Azhar M.A. Faruqui ( Present Address: National Institute of Cardiovascular Diseases, Karachi. )
Maria S. Thurmond ( Department of Medicine, Emory University School of Medicine; the Cardiac Clinics, Grady Memorial Hospital; and the Research Laboratory, V.A. Medical Centre, Atlanta, Georgia. )
Julius Wenger ( Department of Medicine, Emory University School of Medicine; the Cardiac Clinics, Grady Memorial Hospital; and the Research Laboratory, V.A. Medical Centre, Atlanta, Georgia. )
Nanette, K. Wenger ( Department of Medicine, Emory University School of Medicine; the Cardiac Clinics, Grady Memorial Hospital; and the Research Laboratory, V.A. Medical Centre, Atlanta, Georgia. )
Colestipol and muestran comparably and effectively lower scrum cholesterol levels as compared with an Avicel placebo. There is no significant e&ect on serum triglyceride levels. There are no serious adverse effects and few nonserious die effects with either drug. There is no effect: on carotene, carbohydrate, or amino acid absorption with long-term use of either hypocholesterolemic drug (JPMA 31:241, 1981).
This study was designed to assess the efficacy, tolerance, and safety of colestipol HCL as a hypocholesterolemic agent in hyperlipidemic patients; and compare it with the effects of cholestyramine (Questran).
Review of the Literature
Hypercholesterolemia is a major risk factor for the development of atherosclerotic coronary heart disease (Keys, 1970; Primary Prevention, 1970; Arteriosclerosis, 1971). Although neither dietary nor drug intervention which reduces serum cholesterol levels has been documented to alter coronary risk many factors may contribute to this situation (CDP Research Group, 1975; Ischaemic Heart Disease, 1971). Dietary-therapy can reduce serum cholesterol by 10% to 25% at best; many of the populations studied have been older individuals followed for only modest periods of time; and most currently available hypocholesterolemic drugs appear to entail independent risk. The unqeuivocal delineation of atherosclerotic plaque regression in non-human primates, associated with lowering of the scrum cholesterol concentration, has encouraged the continued search for an effective and tolerable pharmacologic agent to supplement dietary therapy (Cooper, 1975; Miskhel, 1977; Kuo, 1979; Gundersen, 1976); a combined pharmacologic regimen may be even more effective (Kane, 1981; Illingworth, 1981).
Colestipol, a resin sequestrant, is a high-molecular weight, insoluble, nonabsorbable, copolymer of tetraethylonepentamine and cpicho-lorohydrin, with an in vitro bile-acid binding capacity of about 1 meq cholic acid per gram (Parkinson, 1970). Cholestyramine (Questrain) (Hashim, 1965) is another bile sequentering agent which effectively lowers serum cholesterol levels.
Material and Methods
The study design was a single-blind comparison of colestipol, palcebo (Avicel.) and cholestyramine (Questran), with treatment assigned on the basis of random number tables. Outpatients in the Cardiac Clinics of Grady Memorial Hospital in Atlanta, Georgia, USA, were recruited for entry into the study. After giving informed consent, patients entered, a 6-week screening (pre-randomization) period;- a history and physical examination were recorded and 12-hour post-prandial serum cholesterol, triglyceride and glucose determinations (as well as other clinical laboratory tests) were performed at 2-week intervals by the Clinical Research Laboratory of the Upjohn Company, Kalamazoo, Michigan. Patients received placebo therapy during the pre-randomization period. Those who qualified for entry into the study were then assigned to treatment with colestipol, chooestyramine, or p.acebo. Clinic follow-up was at monthly intervals during the (first year and bimonthly thereafter.
Patients eligible to enter the study were men and women over age 35 (provided no possibility of pregnancy existed in the women), who had not received any lipid-influencing drugs within the preceeding 3 months. Patients with hepatic or renal disease, hypothyroid patients, and those receiving steroid or anticoagulant drugs were excluded. To qualify for the study, patients had to have at least 2 serum cholesterol values in excess of 250 mg/dl during the pre-randomiza-tion period.
Because there is limited information on the effect of colestipol on human gastrointestinal absorption (Phillips, 1974; Mo, 1974), this was also studied in the three treatment groups. Both colestipol and cholestyramine are known to affect the absorption of lipid-soluble materials, but their long-term effect on carbohydrate and protein absorption has not been well studied. Colestipol does not appear to alter fat-soluble vitamin concentrations (Schwarz, 1980) or phenprocoumon absorption (Harvengt, 1973). However, cholestyramine has been shown to reduce oral digoxin bioavailability, related to the dose of cholestyramine and the proximity of time of administration of the two drugs (Brown, 1978).
