Continuing Education Activity

Colestipol is an FDA-approved antihyperlipidemic drug used for the treatment of primary hypercholesterolemia. It is used as adjunctive therapy to dietary modifications and exercise. Daily doses of 4 to 16 grams are associated with a 12 to 24% reduction in low-density lipoprotein cholesterol (LDL-C) levels. It may also reduce the risk of coronary artery disease. Colestipol is also used off-label to treat cholestatic pruritus and irritable bowel syndrome. This activity reviews the indications, mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of colestipol pertinent for interprofessional team members involved in managing primary hypercholesterolemia and associated conditions.

Objectives:

• Identify the mechanism of action of colestipol.
• Outline the approved and potential indications of colestipol.
• Identify the most common adverse events associated with colestipol therapy.
• Summarize the significance of interprofessional team strategies in improving treatment outcomes for patients undergoing treatment with colestipol.

Indications

Colestipol is a bile acid sequestrant used for various indications. It is FDA-approved as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia who do not respond to diet alone. It may be used as monotherapy or in combination with a statin, niacin, or ezetimibe. Doses of 4 to 16 grams per day are associated with a 12 to 24% reduction in LDL cholesterol, respectively.[1][2] Higher doses may be associated with increased gastrointestinal side effects.[3] 

Combination therapy with simvastatin is associated with a 52% reduction of LDL cholesterol.[1] Dual treatment with niacin demonstrated a 43% reduction in LDL Cholesterol levels and reduced angiographic progression of coronary artery atherosclerotic lesions by 16.2% compared to only 2.4% in individuals receiving a placebo.[4]

Other Clinical Applications

1. Colestipol may be used in the treatment of heterozygous familial hypercholesterolemia. Although it is effective for this indication, it is poorly tolerated due to gastrointestinal side effects.[5]  It may be used in combination with a statin.[3] A trial in children with familial hypercholesterolemia treated with colestipol found a 19.5% reduction in LDL-C levels after eight weeks of therapy.[6]
2. Pruritus associated with cholestasis, particularly in primary sclerosing cholangitis, may be treated with colestipol.[7] It may be better tolerated compared to therapy with cholestyramine.[8] However, clinical experience with colestipol for this indication is limited.
3. A prospective, controlled trial with 92 patients performed by Hagag et al. demonstrated the effectiveness of colestipol as an adjunct therapy to methimazole for treating hyperthyroidism.[9] Greater efficacy was seen in severe cases of thyrotoxicosis.[9]
4. In a study of 141 patients evaluating the role of bile acids in the pathogenesis of irritable bowel syndrome (IBS), treatment with colestipol improved IBS symptoms (IBS severity scoring system 220 +/- 109 vs. 277 +/- 106).[10] As such, colestipol may be used to treat bile acid diarrhea; however, it is often discontinued due to poor tolerability.[11]
5. Colestipol has been successfully used to treat digoxin toxicity in patients taking this drug. Colestipol interrupts the enterohepatic circulation of digoxin and increases its fecal excretion. One case report by Payne et al. reported a reduced half-life of elimination of 55 hours compared to a predicted half-life of elimination of 85 hours.[12]

Mechanism of Action

Colestipol is a large basic anion-exchange resin copolymer.[13] It is nonabsorbable and insoluble in water. Its primary mechanism of action is the formation of insoluble complexes with bile acids in the small intestine that are subsequently excreted in the feces.

As part of normal digestion, bile acids are responsible for emulsifying and solubilizing lipids in the intestinal lumen. The rate-limiting step in bile acid synthesis involves hydroxylation of the steroid nucleus of cholesterol by cholesterol 7-alpha-hydroxylase.[14] Data shows that 95% of bile acids are recycled via enterohepatic circulation to the liver, while 5% are excreted in the feces.[14] 

Increased fecal excretion of bile acids leads to a reduction in the total circulating bile acid pool available for enterohepatic circulation. As a result, upregulation of cholesterol 7-alpha-hydroxylase leads to increased conversion of cholesterol into bile acids, reducing serum total cholesterol levels. Further upregulation of hepatic low-density lipoprotein receptors (LDLR) to replenish intrahepatic cholesterol stores available for bile acid synthesis leads to increased uptake of LDL-C and an overall reduction in plasma LDL cholesterol (LDL-C) levels.

