"The U.S. Food and Drug Administration today approved Kynamro (mipomersen sodium) injection as an addition to lipid-lowering medications and diet to treat patients with a rare type of high cholesterol called homozygous familial hypercholesterolemi"...
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 serum.
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 chloride ion.
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 response.1
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 cholesterol (HDL-C).
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 (colestipol) 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; 269(23):3015–3023.
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; 36(8):1431–1435.
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; 1:296–298.
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; 264:3013–3017.
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. 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.
Last reviewed on RxList: 4/9/2009
This monograph has been modified to include the generic and brand name in many instances.
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