Bile Acid Sequestrants

Introduction

Cholestyramine and colestipol are bile acid binding resins that have been in clinical use since the 1960s. Colesevelam, a nonabsorbable polymer, is a more specific anion binding agent that was subsequently developed to address the gastrointestinal adverse effects and drug interactions of the earlier nonspecific, higher volume bile acid binding resins. Cholestyramine and colestipol are available in various formulations as generics.

Clinical Highlight I

• Bile acid sequestrants have tolerability and/or expense issues that limit their use. They are third- or fourth-line agents for lowering low-density lipoprotein cholesterol (LDL-C) after statins and ezetimibe.
• Consider for high-risk patients with statin-associated side effects or familial hypercholesterolemia on maximal statin and ezetimibe therapy who may benefit from additional LDL-C lowering and are not eligible for the addition of PCSK9 inhibitors.
• Do not use a bile acid sequestrant if triglycerides are >200 to 300 mg/dL or if there is a history of severe constipation or bowel obstruction.

Appropriate Uses

LDL-C Lowering

• Cholestyramine and colestipol are indicated as an adjunct to diet for LDL-C lowering.
• Colesevelam is indicated for LDL-C lowering, alone or with statin or fenofibrate.

Other Uses

• Cholestyramine can also be used to relieve pruritus associated with partial biliary obstruction, and may also lower LDL-C in these patients.
• Colesevelam can also improve glycemic control in adults with type 2 diabetes (T2D).

Per the nonstatin recommendations of the 2018 multi-society cholesterol guideline, nonstatins shown to reduce atherosclerotic cardiovascular disease (ASCVD) events in clinical trials are preferred. Cholestyramine has been shown to modestly reduce LDL-C and coronary artery disease (CAD) events when used as monotherapy in a primary prevention population of hypercholesterolemic men (LRC-CPPT). Therefore, a bile acid sequestrant might be considered for additional LDL-C lowering in high-risk patients, especially in those with statin-associated side effects (SASE) or with familial hypercholesterolemia. Although cholestyramine has been shown to reduce CAD events in a primary prevention population of men with hypercholesterolemia (LRC-CPPT), bile acid sequestrants have not been approved by the FDA for cardiovascular risk reduction.

The 2018 multi-society guideline states that the addition of bile acid sequestrants alongside maximally tolerated statin and ezetimibe therapy may be considered (Class of Recommendation [COR] IIb) in patients 20 to 75 years of age with LDL-C ≥190 mg/dL who did not achieve a satisfactory reduction in LDL-C (at least 50%) and who have fasting triglycerides ≤300 mg/dL. The guideline also states that addition of a bile acid sequestrant to moderate-intensity statin therapy may also be reasonable (COR IIb) in intermediate ASCVD risk primary prevention patients who would benefit from more aggressive LDL-C lowering, but who cannot tolerate high-intensity statin therapy. The 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin therapies is in agreement with the 2018 multi-society guideline, and adds that a bile acid sequestrant may be considered in primary prevention patients 40-75 years of age with diabetes (if fasting triglycerides are <300 mg/dL), owing to their modest hypoglycemic effect (or in patients with an inadequate response to ezetimibe or those who cannot tolerate ezetimibe).

Mechanism of Action and Metabolism

Bile acids sequestering agents bind bile acids in the intestinal lumen leading to their excretion in the feces, thus interrupting the enterohepatic recirculation of the cholesterol-rich bile acids and depleting the intrahepatic cholesterol pool. Decreased intrahepatic cholesterol levels stimulate increased transcription of HMG-CoA reductase and upregulation of LDL receptors on the cell surface, thereby increasing removal of LDL-C from the blood. This is the same final mechanism for lowering blood LDL-C levels as statins, ezetimibe and PCSK9 inhibitors.

Bile acids are synthesized in the liver and stored in the gall bladder, from which the bile acids are secreted into the small intestine to solubilize dietary fats for absorption. Normally, bile acids are then reabsorbed in the distal ileum and transported back to the liver, replenishing the hepatic pool of cholesterol. Bile acids contribute about two thirds (800-1,200 mg) of intestinal sources of cholesterol, with the remainder coming from the diet (300-500 mg) and intestinal sloughing (300 mg).

Bile acids also stimulate absorption of fat-soluble vitamins and are active regulatory molecules. Bile acids activate specific nuclear receptors, including those for farnesoid X (FXR) which suppresses bile acid synthesis, and vitamin D. Bile acids also alter gene expression for glucose, fatty acid, lipoprotein and triglyceride synthesis pathways. Bile acids increase FXR, which ultimately inhibits Liver X receptor (LXR). LXR regulates hepatic triglyceride synthesis and apoA1 expression. This is the pathway whereby bile acid sequestrants can raise triglyceride levels.