Oral tolerance tests are used to study gastrointestinal absorption. These are commonly done by feeding a standard test meal and then obtaining blood levels for 1 to 3 hours following this procedure. Another method of studying gastrointestinal absorption is by collecting urine for 3 to 5 hours following a test meal to see how rapidly the substance is absorbed from the intestine, enters the circulation, and then appears in the urine. All these methods are indirect techniques; they do not have the accuracy of direct absorption methods which are more quantitative. On the other hand, these indirect absorption methods are practical for clinical use.
Simultaneous studies of carbohydrate, amino acid, and protein absorption were carried out. During the performance of these studies, an effort was made to maintain consistency; the same technique was used for each patient each time. Specimens were obtained at the 0, 7, 12, 13 and 26 month visits. The 26-month determination was made after the patient was removed from the test drug and is essentially another "baseline" determination after the cessation of therapy. The test material consisted of 25 mg gelatin mixed with 25 gm xylose, providing a uniform test meal containing protein and carbohydrate; the taste was disguised with an acceptable fruit juice (Thiel, 1963). Fasting, I hour and 3 hour blood levels were obtained for blood xylose and blood hydroxyproline (Roe, 1948; Prockop,1960); fasting blood levels of carotene were also obtained (Wenger et al.„ 1957).
The test drug was colestipol hydrochloride, an odorless, tasteless finely granular, light yellow powder, dispensed in individual-dose 5 gram packets. The control drug was Questran (cholestyramine) powder, dispensed in 9-gram packets each containing 4 grams of cholestyramine resin. The placebo used was Avicel (microcrystalline cellulose coarse powder NF), provided in moisture proof, polyethylene-lined, individual-dose packets containing 2 grams of the white powder. This drug was given to all patients during the 6-week pre-randomization period and to the placebo group after assignment to treatment. Patients were instructed to take a single dose of medication just prior to meals 3 times daily, mixed with aqueous juices, flavored drinks, milk, or soup, allowing 2-3 minutes for hydration of the drug. Drug dosage remained constant during the study, and it was recommended to the patients that their diet remain stable throughout the study.
At each clinic visit, patients were examined and interviewed with specific questions addressing side effects of the drug, tolerance for the powder, and how many of the packets had been taken since the last visit. Body weight and blood pressure were recorded; and blood and urine specimens obtained.
Serum cholesterol, triglyceride, and glucose determinations were performed by the Clinical Research Laboratory of the Upjohn Company at each clinic visit. The following serum assays were also performed in the Clinical Research Laboratory at 1 and 3 months, then every 3 months for the first years every 4 months thereafter: bilirubin, creatinine, SGOT, alkaline phosphatase, uric acid, calcium, phosphate, sodium, chloride, and potassium. Hematocrit, hemoglobin, white blood cell count and differential, platelet count, prothrombin time and complete urinalysis determinations were performed by the Emory University School of Clinical Research Laboratory at the same intervals. The absorption studies were analyzed in the Research Laboratory of the V.A. Medical Center (Atlanta).
Results and Discussion
Forty-two patients were enrolled in the study. There were 14 men and 26 women, and the group included 12 white and 28 black patients. There was 1 patient in the age group 30-39, 8 patients age 40-49,17 patients age 50-59, 13 patients age 60-69, and 1 patient age 70-79.
The Avicel group consisted of 2 men and 13 women, 3 whites and 12 blacks. The colestipolgroup included 4 men and 6 women, 4 whites and 6 blacks; and the Questran group had 8 men and 7 women, 5 white and 10 blacks. Group composition did not differ significantly.
Mean heights and weights were comparable both for the total group and for men and women (Table 1).
Fifteen patients were assigned to the placebo group, 11 to colestipol therapy, and 16 to cholestyramine therapy. Fourteen of the placebo patients completed 3 months of therapy, 9 patients 6 months of therapy, 6 patients 12 months of therapy, 4 patients 18 months of therapy, and 1 patient completed 2 years on placebo. In the colestipol group, 9 patients were followed for 3 months, 8 patients for 6 months, 4 for 12 months, 3 for 18 months, and 1 for 24 months. Thirteen of the cholestyramine patients completed 3 months of therapy, 11 completed 6 months, 8 completed 12 months, 5 completed 18 months, and 3 completed 2 years.
