129
Atherosclerosis, 24 (1976) 129-140 0 Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
RESULTS OF COLESTIPOL HYPERLIPOPROTEINEMIA
THERAPY
IN TYPE II
ANN M. LEES, MARTHA A. MCCLUSKEY and ROBERT S. LEES Arteriosclerosis and Clinical Research Centers, Massachusetts 40 Ames Street, Cambridge, Mass. 02142 (U.S.A.)
Institute
of Technology,
(Received 6th August, 1975) (Revised, received 30th January, 1976) (Accepted 30th January, 1976)
Summary Twenty-five patients with well defined Type II hyperlipoproteinemia were treated with a divided 15 g daily dose of colestipol, a bile acid sequestrant, for periods of up to 20 months. The patients were divided into 3 groups: Those with no obvious sequelae, those with arcus corneae, xanthomas, and/or xanthelasmas only, and those with atherosclerotic complications. Colestipol lowered plasma cholesterol in all 3 groups, but reduced it to normal or near-normal levels in only 9 of the 25 patients (36%). The response of plasma triglycerides was highly variable; the mean for each group was elevated by the drug. Colestip01 was well-tolerated and its effect did not diminish with time. It is a useful drug in the treatment of hypercholesterolemia. Key words:
Bile acid sequestrant emia - Weight-height
- Colestipol index
- Diet therapy - Type II hyperlipoprotein-
Introduction The well-proven statistical correlation between plasma cholesterol concentration and risk of coronary heart disease [ 1,2] , has made it accepted medical practice to attempt to lower the plasma lipids of hyperlipidemic patients. The most commonly used method for accomplishing this is regulation of diet. When dietary management alone is insufficient, prescription of one or more This work was supported by a grant from the National Heart and Lung Institute for a Specialized Center of Research in Arteriosclerosis (HL 14209) and by a grant from the Upjohn Company.
130
lipid-lowering drugs is advisable, in combination with diet. Lipid-lowering drugs vary in effectiveness and toxicity not only from drug to drug, but also, for the same drug, from one patient to another. Drugs which act primarily on the entero-hepatic circulation to alter cholesterol metabolism are among the least toxic agents available. These include fl-sitosterol (Cytellin), a competitive inhibitor of cholesterol absorption from the gastrointestinal tract, and cholestyramine (Questran), a bile-acid binding resin. The latter, however, is found by many patients to be too unpalatable for prolonged therapy. A newer and tasteless bile acid sequestrant, colestipol, is at present available for investigational use. We report here the effect of colestipol therapy on the plasma lipids of 25 Type II hypercholesterolemic patients of both sexes, varying ages, and with and without clinical symptoms of atherosclerosis. Methods Some relevant characteristics of the 25 patients studied are outlined in Table 1. None had any diseases other than atherosclerosis. During an initial assessment period, all patients were determined by 2 to 3 blood lipid estimations plus lipoprotein quantitations and paper electrophoresis [3] to have Type II [ 41. hypercholesterolemia according to the Frederickson-Lees classification Blood samples throughout the study were drawn in the morning after a 12 hour fast. Seven patients were female; 18 were male. Six were children (2 female, 4 male) ranging in age at initial visit from 5 to 14 years. Nineteen were adults (5 female, 14 male) whose age at initial visit ranged from 19 to 50 years. Sixteen patients had first degree relatives with known hypercholesterolemia. An additional 4 patients had parents who died at an early age of coronary heart disease; each of these deceased parents had a surviving sibling with known hypercholesterolemia. Four of the remaining 5 patients had strong family histories of heart disease, or sudden death at an early age, without documented hyperlipidemia. Only patient No. 10 had no family history suggestive of premature atherosclerosis. Ten patients (Group l), all male, had no physical signs (externally visible tissue lipid deposits) or symptoms (atherosclerotic complications) of their hyperlipidemia. Nine others patients (Group 2,4 female, 5 male), with tissue lipid deposits had no atherosclerotic complications. The remaining 6 patients (Group 3, 3 female, 3 male), had coronary atherosclerosis. Their coronary disease was documented by electrocardiogram, coronary angiogram, and/or autopsy. Of these, 2 females and 1 male died during or after the study. None of the patients had symptoms of cerebrovascular or peripheral vascular atherosclerotic disease. While on colestipol, patients in Group 3 were also on cardiotonic drugs and tranquilizers, when necessary. In addition to the 25 patients included in this report, 18 other patients in our clinic were on colestipol at the same time. They were not included in the present study for one of the following reasons: (1) control weights were not comparable to weights during drug treatment for 6 patients; (2) colestipol was used only in combination with other drugs for 5 patients; (3) the time period on colestipol was too short to be meaningful for 2 patients; (4) 2 patients
1
M
M
M
M
M
M
5
6
7
8
9
10
9
266 274 232
40
42
47
47
F
M
F
M
22
23
24
25
b Coronary
226
49
documented
by
index.
available
a
01 autopsy.
(235)
(205)
(235)
(205)
(205)
(235)
(205)
(235)
(205)
(235)
(235)
(235)
(235)
(175)
(161)
(235)
(235)
(235)
(235)
(235)
(235)
(156)
(163)
(156)
maximum
Ideal
weight-height
angiography
of weight-height
235
49
for explanation
atherosclerosis
a See METHODS
255
47
F 254
212
33
44
M
21
244
195
282
36
34
216
192
227
192
256
258
258
200
203
243
166
187
not
159
Actual
index
Initial
20
Group
F
19
M
16
F
M
15
M
M
14
18
19
M
13
23
14
F
10
50
47
25
23
22
20
10
F
-
5
7
12
17
at initial
visit (yrs)
Age
PATIENTS
11
III
M
Group
M
3
4
M M
M
II
I
OF
Sex
2
1
Group
number
Patient
DESCRIPTION
TABLE
x
x
x
x
x
x
x
x
x
x
x
comeae
Arcus
Signs
x
x
x
x
x
x
x
x
Xanthoma
of hyperlipidemia
-___~-
x
x
x
Xanthelasma
xb
.b xb
xb
Eb
pectolis
Angina
Arteriosclerotic
x
x
x
x
x ‘.
