Use and indications of cholestyramine and bile acid sequestrants
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- Scaldaferri, F., Pizzoferrato, M., Ponziani, F.R. et al. Intern Emerg Med (2013) 8: 205. doi:10.1007/s11739-011-0653-0
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Cholestyramine is a bile acid sequestrant, like colestipol and colesevelam. These molecules are positively charged non-digestible resins that bind to bile acids in the intestine to form an insoluble complex, which is excreted in the feces. They are used mainly for the treatment of primary hypercholesterolemia and hypercholesterolemia associated with mild hypertriglyceridemia, in patients not responding to dietary treatment as well as a second line-treatment for pruritus associated with cholestatic disease, in patients with incomplete biliary obstruction. Several data indicate that modulation of bile acid homeostasis has a good clinical effect in managing diabetes mellitus and the diarrhea from bile acid malabsorption. In this review, we present the “in label” use and indication for these compounds, revisiting the other clinical applications that may benefit from the use of bile acid sequestrants in the near future.
KeywordsCholestyramineBile acid sequestrantsColestipolColesevelam
Cholestyramine is a bile acid sequestrant, like colestipol and colesevelam. These molecules are positively charged non-digestible resins that bind to bile acids in the intestine to form an insoluble complex, which is excreted in the feces. This binding reduces the enterohepatic recirculation of bile acids, which releases feedback regulation on the conversion of cholesterol to bile acids in the liver. The resulting decrease in hepatocyte cholesterol content enhances LDL-receptor expression, which in turn lowers serum LDL-cholesterol concentration .
Cholestyramine and colestipol have also been extensively used to treat cholestatic pruritus, especially in Primary Sclerosing Cholangitis , and the recent studies demonstrate the important role of bile acid sequestrants in the treatment of type 2 diabetes mellitus (DMT2), metabolic syndrome  as well as insulin resistance .
Although cheap and with a high safety profile, these compounds are poorly tolerated because of frequent gastrointestinal side effects, including constipation, abdominal pain, bloating, fullness, nausea, and flatulence which lead to therapy discontinuation in 40–70% of patients . BAS may also induce an increase in triglyceride levels. Furthermore, cholestyramine reduces the intestinal absorption of many drugs (warfarin, tetracycline, furosemide, penicillin G, hydrochlorothiazide, propranolol, digoxin and gemfibrozil) and vitamins (vitamin K and vitamin A) . This effect may be overcome by anticipating or delaying the administration of cholestyramine 1 h before or 4 h after meals. On the contrary, colesevelam apparently does not decrease absorption of co-administered drugs . Colesevelam actually has a particular individual structure compared with cholestyramine and colestipol, being a polyallylamine crosslinked with epichlorohydrin and alkylated groups. This results in an “open” structure with side chains that maximize interactions with bile salt and reduce potential interactions with other drugs. Furthermore, colesevelam has a more gelatinous consistency compared with cholestyramine in the enteric environment, with a great improvement in tolerability . Cholestyramine seems to preferentially bind the more hydrophobic acids chenodeoxycholic and deoxycholic acids over the more hydrophilic cholic acid, causing the formation of hydrophilic bile. Instead colesevelam also binds cholic acid, with no bile alterations. The impact of this modification in clinical practice is yet unknown .
In Italy, the only bile acid sequestrant approved by AIFA is cholestyramine (Questran©), produced and marketed by Bristol-Myers Squibb.
treatment of primary hypercholesterolemia and hypercholesterolemia associated with mild hypertriglyceridemia, in patients not responding to dietary treatment;
the pruritus associated with cholestatic disease, in patients with incomplete biliary obstruction.
However, the use of cholestyramine is not limited to the “in label” indications.
In this review, we present the “in label” use, and indications for these compounds, revisiting the other clinical applications that may extend BAS use in the near future.