Analysis of overall data and of data from individual studies indicated that the maximum cholesterol-lowering effect of colestipol and cholestyramine occurred within the first 1-3 months, and was maintained (with fluctuations) during the period of continued treatment. Therefore, the most appropriate statistical method to use in comparing treatment groups was the mean percent change from the pre-treatment value. This was determined as for each patient, the average pre-treatment value and average value during treatment were calculated, and the individual percent change calculated from the difference. Then a group percent change for the total treatment period was calculated from the individual percent change. Group averages are indicated in Tables 2 and 3.
A comparable and significant lowering of cholesterol levels was obtained with both colestipol and cholestyramine as compared with the Avicel placebo. Serum triglyceride levels were not consistently altered.
All intercurrent medical events occurring during the study were recorded. No adverse reactions were recorded before assignment to treatment or during the placebo pre-randomiza-tion period. During treatment, 1 patient receiving Avicel placebo had an episode of bacterial endocarditis. 1 patient receiving cholestyramine had an episode of cholecystitis, and 2 patients receiving cholestyramine died, both of acute myocardial infarction. None of these events was considered drug-related.
Nonserious side effects-abdominal distress, bloating, constipation, nausea, and vomiting- were minimal in all 3 groups. No significant abnormality of the screening laboratory data was encountered.
Serum carotene levels generally parallel serumlipid levels. In this study, fasting serum carotene levels did not change significantly (Table 4);
and there was no correlation between serum carotene and serum cholesterol levels in the simultaneous measurements in any of thethree groups. Since colestipol and cholestyramine affected only cholesterol levels and not triglyceride levels, the absence of changes in serum carotene concentration is not surprising.
Carbohydrate absorption was studied by a fasting and 1 and 3 hour blood levels of xylose. The urine for xylose determination was collected at the end of 3 hours. Particularly in older patients, this technique of urine collection may not be very reliable, because of variability in the rate of glomerular filtration and urinary excredon of any test material. A new technique (Haeney et al., 1978) relates blood levels to body surface area and tends to correct for some abnormalities which might occur in older patients. Blood specimens were collected for fasting xylose levels and all subsequent specimens had this fasting level subtracted. Although xylose is not a normal constituent of blood, some chromogenic materials in blood appear to give the reaction of xylose; therefore, this value was subtracted from the subsequent xylose determinations. In most patients (Table 5),
a rise in xylose levels was readily detected in the 1 and 3 hour blood levels to concentrations of 25 to 35 mg/dl.
The protein mixture that was administered was primarily gelatin. The gelatin contains predominantly the aminoacid hydroxy-proline, but also contains other aminoacids. Three blood specimens: fasting, 1 hour, and 3 hour- were measured for total aminoacids (West, 1946). There was a consistent rise of the blood amino acid level from the fasting to the 1 hour determination in most patients.
Table 6 shows the trend of changes in patients in the three treatment groups. Total blood aminoacid determination is a simple method for studying aminoacid absorption, but is very nonspecific. It does not indicate which aminoacids rose after the test meal, but shows a trend which was fairly reproducible in most patients.
Hydroxy-proline is an aminoacid which is liberated from gelatin. The fasting and 1 and 3 hours blood levels of hydroxy-proline were measured in most patients. Again, the urine was collected for total aminoacid determination, and the change from the fasting to the 3 hours urine determination was measured; however, this is not a very reliable measurement, as the clearance of aminoacids from the blood to the urine is variable. It depends upon many factors, including the state of hydration of the patient and the degree of renal impairment; therefore, the urinary hydroxy-proline determinations are not very reliable.
Blood levels of hydroxy-proline are more dependable. There was a definite rise from the fasting to the 1 and to the 3 hour blood hydroxy-proline levels. Both the free and the total hydroxy-proline measurements showed this rise. How-ever, for the purposes of this study, we may ignore the difference between these two measure-ments and study only the total blood hydroxy-proline. Since there is normally a small amount of hydroxy-proline present in blood, the fasting or basal concentration was substracted from all subsequent determinations. The 1-and the 3hour blood levels show a rise in most patients in all three treatment groups. This rise is consistent and shows almost the same pattern as the total blood amino acid levels, but it is a more precise biochemical measurement.
Table 7 shows the pattern of absorption and the lack of difference between patients receiving placebo and those receiving a cholesterol-binding drug.
1. Arteriosclerosis: A Report by the National Heart and Lung Institute Task Force on Arteriosclerosis, Vol. 2, DHEW Publication No. (NIH) 72-219, National Institute of Health, Bethesda, Md, 1972.