infarction
Myocardial
CompIicatiOns
132
were never on the standard dose of 15 g of colestipol daily; (5) 2 patients were already on drugs when first seen and were too sick to be taken off all drugs to obtain control lipid values; (6) 1 patient could not tolerate the drug because of intractable constipation. Before lipid-lowering drug therapy was begun, the effect of diet alone was assayed for each patient. Both the qualitative and quantitative aspects of diet were considered: low cholesterol, low saturated fat diets were prescribed for patients not already on such a regimen *; overweight patients were also placed on weight reduction diets. Nearly all patients were stabilized on diet for six weeks or longer, i.e., their lipid values and body weight were stable for that length of time before drug was begun. For 4 patients (Nos. 6, 11, 15, 22) the period was 3 to 5 weeks. The average lengths of time on diet alone were 25 weeks for Group 1, 10 weeks for Group 2, and 7 weeks for Group 3. The maximum times for each group, respectively, were 69 weeks, 18 weeks and 9 weeks. Patients were placed on colestipol when they had persistently elevated (2,240 mg/dl) plasma cholesterol (TC) on their best attainable diets. Patients who also had elevated (3140 mg/dl) triglycerides (TG), sometimes referred to as Type II B [5] , were not excluded from the study. The initial assessment showed that seven of the 25 patients had elevations in their mean values for both TC and TG. The dose of colestipol prescribed for the patients described in this study was 15 g daily ( 5 g three times a day). The drug was mixed with fruit or vegetable juice or other liquid and taken after meals. The duration of colestipol therapy is indicated in Table 2. Three patients, whose coronary disease was the most severe before colestipol was begun, were on the drug for only 6-10 weeks. Their average length of time on the drug was 9 weeks. Eighteen patients were on the drug from 3 to 12 months. The average time on drug for this group was just over 6 months. Four patients were on colestipol for more than one year, that is, from 13 to 20 months. Their average time on drug was 17 months. Patients were started on the drug over a 4-year period. The sequence of treatment periods used in the study was as follows: (1) Diet period immediately preceded colestipol period (16 patients); (2) Diet period immediately followed colestipol period (2 patients, Nos. 9 and 10); (3) Diet period precede colestipol period but was separated from it by trials of other drugs, ranging in duration from 4 to 15 months (6 patients, Nos. 2,4, 12,15, 16,17); (4) Diet period followed colestipol period and was separated from it by an 11 month trial of other therapies (1 patient, No. 14). For diet periods, lipid values obtained less than 6 weeks after cessation of any drug therapy were not used to calculate mean TC and TG on diet. For colestipol periods, lipid values obtained less than 6 weeks after cessation of any other drug were not used to calculate mean TC and TG on colestipol. The average number of samples drawn during the diet periods was between * We define a low cholesterol diet as one which has less than 300 saturated fat has a polyunsaturated to saturated fat ratio of from I : 2 common in the “average American” diet.
mg cholesterol 1 : 1 up to 2
per day; a diet low in reducing the ratio of
: 1,
I
20 21 22 23 24
Group III
11 12 13 14 15 16 17 18 19
Group II
Mf?lZfl
1 2 3 4 5 6 7 8 9 10
Group
Patient number
index
235 211 255 235 240
197 222 193 208 281 192 263 228 233
173 204 182 166 236 203 200 242 227 228
Actual
(235) (205) (285) (235) (205) .___
(166) (174) (235) (235) (235) (235) (205) (235) (205)
(155) (167) (165) (166) (235) (235) (235) (235) (235) (235)
Ideal maximum
duringdrugtreatment
Weight-height
EFFECTSOFDAILY15mgDIVIDEDDOSE
TABLE2
394f 2902 496 k 258* 356k
46 24" 56' 30 38
19Ok 5b 163k 19 c 209 f 23' 158k16 129 + 28
125
268
321
411r25b 363+- 21' 547 * 4oc 323i 28 411t 33
117f 39 89 +13 105f 35 80 + 11 98kqb 64* 10 203? 19 124? 19 243k 21
89
77 f 19 120 f 54 53 k 18 5Ok 7 87 f 2Sb 130+ 21 68k14b 122 r 35 82f 7 102* 19
Diet (mg/dU
__~
28 45' 82' 61 35
4 -20 * -20 -13
-15 +37 +81 -16 +25
+10
-17 137
161+ 224k 378 + 132+ 161+
+64 -25 +20 +39 +26 +64 +1 +2 -28
+13
-17 +2 +16 -3 +16 +65 +3 +44 +34
-8
TG
--
-25 -22 -18 --17 -14 -6 -11 -22 -15
-12
-14 -13 -15 -22 -6 -7 -10 -14 +2 -17
TC
Percent change
192f 80 67?15 126 f 41 lllf 32 123 k.18 105* 15 205+ 23 126 f 13 175t 67
101
71? 26 loo+ 53 54?17 58?13 84+11 151* 41 112+ 59 126 f 13 118 k 36 131* 23
(mg/dI)
Diet + drug
Mean plasma triglycerides
325+ 42 205+ 19 218* 22 284+14 305* 13 285? 28 348? 22 209+ 20 231k 28
248
234* 23 211? 62 235+16 198 f 16 293+ 26 3192 33 273k 4 247k 22 26Ok 35 214?4
Diet+ drug (mg/dI)
cholesterol
433* 21 264k 10 266 f 11 342k12 356-r lSb 302+ 18 389 f.29 269 f 27 271k 23
281
273 f 24 243 + 21 278+- 25 254+ 21 311+ 22b 344? 7 304+ 34b 286 * 19 255k 21 264+9
Diet (mg/dI)
Mean plasma
OFCOLESTIPOLONPLASMALIPIDLEVELSINTYPEIIHYPERLIPOPROTEINEMIA ____~~
A A
B
B
B
B
a
Duration of treatment.
z
w
25
Ideal
value
on liquid
formula
diet.
mean
f 55
282
360
368
Diet
cholesterol
months.
plasma
B = 13-20
328
415
437
Qm/dl)
’ In-patient
(235)
maximum
Diet
Mean
value.
combined
227
index
treatment
a A = 6-10 weeks; blank = 3-11 months: b Initial mean value rather than diet mean
Mean
All groups
Mean
Actual
drug
Weight-height
during
number
2 (continued)
Patient
TABLE
t 18
+ drug
126
191
297
plasma
+ 89
(mz/dU
Diet
Mean
157
280
624
Diet
triglycerides
? 163
+ drug
+25
+47
-14
+110
TG
-13
change
-16
TC
Percent
Duration
A
treatment
a
of
135
3 and 4 (range 2-6). The average number of samples drawn during the colestipol periods was 5 (range 3-9). Student’s paired t-test was used to test the significance of differences within groups of lipid values with and without drug therapy. The unpaired t-test was used to test the significance of differences between one group and another. Total cholesterol (TC) and triglyceride (TG) measurements and phenotyping were done as described elsewhere [3,4]. Other blood analyses done on each patient at regular intervals were a complete blood count, alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, creatine phosphokinase, uric acid and prothrombin time. Three or more measurements of cholesterol content of the major lipoprotein fractions [3] were done for 9 patients. Weight and blood pressure were recorded at each visit. Each patient’s diet and mean weight were similar when comparisons were made between his/her lipid values on diet alone and on diet plus colestipol. With two exceptions, indicated in Table 2, all comparisons were made on patients living at home and following their usual living patterns. For two patients (Nos. 21 and 22), data were obtained while the patients were living on a metabolic research ward and receiving their total calories from liquid formula diets. Since each patient’s diet and mean weight were similar for the control and treatment periods, their data were included in the study. Patient No. 21 was on a corn oil based liquid formula diet; patient No. 22 was on a lard based liquid formula diet [6]. Evaluation of patients’adherence to diet and to drug (on a scale of good-fairpoor) was made by the independent observations of a physician (RSL) and nurse (MM). Drug adherence was judged by whether drug consumption was equal to or less than the prescribed daily dose. Because excess body weight is known to influence plasma lipid levels [7,8] , a slight modification of the weight-height index described by Khosla and Lowe [9], was calculated for each patient as an approximate parameter of obesity. The formula was: Index number