FXR and LXR also regulate glucagon synthesis, gluconeogenesis and a number of signaling molecules in glucose synthesis and metabolic pathways. Bile acid sequestrants can thus modestly decrease glucose levels.

Colesevelam is an anion-binding resin that binds negatively charged bile acids with higher affinity than older bile acid sequestrants.

Bile acid sequestrants are not absorbed from the intestine and are excreted in the feces.

Efficacy

Most of the data below is for colesevelam which has been better studied. Given the identical mechanisms of action, it may be reasonable to assume that the three bile acid sequestrants have similar effects at the full dose.

The efficacy of bile acid sequestrants was assessed in multiple clinical trials. The LDL-C lowering efficacy of colesevelam has been evaluated in 9 studies on primary hyperlipidemia (consisting of approximately 1600 patients total), including 8 multicenter, randomized, double-blind, placebo-controlled trials and 1 open-label, uncontrolled, long-term extension study. Colesevelam efficacy in patients with type 2 diabetes was demonstrated in a small study. The efficacy of cholestyramine and colestipol on coronary atherosclerosis was assessed in several randomized, controlled clinical trials.

Bile acid sequestrants have demonstrated LDL-C lowering efficacy both as monotherapy or in combination with other lipid-lowering drugs; however, their adverse event profile limits their usefulness.

Monotherapy

Bile acid sequestrants used as monotherapy can lower LDL-C an additional 15% to 30% depending on the dose, as well as reduce total cholesterol (TC), apolipoprotein B (apoB), and increase triglycerides by 6% to 25%, with little effect on HDL-C. Colesevelam also modestly reduces C-reactive protein.

Add-On to Statin

Bile acid sequestrants lower LDL-C an additional 15% to 25% when added to statin therapy. They also reduce TC, apoB and non–high-density lipoprotein cholesterol (non-HDL-C) when administered alone or in combination with a statin in patients with primary hyperlipidemia. The triglyceride increase is attenuated when coadministered with a statin, although modest HDL-C increases still occur. Colesevelam added to atorvastatin 10 mg has similar LDL-C lowering efficacy to atorvastatin 80 mg (about a 50% reduction) and did not increase triglycerides.

Add-On to Statin-Niacin

Colesevelam nonsignificantly lowered LDL-C by an additional 10% and did not increase triglycerides.

Add-On to Fibrate

Colesevelam lowered LDL-C by 11% and non–HDL-C by 7%, and was without triglyceride increases, when used concomitantly with fenofibrate.

Add-On to Ezetimibe

Colesevelam lowered LDL-C by additional 0 to 20% when added to ezetimibe, with variable triglyceride responses.

Diabetes

Colesevelam can reduce hemoglobin A1C by 0.5% in individuals with poorly controlled diabetes with or without statin therapy.

Cardiovascular Outcomes Trials

Cholestyramine monotherapy reduced CAD events by 19% over a 7-year period in the primary prevention

LRC-CPPT trial (Figure 26-1). This trial was performed in severely hypercholesterolemic men aged 35-59 years without CAD.

No randomized, placebo-controlled cardiovascular outcome trials have been performed with colesevelam or colestipol, nor have bile-acid binding agents been evaluated in the setting of background statin therapy or in women.

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Dosing

Cholestyramine

Start with one packet or one level scoop of cholestyramine powder once or twice a day. Mix each dose (5 or 9 g depending on formulation) of cholestyramine powder in at least 2-6 ounces of fluid. Increase as tolerated to 2 to 6 packets/scoopfuls daily (8-24 g) divided into two doses. Do not take dry. See below for dosing intervals with other drugs.

Colestipol

The starting dose for colestipol tablets is two 1 g tablets once or twice daily. Increase by 2 g at 1- to 2-month intervals to a total of 16 g daily. Take with plenty of water. The starting dose for colestipol granules is one 5 g packet or one level teaspoon once or twice daily. Mix with plenty of water, do not take dry. Increase to one to six packets/teaspoons daily as tolerated.

Colesevelam

Total of 3.8 g daily—six 625-mg tablets once a day or three tablets twice a day taken with a meal and liquids. Also available as an oral suspension given as one 3.75 g packet once daily or one 1.875 g packet twice daily, mixed in ½ to 1 cup water (do not take drug without water as it may cause esophageal obstruction). No dosage adjustment needed for renal or hepatic impairment.

See below for dosing intervals with other drugs.

Contraindications

• Absolute contraindication: Triglycerides ≥500 mg/dL; avoid if triglycerides >300 mg/dL
• History of pancreatitis secondary to hypertriglyceridemia
• Dysbetalipoproteinemia
• History of bowel obstruction or high risk of bowel obstruction
• Complete biliary obstruction
• Hypersensitivity to the bile acid sequestrant.

