. (26, 61) Cholestyramine treatment reduced TC and LDL-C by 13.4% and 20.3%, respectively, which was 8.5% and 12.6% greater than the reductions with placebo (P < 0.001). The aforementioned data are for all enrolled patients; however, some patients took less cholestyramine than the prescribed 24 g/d. When specific dosages were analyzed, a dose response was observed for both TC and LDL-C lowering.
The NHLBI Type II Coronary Intervention Study treated 143 patients with cholestyramine or placebo and found that cholestyramine treatment reduced LDL-C by 26% versus 5% with placebo (P < 0.001). (27,62) Although HDL-C levels increased slightly with cholestyramine, the difference was not significant versus placebo. TG levels increased in both groups, with no significant difference between treatments.
The development of the specifically engineered BAS colesevelam HCl provoked further studies of the effects of BAS on lipid levels. A double-blind placebo-controlled study with colesevelam HCl (1.5, 2.25, 3.0, or 3.75 g/d) was conducted in 137 patients for 6 weeks. (28) Colesevelam HCl decreased LDL-C levels dose-dependently by up to 19% (P < 0.001 versus baseline). At the 2 highest doses, colesevelam HCl also significantly increased HDL-C by 8 to 9%. No significant changes were observed in TG levels in any treatment group.
Another double-blind study double-blind study,
n experimental technique in clinical research in which neither the researcher nor the patient knows whether the treatment administered is considered inactive (placebo) or active (medicinal). compared colesevelam HCl (2.3, 3.0, 3.8, or 4.5 g/d) and placebo for 24 weeks in 494 patients with primary hypercholesterolemia. (29) Colesevelam HCl decreased LDL-C levels by 18% at the highest dose; all doses reduced LDL-C significantly more than placebo (P < 0.001). LDL-C reductions were achieved within 2 weeks and sustained over the 6 months of treatment. A 3 to 4% increase in HDL-C was observed; although this was significantly better versus baseline or placebo, it is a smaller increase than was observed by Davidson and colleagues. (28) This may be due to differences in study design and patient populations. ApoB levels also decreased in a dose-dependent manner in response to colesevelam HCl. Although TG levels increased relative to baseline in all groups, none of the increases were statistically significant versus placebo.
Small, dense LDL LDL - ["LDL: A Logic-Based Data-Language", S. Tsur et al, Proc VLDB 1986, Kyoto Japan, Aug 1986, pp.33-41]. particles are emerging as a risk factor for CAD, (63) and colestipol has been shown to reduce LDL particle size Particle size, also called grain size, refers to the diameter of individual grains of sediment, or the lithified particles in clastic rocks. The term may also be applied to other granular materials. , creating more atherogenic ath·er·o·gen·ic
Initiating, increasing, or accelerating atherogenesis.
atherogenic adjective Referring to the ability to initiate or accelerate atherogenesis—the deposition of atheromas, lipids, and particles. (64) Therefore, the effect of colesevelam HCl on LDL particle size was examined. (65) Colesevelam HCl 3.0 and 3.75 g/d reduced LDL particle number The particle number, N, is the number of so called 'elementary particles' (or elementary constituents) in a thermodynamical system. The particle number is a fundamental parameter in thermodynamics and it is conjugate to the chemical potential. by 6.8% and 13.7%, respectively (P < 0.05 versus baseline). Furthermore, colesevelam HCl 3.75 g/d increased LDL particle size by 1.1% (P < 0.05 versus baseline).
Combination therapy with BAS: lipid effects
Combination therapy is being used more widely because of more stringent recommendations for lowering LDL-C, especially in high-risk patients, (4) and the recognition that improvements in HDL-C and TG are also important. (66) Ideal combinations will provide additive or synergistic efficacy with complementary mechanisms of action, safety profiles similar to or better than each drug as monotherapy, and no adverse drug-drug interactions.
BAS and statin combinations. Although statins (HMG-CoA reductase Noun 1. HMG-CoA reductase - a liver enzyme that is responsible for producing cholesterol
5-hydroxy-3-methylglutaryl-coenzyme A reductase
reductase - an enzyme that catalyses the biochemical reduction of some specified substance inhibitors) are currently the most prescribed lipid-lowering therapy, titration to higher doses typically results in only small additional LDL-C lowering: with each doubling of the statin dose, LDL-C levels fall by an additional 6%. (4) Statin use can be associated with muscle toxicity, including myopathy myopathy /my·op·a·thy/ (mi-op´ah-the) any disease of muscle.myopath´ic
centronuclear myopathy myotubular m. and rhabdomyolysis rhabdomyolysis /rhab·do·my·ol·y·sis/ (-mi-ol´i-sis) disintegration of striated muscle fibers with excretion of myoglobin in the urine.
n. , which is more likely to occur at higher doses. (67) Thus, patients who require more aggressive lipid-lowering can benefit from combination therapy. Because HMG-CoA reductase is upregulated in response to depletion of BA, blocking this enzyme with a statin results in complementary and additive effects on the lipid profile lipid profile,
n a series of tests used to gauge a person's risk for coro-nary heart conditions. Blood levels examined in a lipid profile include those for total cholesterol, LDL- and HDL-cholesterol, and triglycerides. . Thus, a BAS and statin combination is particularly efficacious. Numerous clinical studies have examined this combination (Table 3).
Combination therapy with cholestyramine and pravastatin pravastatin /prav·a·stat·in/ (prav´ah-stat?in) an antihyperlipidemic agent that acts by inhibiting cholesterol synthesis, used as the sodium salt in the treatment of hypercholesterolemia and other forms of dyslipidemia and to lower the or fluvastatin fluvastatin /flu·va·stat·in/ (floo´vah-stat?in) an inhibitor of cholesterol biosynthesis used as the sodium salt in the treatment of hyperlipidemia and to slow the progression of atherosclerosis associated with coronary heart disease. has additive effects on LDL-C and TC lowering, compared with either drug alone. (42,68,69) Pan and colleagues found that pravastatin (5, 10, or 20 mg twice daily) plus cholestyramine (24 g/d) reduced LDL-C by 47 to 56% and increased HDL-C by 11 to 18%. (69) Another study showed that pravastatin (20 mg twice daily) combined with cholestyramine (24 g/d) reduced LDL-C levels by 51%. (68) HDL-C levels in this study increased by 5%, regardless of the treatment group. Furthermore, a pharmacoeconomic study reported that treatment with pravastatin 20 mg/d plus cholestyramine 10 g/d had greater efficacy in lowering LDL-C and was more cost-effective than monotherapy with pravastatin 20 or 40 mg/d. (70) Analogous to the pravastatin studies, low-dose fluvastatin plus cholestyramine reduced LDL-C, more than doubling the fluvastatin dose. (42)
All 3 BAS have been studied in combination with lovastatin. (71-74) Lovastatin 20 mg/d plus colestipol 10 g/d produced greater reductions in LDL-C than did high-dose lovastatin (40 mg/d) monotherapy. (73) Moreover, low-dose combinations were more than 25% more cost-effective than high-dose statin monotherapy. Another low-dose combination, lovastatin 5 mg/d plus cholestyramine 8 g/d, lowered LDL-C to a similar extent compared with lovastatin 20 mg/d monotherapy. (74) A 4-week placebo-controlled study in 135 patients compared low-dose colesevelam HCl (2.3 g/d) and lovastatin (10 mg/d) alone and in combination and found that the combination reduced LDL-C levels by 32 to 34%, a significantly greater reduction than seen with either therapy alone (P < 0.05), (71) and equivalent to the standard statin dose response. (3)
Low-dose colestipol (5-10 g/d) plus simvastatin simvastatin /sim·va·stat·in/ (sim´vah-stat?in) an antihyperlipidemic agent that acts by inhibiting cholesterol synthesis, used in the treatment of hypercholesterolemia and other forms of dyslipidemia and to lower the risks associated (20-40 mg/d) reduced LDL-C by 45 to 50%, a significantly greater reduction than with either therapy alone. (75) Similarly, colesevelam HCl (2.3 or 3.8 g/d) plus simvastatin (20 or 10 mg/d) reduced LDL-C by 42%, which was more than with either agent alone. (76)
Colesevelam HCl (3.8 g/d) plus low-dose atorvastatin atorvastatin /ator·va·stat·in/ (ah-tor?vah-stat´in) an antihyperlipidemic agent that acts by inhibiting cholesterol synthesis, used as the calcium salt in the treatment of hypercholesterolemia and other forms of dyslipidemia. (10 mg/d) lowered LDL-C by 48%, which was greater than the reductions observed with either therapy alone (12% with colesevelam HCl and 38% with atorvastatin; P < 0.01), and similar to reductions achieved with high-dose atorvastatin (80 mg/d; 53% reduction). (77) ApoB decreases mirrored those seen with LDL-C. Interestingly, ApoA-1 levels increased significantly from baseline in response to combination therapy or colesevelam HCl alone, but not with atorvastatin monotherapy.
In summary, BAS have been studied in combination with several statins, and these combinations consistently appear to have additive efficacy. Generally, low-dose combinations lead to greater or similar LDL-C reductions compared with high-dose statin monotherapy and are safe and well tolerated.