= mean weight (kg) x lo5 height’ (cm)
With this system, the index is expressed in whole numbers and a difference of 2 points in the units place is equivalent to approximately a 0.5 kg change in body weight at constant height. The actual equivalence between a given index difference (AI) and a specific weight difference (AW) varies as much as 3 points for people 5 feet tall and under, to as little as 1 point for people over 6 feet tall for the following reason: If I(ndex)
= z(ei$Ei
then
i.e., the sensitivity of the index to weight change is inversely proportional the square of the height. Thus, although the index is not totally independent
to of
136
height, as an ideal index should be, Khosla and Lowe [9] have shown that it is much more independent of height (and also more highly correlated with weight) than the ponder-al index (height divided by cube root of weight). Ideal index values for use as adult standards were calculated for 13 female and 13 male volunteers of varying heights and body builds. Ideal weight was defined as the weight which the person felt was best for her or him with indoor clothes on, but no shoes. (This is the way the patients were weighed). We found that with one exception for each sex, ideal values for women were at or below 205, and ideal values for men were at or below 235. Therefore we called 205 the ideal maximum index values for women and 235 the ideal maximum index for men. The range for women was 190-205; for men, it was 200-235. Index standards for girls and boys were calculated from the State University of Iowa height and weight graphs, using the 50th percentile values at each year of age. Our own graphs based on index value and height were then constructed for each sex so that an ideal index could be found for any observed height of the child. In Tables 1 and 2, ideal maximum index values are given in parentheses after the actual values. Actual weight-height indices were based on the mean weight for any particular observation period. Table 1 gives each patient’s weightheight index during his/her initial assessment period. For patients already on adequate diet therapy, this index number is also the index for the diet period, since initial and diet periods for these patients were the same period. Index numbers for the diet period are not otherwise given, however, because as noted above, mean weights for the diet and treatment period were similar. Table 2 gives the weight-height index values for colestipol treatment periods. Comparison of index values in Table 1 and 2 for an individual patient gives an indication of the relative amount of weight adjustment, if any, during the period of diet therapy alone. Results Ten patients (Nos. 2, 4, 8-10, 12, 13, 17, l&23) were not already on adequate diets when first seen. Thus data were available for these 10 patients to assess the effect of diet alone. The mean initial TG for the group was 322 mg/ dl. Their mean diet TC was 281 mg/dl. The fall between initial and diet periods for the group was 13% (P< 0.005). The range of falls in mean TC for individual patients was from 1 to 28%. The mean group TC went from 161 mg/dl to 116 mg/dl, a fall of 28% (P< 0.02). Seven of these patients had initial mean TG values above 140 mg/dl. After their diets had been established, only 2 of the 7 still had elevated TG values. Three patients (Nos. 5, 7, 20) who were put on diets after initial assessment had a paradoxical elevation of from 8 to 23% in their mean TC on low cholesterol diets. Their lipid values were not included in the assessment of the effect of diet alone. Table 2 indicates the effects of colestipol therapy in the 3 patient groups. There was a significant fall in mean TC for all 3 groups. Patients without visible tissue lipid deposits or known atherosclerosis (Group 1) had a mean cholesterol fall of 12% (P< 0.001). Those with visible tissue lipid deposits but
137
no clinically evident atherosclerosis (Group 2) had a mean cholesterol fall of 17% (P< O.OOl), while in those with atherosclerotic complications (Group 3) the mean cholesterol dropped by 13% (P < 0.002). The absolute difference in mean cholesterol for the three groups were 33, 53, and 55 mg/dl respectively. Mean triglyceride values were higher on colestipol than on diet alone for all three groups: 13, 10, and 47% higher, respectively. While none of these increases (or the mean increase for all 3 groups taken together) was statistically significant, it seems clear that for some individual patients, either with or without elevated triglycerides on diet alone, colestipol causes an increase in triglycerides which might be clinically significant over a long period of time. The elevation on colestipol of the already abnormal mean triglycerides of patient No. 25 was dramatic, although the clinical significance of such an elevation for a short time is unknown. There was no evidence in the great majority of the patients for any reduction in efficacy of the drug with time; such an effect was observed in only 2 patients. Patient No. 23 had a 22% rise (from 232 to 282 mg/dl, P< 0.05) in mean cholesterol between his early (day 1 to 107) and his late (day 245 to 329) periods of colestipol administration, and a 140% rise in mean triglycerides (from 85 to 204 mg/dl, P < 10w4) between the same periods. Patient No. 24 had an 18% rise in mean cholesterol (from 321 to 379 mg/dl, P< 0.1) between her early (day 1 to 70) and her late (day 119 to 182) periods of colestipol therapy. Her rise in mean triglycerides between the two periods was 48% (from 125 to 185 mg/dl, P< 0.02). Since colestipol elevates triglycerides in some patients, and obesity does the same [ll], we divided the patients into 2 groups based on the weight-m-height index to see if there was any correlation between excess weight and degree of change in mean TC and TG induced by colestipol therapy. Patients who were 5 or more index points above their ideal maximum index value were called overweight. There were 12 such patients: Nos. 1, 2, 3, 8, 11, 12, 15, 17, 19, 21, 22, 24. The weights of the remaining 13 patients were considered to be within normal limits. There was no statistically significant difference between the degree of change in mean lipids during colestipol therapy for the 2 groups. This was true both for the percent change and for the absolute change in mean lipid values. Calculation of a correlation coefficient between weight- -height index values and mean triglyceride values showed no significant correlation. In the 9 patients in whom quantitation of cholesterol in the major lipoprotein fractions was performed, during as well as before drug therapy, there was a significant difference between diet and diet plus colestipol only for the mean low density lipoprotein cholesterol. There was no significant difference for the very low density and high density lipoprotein cholesterol. Colestipol had no apparent on any patient’s complete blood count, liver chemistries, uric acid, or prothrombin time. Five patients who appeared to be getting less than full effect from colestipol at 15 g/day were increased to 30 g/day. Doubling the daily dose of colestipol caused no statistically significant difference in the mean TC or TG. Although patient adherence to diet or drug is always difficult to ascertain, nineteen of the patients had fair to good adherence to drug therapy; 6 (Nos. 5, 6,7, 17,20,24) adhered poorly, as best we could tell, to both diet and drug.