Safety

• Colesevelam: No pregnancy risk in animal studies and compatible with lactation since it is not systemically absorbed.
• Cholestyramine: Pregnancy risk in animal studies. The use of cholestyramine in pregnancy or lactation or in women of childbearing requires the potential benefits of the drug be weighed against the possible hazards of lack of proper vitamin absorption to mother and child.
• Colestipol: Not provided, but treat like cholestyramine.

Gastrointestinal

Flatulence and constipation are commonly reported with bile acid sequestrants. Colesevelam is much better tolerated. To minimize these effects, increase fluid and fiber intake and increase the dosage gradually every 5-7 days. Stool softeners may be needed occasionally.

Intestinal and esophageal obstruction has been reported rarely. Avoid bile acid sequestrants in patients with gastroparesis, disorders of low small bowel motility, recent abdominal surgery and patients with a history of bowel obstruction.

Hypertriglyceridemia

Bile acid sequestrants raise triglyceride levels, particularly when used with insulin or sulfonylureas. Hypertriglyceridemia is less when used concomitantly with statin or fibrate therapy. Avoid if triglycerides ≥300 mg/dL. Use with caution is triglycerides 200-<300 mg/dL. Marked hypertriglyceridemia can cause acute pancreatitis.

Muscle

No muscle effects. These agents are not systemically absorbed, nor do they lower LDL-C sufficiently to contribute to muscle adverse effects.

Fat Soluble Vitamin Deficiencies

All bile acid sequestrants can reduce the absorption of fat-soluble vitamins. Bleeding associated with vitamin K deficiency, night blindness due to vitamin A deficiency, and vitamin D deficiency have been reported with cholestyramine. Low red cell folate and osteoporosis has also been reported. Treat with appropriate vitamin replacement. Vitamin supplementation should be taken at least 4 hours prior to taking bile acid sequestrant drugs.

Phenylalanine

Colesevelam, cholestyramine, and colestipol oral suspensions all contain phenylalanine.

Seizures

Increased seizure activity or decreased phenytoin levels in patients receiving phenytoin. Administer phenytoin 4 hours before colesevelam.

Reduced INR

Reduced INR has been reported in patients receiving warfarin. Monitor INR levels.

Elevated TSH

Elevated TSH levels have been reported in patients receiving thyroid replacement therapy. Administer thyroid hormones at least 4 hours before colesevelam.

Renal

Caution should be used with cholestyramine administered to patients with renal insufficiency, volume depletion, younger or smaller patients, or receiving spironolactone due to the risk of hyperchloremic acidosis. Cholestyramine is a chloride form of an anion exchange resin.

Drug-Drug Interactions

Cholestyramine and colestipol are basic anion exchange copolymer resins that bind a number of drugs, including thyroid hormones, statins, ezetimibe, fenofibrate, digoxin, phenobarbital, estrogens, progestins, penicillin G, vitamins A, D, E and K, diuretics (thiazides, furosemide, spironolactone), tricyclic antidepressants, oral corticosteroids, some sulfonylureas, raloxifene, loperamide, diclofenac and some other nonsteroidal anti-inflammatory agents. Administer these drugs 1 hour before or 4 to 6 hours after cholestyramine or colestipol.

Colestipol also reduces levels of propranolol, tetracycline, furosemide, penicillin G, hydrochlorothiazide, gemfibrozil and mycophenolate mofetil and may also interfere with the absorption of oral phosphate supplements and hydrocortisone. Colestipol does not appear to affect absorption of aspirin, clindamycin, clofibrate, methyldopa, nicotinic acid (niacin), tolbutamide, phenytoin, or warfarin.

Colesevelam has a polymer structure that allows for very high affinity for bile acids and more specific anion binding capacity. Colesevelam impairs absorption of cyclosporine, levothyroxine, glyburide, glipizide, glimepiride, oral contraceptives containing ethinyl estradiol and norethindrone and olmesartan. Administer these drugs and other drugs that have not been studied or have a narrow therapeutic index, at least 4 hours before colesevelam. Metformin extended release and verapamil sustained release absorption may be impaired in some patients.

Colesevelam does not impair absorption of statins, fenofibrate, aspirin, atenolol, metoprolol verapamil, digoxin, enalapril, metformin, pioglitazone, rosiglitazone, repaglinide, sitagliptin, phenytoin, warfarin, quinidine, cephalexin, ciprofloxacin, or valproic acid. No significant effect was found on warfarin, although INR should be monitored frequently during drug initiation and periodically after.