BAS and nonstatin combinations. Combinations of BAS and nonstatin lipid-lowering agents may be useful in those patients who require intensive lipid lowering but have a contraindication contraindication /con·tra·in·di·ca·tion/ (-in?di-ka´shun) any condition which renders a particular line of treatment improper or undesirable.
n. to statins, are statin intolerant, or refuse statin therapy.
The combination of a BAS (cholestyramine or colestipol) and niacin appears to be safe and effective for lowering LDL-C by approximately 20 to 40% and increasing HDL-C by up to 40%. (78-82) Thus, this combination may be especially useful in patients who also require an increase in HDL-C. To date, no studies using colesevelam HCl plus niacin have been published.
Studies with BAS and fibrates show that, in general, the combination effectively reduces LDL-C and TG but may be less reliable for increasing HDL-C. (83-89) For example, colesevelam HCl plus fenofibrate decreased LDL-C and TG by 17% and 32%, respectively, and increased HDL-C by 12%. (89)
Another strategy may be to combine a BAS with a cholesterol absorption inhibitor (CAI), such as ezetimibe. (1) One study assessed the additive effects of ezetimibe and a BAS by performing a chart review of patients in whom ezetimibe was added to a BAS-based regimen. (90) The addition of ezetimibe further reduced TC, LDL-C, and TG by 18%, 19%, and 14%, respectively. Another study found that ezetimibe plus colesevelam HCl reduced LDL-C by 37 to 41% in patients who were intolerant to or refused statin therapy. (91) Further studies are needed to determine whether the combination of a BAS and a CAI is additive or synergistic.
Morbidity, mortality, and plaque regression trials with BAS
The ultimate test of the efficacy of BAS has come from studies designed to determine whether BAS, alone or in combination with other lipid-lowering therapies, can reduce cardiovascular outcomes, slow plaque progression, or induce plaque regression (Table 4).
One of the earliest trials to study the effects of BAS on CAD outcomes was reported by Dorr and colleagues in 1978. (92) This early trial had limitations (93) but indicated that colestipol treatment was safe and effectively reduced CAD outcomes.
LRC-CPPT, which compared cardiovascular outcomes in 3,806 men treated double-blind with BAS or placebo, was one of the first large studies to definitively associate a reduction in LDL-C with a reduction in CAD risk. Patients treated for a mean of 7.4 years with cholestyramine had a 19% reduction in CAD risk (P < 0.05 compared with placebo) (26) that was associated with a 13% decrease in LDL-C and TC levels. (61) Follow-up for 6 years posttrial indicated that the reduction of CAD risk was attenuated Attenuated
Alive but weakened; an attenuated microorganism can no longer produce disease.
Mentioned in: Tuberculin Skin Test
having undergone a process of attenuation. after cessation of treatment, suggesting that active lipid-lowering therapy should be continued to maintain improvement in cardiovascular outcomes. (47) In addition, adverse events did not significantly increase with 6 years of follow-up.
The NHLBI Type II Coronary Intervention Study evaluated the effects of cholestyramine versus placebo on the progression of CAD as assessed by coronary angiography coronary angiography Interventional cardiology A diagnostic technique in which a radiocontrast is injected directly into the coronary arteries, allowing visualization and quantification of stenosis and/or obstruction. after 5 years of treatment in 116 patients. (27) LDL-C levels were reduced by 26% with cholestyramine and 5% with placebo (P < 0.001). Overall, CAD progressed in 49% of placebo-treated patients versus 32% of cholestyramine-treated patients (P < 0.05). When evaluating lesions causing 50% or greater stenosis stenosis /ste·no·sis/ (ste-no´sis) pl. steno´ses [Gr.] stricture; an abnormal narrowing or contraction of a duct or canal. at baseline, lesion progression was observed in 33% of placebo-treated patients versus 12% of cholestyramine-treated patients (P < 0.05). Increases in HDL-C, decreases in LDL-C or TC, and increases in the ratio of HDL-C to LDL-C or TC were associated with lower rates of CAD progression. (62)
The St. Thomas' Atherosclerosis Regression Study (STARS) compared, in 90 men with CAD, the effects of dietary intervention or diet combined with cholestyramine treatment on angiographic progression after 39 months. (94) LDL-C was reduced by 16% with diet and 36% with diet plus cholestyramine. The mean absolute lumen diameter of the coronary segments evaluated increased by 0.1 mm more in those patients treated with cholestyramine and diet versus those treated with diet alone (P < 0.05); however, there was no significant difference in cardiovascular events between the 2 groups (3 events occurred in the group treated with diet alone versus 1 in the group treated with diet and cholestyramine). The change in coronary lumen diameter correlated with LDL-C levels and the LDL-C/HDL-C ratio.
Combination therapy including BAS also reduces progression of atherosclerotic lesions. Studies using a combination of niacin and colestipol or lovastatin and cholestyramine have shown that aggressive lowering of LDL-C (<100 mg/dL) in patients with coronary venous (78) or coronary artery coronary artery
1. An artery with origin in the right aortic sinus; with distribution to the right side of the heart in the coronary sulcus, and with branches to the right atrium and ventricle, including the atrioventricular branches and (95) bypass grafts, respectively, reduces progression in the grafts and native arteries. In fact, niacin is specifically indicated with any of the 3 BAS for slowing progression or promoting regression of atherosclerotic disease Atherosclerotic disease
The progressive narrowing and hardening of the arteries over time.
Mentioned in: Retinal Artery Occlusion in patients with a history of CAD. (96)
The Familial Atherosclerosis Treatment Study (FATS) examined angiographic progression and cardiovascular outcomes in response to combination therapy including BAS. After 6 years of treatment, 2-drug (niacin and colestipol or lovastatin and colestipol) combination therapy reduced both the frequency of angiographic progression of coronary lesions and cardiovascular events in men with documented CAD who were at high risk for cardiovascular events, although the differences in progression were not significant compared with usual care. (80) At the conclusion of FATS, patients were invited to continue with nonrandomized 3-drug (niacin, colestipol, and lovastatin) therapy or return to usual care and were followed up for a mean of 8 and 10 years, respectively. Of those patients who chose to continue with triple therapy, 5.3% experienced a cardiovascular event, and the overall mortality rate was 1.3%, compared with 18.8% and 19.8% of patients who returned to usual care (P = 0.05 and P = 0.001, respectively). (97) These results highlight the benefit of long-term lipid-lowering treatment for improving cardiovascular outcomes.
Further studies have shown the benefits of 3-drug therapy including BAS. In patients with familial hypercholesterolemia familial hypercholesterolemia
1. See type II familial hyperlipoproteinemia.
2. See hypercholesterolemia.
familial hypercholesterolemia Metabolic disease A common– , a controlled clinical trial of colestipol, niacin, and lovastatin triple therapy resulted in angiographic regression; levels of LDL-C were found to be the best single predictor of outcome in these patients. (98) Another study found that gemfibrozil, niacin, and cholestyramine triple therapy significantly reduced cardiovascular events versus placebo. (99)
Thus, treatment of patients who have documented CAD or who are at risk for CAD with BAS alone or as part of combination therapy can significantly reduce CAD progression and the risk of CAD-associated outcomes. A recent meta-analysis of 8 randomized ran·dom·ize
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. controlled BAS trials found that BAS monotherapy significantly reduced cardiac mortality. (100) It is also clear that the reduction in cardiovascular outcomes correlates with reductions in LDL-C levels across the range of LDL-C levels studied. (101)
BAS are effective for primary and secondary prevention of CAD and for treating atherosclerotic plaques. Clinical experience indicates that BAS can be beneficial for a range of patient populations, including those of different ages and genders.
Despite the widespread use of statins to lower LDL-C, a 2000 study found that only 40% of patients treated with statins alone achieved NCEP-specified LDL-C targets. (102) Therefore, there is an unmet need for lipid-lowering therapies that are not only effective in lowering LDL-C but can also provide additional LDL-C lowering when combined with a statin. There is also a need for agents that increase HDL-C and decrease TG levels when combined with a fibrate.
Patients who are not able to tolerate treatment with statins due to adverse effects, (67) and patients in whom statin therapy is contraindicated, are candidates for treatment with a BAS. Combination therapy with statins also allows for lower doses of both the statin and the BAS to be administered, leading to fewer adverse effects.
Bile acid sequestrants are also beneficial as part of a combination therapy in patients with very elevated cholesterol levels or in very high-risk patients, as the combination of a BAS and a statin can lower LDL-C more effectively than simply raising the dose of the statin. (42, 70, 73) A semilog sem·i·log
Semilogarithmic. linear relationship between LDL-C levels and CAD has been demonstrated, and suggests that for every 30 mg/dL change in LDL-C (for levels between 40 and 200 mg/dL), the relative risk for CAD is changed by about 30%. (3)
Because BAS are not systemically absorbed, they may be useful for treating patients who require or prefer nonsystemic therapy. Therefore, they may be useful for pregnant women or adolescents; however, these patients should only take BAS if clearly needed. To date, no evidence has suggested that special considerations should be taken when treating elderly patients with BAS.
