BILE ACID SEQUESTRANTS


















  • References [1,2,3,4,5,10,11,13,14]
Effect of BAS on lipids in clinical trials
Medication Total chol
(% decrease)
LDL
(% decrease)
Triglycerides
(% increase)
Cholestyramine (Questran®) 13 - 23% 20 - 31% 11 - 18%
Colesevelam (Welchol™) 10 - 17% 17 - 23% may increase
Colestipol (Colestid®) 7% 15 - 21% may increase
up to 21%



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.
Cholestyramine vs Placebo for Prevention of CAD Events, JAMA (1984) [PubMed abstract]
  • The LRC-CPPT enrolled 3806 men with no history of heart disease
Main inclusion criteria
  • Male sex
  • Age 35 - 59
  • Total cholesterol > 265 mg/dl
  • No history of heart disease
Randomized treatment groups
  • Group 1 - Cholestyramine daily
  • Group 2 - Placebo daily
Primary outcome: Definite coronary heart disease death and/or definite nonfatal myocardial infarction
Results

Duration: Average of 7.4 years
Outcome Cholestyramine Placebo Comparisons
Primary outcome 7% 8.6% p<0.05
  • There was no significant difference in overall mortality between the 2 groups

Findings: The LRC-CPPT findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels. This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD.
Professional guidelines
StraightHealthcare analysis
  • There is limited evidence that cholestyramine improves heart disease outcomes
  • BAS are not widely prescribed and have largely been replaced by statins



  • Baseline A1C was 8.2% in both trials
  • N=357 for monotherapy trial and N=159 in the metformin trial
  • Reference [14]
Effect of Colesevelam (Col) on diabetes in trials lasting 24 - 26 weeks
Col 3.8 g/day
(monotherapy)
Col 3.8 g/day
(added to metformin)
% A1C reduction
(colesevelam - placebo)
-0.27% -0.5%









Gastrointestinal side effects
Overview
  • 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

Elevated triglycerides

Vitamin deficiency





Kidney disease

Liver disease

Vitamin deficiency

Phenylketonuria (Welchol suspension)



Drug interactions

All bile acid sequestrants

Drug absorption
  • In addition to binding bile acids, BAS can bind other drugs. This can interfere with the absorption of a number of drugs. To minimize this risk, other medications should be taken apart from BAS.
  • The Questran and Colestid PIs both say 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. See the Welchol PI [sec 7] for specific recommendations regarding certain medications.
  • A small study looked at the effect of Welchol on the absorption of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide. When taken at the same time, Welchol had no effect on pioglitazone, but it significantly reduced the absorption of the other drugs. When glyburide and estrogen estradiol were given one hour before Welchol, their absorption was decreased. When glyburide, estrogen estradiol, and levothyroxine were given 4 hours before Welchol, absorption was not affected. [PubMed abstract]
  • 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 levels of metformin extended-release. 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 [14,20,21]