In cases of thyrotoxicosis, enterohepatic circulation of thyroid hormones, including thyroxine (T4) and triiodothyronine (T3), is increased.[9] Interaction between positively charged nitrogen atoms of colestipol with negatively charged iodothyronines leads to increased fecal excretion of iodothyronines.[9]

Administration

Colestipol is available to patients in two forms. It is available as an oral tablet or, in granular form, as a powdered suspension. The powdered suspension is also available in a flavored form to improve palatability. However, the flavored suspension must be taken with caution in patients with phenylketonuria (PKU), as it contains phenylalanine.

Patients with PKU must consult their healthcare provider before initiating therapy with a flavored colestipol suspension. Powdered suspensions of colestipol should be mixed with water or other fluids before ingestion to prevent inhalation or esophageal distress. Other medications, such as fat-soluble vitamins, should be taken 1 hour before or 4 hours after the administration of colestipol.[15]

Colestipol tablets are recommended in doses of 2 grams to 16 grams per day. Therapy should be initiated at a dose of 2 grams per day. 

Colestipol powdered suspension is recommended in doses of one packet to six packets per day. One packet contains 5 grams of colestipol.

Colestipol is available in the following formulations and doses:

• Tablet
  • 1 g per tablet, oral
• Powdered suspension
  • 5 g per packet, oral
• Powdered suspension (flavored)
  • 5 g per packet, oral

Adverse Effects

Adverse Effects

• Most adverse effects caused by colestipol therapy are related to the gastrointestinal system. Colestipol can cause a wide range of adverse effects, including constipation, bloating, dyspepsia, and nausea.[16]
• Constipation is the most common side effect and ranges in severity from mild cases to severe cases. It is often a cause of poor compliance and discontinuation of therapy.[17] Patients above the age of 65 and patients using a larger dose of colestipol are more prone to constipation.[18]
• Constipation may be ameliorated with increased fluid and fiber intake, as well as the use of stool softeners.
• Colestipol may aggravate pre-existing hemorrhoids. 
• The usage of colestipol in powdered suspension form may cause decreased palatability. Flavored suspensions of colestipol are used to improve palatability. 
• Non-gastrointestinal side effects are infrequently reported. These include infrequent occurrences of cardiovascular symptoms such as angina, musculoskeletal symptoms such as joint pains and arthritis, and neurologic symptoms such as migraine headaches. 
• Colestipol may cause transient elevations in alkaline phosphatase levels, although the clinical significance of this is unknown.[18]
• Colestipol therapy has been reported to cause asymptomatic hepatotoxicity with elevated serum transaminases. However, the mechanism by which colestipol causes hepatotoxicity is unknown.[19]
• Colestipol may cause hyperchloremic metabolic acidosis. 

Drug Interactions

• Colestipol may induce malabsorption of fat-soluble vitamins (vitamins A, D, E, and K). Patients with pre-existing deficiencies of these vitamins should consult their healthcare provider before commencing therapy with colestipol. These vitamins should be taken 4 hours after taking colestipol.[15]
• Colestipol may reduce the absorption of many drugs if they are given concomitantly with colestipol. Anionic drugs such as warfarin, thiazide diuretics, propanolol, levothyroxine, and digitalis should be given 1 hour before or 4 hours after taking colestipol.[15]

Special Populations

• Pregnant patients: colestipol is safe to use in pregnancy as it is not systemically absorbed. However, colestipol may induce the malabsorption of fat-soluble vitamins (A, D, E, K), which may be hazardous to the mother and child. Therefore, the benefits of drug therapy should be weighed against the risks before the initiation of therapy.
• Breastfeeding patients: as colestipol is not absorbed by the systemic circulation; it is not present in breast milk. Therefore, it is safe for use during breastfeeding.
• Patients under the age of 18: the adverse event profile of colestipol in patients below the age of 18 has not been established. However, colestipol has been used safely in patients under age 18 with familial hypercholesterolemia.[3]
• Patients over the age of 60: the gastrointestinal side effects of colestipol, such as constipation, may be more pronounced in patients over the age of 60.