138
Since all of the less-than-good adherers took the drug at least part of the time their data were included. The mean changes for this group of 6 were TC: -9% TG: +8%. Omission of their data did not significantly alter the mean TC and TG changes of any group. The overall mean change for TC went from -14% to -16%, for TG from +25% to +29%. Discussion Our data show that the bile-acid sequestering agent, colestipol, is effective in lowering plasma cholesterol concentration in patients with well-characterized Type II hyperlipoproteinemia, for long periods of time. The patients were subdivided into 3 groups based on the extent of the clinical expression of their hypercholesterolemia. Patients in Group 1 were entirely asymptomatic. They also tended to be younger than patients in Groups 2 and 3. The rationale for their treatment with a lipid-lowering drug was the correlation between elevated plasma cholesterol and increased risk of atherosclerotic coronary heart disease. The importance of this correlation was strengthened by the frequent family history of such disease. Patients in Group 2 had visible tissue lipid deposits, but were otherwise asymptomatic, while patients in Group 3 all had atherosclerotic coronary heart disease, with or without arcus or xanthomas. In terms of the percent lowering, colestipol was equally effective in lowering plasma cholesterol for all 3 groups of patients: 12% for Group 1, 17% for Group 2, and 13% for Group 3. The percent lowering of each group was similar to the 14% fall for the three groups taken together. In terms of absolute fall, colestipol appeared to be more effective for the more clinically affected groups which had higher mean cholesterol values, since the absolute mean fall in cholesterol was 53 and 55 mg/dl for Groups 2 and 3, respectively, while the absolute fall for Group 1 was only 33 mg/dl. A total of 9 patients had their cholesterol values lowered to normal or near normal levels (240 mg/dl or below) by colestipol. On diet alone the mean cholesterol for this group was 265 mg/dl. When colestipol was added to their regimen the mean was lowered to 217 mg/dl, a 48 mg/dl or 18% fall. Our results are not in agreement with those of Nye and his colleagues who found only a 4% fall in plasma cholesterol for patients with a Type II pattern and familial hyperlipidemia as opposed to a 14% fall for those with non-familial disease [ 121. We found no difference between the responses of our Type II patients with documented familial disease and those without such documentation. Other authors have not analyzed their results using colestipol in terms of familial and non-familial hypercholesterolemia. It is difficult to make a direct comparison between our results and those of Parkinson and co-workers, who found a 20% fall in plasma cholesterol [13] , because they compared placebo and colestipol treatment in 2 different groups of patients. Dujovne and co-workers [ 141 did study the same patients during control and treatment periods. They found a 13% fall in plasma cholesterol for their group of patients. The patients were apparently not on controlled diets. Our study is most similar to that of Glueck and his colleagues [15] who found a 19% fall in plasma cholesterol for their patients, who were on low
139
cholesterol, low saturated fat diets. These patients received 20 g of colestipol daily. One of the most significant features of any lipid-lowering drug is the length of time it must be administered. The average length of time on drug for the patients in the 3-11 month time period was 6 months. For those in the 13-20 month time period the average time was 17 months. One should ask several questions about such a drug. Does it lower lipids significantly without losing its effect after prolonged administration? What are its side effects? Does the patient find it tolerable? Our results indicate that colestipol does lower plasma cholesterol for patients at all points in the atherosclerotic disease spectrum for periods up to 20 months. On the other hand, in only 9 of our 25 patients did the cholesterol fall below 240 mg/dl, a level which we consider to be the upper limit of normal. For the great majority of patients, it does not appear to lose its effect with time. The effect on triglycerides is more variable. In each of the groups there was an increase in mean triglycerides; however, for most patients, the increase was either not to levels above the normal range, or not greater than lo%, if already abnormal. For those patients, on the other hand, who do have large elevations in triglycerides on colestipol, caution should be observed. If colestipol is especially useful in lowering cholesterol in such a patient, efforts should be made to lower triglycerides by adding another drug, such as clofibrate or nicotinic acid, to the patient’s regimen. We have found such combined drug therapy be be very helpful for several patients not included in this study. Side effects were minimal with colestipol. It had no observable effect on the hematologic or chemical values of patients. Patients occasionally commented on a feeling of fullness or a change in their stools. One patient, not included in the study, could not tolerate the drug because of intractable constipation; he was later found to have ulcerative colitis. Fourteen of the 25 patients described in this study were still on colestipol alone or in combination with other drugs at the conclusion of the study. Six of the 18 patients described under methods but not included in this study were still taking colestipol alone or in combination when the study concluded. The ultimate aim of lipid-lowering drug therapy in atherosclerosis is twofold: to prevent progression of the disease, and if possible, to encourage regression of already established pathology. We have no direct or indirect evidence from this study that colestipol promoted regression of atherosclerosis. For example, no change was observed in the size of xanthomas in any of the 8 patients who had such lesions. Furthermore, 2 severely symptomatic patients (Nos. 21, 25) died while on the drug and a third (No. 22) died 6 months later. Although it is highly unlikely that colestipol in any way contributed to the deaths of these patients, whose atherosclerotic disease was far advanced before the drug was begun, it is equally clear that any beneficial effect it had was not enough to reverse the inexorable course of their severe disease. A more encouraging observation was that no patient in Group 1 or 2 had apparent progression of his/her disease during the course of the study. This is particularly encouraging for the 4 young people (Nos. 2, 4, 12, 13) who were on the drug for the longest period of time, from 13 to 20 months. Colestipol gave no indication of reducing the number of anginal episodes of
140
any patients. Patient No. 24 had had a coronary artery bypass graft shortly before her first visit to our clinic and was free of angina briefly following surgery. Angina returned within a few months and was not lessened while she was on either colestipol or clofibrate. Patient No. 23 had progressively worsening angina while on colestipol alone, and in combination with clofibrate and neomycin. Because of the severity of his symptoms a coronary artery by-pass graft was performed. He has remained symptom-free for more than 2 years following the surgery and has maintained his lipid levels well within the normal range on a combination of colestipol, clofibrate and neomycin. It seems clear from these findings and similar experience with other drugs [ 161, that prevention of atherosclerosis is a far more promising approach than trying to reverse the disease once it is well established. For this purpose, colestipol appears to be an effective drug on a long-term basis for a significant number of patients. Acknowledgements The dietetic assistance of Mrs. Sheila Joyce and Mrs. Margaret Miller Mikkola and the analytical assistance of Mr. Sidney David, Mr. Joseph Benson, Mr. Gene DeBenedetto and Mrs. Bernadette Cusack are gratefully acknowledged. Colestipol was supplied through the kindness of Dr. Kare Gunderson of the Upjohn Company, Kalamazoo, Michigan. References 1 Kannel, W.B.. Castelli. W.P., Gordon, T. and McNamara, P.M., Serum cholesterol, lipoproteins, and the risk of coronary heart disease, Ann. Intern. Med., 74 (1971) 1. 2 Chapman. J.M. and Massey, F.J.. The interrelationship of serum cholesterol, hypertension, body weight, and risk of coronary disease - Results of the first ten years’ follow-up in the Los Angeles heart study, J. Chron. Dis., 17 (1964) 933. 3 Hatch. F.T. and Lees, R.S., Practical methods for plasma lipoprotein analysis, Adv. Lipid Res., 6 (1968) 1. 4 Fredrickson. D.S. and Lees, R.S.. A system for phenotyping hyperlipoproteinemia, Circulation, 31 (1965) 321. 5 Beaumont. J.L.. Carlson, L.A., Cooper, G.R., Fejfar, Z., Fredrickson, D.S. and Strasser, T.. Classification of hyperlipidaemias and hyperlipoproteinaemias, Bull. Wld. Hlth. Org., 43 (1970) 891. 6 Ahrens. Jr., E.H.. Dole, V.P. and Blankenhorn, D.H.. The use of orally-fed liquid formulas in metabolic studies, Amer. J. Clin. Nutr., 2 (1954) 336. 7 Wilson, D.E. and Lees, R.S.. Metabolic relationships among the plasma lipoproteins - Reciprocal changes in the concentrations of very low and low density lipoproteins in man. J. Clin. Invest., 51 (1972) 1051. 8 Olefsky, J.. Raven. G.M. and Farquhar, J.W.. Effects of weight reduction on obesity - Studies of lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects, J. Clin. Invest., 53 (1974) 64. 9 Khosla. T. and Lowe. C.R., Indices of obesity derived from body weight and height, Brit. J. Prev. Sot. Med., 21 (1967) 122. 10 Metropolitan Life Insurance Co., Statistical Bulletin 40. New York, 1959. 11 Sims. E.A.H.. Horton, E.S. and Salans, L.B., Inducible metabolic abnormalities during development of obesity. Ann. Rev. Med., 22 (1971) 235. I2 Nye, E.R.. Jackson, D. and Hunter, J.D.. Treatment of hypercholesterolaemia with colestipol: a bile sequestrating agent, N.Z. Med., 22 (1971) 235. 13 Parkinson, T.M., Gundersen. K. and Nelson, N.A., Effects of colestipol (U-26, 597A). a new bile acid sequestrant. on serum lipid in experimental animals and man. Atherosclerosis, 11 (1970) 531. 14 Dujovne. CA.. Hurwitz. A.. Kauffman, R.E. and Azarnoff, D.L.. Colestipol and clofihrate in hypercholesterolemia, Clin. Pharmacol. Ther., 16 (1974) 291. 15 Glueck, C.J., Ford, S., Scheel. D. and Steiner, P., Colestipol and cholestyramine resin, J. Amer. Med. Ass., 222 (1972) 676. 16 Stamler. J. (Chrmn), The coronary drug project - Clofibrate and niacin in coronary heart disease, J. Amer. Med. Ass., 231 (1975) 360.
