Cholesterol is the major, and probably the sole precursor
of bile acids. During normal digestion, bile acids are secreted via the bile
from the liver and gall bladder into the intestines. Bile acids emulsify the
fat and lipid materials present in food, thus facilitating absorption. A major
portion of the bile acids secreted is reabsorbed from the intestines and
returned via the portal circulation to the liver, thus completing the
enterohepatic cycle. Only very small amounts of bile acids are found in normal
Colestipol hydrochloride binds bile acids in the
intestine forming a complex that is excreted in the feces. This nonsystemic
action results in a partial removal of the bile acids from the enterohepatic
circulation, preventing their reabsorption. Since colestipol hydrochloride is
an anion exchange resin, the chloride anions of the resin can be replaced by
other anions, usually those with a greater affinity for the resin than the
Colestipol hydrochloride is hydrophilic, but it is
virtually water insoluble (99.75%) and it is not hydrolyzed by digestive
enzymes. The high molecular weight polymer in colestipol hydrochloride
apparently is not absorbed. In humans, less than 0.17% of a single 14Clabeled
colestipol hydrochloride dose is excreted in the urine when given following 60
days of dosing of 20 grams of colestipol hydrochloride per day.
The increased fecal loss of bile acids due to colestipol
hydrochloride administration leads to an increased oxidation of cholesterol to
bile acids. This results in an increase in the number of low-density
lipoprotein (LDL) receptors, increased hepatic uptake of LDL and a decrease in
beta lipoprotein or LDL serum levels, and a decrease in serum cholesterol
levels. Although colestipol hydrochloride produces an increase in the hepatic
synthesis of cholesterol in man, serum cholesterol levels fall.
There is evidence to show that this fall in cholesterol
is secondary to an increased rate of clearance of cholesterol-rich lipoproteins
(beta or low-density lipoproteins) from the plasma. Serum triglyceride levels
may increase or remain unchanged in colestipol hydrochloride treated patients.
The decline in serum cholesterol levels with colestipol
hydrochloride treatment is usually evident by one month. When colestipol
hydrochloride is discontinued, serum cholesterol levels usually return to
baseline levels within one month. Periodic determinations of serum cholesterol
levels as outlined in the National Cholesterol Education Program (NCEP)
guidelines, should be done to confirm a favorable initial and long-term response1.
In a large, placebo-controlled, multiclinic study, the
LRC-CPPT2, hypercholesterolemic subjects treated with cholestyramine,
a bile-acid sequestrant with a mechanism of action and an effect on serum
cholesterol similar to that of colestipol hydrochloride, had reductions in
total and LDL-C. Over the 7-year study period the cholestyramine group
experienced a 19% reduction (relative to the incidence in the placebo group) in
the combined rate of coronary heart disease (CHD) death plus nonfatal
myocardial infarction (cumulative incidences of 7% cholestyramine and 8.6%
placebo). The subjects included in the study were middle-aged men (aged 35–59)
with serum cholesterol levels above 265 mg/dL, LDL-C above 175 mg/dL on a
moderate cholesterol-lowering diet, and no history of heart disease. It is not
clear to what extent these findings can be extrapolated to other segments of
the hypercholesterolemic population not studied.
Treatment with colestipol results in a significant
increase in lipoprotein LpAI. Lipoprotein LpAI is one of the two major
lipoprotein particles within the high-density lipoprotein (HDL) density range3,
and has been shown in cell culture to promote cholesterol efflux or removal
from cells4. Although the significance of this finding has not been
established in clinical studies, the elevation of the lipoprotein LpAI particle
within the HDL fraction is consistent with an antiatherogenic effect of
colestipol hydrochloride, even though little change is observed in HDL
In patients with heterozygous familial
hypercholesterolemia who have not obtained an optimal response to colestipol
hydrochloride alone in maximal doses, the combination of colestipol
hydrochloride and nicotinic acid has been shown to further lower serum
cholesterol, triglyceride, and LDL-cholesterol (LDL-C) values. Simultaneously,
HDL-C values increased significantly. In many such patients it is possible to
normalize serum lipid values.5-7
Preliminary evidence suggests that the
cholesterol-lowering effects of lovastatin and the bile acid sequestrant,
colestipol hydrochloride, are additive.
The effect of intensive lipid-lowering therapy on
coronary atherosclerosis has been assessed by arteriography in hyperlipidemic
patients. In these randomized, controlled clinical trials, patients were
treated for two to four years by either conventional measures (diet, placebo,
or in some cases low-dose resin), or with intensive combination therapy using
diet and COLESTID Granules plus either nicotinic acid or lovastatin. When
compared to conventional measures, intensive lipid-lowering combination therapy
significantly reduced the frequency of progression and increased the frequency
of regression of coronary atherosclerotic lesions in patients with or at risk
for coronary artery disease.8-11
1. Summary of the Second Report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment
of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;
2. Lipid Metabolism-Atherogenesis Branch, National Heart,
Lung, and Blood Institute, Bethesda, MD: The Lipid Research Clinics Coronary
Primary Prevention Trial Results. I. Reduction in Incidence of Coronary Heart
Disease. JAMA 1984; 251:351–364.
3. Parra HJ, et al. Differential electroimmunoassay of
human LpA-I lipoprotein particles on ready-to-use plates. Clin. Chem. 1990;
4. Barbaras R, et al. Cholesterol efflux from cultured
adipose cells is mediated by LpAI particles but not by LpAI:AII particles. Biochem.
Biophys. Res. Comm. 1987; 142(1):63–69.
5. Kane JP, et al. Normalization of
low-density-lipoprotein levels in heterozygous familial hypercholesterolemia
with a combined drug regimen. N Engl. J. Med. 1981; 304:251–258.
6. Illingworth DR, et al. Colestipol plus nicotinic acid
in treatment of heterozygous familial hypercholesterolemia. Lancet 1981;
7. Kuo PT, et al. Familial type II hyperlipoproteinemia
with coronary heart disease: Effect of diet-colestipol-nicotinic acid
treatment. Chest 1981; 79:286–291.
8. Blankenhorn DH, et al. Beneficial Effects of Combined
Colestipol-Niacin Therapy on Coronary Atherosclerosis and Coronary Venous
Bypass Grafts. JAMA 1987; 257(23):3233–3240.
9. Cashin-Hemphill L, et al. Beneficial Effects of
Colestipol-Niacin on Coronary Atherosclerosis: A 4-Year Follow-up. JAMA 1990;
10. Brown G. et al. Regression of Coronary Artery Disease
as a Result of Intensive Lipid-Lowering Therapy in Men with High Levels of
Apolipoprotein B. N. Engl. Â J. Med. 1990; 323:1289–1298.
11. Kane JP, et al. Regression of Coronary
Atherosclerosis During Treatment of Familial Hypercholesterolemia with Combined
Drug Regimens. JAMA 1990; 264:3007–3012.