Colesevelam: bile acid sequestrant as a lipid lowering agent and in diabetes

Colesevelam (brand name Cholestagel) is a non-absorbable polymer in the class of bile acid sequestrants. It binds bile acids in the gut, inhibits their enterohepatic recycling and thereby lowers LDL cholesterol while improving glycaemic control in type 2 diabetes.

Colesevelam is a more modern development of the older anion exchangers cholestyramine and colestipol. The major improvements are higher binding capacity for bile acids at substantially lower daily dose and overall better tolerability.

Mechanism of action

Bile acids are synthesised from cholesterol in the liver, stored in the gallbladder and secreted post-prandially into the small intestine. Most are reabsorbed in the terminal ileum (enterohepatic circulation), only a small fraction leaves the body in the stool.

Colesevelam is a hydrophilic polymer functionalised with trimethylammonium groups. It binds bile acids electrostatically and hydrophobically in the gut so they can no longer be reabsorbed and are excreted in stool. The liver responds with increased bile acid synthesis from cholesterol and increased uptake of LDL cholesterol from blood via LDL receptors. Result: LDL reduction by about 15 to 20 %.

In type 2 diabetes colesevelam additionally improves glycaemic control. The exact mechanisms are not fully understood; effects on the farnesoid X receptor (FXR), TGR5 and incretins have been discussed. Clinically HbA1c falls by about 0.5 percentage points.

Indications

• Primary hypercholesterolaemia: as monotherapy in statin intolerance or contraindication; combined with a statin when LDL targets are not reached
• Heterozygous familial hypercholesterolaemia: in combination with statins or ezetimibe
• Type 2 diabetes: add-on therapy to improve glycaemic control, especially when there is concomitant hypercholesterolaemia (US approval; in the EU primarily as a lipid lowering agent)
• Bile acid diarrhoea (cholerheic diarrhoea): off-label, very effective due to binding of excess bile acids

Dosing and administration

Standard dose: 3 tablets of 625 mg twice daily (total daily dose 3.75 g) or 6 tablets once daily. Take with meals and plenty of fluid. Tablets are large; some patients prefer the granular formulation in water.

Maximum dose: 4.375 g per day (7 tablets).

Onset of action: first LDL reduction after 2 to 4 weeks, full effect after 8 to 12 weeks.

Important for absorption of other medicines: colesevelam can affect the uptake of many drugs and vitamins. Other medications should ideally be taken 4 hours before, or at least 1 hour before colesevelam. With critical substances (thyroxine, thyroid medication, oral contraceptives, vitamin K antagonists), strict timing is needed.

Side effects

Common (1 to 10 %): constipation, flatulence, dyspepsia, nausea, abdominal pain, mild rise in triglycerides.

Uncommon: vomiting, diarrhoea, headache, myalgia, raised liver transaminases.

Rare: pancreatitis, bowel obstruction (especially in patients with strictures or slow transit), vitamin K deficiency with bleeding tendency, steatorrhoea.

Tolerability points:

• Better tolerated than cholestyramine and colestipol because colesevelam does not swell in the gut
• Triglycerides can rise by 5 to 10 %, so caution in pre-existing hypertriglyceridaemia above 500 mg/dL
• In some patients colesevelam can worsen IBS or constipation
• Adequate fluid intake and a fibre-rich diet improve tolerability

Interactions

Colesevelam is not absorbed systemically. Interactions arise solely through binding of other substances in the gut lumen.

• Levothyroxine: markedly reduced absorption, minimum spacing of 4 hours, monitor TSH
• Vitamin K antagonists (warfarin, phenprocoumon): reduced uptake, INR fluctuations
• Glipizide, glimepiride and other sulfonylureas: reduced absorption
• Ciclosporin, mycophenolate mofetil: reduced bioavailability
• Oral contraceptives: reduced absorption of ethinylestradiol, minimum spacing of 4 hours
• Phenytoin: reduced bioavailability, monitor levels
• Fat-soluble vitamins (A, D, E, K): uptake can be reduced; supplementation in long-term therapy

Special considerations

Pregnancy: data limited. Since colesevelam is not absorbed, use is acceptable in exceptional circumstances. Important: risk of vitamin K deficiency with neonatal bleeding tendency, requiring close monitoring.

Breastfeeding: not absorbed and does not pass into milk. Clinically acceptable.

Children: approved from 10 years for familial hypercholesterolaemia.

Phenylketonuria: the granular formulation contains aspartame and is not suitable for phenylketonuria.

Before and during therapy: monitor lipid profile and triglycerides. Above 300 mg/dL of triglycerides, careful evaluation; above 500 mg/dL, contraindication.

Use in cholerheic diarrhoea: colesevelam is highly effective off-label in bile acid loss syndrome after cholecystectomy, ileal resection or Crohn's disease with ileal involvement. Patients often report rapid symptom relief.

Related substances

• Simvastatin, classic HMG-CoA reductase inhibitor
• Bempedoinsäure, ATP citrate lyase inhibitor
• Linagliptin, DPP-4 inhibitor for type 2 diabetes
• Metformin, standard first-line for type 2 diabetes

Frequently asked questions

Sources

• EMA Cholestagel (colesevelam) EPAR
• BfArM Federal Institute for Drugs and Medical Devices
• AWMF guideline hyperlipidaemia
• Gelbe Liste colesevelam monograph