Use of bile acid sequestrants in dyslipidemia
Cholestyramine, as well as the other bile acid sequestrants, is able to lower LDL-cholesterol by 12–20%, when dispensed alone, and to increase HDL cholesterol by 3–5%. It is usually given once or twice daily with meals. The LDL-cholesterol lowering effect of 4 g of cholestyramine equals that of 5 g of colestipol. Eight to ten grams per day cholestyramine or 10–20 g/day colestipol reduce LDL-cholesterol concentrations by 10–20%. Low doses of sequestrants (8–10 g/day) generally are well tolerated while higher doses (16–20 g/day) are associated with more side effects. Colesevelam, a recently marketed drug, is a much more potent bile acid sequestrant. It has been primarily tested at doses of 2.6–3.8 g/day, with a 12–18% reduction in LDL-cholesterol. Since sequestrants induce an increase in serum triglycerides, they are contraindicated as monotherapy in patients with hypertriglyceridemia (>400 mg/dL), as well as in familial dysbetalipoproteinemia; on the contrary, monotherapy can be proposed in patients with triglyceride levels lower than 200 mg/dL .
The European Society of Cardiology and the National Cholesterol Education Program guidelines recommend monotherapy with BAS for patients with a moderate elevation of LDL-cholesterol, especially in the young or women who wish to have a pregnancy [1, 8].
Furthermore, bile acid sequestrants can be useful in combined drug therapy, especially with statins. Cholestyramine may be added to statins when their maximal doses have not achieved target goals, or can be added to lower doses of statin in case of poor tolerability and side effects, as second-line therapy .On the contrary, if cholestyramine is not tolerated, ezetimibe or nicotinic acid can be added to the statin  or used alone.
One large trial reports that an aggressive lowering of LDL-cholesterol with such a combination of lovastatin and cholestyramine in patients with coronary artery bypass grafts may reduce lesion progression better than moderate lovastatin treatment alone[9, 10]. In another study, a combination of colestipol and lovastatin reduces both the frequency of angiographic progression of coronary lesions and cardiovascular events in men with CHD .
Moreover, when associated with gemfibrozil and niacin, cholestyramine significantly reduces cardiovascular events compared to placebo .
However, other studies do not confirm the efficacy of cholestyramine in lowering LDL-cholesterol to the target levels. In particular, Ballantyne et al.  show that a combination of a high dose of rosuvastatin with cholestyramine does not provide significantly better LDL lowering than rosuvastatin alone; furthermore, in another study, Lal et al.  demonstrate that triple combination therapy of lovastatin, nicotinic acid and cholestyramine fails to lower LDL-cholesterol to the recommended target levels.
On the contrary, colesevelam seems to be more effective in lowering cholesterol levels than cholestyramine/colestipol with statins or statins alone [15–17]. A recent 12-week multicenter trial demonstrates that colesevelam added to a combination of statin + ezetimibe is associated with better LDL-cholesterol concentrations compared to placebo, and it is generally well tolerated . Colesevelam can also be added to Ezetimibe without any statin. A 6-week multicenter, randomized placebo-controlled study demonstrates an important reduction in LDL and total cholesterol concentrations in patients with primary hypercholesterolemia treated with Ezetimibe + colesevelam when compared to patients treated with Ezetimibe only . Another study indicates an important reduction in LDL and total cholesterol concentrations with an increase of triglyceride concentration, in patients treated with ezetimibe + colesevelam compared to ezetimibe alone .
Finally, other studies indicate that the combination of statin + ezetimibe is more effective that statin + bile acid sequestrants in controlling cholesterol levels [21, 22]; however, bile acids sequestrants are a good rescue therapy for patients who present statin intolerance or myopathy: colesevelam, added to Ezetimibe or to low doses of Fenofibrate, represents the first choice therapy in multiple statin intolerances [23, 24].
Taken together, these studies suggest that bile acid sequestrants added to statins induce a 10–15% lowering in LDL levels; in contrast to 20% of ezetimibe + statins combined treatment.
Use of bile acid sequestrants in cholestatic pruritus
Cholestyramine and colestipol represent two resins that have been extensively used for the treatment of cholestatic pruritus. Up to 80% of patients have at least a partial response to these drugs after 2 weeks . Cholestyramine should be started at 4 g/day and should be increased, in case of therapeutic failure, until a maximum of 16 g/day. As “pruritogens” accumulate in the gallbladder during the night, it is reasonable to administer BAS 1 h before and after breakfast .