Contraindications

• Colestipol should not be used in patients with known hypersensitivity to the drug or any of its components.
• Colestipol is contraindicated in patients undergoing therapy with mycophenolic acid. As colestipol binds to bile acids, it reduces the absorption of mycophenolic acid and may reduce its efficacy.
• Colestipol has been shown to cause elevated triglyceride levels. A study by Lyons et al. demonstrated an 8.9% rise in triglyceride levels in patients treated with colestipol.[19] Colestipol should be avoided in patients with triglyceride levels above 400 mg/dL. It may be used in patients with triglyceride levels below 200 mg/dL.[15] Therefore, as a precaution, clinicians should reserve this drug for use in patients with hypercholesterolemia without associated hypertriglyceridemia.[13]
• Colestipol is a bile acid sequestrant. It is a large anion exchange resin and may bind numerous molecules in the intestine. Of note, colestipol may bind to free triiodothyronine (T3), resulting in increased fecal excretion of T3 and reduced enterohepatic circulation.[20] As a result, colestipol therapy may worsen symptoms in patients with pre-existing hypothyroidism. Therefore, patients on colestipol therapy should consider consulting their healthcare provider before commencing treatment with this medication.
• Colestipol should be avoided for use in patients with disorders that cause decreased intestinal motility, in patients with a recent history of abdominal surgery, and patients with a history of recent episodes of intestinal obstruction.[15]
• Colestipol is contraindicated in patients with complete biliary obstruction.[15]

Monitoring

Periodic monitoring of serum lipoproteins is recommended in patients taking colestipol to assess treatment response and further dosage modifications.

As colestipol is known to cause constipation of varying severity and may cause intestinal obstruction, monitoring of constipation at 4 to 6-week intervals is recommended. Worsening constipation or failure to meet therapeutic goals may require combination therapy or replacement with alternate therapy.

Patients with pre-existing fat-soluble vitamin deficiencies (A, D, E, K) should monitor their vitamin levels regularly while on colestipol therapy. Colestipol may impede the absorption of fat-soluble vitamins through its action as a bile acid sequestrant.[21] If deficiencies of any of these vitamins occur, signs of deficiency should be recognized, and treatment should be promptly started.

As colestipol may cause hyperchloremic metabolic acidosis, signs of hyperchloremic acidosis should be monitored. These include headaches, seizures, increased respiratory rate, and arrhythmias.

Patients on warfarin therapy should have their International Normalized Ratio (INR) monitored regularly.

Toxicity

As it is not systemically absorbed, colestipol does not cause severe side effects; therefore, it is very safe to prescribe to patients. No reports of toxicity associated with colestipol therapy have been reported other than the adverse events described above.

Patients often report poor tolerability to colestipol due to its many gastrointestinal adverse effects and decreased palatability. Therefore, healthcare providers should consider this and modify treatment accordingly, such as offering a different formulation of the drug.

Enhancing Healthcare Team Outcomes

Colestipol is a bile acid sequestrant that may be offered to patients to treat various conditions, such as hypercholesterolemia or pruritus associated with chronic liver disease. Although colestipol has been available for many years, it is less commonly prescribed in the current age due to poor compliance with use and poor tolerability. Despite this, colestipol is highly effective in managing hypercholesterolemia and pruritus. Therefore, health professionals treating patients with these conditions should be familiar with its properties, as they may offer it to patients and improve their quality of life.

Nurses should be aware of colestipol's most commonly encountered adverse effects to develop strategies to monitor their occurrence and report them to physicians. The pharmacist should serve as the main point of contact for those members of the interprofessional team seeking advice on the dosage and administration of colestipol and, checking for drug interactions, giving clear instructions to patients on how to use the drug and manage any adverse effects. As such, coordination between all interprofessional healthcare team members plays a crucial role in improving treatment outcomes and patient safety in those taking colestipol. [Level 5]