BILE ACID SEQUESTRANTS

• ACRONYMS AND DEFINITIONS

• ACC - American College of Cardiology
• A1C - Hemoglobin A1C
• ADA - American Diabetes Association
• BAS - Bile acid sequestrants
• GI - GastroIntestinal
• RCT - Randomized controlled trial

• DRUGS IN CLASS

• Bile acid sequestrants
• Cholestyramine (Questran®)
• Colesevelam (Welchol™)
• Colestipol (Colestid®)

• MECHANISM OF ACTION

• Bile acids are water-soluble molecules formed from cholesterol metabolism. Their amphipathic (dual hydrophilic and lipophilic) properties allow them to solubilize cholesterol in the liver, facilitating its elimination. In the small intestine, where they are secreted in response to fatty food consumption, they solubilize dietary fats and promote their absorption.
• Bile acid sequestrants bind bile acids in the intestine, inhibiting their reabsorption and causing them to be eliminated in the stool. As the bile acid pool is depleted, the liver must produce more, which requires it to remove cholesterol from the blood, thus lowering serum LDL levels.
• In liver disease, cholestasis can cause serum bile acid levels to rise. High levels can lead to tissue deposition, which induces pruritis. [23,24]

• FDA-APPROVED INDICATIONS

• Cholestyramine (Questran®)
• Reduction of LDL cholesterol
• To retard the rate of progression and increase the rate of regression of coronary atherosclerosis
• Relief of pruritus associated with partial biliary obstruction


• Colesevelam (Welchol™)
• Primary hyperlipidemia - as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia
• Heterozygous familial hypercholesterolemia (HeFH) - to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (HeFH) who are unable to reach LDL-C target levels despite an adequate trial of dietary therapy and lifestyle modification
• Type 2 diabetes - as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus


• Colestipol (Colestid®)
• Reduction of LDL cholesterol

• LIPID EFFECTS

• HEART DISEASE

• Overview
• The effects of BAS on CVD outcomes have not been studied extensively. Their side effects, dosing requirements, and numerous drug interactions make them less desirable, and they were largely overtaken by statins.
• One randomized controlled trial that evaluated the effects of cholestyramine on heart disease outcomes is summarized below.

• Professional guidelines
• See cholesterol treatment guidelines

• Summary
• There is limited evidence that cholestyramine improves heart disease outcomes
• BAS are not widely prescribed and have largely been replaced by statins

• TYPE TWO DIABETES (WELCHOL)

• Overview
• BAS help lower blood sugars by an unknown mechanism
• Colesevelam (Welchol®) has been FDA-approved to treat type two diabetes
• The effect of colesevelam on blood sugars in two trials is summarized in the table below

• ADA recommendations
• See ADA type 2 diabetes treatment recommendations


• Summary
• Colesevelam has a very modest effect on blood sugars
• Colesevelam can raise triglyceride levels which can be an issue in diabetics
• Other classes of diabetes medications are more effective and are preferred

• PRURITUS IN LIVER DISEASE

• BAS are often used to treat itching in patients with chronic liver disease, and cholestyramine is FDA-approved for the relief of pruritus associated with partial biliary obstruction.
• While it is widely believed that BAS are effective for pruritus in liver disease, no randomized, placebo-controlled trial has ever been performed to substantiate their effectiveness [6,7,9]
• A trial published in 2010 that compared colesevelam to placebo for cholestatic pruritus found no significant difference between the two [8]

• CHRONIC DIARRHEA

• Because constipation is a predominant side effect of BAS, they are sometimes used to treat chronic diarrhea in various syndromes (e.g. short bowel syndrome, dumping syndrome, postvagotomy)
• A number of small clinical trials have found cholestyramine to be effective in reducing chronic diarrhea [16,17,18]

• SIDE EFFECTS

• Gastrointestinal side effects
• BAS cause gastrointestinal side effects in up to 58% of patients in some trials
• The frequency of specific side effects is not well-defined
• Colesevelam (Welchol™) appears to have less gastrointestinal effects than cholestyramine and colestipol [13,14]
• Predominant symptoms include:
• Constipation
• Dyspepsia (indigestion, heartburn)
• Nausea
• Abdominal pain

• Elevated liver enzymes
• BAS have been shown to raise liver enzymes in some trials
• Elevations are not typically clinically significant [2]

• Elevated triglycerides
• BAS can raise triglyceride levels up to 20% in some trials
• Lipid parameters should be checked before therapy and periodically thereafter. Patients with triglyceride levels > 300 mg/dl should have more frequent monitoring.
• Patients with triglyceride levels > 500 mg/dl should not take a BAS [14]