The gastrointestinal side effects and the interaction with the adsorption of other drugs make these compounds less preferable than Ursodeoxycholic Acid (UDCA). Unfortunately colesevelam, which is not associated with gastrointestinal side effect and is not influencing the absorption of other drugs, has been demonstrated to be no more efficacious than placebo in alleviating the severity of pruritus in cholestasis .
Several studies demonstrate the efficacy of a first-line therapy with UDCA, and, only in non responders, a second-line therapy with bile acid sequestrants .
In hypercholesterolaemic patients, cholestyramine associated with UDCA is considered as a first-line therapy for cholestatic pruritus, while statins should be limited to hypercholesterolaemic patients with serum levels of HDL lower than the protective range, or if additional risk factors for cardiovascular disease are present .
Bile acid sequestrants in treatment of diabetes
The first clinical indication that bile acid sequestrants play a role in glucose metabolism goes back to 1994, when a study conducted by Garg and Grundy demonstrates that, in patients with type 2 DM and dyslipidemia, cholestyramine decreases LDL-cholesterol levels by 28%. It also reports an improved glycemic control with lower glycosylated hemoglobin A1c (HbA1c) . More recently, in three 26-week, double-blind, placebo-controlled trials, the addition of colesevelam to the anti-diabetes regimen in patients with type 2 DM, who were inadequately controlled by their usual therapy, resulted in additional important reductions in HbA1c [30–32]. The exact mechanism of action of bile acid sequestrants in lowering glucose level is largely unknown. There is evidence that cholestyramine and colesevelam modify bile acid pool size and composition, which is altered in animal models as well as in humans of either type 1 and type 2 diabetes .The reduction of enterohepatic circulation decreases the activation of Farnesoid X receptor (FXR); in physiologic conditions, bile acids bind to FXR, and activation of FXR results in the inhibition of CYP7A1, thereby reducing bile acid synthesis and promoting gluconeogenesis. A decrease in enterohepatic availability of bile acids inhibits FXR, which in turn induces a downregulation of gluconeogenetic gene expression, like phosphoenolpyruvate, a key enzyme in this biochemical process .
Moreover, bile acid sequestrants seem able to upregulate incretin, like intestinal glucagon like peptide (GLP1) secretion . The molecular mechanisms of this process are still not clear, but bile acid sequestrants seem able to affect the TGR5 pathway, a G protein-coupled cell surface receptor, whose major agonist is represented by lithocolic acid, resulting in GLP1 secretion .
A recent 16-week, randomized, double-blind, placebo-controlled study demonstrates that metformin plus colesevelam can be a valid option as initial therapy to achieve glycemic and lipid levels control safely in early type 2 diabetes, reducing also HbA2 by 1.1%; furthermore, the combination of colesevelam and metformin compared to metformin alone, is also able to significantly reduce LDL and total cholesterol, apolipoprotein B and high-sensitivity C-reactive protein levels, although increasing apolipoprotein A-I and triglycerides .
Bile acid sequestrants in treatment of diarrhea
The role of cholestyramine in the treatment of diarrhea has been known for a long time, particularly during diarrhea related to bile acid malabsorption .
In this condition, the failure of bile salts absorption in the distal ileum leads to watery chronic diarrhea because of several mechanisms including: secretion of sodium and water, increase in colonic motility, increase in mucus secretion and also increase in intestinal epithelial cell damage .
type 1, the most common in clinical practice, related to ileal dysfunction, as happens in ileal Crohn’s disease or ileal resections ;
type 2, related to idiopathic bile acid malabsorption;
type 3, related to other conditions, like cholecystectomy, vagotomy, celiac disease and bacterial overgrowth.
Oral BAS sequestrants are particularly active in controlling diarrhea for type 2 idiopathic bile acid malabsorption; in this condition, the enterocyte’s inability to synthesize FGF19 protein, involved in the downregulation of hepatic bile acid synthesis, causes the bile acid pool expansion and the saturation of ileal absorption mechanisms with an increased flux of bile acid into the colon causing diarrhea . In this pathophysiological context, cholestyramine seems to be effective in reducing the number and intensity of evacuations daily , even in a single dose .