Although fewer adverse effects appear to occur with BAS specifically engineered for selective BA absorption compared with conventional BAS, lower compliance may still occur with some patients. To achieve better efficacy with BAS therapy, clinicians should counsel patients on appropriate use and consider using compliance aids, such as telephone and computer-based reminders. (4)
The successful LDL-C lowering, reduction in CAD events, atherosclerotic regression, and safety observed with 2-drug combination therapy including a BAS argues that therapy with 3 or even 4 drugs might be more efficacious when acting by complementary mechanisms. Typically, the triple combination that has been employed is a BAS, a statin, and niacin (Table 3). (103, 104) This combination appears to be more effective than monotherapy or 2-drug therapy, but more studies are needed to prove this a valid treatment alternative. A BAS and CAI combination may also prove to be additive or synergistic, and more potent bile acid sequestrants may be developed. Such additional treatment options may increase the capability to lower LDL-C to <70 mg/dL in very high-risk patients, as recommended by the NCEP. (3)
BAS and other treatments that target the BA pathway may have additional, nonlipid-lowering therapeutic effects. For example, BAS may indirectly affect nonlipid parameters that play a role in CAD development. The BA synthetic pathway and the nuclear hormone receptors LXR and FXR play roles in glucose metabolism glucose metabolism,
n the process by which simple sugars found in many foods are processed and used to produce energy in the form of ATP. Once consumed, glucose is absorbed by the intestines and into the blood. and thus are interesting potential targets for diabetes therapies. Treatment of patients with dyslipidemia and type 2 diabetes with cholestyramine significantly reduced mean plasma glucose levels and median urinary glucose excretion. (105) Activated LXR inhibits hepatic gluconeogenesis gluconeogenesis /glu·co·neo·gen·e·sis/ (gloo?ko-ne?o-jen´e-sis) the synthesis of glucose from molecules that are not carbohydrates, such as amino and fatty acids.
n. and lowers serum glucose levels, thus improving glucose tolerance. (106-108) Therefore, an LXR agonist might be beneficial for diabetics. However, this is coupled with an increase in circulating lipids and TG, (109) and therefore, the beneficial and deleterious effects must be balanced. It remains to be seen how BAS effects LXR and FXR.
Twenty-five years of controlled clinical trials have demonstrated that BAS therapy is both safe and effective for treating dyslipidemia, alone and in combination with other lipid-lowering therapies such as statins. In addition to lowering LDL-C and slightly raising HDL-C levels, bile acid sequestrants reduce the progression of atherosclerotic plaques and the incidence of clinical cardiovascular events. Bile acid sequestrants, as the only nonsystemic lipid-lowering agents, have a demonstrated safety record. Newer, specifically engineered BAS have greater potency, limited binding of comedications due to selective absorption, and a lower incidence of gastrointestinal side effects compared with older BAS. It is also becoming clear that BAS and other therapies that manipulate the BA synthetic pathway may have therapeutic effects on other metabolic disorders such as type 2 diabetes.
The preparation of this manuscript was supported in part by a grant from Sankyo Pharma Inc. Thank you to Sarah Seton-Rogers, PhD for assistance in conducting the literature search and the development of this manuscript. The opinions expressed in this report are those of the author.
1. Iglesias P, Diez JJ. New drugs for the treatment of hypercholesterolaemia. Expert Opin Investig Drugs 2003;12:1777-1789.
2. Manhas A, Farmer JA. Hypolipidemic therapy and cholesterol absorption. Curr Atheroscler Rep 2004;6:89-93.
3. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel IIIguidelines. Circulation 2004;110:227-239.
4. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-3421.
5. Packard CJ, Shepherd J. The hepatobiliary axis and lipoprotein metabolism: effects of bile acid sequestrants and ileal bypass surgery Bypass surgery
A surgical procedure that grafts blood vessels onto arteries to reroute the blood flow around blockages in the arteries (arteriosclerosis). . J Lipid Res 1982;23:1081-1098.
6. Chiang JY. Bile acid regulation ofgene expression: roles of nuclear hormone receptors. Endocr Rev 2002;23:443-463.
7. Einarsson K, Ericsson S, Ewerth S, et al. Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism. Eur J Clin Pharmacol 1991;40 Suppl 1:S53-S58.
8. St-Pierre MV, Kullak-Ublick GA, Hagenbuch B, et al. Transport of bile acids in hepatic and non-hepatic tissues. J Exp Biol 2001;204:1673-1686.
9. Redinger RN. The coming of age of our understanding of the enterohepatic circulation of bile salts. Am J Surg 2003;185:168-172.
10. Li-Hawkins J, Lund EG, Turley SD, et al. Disruption of the oxysterol 7alpha-hydroxylasegene in mice. J Biol Chem 2000;275:16536-16542.
11. Schwartz CC, Halloran LG, Vlahcevic ZR, et al. Preferential utilization of free cholesterol from high-density lipoproteins for biliary cholesterol secretion in man. Science 1978;200:62-64.
12. Bravo E, Cantafora A, Argiolas L. Hepatie uptake and metabolism of free cholesterol from different lipoprotein classes. An in vivo in vivo /in vi·vo/ (ve´vo) [L.] within the living body.
Within a living organism.
in vivo adv. study in the rat. Biochim Biophys Acta 1989;1003:315-320.
13. Robins SJ, Fasulo JM. High density lipoproteins High density lipoprotein (HDL)
A fraction of total serum lipids, the so called "good" cholesterol.
Mentioned in: Hypercholesterolemia , but not other lipoproteins Lipoproteins
The packages in which cholesterol and triglycerides travel throughout the body.
Mentioned in: Lipoproteins Test
n. , provide a vehicle for sterol Sterol
Any of a group of naturally occurring or synthetic organic compounds with a steroid ring structure, having a hydroxyl (—OH) group, usually attached to carbon-3. transport to bile. J Clin Invest 1997;99:380-384.
14. Data on file. Sankyo Pharma, Inc, Parsippany, NJ, 2003.
15. Lehmann JM, Kliewer SA, Moore LB, et al. Activation of the nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of hormones and certain other molecules. LXR by oxysterols defines a new hormone response pathway. J Biol Chem 1997;272:3137-3140.
16. Joseph SB, McKilligin E, Pei L, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A 2002:99:7604-7609.
17. Miao B, Zondlo S, Gibbs S, et al. Raising HDL cholesterol HDL cholesterol
See high-density lipoprotein.
About one-third or one-fourth of all cholesterol is high-density lipoprotein cholesterol. without inducing hepatic steatosis steatosis /ste·a·to·sis/ (ste?ah-to´sis) fatty change.
See fatty degeneration.
fatty degeneration. See also muscular steatosis. and hypertriglyceridemia by a selective LXR modulator Modulator
Any device or circuit by means of which a desired signal is impressed upon a higher-frequency periodic wave known as a carrier. The process is called modulation. The modulator may vary the amplitude, frequency, or phase of the carrier. . J Lipid Res 2004;45:1410-1417.
18. Wang H, Chen J, Hollister K, et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 1999;3:543-553.
19. Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science 1999;284:1362-1365.
20. Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999;284:1365-1368.
21. Claudel T, Sturm E, Duez H, et al. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I apolipoprotein A-I A 28 kD single chain protein that comprises 75% of the ApoA in HDL; apoA-I is the major protein constituent of lipoproteins, and participates in cholesterol transport by activating LCAT-lecithin:cholesterol acyltransferase; apoA-I levels are transcription via a negative FXR response element. J Clin Invest 2002;109:961-971.
22. Cui J, Huang L, Zhao A, et al. Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. J Biol Chem 2003;278:10214-10220.
23. De Palma Palma or Palma de Mallorca (päl`mä thā mälyôr`kä), city (1990 pop. 325,120), capital of Majorca island and of Baleares prov., Spain, on the Bay of Palma. RG, Hubay CA, Insull W, Jr. The effect of t-tube drainage on cholesterol and bile acid metabolism in man. Surg Gynecol Obstet 1966;123:269-273.
24. DePalma RG, Levey S, Hartman PH, et al. Bile acids and serum cholesterol following T tube drainage. Arch Surg 1967;94:271-276.
25. Myant NB, Mitropoulos KA. Cholesterol 7 alpha-hydroxylase Cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the synthesis of bile acid from cholesterol, catalyzing the formation of 7-alpha-hydroxycholesterol. . J Lipid Res 1977;18:135-153.
26. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease coronary heart disease: see coronary artery disease.
coronary heart disease
or ischemic heart disease
Progressive reduction of blood supply to the heart muscle due to narrowing or blocking of a coronary artery (see atherosclerosis). . JAMA JAMA
Journal of the American Medical Association 1984;251::351-364.
27. Brensike JF, Levy RI, Kelsey SF, et al. Effects of therapy with cholestyramine on progression of coronary arteriosclerosis arteriosclerosis (ärtĭr'ēōsklərō`sis), general term for a condition characterized by thickening, hardening, and loss of elasticity of the walls of the blood vessels. : results of the NHLBI Type II Coronary Intervention Study. Circulation 1984;69:313-324.
