Bile acid sequestrants, including colesevelam, colestipol, and cholestyramine, are approved by the Food and Drug Administration (FDA) in combination with restriction of dietary saturated and trans-fatty acids to manage hypercholesterolemia. They are indicated for patients with hypercholesterolemia without hypertriglyceridemia.[1] As monotherapy in the Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT) they reduced low-density lipoprotein cholesterol (LDL-C)  by 20 % and cardiovascular events[2] In this trial, cholestyramine (24g/d) versus placebo reduced the primary outcome of combined coronary heart disease and non-fatal myocardial infarction by 19% in patients with primary hypercholesterolemia. They can be used in combination with HMG-CoA reductase inhibitors (statins) or as monotherapy.

Three double-blind, placebo-controlled trials with the use of colesevelam HCL (COL) in patients with Type II diabetes mellitus (T2D) patients showed reductions in LDL-C and hemoglobin (Hb)A1c. These results led to the FDA approval of COL as an adjuvant to exercise and dietary restriction for improving glycemic control in patients with T2D. Therefore, COL therapy is effective for patients with diabetes who have not met their HbA1c goal of below 7% or LDL-C goal of under 100 mg/dL or 30 to 49 %  or over 50 % reduction in LDL-C.[3] The main advantage of using bile acid sequestrants is that it is safe for administration in combination with other anti-diabetic medications and statins. They are the safest LDL-C lowering therapy to date.

In an early study assessing bile acid sequestrants use in Type IIA hyperproteinemia, subjects were randomized to a low cholesterol diet with either placebo or colestipol (30 mg) over seven years. The colestipol group had a decrease of LDL-C from 331.1 +/- 22.8 to 188.1 +/- 13.8 mg/dL.  Diet plus placebo group showed no improvement.[4] The National Heart Lung and Blood Institute (NHLBI) studied the effects of cholestyramine on coronary atherosclerosis. The study looked at 116 people who had type II hyperlipoproteinemia and coronary artery disease. Patients were all on a low-fat, low-cholesterol diet and assigned either placebo or 6 g of cholestyramine, four times daily. Cholestyramine decreased LDL-C by 26% after randomization. Coronary artery disease progressed in 32% vs. 49% of patients in cholestyramine vs. placebo, respectively. The cardioprotective effects of cholestyramine appear to be largely due to a reduction of LDL-C.[5][6] These results illustrate that bile acid sequestrants can be effective in reducing cardiovascular disease and reducing LDL-C compared to lifestyle changes alone.

Bile acid sequestrants are beneficial therapy in statin-intolerant patients (myalgia and myopathy). They can be used in combination with niacin and the cholesterol absorption inhibitor, ezetimibe, to achieve target goals in patients in both primary and secondary prevention. They can lower LDL-C between 15 to 30% if tolerated at full doses by patients.

Some bile acid sequestrants are also FDA approved for adolescent patients (10 to 17 years of age).[3] Therefore, bile acid sequestrants are one of the few drugs safe for children with heterozygous familial hypercholesterolemia. Studies have assessed the use of cholestyramine in children with type II hyperlipoproteinemia (12 g/day), and while most patients had normal cholesterol blood concentrations after six months, adherence was often poor. Only 55% of children were still on treatment at six years, and 48% after eight years. Adherence plays a critical role in this population since this group will likely require lifelong lipid-lowering therapies.[4]

Bile acid sequestrants are also safe to use in pregnant patients with hypercholesterolemia. As an off label use, cholestyramine can treat chronic diarrhea due to bile acid malabsorption. They can also help with the treatment of pruritus resulting from elevated concentrations of bile acids and as adjunctive therapy to Graves disease hyperthyroid patients.[7][8]

The mechanism by which bile acid sequestrants reduce LDL-C involves malabsorption of bile acids in the intestine, where it forms an insoluble complex that gets excreted in the feces, causing the depletion of bile acids from the enterohepatic circulation. Since it is not intestinally digestible, it is biochemically unchanged when passing through the intestines. As bile acid concentrations decrease, more hepatic cholesterol converts to bile acids due to disinhibition of cholesterol 7-alpha hydroxylase, the rate-limiting step in bile acid production; this results in a decrease in hepatic cholesterol and upregulation of hepatic  LDL receptors, and consequentially there is a decrease in LDL-C blood concentrations. Some evidence suggests that bile acid sequestrants also causes an increase in 3-hydroxy-3-methyl glutaryl-coenzyme A, the rate-limited step in hepatic cholesterol synthesis.[9] Although cholesterol synthesis increases with bile acid sequestrants use, the plasma cholesterol does not rise due to the shunting of newly formed cholesterol to bile acid synthesis pathways. Bile acid sequestrants may also have a role in reducing inflammation. One study found that colesevelam HCL monotherapy (3.75 g/day for six weeks) lowered high sensitivity-C reactive protein by 15.9%  in a double-blind, placebo-controlled study.[10]

