J. David Schnatz, M.D.
Director, Lipid Education Service
Saint Francis Hospital and Medical Center
114 Woodland Street, Hartford, CT 06105
Telephone: (860) 714-5555

September/October 2000

Bile acid binding resins have been used for decades to lower LDL cholesterol. Before the statin drugs became available, the resins were among the few drugs available for lowering LDL. In fact, in the Lipid Research Clinics-Primary Prevention Trial (LRC-PPT), in contrast to placebo, there was a 12.6% decrease in LDL cholesterol due to Cholestyramine and this was associated with a 24% decrease in coronary artery disease (CAD) death and a 19% decrease in non-fatal myocardial infarctions (1). A decrease in coronary artery disease was seen by angiography in the Cholesterol Lowering Atherosclerosis Study (CLAS) with Colestipol and Nicotinic Acid (2) and in the Familial Atherosclerosis Study (FATS) with Colestipol and Lovastatin (3).

The problem with the resins has been that many patients experience gastrointestinal side effects of constipation, flatulence and rarely, diarrhea. These are so pronounced in some patients that they cannot or will not take the desired dose of the drug, or completely refuse to take it. In the LRC-PPT, this was a problem in that patients did not take all the drug that was supplied. Still, there was an overall beneficial effect. Another problem with the resins is that they can aggravate pre-existing hypertriglyceridemia or unmask a tendency to hypertriglyceridemia. In May, a new drug, Colesevelam Hydrochloride, trade name Welchol, was approved by the Food and Drug Administration. Gel Tex Pharmaceuticals, maker of Welchol, has licensed Sankyo Parke Davis to market the drug in the U.S., with the plan to begin in September 2000. This drug offers a potentially important addition to our medical therapy of lipid disorders since "compared to historical data with other bile acid sequestrants, Colesevelam Hydrochloride was 4-6 times more potent, and the incidence of treatment related gastrointestinal side effects was not statistically different from placebo" (4).

Colesevelam is a non-absorbable gel which binds bile acids in the gastrointestinal tract. Its lipid lowering effect was compared with placebo in a recently published study (5). Two hundred seventy-five men and women over 18 years of age were screened in six clinical research centers. Individuals were excluded, if they used fibrates during the preceding month or Probucol during the preceding year. They were excluded, if they had a recent history of ethanol or drug use, a history of dysphagia, swallowing disorder, or motility disorder of the intestines, unstable cardiac disease, recent myocardial infarction or cardiac bypass surgery within two months. Other grounds for exclusion were: malignant neoplasm, unstable medical condition, tendon xanthoma, thyroid disease, liver or renal disease, vasculitis, HIV infection, poorly controlled diabetes mellitus, systolic blood pressure greater than 160, or diastolic blood pressure greater than 105 mm/Hg. Women were excluded, if pregnant or nursing an infant. Concurrent administration of lipid lowering medication was not allowed.

One hundred forty-nine patients went through a period of diet/drug wash-out which was six weeks for those receiving lipid lowering drugs and four weeks for all others. Next, was a four week placebo run-in to assess compliance with randomization and, finally, a six week drug treatment phase during which four drug doses were compared with placebo in double blind fashion: 1.5 grams, 2.25 grams, 3.0 grams, and 3.75 grams per day. Patients were seen at 2, 4 and 6 weeks during the study and compliance determined by counting the remaining pills.

The mean age was 56 years (range =31 to 80) for 44% men and 56% women. One hundred thirty-seven (92%) completed the study. LDL levels decreased by 4.2 mg/dl (1.8%), 11 mg/dl (4.9%), 18 mg/dl (9%), and 39 mg/dl (19%) in the four dosage groups, going from lowest to highest. The decrease was significant at the third highest and highest dosages, being p=0.01 and p<0.001, respectively.

HDL increased by 0.5, 0.5, 4.4 and 4.3 mg/dl across the dose range from low to high. The latter two values were significant, p<0.01 and p<0.05. Triglyceride did not change significantly, although it did appear to rise at the highest dose.

Four patients out of the 149 left the study because of GI side effects; one with diarrhea and gas, 2 because of constipation, and one with stomach burning. Flatulence and constipation were the most common GI complaints, occurring in 7% of those on placebo and 12% on drug. Transaminase levels increased in the range of 6 to 7 units, but remained within normal limits. There were no significant changes in hematological parameters, prothrombin time, thromboplastin time, vitamins A or E, or in body weight.

Colesevelam has been evaluated in conjunction with Simvastatin and Atorvastatin and the results indicated a significantly greater effect than when either drug was used alone (6). Colesevelam is said to be as effective in once daily dosing as it is in split dosing (6), but the reference to this was not able to be verified.

Although time and use will confirm how much of an advance Colesevelam will be, the promise is great for being a more palatable substitute for resins, thereby assisting with LDL lowering in patients where statins are undesirable or not tolerated, or in conjunction with statins.

References:

1. JAMA 251: 351 and 365, 1984
2. JAMA 257: 3233, 1987 and JAMA 264: 3013, 1990
3. NEJ Med 323: 1289, 1990
4. American College of Cardiology 49th annual meeting, March 2000, abstract #1046-24
5. Arch Int Med 159: 1893, 1999
6. Drugs R&D 1: 479, 1999

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