Atherosclerosis, 24 (1976) 129-140 0 Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
RESULTS OF COLESTIPOL HYPERLIPOPROTEINEMIA
THERAPY
IN TYPE II
ANN M. LEES, MARTHA A. MCCLUSKEY and ROBERT S. LEES Arteriosclerosis and Clinical Research Centers, Massachusetts 40 Ames Street, Cambridge, Mass. 02142 (U.S.A.)
Institute
of Technology,
(Received 6th August, 1975) (Revised, received 30th January, 1976) (Accepted 30th January, 1976)
Summary Twenty-five patients with well defined Type II hyperlipoproteinemia were treated with a divided 15 g daily dose of colestipol, a bile acid sequestrant, for periods of up to 20 months. The patients were divided into 3 groups: Those with no obvious sequelae, those with arcus corneae, xanthomas, and/or xanthelasmas only, and those with atherosclerotic complications. Colestipol lowered plasma cholesterol in all 3 groups, but reduced it to normal or near-normal levels in only 9 of the 25 patients (36%). The response of plasma triglycerides was highly variable; the mean for each group was elevated by the drug. Colestip01 was well-tolerated and its effect did not diminish with time. It is a useful drug in the treatment of hypercholesterolemia. Key words:
Bile acid sequestrant emia - Weight-height
- Colestipol index
- Diet therapy - Type II hyperlipoprotein-
Introduction The well-proven statistical correlation between plasma cholesterol concentration and risk of coronary heart disease [ 1,2] , has made it accepted medical practice to attempt to lower the plasma lipids of hyperlipidemic patients. The most commonly used method for accomplishing this is regulation of diet. When dietary management alone is insufficient, prescription of one or more This work was supported by a grant from the National Heart and Lung Institute for a Specialized Center of Research in Arteriosclerosis (HL 14209) and by a grant from the Upjohn Company.
130
lipid-lowering drugs is advisable, in combination with diet. Lipid-lowering drugs vary in effectiveness and toxicity not only from drug to drug, but also, for the same drug, from one patient to another. Drugs which act primarily on the entero-hepatic circulation to alter cholesterol metabolism are among the least toxic agents available. These include fl-sitosterol (Cytellin), a competitive inhibitor of cholesterol absorption from the gastrointestinal tract, and cholestyramine (Questran), a bile-acid binding resin. The latter, however, is found by many patients to be too unpalatable for prolonged therapy. A newer and tasteless bile acid sequestrant, colestipol, is at present available for investigational use. We report here the effect of colestipol therapy on the plasma lipids of 25 Type II hypercholesterolemic patients of both sexes, varying ages, and with and without clinical symptoms of atherosclerosis. Methods Some relevant characteristics of the 25 patients studied are outlined in Table 1. None had any diseases other than atherosclerosis. During an initial assessment period, all patients were determined by 2 to 3 blood lipid estimations plus lipoprotein quantitations and paper electrophoresis [3] to have Type II [ 41. hypercholesterolemia according to the Frederickson-Lees classification Blood samples throughout the study were drawn in the morning after a 12 hour fast. Seven patients were female; 18 were male. Six were children (2 female, 4 male) ranging in age at initial visit from 5 to 14 years. Nineteen were adults (5 female, 14 male) whose age at initial visit ranged from 19 to 50 years. Sixteen patients had first degree relatives with known hypercholesterolemia. An additional 4 patients had parents who died at an early age of coronary heart disease; each of these deceased parents had a surviving sibling with known hypercholesterolemia. Four of the remaining 5 patients had strong family histories of heart disease, or sudden death at an early age, without documented hyperlipidemia. Only patient No. 10 had no family history suggestive of premature atherosclerosis. Ten patients (Group l), all male, had no physical signs (externally visible tissue lipid deposits) or symptoms (atherosclerotic complications) of their hyperlipidemia. Nine others patients (Group 2,4 female, 5 male), with tissue lipid deposits had no atherosclerotic complications. The remaining 6 patients (Group 3, 3 female, 3 male), had coronary atherosclerosis. Their coronary disease was documented by electrocardiogram, coronary angiogram, and/or autopsy. Of these, 2 females and 1 male died during or after the study. None of the patients had symptoms of cerebrovascular or peripheral vascular atherosclerotic disease. While on colestipol, patients in Group 3 were also on cardiotonic drugs and tranquilizers, when necessary. In addition to the 25 patients included in this report, 18 other patients in our clinic were on colestipol at the same time. They were not included in the present study for one of the following reasons: (1) control weights were not comparable to weights during drug treatment for 6 patients; (2) colestipol was used only in combination with other drugs for 5 patients; (3) the time period on colestipol was too short to be meaningful for 2 patients; (4) 2 patients
1
M
M
M
M
M
M
5
6
7
8
9
10
9
266 274 232
40
42
47
47
F
M
F
M
22
23
24
25
b Coronary
226
49
documented
by
index.
available
a
01 autopsy.
(235)
(205)
(235)
(205)
(205)
(235)
(205)
(235)
(205)
(235)
(235)
(235)
(235)
(175)
(161)
(235)
(235)
(235)
(235)
(235)
(235)
(156)
(163)
(156)
maximum
Ideal
weight-height
angiography
of weight-height
235
49
for explanation
atherosclerosis
a See METHODS
255
47
F 254
212
33
44
M
21
244
195
282
36
34
216
192
227
192
256
258
258
200
203
243
166
187
not
159
Actual
index
Initial
20
Group
F
19
M
16
F
M
15
M
M
14
18
19
M
13
23
14
F
10
50
47
25
23
22
20
10
F
-
5
7
12
17
at initial
visit (yrs)
Age
PATIENTS
11
III
M
Group
M
3
4
M M
M
II
I
OF
Sex
2
1
Group
number
Patient
DESCRIPTION
TABLE
x
x
x
x
x
x
x
x
x
x
x
comeae
Arcus
Signs
x
x
x
x
x
x
x
x
Xanthoma
of hyperlipidemia
-___~-
x
x
x
Xanthelasma
xb
.b xb
xb
Eb
pectolis
Angina
Arteriosclerotic
x
x
x
x
x ‘.