Bile acid sequestrants are administered orally as a prepared suspension or tablets, preferably at mealtime. It is recommended to be taken at various times during the day, depending on the resin and dosage form. The three that are available are cholestyramine, colestipol, and colesevelam; maximum doses are 24, 20, and 3.75g, respectively. For cholestyramine, 4 g 1 to 2 times/day is desirable to lower LDL-C. Twice daily dosing is the recommendation, but it can be used up to 6 times daily. Colestipol can be used as 2 g tablets once or twice daily and can be increased by 2 g once or twice daily at 1 to 2-month intervals. Both cholestyramine and colestipol are powders mixed with water or juice. Colesevelam oral dosing is 3.75 g/day in 1 or 2 divided doses for diarrhea associated with bile acid malabsorption, hyperlipidemia, and/or T2DM. The FDA recently approved a form of colesevelam as a chewable bar intended for administration with meals. To minimize side effects, they should be started at the lowest dose and titrated up gradually. Also, increasing fiber in the diet, such as bran and psyllium husk, can help with adherence. However, there tends to be poor adherence with large doses of bile acid sequestrants making bile acid sequestrants greater than 15 g two times daily ineffective.[11] If resin treatment gets discontinued, cholesterol blood concentrations return to pretreatment blood concentrations in approximately one month.[12]

Since bile acid sequestrants are not absorbed in the gastrointestinal tract, they have limited systemic side effects. Some of the most common adverse effects are gastrointestinal, including constipation, stomach pain, bloating, vomiting, heartburn, loss of appetite, indigestion, and upset stomach. One of the most common side effects is constipation (10% in those taking colestipol and 28% in those taking cholestyramine). These side effects occur more commonly in those taking larger doses and in older patients (older than 65 years). They can exacerbate peptic ulcer disease and hemorrhoids. Cholestyramine use requires caution in renally impaired patients as it can cause hyperchloremia acidosis, especially at higher doses. Some report a wide array of adverse effects including edema, syncope, dizziness, drowsiness, headaches, neuralgia, paresthesia, skin rashes, irritation, weight gain or loss, abdominal pain, biliary colic, constipation, dental discoloration, diarrhea, steatorrhea, abnormal hepatic function test, anemia, adenopathy, dyspnea,  or wheezing, less than 1 in 1000 patients on colestipol have hypersensitivity including urticaria or dermatitis. Asthma-like symptoms were not observed with colestipol but can occur with cholestyramine. Resin therapy has reportedly produced transient and modest increases in serum transaminases and alkaline phosphatase.[1]

Indications for bile acid sequestrants do not include patients with complete biliary obstruction. If used chronically, it has correlations with bleeding problems in high doses, which is preventable by using oral vitamin K therapy. Bile acid sequestrants may also decrease the absorption of many drugs by binding and excretion in the feces when taken concomitantly. To avoid interference with the other drugs commonly, thyroxine, digoxin, and warfarin, hydrochlorothiazide, they should be taken 1 hour before or 4 hours after the bile acid sequestrants. It can also induce malabsorption of fat-soluble vitamins, and therefore patients with fat-soluble vitamin deficiencies should avoid bile acid sequestrants use. If using bile acid sequestrants with fat-soluble vitamins (vitamins A, D, E, and K ) and folic acid, the patient should take the vitamins over 4 hours before. Some studies have shown that colestipol can bind T4 in the gut in vitro. Theoretically, this binding can disrupt normal T4 reabsorption causing hypothyroidism. However, further investigation found that euthyroid patients had normal thyroid concentrations throughout resin treatment. As a precaution, patients taking supplemental thyroid should not take their thyroid medications at the same time as taking bile acid sequestrants.[13]

Bile acid sequestrants are inappropriate for use in patients with serum triglycerides greater than 300 mg/dl or in those who have type III hyperlipoproteinemia since they can exacerbate hypertriglyceridemia and put the patient at risk for pancreatitis. Bile acid sequestrants are used with caution in patients with triglyceride concentrations of 250 to 299 mg/dL with regular monitoring every 4 to 6 weeks after administration, with discontinuation of therapy if triglycerides exceed 400 mg/dL.[14]