28. Davidson MH, Dillon MA, Gordon B, et al. Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence ofgastrointestinal side effects. Arch Intern Med 1999;159:1893-1900.
29. Insull WJr, Toth P, Mullican W, et al. Effectiveness of colesevelam hydrochloride in decreasing LDL cholesterol LDL cholesterol
See low-density lipoprotein.
Low-density lipoprotein cholesterol is the primary cholesterol molecule. High levels of LDL increase the risk of coronary heart disease. in patients with primary hypercholesterolemia: a 24-week randomized controlled trial A randomized controlled trial (RCT) is a scientific procedure most commonly used in testing medicines or medical procedures. RCTs are considered the most reliable form of scientific evidence because it eliminates all forms of spurious causality. . Mayo Clin Proc 2001;76:971-982.
30. Aldridge MA, Ito MK. Colesevelam hydrochloride: a novel bile acid-binding resin. Ann Pharmacother 2001;35:898-907.
31. Bard JM, Parra HJ, Douste-Blazy P, et al. Effect of pravastatin, an HMG CoA reductase inhibitor HMG CoA reductase inhibitor Any of a family of drugs, statins, that inhibits the activity of 3-hydroxy-3-methylglutaryl coenzyme A, which is involved in early cholesterol synthesis. See Atherosclerosis, Cholesterol. , and cholestyramine, a bile acid sequestrant, on lipoprotein particles defined by their apolipoprotein composition. Metabolism 1990;39:269-273.
32. WelChol (colesevelam hydrochloride) Prescribing Information v8. Sankyo Pharma Inc, Parsippany, NJ. Available at www.welchol.com. Accessed February 15, 2006.
33. Colestid (colestipol) Prescribing Information. Pharmacia & Upjohn Company, Kalamazoo, MI. Available at www.pdr.net. Accessed February 15, 2006.
34. Questran (cholestyramine) Prescribing Information. Bristol-Myers Squibb Bristol-Myers Squibb (NYSE: BMY), colloquially referred to as BMS, is a pharmaceutical corporation, formed by a 1989 merger between pharmaceutical companies Bristol-Myers Company, founded in 1887 by William McLaren Bristol and John Ripley Myers in Clinton, NY (both were , New York New York, state, United States
New York, Middle Atlantic state of the United States. It is bordered by Vermont, Massachusetts, Connecticut, and the Atlantic Ocean (E), New Jersey and Pennsylvania (S), Lakes Erie and Ontario and the Canadian province of , NY. Available at www.pdr.net. Accessed February 15, 2006.
35. Ast M, Frishman WH. Bile acid sequestrants. J Clin Pharmacol 1990;30:99-106.
36. Mandeville WH, Goldberg DI. The sequestration of bile acids, a nonabsorbed method for cholesterol reduction. A review. Curr Pharm Des 1997;3:15-28.
37. Bays H, Dujovne C. Colesevelam HCl: a non-systemic lipid-altering drug. Expert Opin Pharmacother 2003;4:779-790.
38. Holmes-Farley SR, Mandeville WH, Miller KL, et al. Colesevelam hydrochloride: synthesis and testing of a novel polymergel pharmaceutical. Polymer Prepr 2000;41:735-736.
39. Braunlin W, Zhorov E, Smisek D, et al. In vitro comparison of bile acid binding to coleseveleam HCl and other bile acid sequestrants. Polymer Prepr 2000;41:708-709.
40. Heller DP, Burke SK, Davidson DM, et al. Absorption of colesevelam hydrochloride in healthy volunteers. Ann Pharmacother 2002;36:398-403.
41. Leren TP, Hjermann 1, Berg K, et al. Effects of lovastatin alone and in combination with cholestyramine on serum lipids and apolipoproteins in heterozygotes for familial hypercholesterolemia. Atherosclerosis 1988;73:135-141.
42. Sprecher DL, Abrams J, Allen JW, et al. Low-dose combined therapy with fluvastatin and cholestyramine in hyperlipidemic patients. Ann Intern Med 1994;120:537-543.
43. Andrade SE, Walker AM, Gottlieb LK, et al. Discontinuation of anti-hyperlipidemic drugs--do rates reported in clinical trials reflect rates in primary care settings? N Engl J Med 1995;332:1125-1131.
44. Avorn J, Monette J, Lacour A, et al. Persistence of use of lipid-lowering medications: a cross-national study. JAMA 1998;279:1458-1462.
45. Vahouny GV, Cassidy MM, Lightfoot F, et al. Ultrastructural modifications of intestinal and colonic mucosa induced by free or bound bile acids. Cancer Res 1981;41:3764-3765.
46. Nigro ND, Bhadrachari N, Chomchai C. A rat model for studying colonic cancer: effect of cholestyramine on induced tumors. Dis Colon Rectum rectum: see intestine.
End segment of the large intestine (see digestion) in which feces accumulate just prior to discharge. It is 5–6 in. (13–15 cm) long and lined with mucous membrane. 1973;16:438-443.
47. The Lipid Research Clinics Coronary Primary Prevention Trial. Results of 6 years of post-trial follow-up. The Lipid Research Clinics Investigators. Arch Intern Med 1992;152::1399-1410.
48. Gallo DG, Bailey KR, Sheffner AL. The interaction between cholestyramine and drugs. Proc Soc Exp Biol Med 1965;120:60-65.
49. Kivisto KT, Neuvonen PJ. The effect of cholestyramine and activated charcoal Charcoal, Activated Definition
Activated charcoal is a fine black odorless and tasteless powder made from wood or other materials that have been exposed to very high temperatures in an airless environment. onglipizide absorption. Br J Clin Pharmacol 1990;30:733-736.
50. Malloy MJ, Ravis WR, Pennell AT, et al. Effect of cholestyramine resin on single dose valproate valproate /val·pro·ate/ (val-pro´at) a salt of valproic acid; the sodium salt has the same uses as the acid.
n. pharmacokinetics. Int J Clin Pharmacol Ther 1996;34:208-211.
51. Hunninghake DB, King S, LaCroix K. The effect of cholestyramine and colestipol on the absorption of hydrochlorothiazide hydrochlorothiazide /hy·dro·chlo·ro·thi·a·zide/ (-klor?o-thi´ah-zid) a thiazide diuretic, used for treatment of hypertension and edema.
n. Abbr. . Int J Clin Pharmacol Ther Toxicol 1982;20:151-154.
52. Neuvonen PJ, Kivisto K, Hirvisalo EL. Effects of resins and activated charcoal on the absorption of digoxin, carbamazepine carbamazepine /car·ba·maz·e·pine/ (kahr?bah-maz´e-pen) an anticonvulsant and analgesic used in the treatment of pain associated with trigeminal neuralgia and in epilepsy manifested by certain types of seizures. and frusemide frusemide
a diuretic that acts by blocking reabsorption of sodium and chloride in the ascending loop of Henle. . Br J Clin Pharmacol 1988;25:229-233.
53. Donovan JM, Stypinski D, Stiles Stiles can refer to: People
54. Donovan JM, Kisicki JC, Stiles MR, et al. Effect of colesevelam on lovastatin pharmacokinetics. Ann Pharinacother 2002;36:392-397.
55. Jones MR, Baker BA, Mathew P. Effect of colesevelam HCl on single-dose fenofibrate pharmacokinetics. Clin Pharmacokinet 2004;43:943-950.
56. Marquis JK, Dagher R, Jones M. Dietary administration of colesevelam hydrochloride does not affect fertility or reproductive performance in rats. Int J Toxicol 2004;23:357-367.
57. Marquis JK, Dagher R, Baker BA, et al. Colesevelam hydrochloride does not cause maternal or fetal toxicity in rats and rabbits. Reprod Toxicol:in press, 2005.
58. Bergen SS Jr., Van Itallie TB, Tennent DM, et al. Effect of an anion exchange resin on serum cholesterol in man. Proc Soc Exp Biol Med 1959;102:676-679.
59. Hashim SA, Vanltallie TB, Cholestyramine Resin Therapy For Hyper-cholesteremia: Clinical And Metabolic Studies. JAMA 1965;192:289-293.
60. Khachadurian AK. Cholestyramine therapy in patients homozygous ho·mo·zy·gous
Having the same alleles at one or more gene loci on homologous chromosome segments.
Identical genes controlling a specified inherited trait. for familial hypercholesterolemia (familial hypercholesterolemic xanthomatosis xanthomatosis /xan·tho·ma·to·sis/ (zan?tho-mah-to´sis) a condition marked by the presence of xanthomas.
xanthomatosis bul´bi fatty degeneration of the cornea. ). J Atheroseler Res 1968;8:177-188.
61. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251::365-374.
62. Levy RI, Brensike JF, Epstein SE, et al. The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: results of NHLBI Type II Coronary Intervention Study. Circulation 1984;69:325-337.
63. Lamarche B. Tchernof A, Mauriege P, et al. Fasting insulin and apolipoprotein B Apolipoprotein B (APOB) is the primary apolipoprotein of low density lipoproteins (LDL or "bad cholesterol"), which is responsible for carrying cholesterol to tissues. While it is unclear exactly what functional role APOB plays in LDL, it is the primary apolipoprotein component levels and low-density lipoprotein low-density lipoprotein
n. Abbr. LDL
A lipoprotein that contains relatively high amounts of cholesterol and is associated with an increased risk of atherosclerosis and coronary artery disease. particle size as risk factors for ischemic heart disease Ischemic heart disease
Insufficient blood supply to the heart muscle (myocardium).