infarction
Myocardial
CompIicatiOns
132
were never on the standard dose of 15 g of colestipol daily; (5) 2 patients were already on drugs when first seen and were too sick to be taken off all drugs to obtain control lipid values; (6) 1 patient could not tolerate the drug because of intractable constipation. Before lipid-lowering drug therapy was begun, the effect of diet alone was assayed for each patient. Both the qualitative and quantitative aspects of diet were considered: low cholesterol, low saturated fat diets were prescribed for patients not already on such a regimen *; overweight patients were also placed on weight reduction diets. Nearly all patients were stabilized on diet for six weeks or longer, i.e., their lipid values and body weight were stable for that length of time before drug was begun. For 4 patients (Nos. 6, 11, 15, 22) the period was 3 to 5 weeks. The average lengths of time on diet alone were 25 weeks for Group 1, 10 weeks for Group 2, and 7 weeks for Group 3. The maximum times for each group, respectively, were 69 weeks, 18 weeks and 9 weeks. Patients were placed on colestipol when they had persistently elevated (2,240 mg/dl) plasma cholesterol (TC) on their best attainable diets. Patients who also had elevated (3140 mg/dl) triglycerides (TG), sometimes referred to as Type II B [5] , were not excluded from the study. The initial assessment showed that seven of the 25 patients had elevations in their mean values for both TC and TG. The dose of colestipol prescribed for the patients described in this study was 15 g daily ( 5 g three times a day). The drug was mixed with fruit or vegetable juice or other liquid and taken after meals. The duration of colestipol therapy is indicated in Table 2. Three patients, whose coronary disease was the most severe before colestipol was begun, were on the drug for only 6-10 weeks. Their average length of time on the drug was 9 weeks. Eighteen patients were on the drug from 3 to 12 months. The average time on drug for this group was just over 6 months. Four patients were on colestipol for more than one year, that is, from 13 to 20 months. Their average time on drug was 17 months. Patients were started on the drug over a 4-year period. The sequence of treatment periods used in the study was as follows: (1) Diet period immediately preceded colestipol period (16 patients); (2) Diet period immediately followed colestipol period (2 patients, Nos. 9 and 10); (3) Diet period precede colestipol period but was separated from it by trials of other drugs, ranging in duration from 4 to 15 months (6 patients, Nos. 2,4, 12,15, 16,17); (4) Diet period followed colestipol period and was separated from it by an 11 month trial of other therapies (1 patient, No. 14). For diet periods, lipid values obtained less than 6 weeks after cessation of any drug therapy were not used to calculate mean TC and TG on diet. For colestipol periods, lipid values obtained less than 6 weeks after cessation of any other drug were not used to calculate mean TC and TG on colestipol. The average number of samples drawn during the diet periods was between * We define a low cholesterol diet as one which has less than 300 saturated fat has a polyunsaturated to saturated fat ratio of from I : 2 common in the “average American” diet.
mg cholesterol 1 : 1 up to 2
per day; a diet low in reducing the ratio of
: 1,
I
20 21 22 23 24
Group III
11 12 13 14 15 16 17 18 19
Group II
Mf?lZfl
1 2 3 4 5 6 7 8 9 10
Group
Patient number
index
235 211 255 235 240
197 222 193 208 281 192 263 228 233
173 204 182 166 236 203 200 242 227 228
Actual
(235) (205) (285) (235) (205) .___
(166) (174) (235) (235) (235) (235) (205) (235) (205)
(155) (167) (165) (166) (235) (235) (235) (235) (235) (235)
Ideal maximum
duringdrugtreatment
Weight-height
EFFECTSOFDAILY15mgDIVIDEDDOSE
TABLE2
394f 2902 496 k 258* 356k
46 24" 56' 30 38
19Ok 5b 163k 19 c 209 f 23' 158k16 129 + 28
125
268
321
411r25b 363+- 21' 547 * 4oc 323i 28 411t 33
117f 39 89 +13 105f 35 80 + 11 98kqb 64* 10 203? 19 124? 19 243k 21
89
77 f 19 120 f 54 53 k 18 5Ok 7 87 f 2Sb 130+ 21 68k14b 122 r 35 82f 7 102* 19
Diet (mg/dU
__~
28 45' 82' 61 35
4 -20 * -20 -13
-15 +37 +81 -16 +25
+10
-17 137
161+ 224k 378 + 132+ 161+
+64 -25 +20 +39 +26 +64 +1 +2 -28
+13
-17 +2 +16 -3 +16 +65 +3 +44 +34
-8
TG
--
-25 -22 -18 --17 -14 -6 -11 -22 -15
-12
-14 -13 -15 -22 -6 -7 -10 -14 +2 -17
TC
Percent change
192f 80 67?15 126 f 41 lllf 32 123 k.18 105* 15 205+ 23 126 f 13 175t 67
101
71? 26 loo+ 53 54?17 58?13 84+11 151* 41 112+ 59 126 f 13 118 k 36 131* 23
(mg/dI)
Diet + drug
Mean plasma triglycerides
325+ 42 205+ 19 218* 22 284+14 305* 13 285? 28 348? 22 209+ 20 231k 28
248
234* 23 211? 62 235+16 198 f 16 293+ 26 3192 33 273k 4 247k 22 26Ok 35 214?4
Diet+ drug (mg/dI)
cholesterol
433* 21 264k 10 266 f 11 342k12 356-r lSb 302+ 18 389 f.29 269 f 27 271k 23
281
273 f 24 243 + 21 278+- 25 254+ 21 311+ 22b 344? 7 304+ 34b 286 * 19 255k 21 264+9
Diet (mg/dI)
Mean plasma
OFCOLESTIPOLONPLASMALIPIDLEVELSINTYPEIIHYPERLIPOPROTEINEMIA ____~~
A A
B
B
B
B
a
Duration of treatment.
z
w
25
Ideal
value
on liquid
formula
diet.
mean
f 55
282
360
368
Diet
cholesterol
months.
plasma
B = 13-20
328
415
437
Qm/dl)
’ In-patient
(235)
maximum
Diet
Mean
value.
combined
227
index
treatment
a A = 6-10 weeks; blank = 3-11 months: b Initial mean value rather than diet mean
Mean
All groups
Mean
Actual
drug
Weight-height
during
number
2 (continued)
Patient
TABLE
t 18
+ drug
126
191
297
plasma
+ 89
(mz/dU
Diet
Mean
157
280
624
Diet
triglycerides
? 163
+ drug
+25
+47
-14
+110
TG
-13
change
-16
TC
Percent
Duration
A
treatment
a
of
135
3 and 4 (range 2-6). The average number of samples drawn during the colestipol periods was 5 (range 3-9). Student’s paired t-test was used to test the significance of differences within groups of lipid values with and without drug therapy. The unpaired t-test was used to test the significance of differences between one group and another. Total cholesterol (TC) and triglyceride (TG) measurements and phenotyping were done as described elsewhere [3,4]. Other blood analyses done on each patient at regular intervals were a complete blood count, alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, creatine phosphokinase, uric acid and prothrombin time. Three or more measurements of cholesterol content of the major lipoprotein fractions [3] were done for 9 patients. Weight and blood pressure were recorded at each visit. Each patient’s diet and mean weight were similar when comparisons were made between his/her lipid values on diet alone and on diet plus colestipol. With two exceptions, indicated in Table 2, all comparisons were made on patients living at home and following their usual living patterns. For two patients (Nos. 21 and 22), data were obtained while the patients were living on a metabolic research ward and receiving their total calories from liquid formula diets. Since each patient’s diet and mean weight were similar for the control and treatment periods, their data were included in the study. Patient No. 21 was on a corn oil based liquid formula diet; patient No. 22 was on a lard based liquid formula diet [6]. Evaluation of patients’adherence to diet and to drug (on a scale of good-fairpoor) was made by the independent observations of a physician (RSL) and nurse (MM). Drug adherence was judged by whether drug consumption was equal to or less than the prescribed daily dose. Because excess body weight is known to influence plasma lipid levels [7,8] , a slight modification of the weight-height index described by Khosla and Lowe [9], was calculated for each patient as an approximate parameter of obesity. The formula was: Index number