• Vitamin deficiency
• BAS may decrease the absorption of fat soluble vitamins (A,D,E,K) and folic acid
• These effects are not typically clinically significant [19]
• Patients susceptible to vitamin deficiency (ex. elderly) may want to take vitamin supplements while taking BAS

• CONTRAINDICATIONS

• High triglycerides
• BAS can raise triglyceride levels
• Patients with triglyceride levels > 500 mg/dl should not take BAS [14]


• Hypertriglyceridemia-induced pancreatitis
• Because BAS can raise triglyceride levels, patients with a history of hypertriglyceridemia-induced pancreatitis should not take BAS


• Decreased gastrointestinal motility
• BAS can cause or worsen constipation
• Patients with bowel diseases (ex. diabetic gastroparesis) that decrease gastrointestinal motility should not take BAS
• Patients at risk for bowel obstruction (ex. after bowel surgery) should not take BAS
• Patients with swallowing disorders should not take BAS [14,20,21]


• History of bowel obstruction
• BAS are contraindicated in patients with a history of bowel obstruction

• PRECAUTIONS

• Kidney disease
• No dose adjustment necessary

• Liver disease
• No dose adjustment necessary

• Vitamin deficiency
• BAS can decrease the absorption of some vitamins (A,D,E,K, and folic acid)
• Patients with vitamin deficiencies should use caution when taking BAS

• Phenylketonuria (Welchol suspension)
• Each 3.75 gram packet of Welchol for oral suspension contains 27 mg of phenylalanine. Patients with phenylketonuria should use caution.

• DRUG INTERACTIONS

• NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.


• All bile acid sequestrants
• Drug absorption
• Bile acid sequestrants can bind other drugs and inhibit their absorption. To help prevent this, dosing of BAS and other drugs should be spaced out. The Questran and Colestid PIs state that other medications should be taken at least 1 hour before or 4 hours after BAS are taken. The Welchol PI states that other medications should be taken at least 4 hours before Welchol is taken.
• A small study looked at the effect of Welchol on the absorption of pioglitazone, repaglinide, estradiol, norethindrone, levothyroxine, and glyburide. When taken simultaneously, Welchol did not affect pioglitazone, but it significantly reduced the absorption of the other drugs. When glyburide and estradiol were given one hour before Welchol, their absorption was reduced. When glyburide, estradiol, and levothyroxine were given 4 hours before Welchol, their absorption was unaffected. [PMID 19789374]
• Below is an abbreviated list of drugs whose absorption is known to be affected by BAS. Patients should consult their pharmacist when taking other medications with BAS.
• Drugs that are known to be affected by BAS:
• Cyclosporine
• Valproic acid (Depakene®)
• Digoxin (Lanoxin®)
• Furosemide (Lasix®)
• Gemfibrozil (Lopid®)
• Glimepiride (Amaryl®)
• Glipizide (Glucotrol®)
• Glyburide (Diabeta®, Micronase®)
• Hydrochlorothiazide (HCTZ)
• Tetracycline
• Thyroid medications (Synthroid®, Levoxyl®)
• Mycophenolic acid (Myfortic®)
• Olmesartan (Benicar®)
• Oral Contraceptives
• Penicillin (Pen G®)
• Phenobarbital
• Phenytoin (Dilantin®)
• Propranolol (Inderal®)
• Repaglinide (Prandin®)
• Vitamin supplements
• Warfarin (Coumadin®) [14,20,21]


• Colesevelam
• Metformin, extended-release - colesevelam has been shown to increase extended-release metformin exposure. Monitor for side effects when combining.

• Metabolism and clearance
• BAS are not absorbed systemically, and therefore, they do not undergo metabolism or significant renal clearance

• LONG-TERM SAFETY

• BAS have been prescribed since the 1970s. They are not widely prescribed anymore, but they do have a long track record of being safe.

• DOSING

• Bile acid sequestrant dosing chart

• BIBLIOGRAPHY

• 1 - PMID 1611329
• 2 - PMID 2898027
• 3 - PMID 8053615
• 4 - PMID 6360414
• 5 - PMID 6361299
• 6 - PMID 12656688
• 7 - PMID 18528929
• 8 - PMID 20683930
• 9 - PMID 17403073
• 10 - PMID 8148218
• 11 - PMID 7471860
• 12 - PMID 18078024
• 13 - PMID 21537442
• 14 - Colesevelam PI
• 15 - PMID 1347091
• 16 - PMID 326641
• 17 - PMID 3922471
• 18 - PMID 6386762
• 19 - PMID 1168607
• 20 - Cholestyramine PI
• 21 - Colestipol PI
• 22 - PMID 18945920
• 23 - PMID 10597755 - The continuing importance of bile acids in liver and intestinal disease, Arch Intern Med (1999)
• 24 - Welchol PI