Mentioned in: Myocarditis
ischemic heart disease . JAMA 1998;279:1955-1961.
64. Zambon A, Hokanson JE, Brown BG, Brunzell JD. Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density. Circulation 1999;99:1959-1964.
65. Rosenson RS. Colesevelam HCl reduces LDL particle number and increases LDL size in hypercholesterolemia. Atherosclerosis :in press, 2005.
66. Davidson MH, Toth PP. Combination therapy in the management of complex dyslipidemias. Curr Opin Lipidol 2004;15:423-431.
67. Pasternak RC, Smith SC Jr., Bairey-Merz CN, et al. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Circulation 2002;106:1024-1028.
68. Pravastatin Multicenter Study Group II. Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia. Arch Intern Med 1993;153:1321-1329.
69. Pan HY, DeVault AR, Swites BJ, et al. Pharmacokinetics and pharmacodynamics pharmacodynamics /phar·ma·co·dy·nam·ics/ (-di-nam´iks) the study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of their actions and effects with their chemical of pravastutin alone and with cholestyramine in hypercholesterolemia. Clin Pharmacol Ther 1990;48:201-207.
70. Ito MK, Shabetai R. Pravastatin alone and in combination with low-dose cholestyramine in patients with primary hypercholesterolemia and coronary artery disease. Am J Cardiol 1997;80:799-802.
71. Davidson MH, Toth P, Weiss S, et al. Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia. Clin Cardiol 2001;24:467-474.
72. Vega GL, Grundy SM. Treatment of primary moderate hypercholesterolemia with lovastatin (mevinolin) and colestipol. JAMA 1987;257:33-38.
73. Schrott HG, Stein EA. Dujovne CA, et al. Enhanced low-density lipoprotein cholesterol reduction and cost-effectiveness by low-dose colestipol plus lovastatin combination therapy. Am J Cardiol 1995;75:34-39.
74. Denke MA, Grundy SM. Efficacy of low-dose cholesterol-lowering drug cholesterol-lowering drug Therapeutics Any of a family of agents that ↓ serum cholesterol; the most cost-effective agents for lowering LDL-C are nicotinic acid and lovastatin; the most efficient for ↑ HDL-C are nicotinic acid and gemfibrozil therapy in men with moderate hypercholesterolemia. Arch Intern Med 1995;155:393-399.
75. Simons LA, Simons J, Parfitt A. Successful management of primary hypercholesterolaemia with simvastatin and low-dose colestipol. Med J Aust 1992;157:455-459.
76. Knapp HH, Schrott H, Ma P, et al. Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia. Am J Med 2001;110:352-360.
77. Hunninghake D, Insull W Jr., Toth P, et al. Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively. Atherosclerosis 2001;158:407-416.
78. Blankenhorn DH, Nessim SA, Johnson RL, et al. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypassgrafts. JAMA 1987;257:3233-3240.
79. Cashin-Hemphill L, Mack WJ, Pogoda JM, et al. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA 1990;264:3013-3017.
80. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990;323:1289-1298.
81. Guyton JR, Goldberg AC, Kreisberg RA, et al. Effectiveness of oncenightly dosing of extended-release niacin alone and in combination for hypercholesterolemia. Am J Cardiol 1998;82:737-743.
82. Series JJ, Gaw A, Kilday C, et al. Acipimox in combination with low dose cholestyramine for the treatment of type II hyperlipidaemia Noun 1. hyperlipidaemia - presence of excess lipids in the blood
hyperlipaemia, hyperlipemia, hyperlipidemia, hyperlipoidaemia, hyperlipoidemia, lipaemia, lipemia, lipidaemia, lipidemia, lipoidaemia, lipoidemia . Br J Clin Pharmacol 1990;30:49-54.
83. Weisweiler P, Schwandt P. Colestipol plus fenofibrate versus synvinolin in familial hypercholesterolaemia. Lancet 1986;2:1212-1213.
84. Barbir M, Hunt BJ, Galloway D, et al. A randomized pilot trial of low-dose combination lipid-lowering therapy following coronary artery bypassgrafting. Clin Cardiol 1994;17:59-64.
85. Houlston R, Quiney J, Watts GF, et al. Gemfibrozil in the treatment of resistant familial hypercholesterolaemia and type III Type III may stand for:
86. Series JJ, Caslake MJ, Kilday C, et al. Effect of combined therapy with bezafibrate and cholestyramine on low-density lipoprotein metabolism in type IIa hypercholesterolemia. Metabolism 1989;38:153-158.
87. Sommariva D, Tirrito M, Bonfiglioli D, et al. Long-term effects of bezafibrate and of a bezafibrate and cholestyramine combination on lipids and lipoprotein lipids in type IIa hypercholesterolaemic patients. Int J Clin Pharmacol Res 1986;6:249-253.
88. Curtis LD, Dickson AC, Ling KL, et al. Combination treatment with cholestyramine and bezafibrate for heterozygous het·er·o·zy·gous
1. Having different alleles at one or more corresponding chromosomal loci.
2. Of or relating to a heterozygote. familial hypercholesterolaemia. BMJ BMJ n abbr (= British Medical Journal) → vom BMA herausgegebene Zeitschrift 1988;297:173-175.
89. McKenney J, Jones M, Abby S. Safety and efficacy of colesevelam hydrochloride in combination with fenofibrate for the treatment of mixed hyperlipidemia hyperlipidemia /hy·per·lip·id·emia/ (-lip?i-de´me-ah) elevated concentrations of any or all of the lipids in the plasma, including hypertriglyceridemia, hypercholesterolemia, etc. . Curr Med Res Opin 2005;21:1403-1412.
90. Xydakis AM, Guyton JR, Chiou P, et al. Effectiveness and tolerability of ezetimibe add-on therapy to a bile acid resin-based regimen for hypercholesterolemia. Am J Cardiol 2004;94:795-797.
91. Zema MJ. Colesevelam HCl and ezetimibe combination therapy provides effective lipid-lowering in difficult-to-treat patients with hypercholesterolemia. Am J Ther :in press, 2005.
92. Dorr AE, Gundersen K, Schneider JC Jr., et al Colestipol hydrochloride colestipol hydrochloride
Pharmacologic class: Bile acid sequestrant
Therapeutic class: Antihyperlipidemic
Pregnancy risk category NR
Actionin hypercholesterolemic patients--effect on serum cholesterol and mortality. J Chronic Dis 1978;31:5-14.
93. Stone NJ. Cholesterol, colestipol and coronary heart disease. J Chronic Dis 1978;31:1-3.
94. Watts GF, Lewis B, Brunt JN, et al. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS). Lancet 1992;339:563-569.
95. The Post Coronary Artery Bypass Graft coronary artery bypass graft
n. Abbr. CABG
A surgical procedure in which a section of vein or other conduit is grafted between the aorta and a coronary artery below the region of an obstruction in that artery. Trial Investigators: The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypassgrafts. N Engl J Med 1997;336:153-162.
96. Niaspan (niacin extended release tablets) Prescribing Information. Kos Pharmaceuticals, Inc, Cranbury, NJ. Available at: http://www.niaspan.com. Accessed February 15, 2006.
97. Brown BG, Brockenbrough A, Zhao X-Q, et al. Very intensive lipid therapy with lovastatin, niacin, and colestipol for prevention of death and myocardial infarction myocardial infarction: see under infarction. : a 10-year Familial Atherosclerosis Treatment Study (FATS) follow-up. Circulation 1998;98:1-635 (abstract 3341).
98. Kane JP, Malloy MJ, Ports TA, et al. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 1990;264:3007-3012.
99. Whitney EJ, Krasuski RA, Personius BE, et al. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events. Ann Intern Med 2005;142:95-104.
100. Studer M, Briel M, Leimenstoll B, et al. Effect of different antilipidemic agents and diets on mortality: a systematie review. Arch Intern Med 2005;165:725-730.
101. Waters DD, Azar RR Should intensive cholesterol lowering play a role in the management of acute coronary syndromes acute coronary syndrome
A sudden, severe coronary event that mimics a heart attack, such as unstable angina.
acute coronary syndrome ? Am J Cardiol 2000;86:35J-42J (discussion 42J-43J).
102. Pearson TA, Laurora I, Chu H, et al. The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterolgoals. Arch Intern Med 2000;160:459-467.
103. Brown BG, Bardsley J, Poulin D, et al. Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease. Am J Cardiol 1997;80:111-115.
104. Malloy MJ, Kane JP, Kunitake ST, et al. Complementarity com·ple·men·tar·i·ty
1. The correspondence or similarity between nucleotides or strands of nucleotides of DNA and RNA molecules that allows precise pairing.
2. of colestipol, niacin, and lovastatin in treatment of severe familial hypercholesterolemia. Ann Intern Med 1987;107:616-623.