= mean weight (kg) x lo5 height’ (cm)
With this system, the index is expressed in whole numbers and a difference of 2 points in the units place is equivalent to approximately a 0.5 kg change in body weight at constant height. The actual equivalence between a given index difference (AI) and a specific weight difference (AW) varies as much as 3 points for people 5 feet tall and under, to as little as 1 point for people over 6 feet tall for the following reason: If I(ndex)
= z(ei$Ei
then
i.e., the sensitivity of the index to weight change is inversely proportional the square of the height. Thus, although the index is not totally independent
to of
136
height, as an ideal index should be, Khosla and Lowe [9] have shown that it is much more independent of height (and also more highly correlated with weight) than the ponder-al index (height divided by cube root of weight). Ideal index values for use as adult standards were calculated for 13 female and 13 male volunteers of varying heights and body builds. Ideal weight was defined as the weight which the person felt was best for her or him with indoor clothes on, but no shoes. (This is the way the patients were weighed). We found that with one exception for each sex, ideal values for women were at or below 205, and ideal values for men were at or below 235. Therefore we called 205 the ideal maximum index values for women and 235 the ideal maximum index for men. The range for women was 190-205; for men, it was 200-235. Index standards for girls and boys were calculated from the State University of Iowa height and weight graphs, using the 50th percentile values at each year of age. Our own graphs based on index value and height were then constructed for each sex so that an ideal index could be found for any observed height of the child. In Tables 1 and 2, ideal maximum index values are given in parentheses after the actual values. Actual weight-height indices were based on the mean weight for any particular observation period. Table 1 gives each patient’s weightheight index during his/her initial assessment period. For patients already on adequate diet therapy, this index number is also the index for the diet period, since initial and diet periods for these patients were the same period. Index numbers for the diet period are not otherwise given, however, because as noted above, mean weights for the diet and treatment period were similar. Table 2 gives the weight-height index values for colestipol treatment periods. Comparison of index values in Table 1 and 2 for an individual patient gives an indication of the relative amount of weight adjustment, if any, during the period of diet therapy alone. Results Ten patients (Nos. 2, 4, 8-10, 12, 13, 17, l&23) were not already on adequate diets when first seen. Thus data were available for these 10 patients to assess the effect of diet alone. The mean initial TG for the group was 322 mg/ dl. Their mean diet TC was 281 mg/dl. The fall between initial and diet periods for the group was 13% (P< 0.005). The range of falls in mean TC for individual patients was from 1 to 28%. The mean group TC went from 161 mg/dl to 116 mg/dl, a fall of 28% (P< 0.02). Seven of these patients had initial mean TG values above 140 mg/dl. After their diets had been established, only 2 of the 7 still had elevated TG values. Three patients (Nos. 5, 7, 20) who were put on diets after initial assessment had a paradoxical elevation of from 8 to 23% in their mean TC on low cholesterol diets. Their lipid values were not included in the assessment of the effect of diet alone. Table 2 indicates the effects of colestipol therapy in the 3 patient groups. There was a significant fall in mean TC for all 3 groups. Patients without visible tissue lipid deposits or known atherosclerosis (Group 1) had a mean cholesterol fall of 12% (P< 0.001). Those with visible tissue lipid deposits but
137
no clinically evident atherosclerosis (Group 2) had a mean cholesterol fall of 17% (P< O.OOl), while in those with atherosclerotic complications (Group 3) the mean cholesterol dropped by 13% (P < 0.002). The absolute difference in mean cholesterol for the three groups were 33, 53, and 55 mg/dl respectively. Mean triglyceride values were higher on colestipol than on diet alone for all three groups: 13, 10, and 47% higher, respectively. While none of these increases (or the mean increase for all 3 groups taken together) was statistically significant, it seems clear that for some individual patients, either with or without elevated triglycerides on diet alone, colestipol causes an increase in triglycerides which might be clinically significant over a long period of time. The elevation on colestipol of the already abnormal mean triglycerides of patient No. 25 was dramatic, although the clinical significance of such an elevation for a short time is unknown. There was no evidence in the great majority of the patients for any reduction in efficacy of the drug with time; such an effect was observed in only 2 patients. Patient No. 23 had a 22% rise (from 232 to 282 mg/dl, P< 0.05) in mean cholesterol between his early (day 1 to 107) and his late (day 245 to 329) periods of colestipol administration, and a 140% rise in mean triglycerides (from 85 to 204 mg/dl, P < 10w4) between the same periods. Patient No. 24 had an 18% rise in mean cholesterol (from 321 to 379 mg/dl, P< 0.1) between her early (day 1 to 70) and her late (day 119 to 182) periods of colestipol therapy. Her rise in mean triglycerides between the two periods was 48% (from 125 to 185 mg/dl, P< 0.02). Since colestipol elevates triglycerides in some patients, and obesity does the same [ll], we divided the patients into 2 groups based on the weight-m-height index to see if there was any correlation between excess weight and degree of change in mean TC and TG induced by colestipol therapy. Patients who were 5 or more index points above their ideal maximum index value were called overweight. There were 12 such patients: Nos. 1, 2, 3, 8, 11, 12, 15, 17, 19, 21, 22, 24. The weights of the remaining 13 patients were considered to be within normal limits. There was no statistically significant difference between the degree of change in mean lipids during colestipol therapy for the 2 groups. This was true both for the percent change and for the absolute change in mean lipid values. Calculation of a correlation coefficient between weight- -height index values and mean triglyceride values showed no significant correlation. In the 9 patients in whom quantitation of cholesterol in the major lipoprotein fractions was performed, during as well as before drug therapy, there was a significant difference between diet and diet plus colestipol only for the mean low density lipoprotein cholesterol. There was no significant difference for the very low density and high density lipoprotein cholesterol. Colestipol had no apparent on any patient’s complete blood count, liver chemistries, uric acid, or prothrombin time. Five patients who appeared to be getting less than full effect from colestipol at 15 g/day were increased to 30 g/day. Doubling the daily dose of colestipol caused no statistically significant difference in the mean TC or TG. Although patient adherence to diet or drug is always difficult to ascertain, nineteen of the patients had fair to good adherence to drug therapy; 6 (Nos. 5, 6,7, 17,20,24) adhered poorly, as best we could tell, to both diet and drug.