2. Atherosclerosis Study Group (1971) Primary prevention of the atherosclerotic disease. Circulation, 42:A-55.
3. Brown, D.D., Juhl, R.P. and Warner, S.L. (1978) Decreased bioavailability of digoxin due to hypocholesterolemic interventions. Circulation, 58:164.
4. Cooper, E.E. and Michel, A.M. (1975) Colestipol hydrochloride, a new hypolipidemic drug; a two-year study. South Med. J; 68:3030.
5. Gundersen, K., Cooper, E.E., Ruoff, G., Nikolai, T. and Assenzo, J.R. (1976)
6. Cholesterol-lowering effect of colestipol hydrocholoride given twice daily in hypercholesterolemic patients. Atherosclerosis, 24:303.
7. Haeney, M.R., Culank, L.S., Montgomery, R.D. and Sammons, H.G. (1978) A one-hour blood xylose screening test in malabsorption. Gastroenterology, 75:393.
8. Hashim, S.A. and Van Italie, T.B. (1965) Cholestyramine resin therapy for hypercholesterolemia; clinical and metabolic studies. JAMA, 192:289.
9. Harvengt, C. and Desager, J.P. (1973) Effects of colestipol a new bile acid sequestrant, on the absorption of pheno-procoumon in man. Eur. J. Clin. Pharmacol., 6:19.
10. Illingworth, D.R., Phillipson, B.E., Rapp, J.H. and Connor, W.E. (1981) Colestipol plus nicotinic acid in treatment of heterozygous familial hypercholesterolaemia. Lancet, 1:296.
11. Kane, J.P., Malloy, M.J., Tun, P., Phillips, N.R., Freedman, D.D., Williams, M.L., Rowe, J.S. and Havel, R.J. (1981) Normalization of low-density lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen. N. Engl. J. Med., 304:251.
12. Keys, A. (1970) Coronary heart disease in seven countries. American Heart Association Monograph No. 29 Circulation, 41(suppl I):l.
13. Kuo, P.T., Hayase, K., Kostis, J.B. and Moreyra, A.E. (1979) Use of combined diet and colestipol in long-term (7-7$ years) treatment of patients with type II hyperlipoproteinemia. Circulation, 59:199.
14. Mishkel, M.A. and Crowther, S.M. (1977) Long-term therapy of diet-resistant hypercholesterolemia with colestipol. Curr. Ther. Res; 22:398.
15. Mo, H. and Boyer, M.E. (1974) In vitro binding of drugs to colestipol hydrocholoride. J. Pharm. Sci., 63:1915.
16. Parkinson, T.M., Gundersen, K. and Nelson, N.A. (1970) Effects of colestipol (U 26,597A), a new bile acid sequestrant, on serum lipids(in experimental animals and man. Atherosclerosis, 11:531.
17. Phillips, W.A., Schultz, J.R. and Stafford, W.W. (1974) Effects of colestipol hydrocholoride on drug absorption in the rat. I. Aspirin, 1-thyroxine, phenobarbital, cortisone, and sulfadiazine. J Pharm. Sci., 63:1097.
18. Prockop, D.J. and Udenfriend, S. (1960) A specific method for analysis of hydroxyproline in tissues and urine. Anal Bio-chem., 1:229.
19. Research committee of the Scottish Society of Physicians (1971) Ischaemic Heart Disease: A secondary prevention trial using clofibrate. Br. Med. J; 4:775.
20. Roe, J.H. and Rice, E.W. (1948) Photometric method for the determination of free pentoses in animal tissues. J. Biol. Chem., 173:507.
21. Schwarz, K.B., Goldstein, P.D., Witztum, J.L. and Schon-feld. (1980) Fat-soluble vitamin concentrations in hypercholesterolemic children treated with colestipol. Pediatrics, 65:243.
22. The Coronary Drug Project Research Group (1975): Clofibrate and niacin in coronary heart disease. JAMA; 231:260.
23. Thiel, C.B., Benoit, F.L. and Watten, R.H. (1963) An oral gelatin-xylose test for estimating pancreatic proteolytic activity. Am. J. Dig. Dis., 8:1008.
24. Wenger, J., Kirsner, J.B. and Palmer, W.L. (1957) Blood carotene in steatorrhea and the malabsorptivc syndromes. Am. J. Med., 22:373.
25. West, C.D., Wilson, J.L. and Eyles, R. (1946) Blood amino nitrogen levels. Am. J. Dis. Child., 72:251.