105. Garg A, Grundy SM. Cholestyramine therapy for dyslipidemia in noninsulin-dependent diabetes mellitus diabetes mellitus
Disorder of insufficient production of or reduced sensitivity to insulin. Insulin, synthesized in the islets of Langerhans (see Langerhans, islets of), is necessary to metabolize glucose. In diabetes, blood sugar levels increase (hyperglycemia). . A short-term, double-blind, cross-over trial. Ann Intern Med 1994;121:416-422.
106. Steffensen KR, Gustafsson JA. Putative metabolic effects of the liver X receptor (LXR). Diabetes 2004;53 Suppl 1:S36-S42.
107. Stulnig TM, Oppermann U, Steffensen KR, et al. Liver X receptors downregulate 11 beta-hydroxysteroid dehydrogenase dehydrogenase /de·hy·dro·gen·ase/ (de-hi´dro-jen-as?) an enzyme that catalyzes the transfer of hydrogen or electrons from a donor, oxidizing it, to an acceptor, reducing it.
n. type 1 expression and activity. Diabetes 2002;51:2426-2433.
108. Laffitte BA, Chao LC, Li J, et al. Activation of liver X receptor improvesglucose tolerance through coordinate regulation ofglucose metabolism in liver and adipose tissue adipose tissue (ăd`əpōs'): see connective tissue.
or fatty tissue
Connective tissue consisting mainly of fat cells, specialized to synthesize and contain large globules of fat, within a . Proc Natl Acad Sci U S A 2003;100:5419-5424.
109. Ou J, Tu H, Shan B, et al. Unsaturated fatty acids unsaturated fatty acids,
n.pl the double- or triple-bonded fatty acids contained primarily in vegetable oils and fish, which remain liquid at room temperature; linked to a reduction in the risk of developing heart disease. inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c)gene by antagonizing ligand-dependent activation of the LXR. Proc Natl Acad Sci U S A 2001;98:6027-6032.
110. Dawson PA. Bile secretion and the enterohepatic circulation of bile acids. In: Feldman M, Friedman LS, Sleisenger MH. eds. Gastrointestinal and Liver Disease Liver Disease Definition
Liver disease is a general term for any damage that reduces the functioning of the liver.
The liver is a large, solid organ located in the upper right-hand side of the abdomen. , 7th ed. Philadelphia, Saunders, 2002, pp 1051-1064.
111. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med 1999;159:2647-2658.
112. RedBook Drug Topics, 108th ed. Stamford, CT: Thomson Healthcare Thomson Healthcare is one of the five operating divisions of the Thomson Corporation. The division provides information and solutions to improve the cost and quality of healthcare.
Thomson Healthcare is based in Connecticut with about 2,600 staff around the globe. , 2004.
113. A multicenter comparison of lovastatin and cholestyramine therapy for severe primary hypercholesterolemia. The Lovastatin Study Group III In the periodic table Group III covered what are now called
114. Hunninghake DB, Stein EA, Bremner WF, et al. Dose-Response Study of Colestipol Tablets in Patients with Moderate Hypercholesterolemia. Am J Ther 1995;2:180-189.
115. Wierzbicki AS, Lumb-PJ, Semra Y, et al. Atorvastatin compared with simvastatin-based therapies in the management of severe familial hyperlipidaemias. QJM QJM Quarterly Journal of Medicine (Association of Physicians)
QJM Quantified Judgement Model
QJM Quantified/Quantitative Judgment Method 1999;92:387-394.
116. Sacks FM, Pasternak RC, Gibson CM, et al. Effect on coronary atherosclerosis of decrease in plasma cholesterol concentrations in normocholesterolaemie patients. Lancet 1994;344:1182-1186.
117. Walldius G, Erikson U, Olsson AG, et al. The effect of probucol on femoral femoral /fem·o·ral/ (fem´or-al) pertaining to the femur or to the thigh.
Of or relating to the femur or thigh. atherosclerosis: the Probucol Quantitative Regression Swedish Trial (PQRST PQRST Palliative/Provoking, Quality, Radiation, Severity, Timing (Chest Pain Evaluation) ). Am J Cardiol 1994;74:875-883.
118. Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH POSCH GI disease A clinical trial–Program on the Surgical Control of the Hyperlipidemias–of the effect of partial ileal bypass on M&M due to CAD in Pts with hypercholesterolemia. See Hypercholesterolemia, Ileal bypass surgery. ). N Engl J Med 1990;323:946-955.
William Insull, Jr, MD
From Baylor College of Medicine Baylor College of Medicine is a private medical school located in Houston, Texas, USA on the grounds of the Texas Medical Center. It has been consistently rated the top medical school in Texas and among the best in the United States. , Lipid Research Clinic, Houston, TX.
The preparation of this manuscript was supported in part by a grant from Sankyo Pharma Inc.
Reprint requests to: Dr. William Insull Jr, Director, Lipid Research Clinic, Professor of Medicine and Pediatrics, Baylor Faculty Center (BCM BCM Baylor College of Medicine
BCM Business Communications Manager (Nortel)
BCM Broadcom Corporation
BCM Business Continuity Management
BCM Business Contact Manager (Microsoft) 620), 1709 Dryden Rd. Suite 08.08, Houston, TX 77030. Email: email@example.com
Accepted January 20, 2006.
RELATED ARTICLE: Key Points
* Partial diversion of the enterohepatic circulation using BAS depletes the endogenous bile acid pool by approximately 40%, stimulating an increase in bile acid synthesis from cholesterol, and consequently lowering serum LDL-C by 15% to 25%.
* Low-dose combination therapy with BAS and statins is becoming more common due to these agents' complementary mechanisms of action, and leads to greater or similar LDL-C reductions compared with high-dose statin monotherapy, perhaps with a better safety profile.
* BAS therapy, alone or in combination with other lipid-modifying therapies, can significantly reduce coronary artery disease progression and the risk of associated outcomes.
* Compared with the older BAS, cholestyramine and colestipol, the newer specifically engineered BAS, colesevelam HCl, has enhanced specificity, greater affinity, and higher capacity for binding bile acids, due to its unique polymer structure.
* BAS are not absorbed by the intestine, and thus have no systemic metabolism or drug-drug interactions, but may interfere with the absorption of some drugs.
Table 1. Comparison of bile acid sequestrant characteristics Formulation Dose range Cholestyramine (34) Powder (4 g 4-24 g/d packet or (1-6 packets or in bulk) scoopfuls) Colestipol (33) Powder (5 g 5-30 g/d packet) (1-6 packets) Tablet (1 g) 2-16 g/d (2-16 tablets) Colesevelam HCl (32) Tablet (625 3.8-4.5 g/d mg) (6-7 tablets) Indications (a) Contraindications Cholestyramine (34) Reduction in TC and LDL-C Patients with in patients with primary bowel hypercholesterolemia obstruction (adjunctive therapy to diet) Patients hypersensitive to any components Colestipol (33) Reduction in LDL-C in Patients patients with primary hypersensitive hypercholesterolemia to any (adjunctive therapy to diet) components Colesevelam HCl (32) Reduction in LDL-C in Patients with patients with primary bowel hypercholesterolemia obstruction (adjunctive therapy to diet) Patients Can be administered alone or hypersensitive in combination with statins to any components Mean % Cost Pregnancy LDL-C (AWP), category Adverse effects lowering 2004 (112) Cholestyramine (34) C (b) GI distress 9-28% Packet: Constipation across 4 g $2.37 Decreased dosing 16 g $9.48 absorption range 24 g $14.22 of some other Bulk: drugs 4 g $0.59 16 g $2.36 24 g $3.54 Colestipol (33) C (b) GI distress 5-26% 5 g $1.92 Constipation across 30 g $11.52 Decreased dosing absorption range of some other drugs 2 g $1.20 16 g $9.60 Colesevelam HCl (32) B (c) GI distress 15-19% 3.8 g $5.70 Constipation across 4.5 g $6.65 Decreased dosing absorption range of sustained- release verapamil Effects may be less than observed with cholestyramine and colestipol (a) Niacin is indicated, in combination with any of the 3 BAS, for slowing progression or promoting regression of atherosclerotic disease in patients with a history of CAD. (96) (b) A pregnancy category C rating is given to drugs that should only be given if potential benefit justifies potential risk: either studies in animals have revealed adverse effects on the fetus and there are no controlled studies in pregnant women or studies in women and animals are not available. (c) A pregnancy category B rating is given to a drug in which either animal study has not demonstrated a fetal risk but there are no controlled studies in pregnant women or animal studies have shown an adverse effect that was not confirmed in controlled studies in women; if there is a clear clinical need for the drug, then it is acceptable to use it. AWP, average wholesale price; GI, gastrointestinal; LDL-C, low-density lipoprotein cholesterol. Table 2. Bile acid sequestrant monotherapy: summary of serum lipid effects from clinical trials Study Study Agent Dosage N duration LRC-CPPT Cholestyramine 4-8 g/d (b) 3806 7.4 years 1984 (26, 61) Placebo Cholestyramine 16-20 g/d (b) Placebo Cholestyramine >20 g/d (b) Placebo NHLBI Type II Study Cholestyramine 24 g/d 143 5 years 1984 (27, 62) Placebo Lovastatin Study Cholestyramine 24 g/d 264 12 weeks Group 1988 (113) Dorr et al Colestipol 15 g/d 2278 2 years 1978 (92) (powder) Placebo Hunninghake et al Colestipol 2 g/d 196 8 weeks 1995 (114) (tablets) 4 g/d 8 g/d 16 g/d Placebo Davidson et al Colesevelam 1.5 g/d 137 6 weeks 1999 (28) HCl (f) 2.25 g/d 3.0 g/d 3.75 g/d Placebo Insull et al Colesevelam 2.3 g/d 494 24 weeks 2001 (29) HCl 3.0 g/d 3.8 g/d 4.5 g/d Placebo % Change from baseline in lipids and lipoproteins (a) Study Agent TC LDL-C HDL-C LRC-CPPT Cholestyramine -5% -9% 2% 1984 (26, 61) Placebo -2% -4% 5% Cholestyramine -14% -21% 4% Placebo -4% -6% 2% Cholestyramine -19% -28% 4% Placebo -5% -8% 1% NHLBI Type II Study Cholestyramine -17% (c,d) -26% (c,d) 8% (c) 1984 (27, 62) Placebo -1% -5% (c) 2% Lovastatin Study Cholestyramine -17% (c) -23% (c) 8% (c) Group 1988 (113) Dorr et al Colestipol -12% (d) ND ND 1978 (92) (powder) Placebo -2% ND ND Hunninghake et al Colestipol -3% (c,d) -5% (c,d) -1% 1995 (114) (tablets) -7% (c,d) -11% (c,d) 0% -13% (c,d) -20% (c,d) -1% -17% (c,d) -26% (c,d) -1% Placebo 1% 0% 0% Davidson et al Colesevelam -2% -2% 1% 1999 (28) HCl (f) -4% (c) -5% 1% -5% -9% (c) 9% (c) -8% (c) -19% (c) 8% (c) Placebo 0% 0% -1% Insull et al Colesevelam -4% (c,d) -9% (c,d) 3% (c,d,e) 2001 (29) HCl -6% (c,d) -12% (c,d) 4% (c,d,e) -7% (c,d) -15% (c,d) 3% (c,d,e) -10% (c,d) -18% (c,d) 3% (c,e) Placebo 1% 0% -1% (e) % Change from baseline in lipids and lipoproteins (a) Study Agent TG ApoB LRC-CPPT Cholestyramine 13% ND 1984 (26, 61) Placebo 8% ND Cholestyramine 16% ND Placebo 11% ND Cholestyramine 17% ND Placebo 8% ND NHLBI Type II Study Cholestyramine 28% (c) ND 1984 (27, 62) Placebo 26% (c) ND Lovastatin Study Cholestyramine 11% (c) -21% (c,e) Group 1988 (113) Dorr et al Colestipol 12% ND 1978 (92) (powder) Placebo 11% ND Hunninghake et al Colestipol 15% (c) 2% 1995 (114) (tablets) 10% (c) -10% (c,d) 12% (c) -19% (c,d) 15% (c) -23% (c,d) Placebo 11% (c) 2% Davidson et al Colesevelam 1% (e) ND 1999 (28) HCl (f) -1% (e) ND 1% (e) ND 9% (e) ND Placebo 3% (e) ND Insull et al Colesevelam 9% (c,e) -6% (c,d) 2001 (29) HCl 5% (e) -8% (c,d) 10% (c,e) -12% (c,d) 9% (c,e) -12% (c,d) Placebo 5% (e) 0% (a) Values are means unless otherwise indicated. (b) Prescribed dose of cholestyramine in LRC-CPPT was 24 g/d, but some patients took less. Statistical analyses for cholestyramine vs placebo were not reported. (c) Significant (P < 0.05) compared with baseline. (d) Significant (P < 0.05) compared with placebo. (e) Median values reported. (f) Statistical analyses for colesevelam HCl vs placebo were not reported. ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LRC-CPPT, Lipid Research Clinics Coronary Primary Prevention Trial; NHLBI, National Heart, Lung, and Blood Institute (NHLBI) Type II Coronary Intervention Study; ND, not determined (values were not determined or not reported); TC, total cholesterol; TG, triglycerides. Table 3. Bile acid sequestrant combination therapy: summary of serum lipid effects from clinical trials Study Agents N (a) Study duration BAS + statin combinations Pan et al 1990 (69) Cholestyramine (24 33 4 weeks g/d) + pravastatin (5, 10, or 20 mg BID) PMS II 1993 (68) Cholestyramine (24 64 8 weeks g/d) + pravastatin (40 mg/d) Ito and Shabetai Cholestyramine (10 28 18 weeks 1997 (70) g/d) + pravastatin (20 mg/d) Sprecher et al 1994 (42) Cholestyramine (8-16 73 24 weeks g/d) + fluvastatin (10-20 mg/d) FATS 1990 (80) Colestipol (30 g/d) + 38 2.5 years lovastatin (40 mg/d) Denke and Grundy Cholestyramine (8 26 12 weeks 1995 (74) mg/d) + lovastatin (5 mg/d) Schrott et al 1995 (73) Colestipol (10 g/d) + 23 12 weeks lovastatin (20 mg/d) Simons et al 1992 (75) Colestipol (5-10 g/d) 64 18 weeks + simvastatin (20-40 mg/d) Davidson et al 2001 (71) Colesevelam HCl (2.3 50 4 weeks g/d) + lovastatin (10 mg/d) Knapp et al 2001 (76) Colesevelam HCl (2.3 71 6 weeks or 3.8 g/d) + simvastatin (20 or 10 mg/d) Hunninghake et al Colesevelam HCl (3.8 19 4 weeks 2001 (77) g/d) + atorvastatin (10 mg/d) BAS + niacin combinations Series et al 1990 (82) Cholestyramine (12 12 12 weeks g/d) + niacin (750 mg/d) CLAS 1987, 1990 (78, 79) Colestipol (30 g/d) + 94 2 years niacin (3-12 g/d) 56 4 years FATS 1990 (80) Colestipol (30 g/d) + 36 2.5 years niacin (4 g/d) BAS + fibrate combinations Houlston et al 1988 (85) Cholestyramine/ 13 16 months colestipol + gemfibrozil (no doses given) Sommariva et al Cholestyramine (16 6 1 year 1986 (87) g/d) + bezafibrate (600 mg/d) Curtis et al 1988 (88) Cholestyramine (24 18 8 weeks g/d) + bezafibrate (600 mg/d) Series et al 1989 (86) Cholestyramine (16 21 12 weeks g/d) + bezafibrate (400 mg/d) Weisweiler and Colestipol (15 g/d) + 6 8 weeks Schwandt 1986 (83) fenofibrate (250 mg/d) Barbir et al 1994 (84) Colestipol (10 g/d) + 11 8 weeks bezafibrate (400 mg/d) McKenney 2005 (89) Colesevelam HCl (3.8 64 6 weeks g/d) + fenofibrate (160 mg/d) BAS + CAI combinations Zema 2005 (91) Colesevelam HCl (3.8 12 12 weeks g/d) + ezetimibe (10 mg/d) BAS in 3 drug combinations Malloy et al 1987 (104) Colestipol (30 g/d) + 21 15 months lovastatin (40-60 mg/d) + niacin (1.5-7.5 g/d) FATS Extension Colestipol (20 g/d) + 29 1 year 1997 (103) lovastatin (38 mg/d) + niacin (2 g/d) Wierzbicki et al Cholestyramine (32 51 3 months 1999 (115) g/d) + simvastatin (40 mg/d) + fenofibrate (200 mg/d) % Change from baseline in lipids and lipoproteins Study TC LDL-C HDL-C BAS + statin combinations Pan et al 1990 (69) -32 to -47 to +11 to 18% (b) 38% (b) 56% (b) PMS II 1993 (68) -37% (b,c) -51% (b,c) +6% (b) Ito and Shabetai -29% (d) -41% (d,e) -4% (d) 1997 (70) Sprecher et al 1994 (42) -18 to 22% -26 to +2 to 3% 31% (b,e) FATS 1990 (80) -34% (b) -45% (b) +16% (b) Denke and Grundy -13% (b) -24% (b) +5% 1995 (74) Schrott et al 1995 (73) -32% (b) -48% (b,e) +4% Simons et al 1992 (75) -37 to -45 to +3 to 9% (c,d) 41% (c,d) 50% (c,d) Davidson et al 2001 (71) -21% (b,c) -32 to +3% 34% (b,c) Knapp et al 2001 (76) -28 to -42% (b,c) +7 to 10% (b) 29% (b,c) Hunninghake et al -31% (b,c) -48% (b,c) +11% (b) 2001 (77) BAS + niacin combinations