Unfortunately, the gastrointestinal side effects of cholestyramine are responsible for the treatment failure; moreover, a recent study  questions the efficacy of cholestyramine in patients with severe bile acid malabsorption, since the treatment not only does not benefit but also worsens symptoms . Nevertheless, these patients respond to a low-fat diet supplemented with medium-chain triglycerides .
Colesevelam, instead, seemed to be more effective than cholestyramine, and associated with lower incidence of adverse events .
Although in Crohn’s disease bile acid malabsorption (type 1 BAM) is frequent, and sequestrant therapy can improve diarrhea, it is not recommended by ECCO guidelines . The same is also true for postoperative recurrence of Crohn’s disease . Another report  shows that, when added to Mesalazine, cholestyramine is effective in ameliorating the symptoms of Collagenous Colitis.
Ileal resection may lead to impaired adsorption of bile acids with consequent chronic watery diarrhea. Since the 70s, many studies have demonstrated the role of bile acid malabsorption in the pathogenesis of diarrhea and steatorrhea in patients with ileal resections , and indicate that cholestyramine can improve this type of diarrhea .
More recently, especially in patients with intestinal resection >100 cm, bile acid sequestrants represent only a third-line therapy and cholestyramine should be avoided, as it may exacerbate steatorrhea and may reduce the absorption of vitamins and other drugs. First-line medical therapy for diarrhea in ileal resections includes Loperamid and other opioids, H2 blockers, PPIs, pancreatic enzymes and antimicrobials; probiotics and somatostatin analogs are considered second-line drugs [49, 50].
Bile acid sequestrants availability worldwide
Bile acid sequestrants are used in many countries and among these drugs, cholestyramine is the most utilized. According to a search made from public domain databases, Cholestyramine is commercially available in 50 different countries, while colestipol is available in only a few regions, and colesevelam is marketed only in Holland and USA. In many countries, cholestyramine is sold under the brand name Questran©, and, less often, Quantalan© (Austria, Switzerland, Germany and Portugal), produced by Bristol-Myers Squibb. In 17 countries, other brand names for cholestyramine were identified from different companies (Bestpharma, Medicalex, Faes, Lagap, Sandoz, Pharmascience, Upsher-SmithPar, Sanofi-Aventis, Pharose, EURO, Rubio, Felgenträger), but none of them is available at present in the Italian Formulary. Furthermore, colestipol and colesevelam are not yet available in Italy.
This situation probably reflects a lack of information about these compounds and their indications, both deriving from the low number of good studies assessing efficacy of these drugs for both “in label” and “off label” applications (including dyslipidemia, cholestatic pruritus, diabetes mellitus and diarrhea). Moreover, a few studies are available to compare these compounds to other to-date more valuable alternative drugs.
Conclusions and recommendations
Bile acid sequestrants are able to modulate cholesterol metabolism. According to the European Society of Cardiology guidelines, cholestyramine or other bile acid sequestrants are recommended as a second- or third-line monotherapy for patients with moderate elevations of LDL-cholesterol levels in the absence of hypertriglyceridemia, especially in the young or women who are considering pregnancy. They are more frequently combined with statins alone or with ezetimibe, although the combination of ezetimibe and statins is more effective. Bile acid sequestrants are still the best choice in patient with a dyslipidemia intolerant to statins.
Their efficacy, however, is not so strong, and sometimes they are complicated by important side effects, particularly evident for the older formulations, which may limit their use.
Furthermore, cholestyramine together with colestipol (but nor colesevelam) is also indicated for the treatment of cholestatic disease, in patients with incomplete biliary obstruction. Their use is considered as a second-line association treatment, upon the failure of Ursodeoxycholic Acid (UDCA).
Recent reports indicate colesevelam and other sequestrants as adjuvants for type 2 DM treatment.
Finally bile acids sequestrants are used in bile acid malabsorption associated diarrhea, particularly if mild to moderate. Their use has also been indicated for the conditions leading to a secondary bile acid malabsorption, like Crohn’s disease, however, their indications and efficacy should be better assessed.
Taken together, bile acid sequestrants can be considered interesting products, whose present and possible future indications should be taken into account for several clinical conditions, although more studies are needed to assess their tolerability and efficacy.
Conflict of interest