Series et al 1990 (82) -27% (b) -32% (b) +45% CLAS 1987, 1990 (78, 79) -26% (b) -43% (b) +37% (b) -25% (b) -40% (b) +37% (b) FATS 1990 (80) -23% (b) -32% (b) +43% (b) BAS + fibrate combinations Houlston et al 1988 (85) -32% (d,f) ND +15% (d) Sommariva et al -33% (d,g) -37% (d) +1% (d) 1986 (87) Curtis et al 1988 (88) -35% (c,d) -39% (c,d) +2% (d) Series et al 1989 (86) -28% (c,d) -37% (c,d) +22% (d) Weisweiler and -36% (b) -41% (b) +14% (b) Schwandt 1986 (83) Barbir et al 1994 (84) -17% (d) -23% (d) +14% (d) McKenney 2005 (89) -15% (d,h) -17% (d,h) +12% (d) BAS + CAI combinations Zema 2005 (91) -23 to -37 to -2 to + 6% (d) 29% (c,d) 41% (c,d) BAS in 3 drug combinations Malloy et al 1987 (104) -55% (i) -66% (i) +32% (i) FATS Extension -43% (d) -57% (d) +27% (d) 1997 (103) Wierzbicki et al -31% (d) -39% (d) +16% (d) 1999 (115) % Change from baseline in lipids and lipoproteins Study TG ApoB BAS + statin combinations Pan et al 1990 (69) +5 to 13% ND PMS II 1993 (68) 0% ND Ito and Shabetai -3% (d) -33% (d) 1997 (70) Sprecher et al 1994 (42) +3 to 7% ND FATS 1990 (80) -9% -35% (b) Denke and Grundy +29% (b,c) ND 1995 (74) Schrott et al 1995 (73) +5% -40% (b) Simons et al 1992 (75) -15 to 24% (d) -41 to 43% (c,d) Davidson et al 2001 (71) -3 to +9% -24% (b) Knapp et al 2001 (76) -12% (b) -32 to 33% (b,c) Hunninghake et al -1% (c) -38% (b,c) 2001 (77) BAS + niacin combinations Series et al 1990 (82) -13% (b) ND CLAS 1987, 1990 (78, 79) -22% (b) -33% (b) -18% (b) -32% (b) FATS 1990 (80) -29% (b) -28% (b) BAS + fibrate combinations Houlston et al 1988 (85) -54% (d,f) ND Sommariva et al -20% (d) ND 1986 (87) Curtis et al 1988 (88) -19% (c,d) -30% (c,d) Series et al 1989 (86) -39% (d) ND Weisweiler and -30% (b) -28% (b) Schwandt 1986 (83) Barbir et al 1994 (84) -19% (d) ND McKenney 2005 (89) -32% (d) -20% (d, h) BAS + CAI combinations Zema 2005 (91) 4 to 19% (d) ND BAS in 3 drug combinations Malloy et al 1987 (104) -42% (i) ND FATS Extension -38% (d) -45% (d) 1997 (103) Wierzbicki et al -25% (d) -27% (d) 1999 (115) (a) N indicates the number of patients treated with combination therapy within the study. (b) Significant compared with baseline. (c) Significant compared with either treatment alone. (d) Comparisons vs baseline not reported. (e) Significantly better compared with high-dose statin monotherapy. (f) Significant additional reductions vs BAS monotherapy. (g) Significant reduction vs bezafibrate monotherapy. (h) Significant additional reduction vs fenofibrate monotherapy. (i) Significant compared with colestipol + niacin. (j) Mean dosages ApoB, apolipoprotein B; BAS, bile acid sequestrant; BID, twice daily; CAI, cholesterol absorption inhibitor; CLAS, Cholesterol-Lowering Atherosclerosis Study; FATS, Familial Atherosclerosis Treatment Study; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ND, not determined (values were not determined or not reported); PMS, Pravastatin Multicenter Study Group; TC, total cholesterol; TG, triglycerides. Table 4. Bile acid sequestrant therapy: summary of cardiovascular outcome and plaque regression clinical trials Men Study Agents N (%) BAS monotherapy Dorr et al 1978 (92) Colestipol 1149 48% Placebo 1129 48% LRC-CPPT 1984 (26, 61) Cholestyramine 1906 100% Placebo 1900 100% NHLBI Type II Study Cholestyramine 59 81% 1984 (27, 62) Placebo 57 81% STARS 1992 (94) Cholestyramine + diet 24 100% Diet 26 100% Usual care 24 100% BAS combination therapy CLAS 1987 (78) Colestipol + niacin 94 100% Placebo 94 100% FATS 1990 (80) Colestipol + niacin 36 100% Colestipol + lovastatin 38 100% Usual care 46 100% Kane et al 1990 (98) Colestipol + niacin + lovastatin 40 45% Control (plus low-dose colestipol 32 41% [14/32 patients]) HARP 1994 (116) Stepwise: pravastatin + niacin + 40 90% cholestyramine + gemfibrozil Placebo 30 87% PQRST 1994 (117) Cholestyramine + probucol 138 57% Cholestyramine + placebo 136 58% AFREGS 2005 (90) Cholestyramine + niacin + 71 90% gemfibrozil Placebo 72 94% Partial ileal bypass POSCH 1990 (118) Partial ileal bypass 421 91% Control 417 91% Study LDL-C Patients duration reduction with CV Study (years) (%) events (%) BAS monotherapy Dorr et al 1978 (92) 2 (b) -12% (c) 4% (d,e) -2% (c) 9% (e) LRC-CPPT 1984 (26, 61) 7.4 (b) -20% (d) 8% (d,f) -8% 10% (f) NHLBI Type II Study 5 -26% (d) ND 1984 (27, 62) -5% ND STARS 1992 (94) 3.3 (b) -36% (h,i) 4% (d) -16% (h,i) 11% (c) 0% 36% BAS combination therapy CLAS 1987 (78) 2 -43% (d,h) 25% -5% (h) 25% FATS 1990 (80) 2.5 -32% (h,i) 4% (d) -46% (h,i) 7% (d) -7% (h) 19% Kane et al 1990 (98) 2.2 -38% (d) ND -11% ND HARP 1994 (116) 2.5 -38% (d) 14% +3% 21% PQRST 1994 (117) 3 -3% (d) 28% +8% 21% AFREGS 2005 (99) 2.5 -22% (d) 13% (d) +5% 26% Partial ileal bypass POSCH 1990 (118) 10 -39% (i) 19% (d,n,o) -6% (i) 30% (o) Patients with Patients with CAD CAD Study progression (%) (a) regression (%) (a) BAS monotherapy Dorr et al 1978 (92) ND ND ND ND LRC-CPPT 1984 (26, 61) ND ND ND ND NHLBI Type II Study 32% (d,g) 7% 1984 (27, 62) 49% (g) 7% STARS 1992 (94) 12% (d) ND 15% (d) ND 46% ND BAS combination therapy CLAS 1987 (78) 10% (d,j) ND 22% (j) ND FATS 1990 (80) 25% (d,g) 39% (d,g) 21% (d,g) 32% (d,g) 46% (g) 11% (g) Kane et al 1990 (98) 20% (k) 33% (k) 41% (k) 13% (k) HARP 1994 (116) 33% (g) 13% (g) 38% (g) 15% (g) PQRST 1994 (117) ND 0.6%, 3% (l) ND 4% (h), 4% (l) AFREGS 2005 (90) 30% (m) 52% 50% (m) 42% Partial ileal bypass POSCH 1990 (118) 55% (d,p) 6% (i) 85% 4% (i) (a) Includes patients who may have also had regression/progression, except where indicated. (b) Mean follow-up time reported. (c) Total cholesterol levels reported because LDL-C levels not available. (d) P <0.05 compared with placebo, usual care, or control. (e) Percentage represents only the men enrolled in the study (n = 1094). Differences were nonsignificant for women. (f) Only CAD deaths and nonfatal myocardial infarctions are included. Risk reduction was 19% relative to the incidence of CV events in the placebo-treated group. (g) Definite or probable progression with no regression or regression with no progression. (h) P<0.05 compared with baseline. (i) Statistical comparisons not conducted between treatment groups. (j) Number represents percentage of patients with new lesions in native vessels. (k) Although not statistically significant, there was a strong trend towards favoring active treatment over control. (l) Numbers represent % increase in femoral artery lumen volume from baseline and % decrease in roughness of arterial edge. (m) Statistical comparisons were only conducted for the percentage of patients who had "controlled" CAD (that is, patients who had regression or no change). That comparison (70% vs 50% for drug therapy vs placebo) was significant (p<0.05). (n) Only CAD deaths and nonfatal myocardial infarctions are included. (o) Represents a 35% risk reduction. (p) Data on 10 years of follow-up reported; a significant difference was also observed after 3, 5, and 7 years of follow-up. AFREGS, Armed Forces Regression Study; BAS, bile acid sequestrant; CAD, coronary artery disease; CV, cardiovascular; FATS, Familial Atherosclerosis Treatment Study; HARP, Harvard Atherosclerosis Reversibility Project; LRC-CPPT, Lipid Research Clinics Coronary Primary Prevention Trial; ND, not determined (values were not determined or not reported); NHLBI, National Heart, Lung, and Blood Institute (NHLBI) Type II Coronary Intervention Study; POSCH, Program on the Surgical Control of the Hyperlipidemias; PQRST, Probucol Quantitative Regression Swedish Trial; STARS, St. Thomas' Atherosclerosis Regression Study.