138
Since all of the less-than-good adherers took the drug at least part of the time their data were included. The mean changes for this group of 6 were TC: -9% TG: +8%. Omission of their data did not significantly alter the mean TC and TG changes of any group. The overall mean change for TC went from -14% to -16%, for TG from +25% to +29%. Discussion Our data show that the bile-acid sequestering agent, colestipol, is effective in lowering plasma cholesterol concentration in patients with well-characterized Type II hyperlipoproteinemia, for long periods of time. The patients were subdivided into 3 groups based on the extent of the clinical expression of their hypercholesterolemia. Patients in Group 1 were entirely asymptomatic. They also tended to be younger than patients in Groups 2 and 3. The rationale for their treatment with a lipid-lowering drug was the correlation between elevated plasma cholesterol and increased risk of atherosclerotic coronary heart disease. The importance of this correlation was strengthened by the frequent family history of such disease. Patients in Group 2 had visible tissue lipid deposits, but were otherwise asymptomatic, while patients in Group 3 all had atherosclerotic coronary heart disease, with or without arcus or xanthomas. In terms of the percent lowering, colestipol was equally effective in lowering plasma cholesterol for all 3 groups of patients: 12% for Group 1, 17% for Group 2, and 13% for Group 3. The percent lowering of each group was similar to the 14% fall for the three groups taken together. In terms of absolute fall, colestipol appeared to be more effective for the more clinically affected groups which had higher mean cholesterol values, since the absolute mean fall in cholesterol was 53 and 55 mg/dl for Groups 2 and 3, respectively, while the absolute fall for Group 1 was only 33 mg/dl. A total of 9 patients had their cholesterol values lowered to normal or near normal levels (240 mg/dl or below) by colestipol. On diet alone the mean cholesterol for this group was 265 mg/dl. When colestipol was added to their regimen the mean was lowered to 217 mg/dl, a 48 mg/dl or 18% fall. Our results are not in agreement with those of Nye and his colleagues who found only a 4% fall in plasma cholesterol for patients with a Type II pattern and familial hyperlipidemia as opposed to a 14% fall for those with non-familial disease [ 121. We found no difference between the responses of our Type II patients with documented familial disease and those without such documentation. Other authors have not analyzed their results using colestipol in terms of familial and non-familial hypercholesterolemia. It is difficult to make a direct comparison between our results and those of Parkinson and co-workers, who found a 20% fall in plasma cholesterol [13] , because they compared placebo and colestipol treatment in 2 different groups of patients. Dujovne and co-workers [ 141 did study the same patients during control and treatment periods. They found a 13% fall in plasma cholesterol for their group of patients. The patients were apparently not on controlled diets. Our study is most similar to that of Glueck and his colleagues [15] who found a 19% fall in plasma cholesterol for their patients, who were on low
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cholesterol, low saturated fat diets. These patients received 20 g of colestipol daily. One of the most significant features of any lipid-lowering drug is the length of time it must be administered. The average length of time on drug for the patients in the 3-11 month time period was 6 months. For those in the 13-20 month time period the average time was 17 months. One should ask several questions about such a drug. Does it lower lipids significantly without losing its effect after prolonged administration? What are its side effects? Does the patient find it tolerable? Our results indicate that colestipol does lower plasma cholesterol for patients at all points in the atherosclerotic disease spectrum for periods up to 20 months. On the other hand, in only 9 of our 25 patients did the cholesterol fall below 240 mg/dl, a level which we consider to be the upper limit of normal. For the great majority of patients, it does not appear to lose its effect with time. The effect on triglycerides is more variable. In each of the groups there was an increase in mean triglycerides; however, for most patients, the increase was either not to levels above the normal range, or not greater than lo%, if already abnormal. For those patients, on the other hand, who do have large elevations in triglycerides on colestipol, caution should be observed. If colestipol is especially useful in lowering cholesterol in such a patient, efforts should be made to lower triglycerides by adding another drug, such as clofibrate or nicotinic acid, to the patient’s regimen. We have found such combined drug therapy be be very helpful for several patients not included in this study. Side effects were minimal with colestipol. It had no observable effect on the hematologic or chemical values of patients. Patients occasionally commented on a feeling of fullness or a change in their stools. One patient, not included in the study, could not tolerate the drug because of intractable constipation; he was later found to have ulcerative colitis. Fourteen of the 25 patients described in this study were still on colestipol alone or in combination with other drugs at the conclusion of the study. Six of the 18 patients described under methods but not included in this study were still taking colestipol alone or in combination when the study concluded. The ultimate aim of lipid-lowering drug therapy in atherosclerosis is twofold: to prevent progression of the disease, and if possible, to encourage regression of already established pathology. We have no direct or indirect evidence from this study that colestipol promoted regression of atherosclerosis. For example, no change was observed in the size of xanthomas in any of the 8 patients who had such lesions. Furthermore, 2 severely symptomatic patients (Nos. 21, 25) died while on the drug and a third (No. 22) died 6 months later. Although it is highly unlikely that colestipol in any way contributed to the deaths of these patients, whose atherosclerotic disease was far advanced before the drug was begun, it is equally clear that any beneficial effect it had was not enough to reverse the inexorable course of their severe disease. A more encouraging observation was that no patient in Group 1 or 2 had apparent progression of his/her disease during the course of the study. This is particularly encouraging for the 4 young people (Nos. 2, 4, 12, 13) who were on the drug for the longest period of time, from 13 to 20 months. Colestipol gave no indication of reducing the number of anginal episodes of
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any patients. Patient No. 24 had had a coronary artery bypass graft shortly before her first visit to our clinic and was free of angina briefly following surgery. Angina returned within a few months and was not lessened while she was on either colestipol or clofibrate. Patient No. 23 had progressively worsening angina while on colestipol alone, and in combination with clofibrate and neomycin. Because of the severity of his symptoms a coronary artery by-pass graft was performed. He has remained symptom-free for more than 2 years following the surgery and has maintained his lipid levels well within the normal range on a combination of colestipol, clofibrate and neomycin. It seems clear from these findings and similar experience with other drugs [ 161, that prevention of atherosclerosis is a far more promising approach than trying to reverse the disease once it is well established. For this purpose, colestipol appears to be an effective drug on a long-term basis for a significant number of patients. Acknowledgements The dietetic assistance of Mrs. Sheila Joyce and Mrs. Margaret Miller Mikkola and the analytical assistance of Mr. Sidney David, Mr. Joseph Benson, Mr. Gene DeBenedetto and Mrs. Bernadette Cusack are gratefully acknowledged. Colestipol was supplied through the kindness of Dr. Kare Gunderson of the Upjohn Company, Kalamazoo, Michigan. References 1 Kannel, W.B.. Castelli. W.P., Gordon, T. and McNamara, P.M., Serum cholesterol, lipoproteins, and the risk of coronary heart disease, Ann. Intern. Med., 74 (1971) 1. 2 Chapman. J.M. and Massey, F.J.. The interrelationship of serum cholesterol, hypertension, body weight, and risk of coronary disease - Results of the first ten years’ follow-up in the Los Angeles heart study, J. Chron. Dis., 17 (1964) 933. 3 Hatch. F.T. and Lees, R.S., Practical methods for plasma lipoprotein analysis, Adv. Lipid Res., 6 (1968) 1. 4 Fredrickson. D.S. and Lees, R.S.. A system for phenotyping hyperlipoproteinemia, Circulation, 31 (1965) 321. 5 Beaumont. J.L.. Carlson, L.A., Cooper, G.R., Fejfar, Z., Fredrickson, D.S. and Strasser, T.. Classification of hyperlipidaemias and hyperlipoproteinaemias, Bull. Wld. Hlth. Org., 43 (1970) 891. 6 Ahrens. Jr., E.H.. Dole, V.P. and Blankenhorn, D.H.. The use of orally-fed liquid formulas in metabolic studies, Amer. J. Clin. Nutr., 2 (1954) 336. 7 Wilson, D.E. and Lees, R.S.. Metabolic relationships among the plasma lipoproteins - Reciprocal changes in the concentrations of very low and low density lipoproteins in man. J. Clin. Invest., 51 (1972) 1051. 8 Olefsky, J.. Raven. G.M. and Farquhar, J.W.. Effects of weight reduction on obesity - Studies of lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects, J. Clin. Invest., 53 (1974) 64. 9 Khosla. T. and Lowe. C.R., Indices of obesity derived from body weight and height, Brit. J. Prev. Sot. Med., 21 (1967) 122. 10 Metropolitan Life Insurance Co., Statistical Bulletin 40. New York, 1959. 11 Sims. E.A.H.. Horton, E.S. and Salans, L.B., Inducible metabolic abnormalities during development of obesity. Ann. Rev. Med., 22 (1971) 235. I2 Nye, E.R.. Jackson, D. and Hunter, J.D.. Treatment of hypercholesterolaemia with colestipol: a bile sequestrating agent, N.Z. Med., 22 (1971) 235. 13 Parkinson, T.M., Gundersen. K. and Nelson, N.A., Effects of colestipol (U-26, 597A). a new bile acid sequestrant. on serum lipid in experimental animals and man. Atherosclerosis, 11 (1970) 531. 14 Dujovne. CA.. Hurwitz. A.. Kauffman, R.E. and Azarnoff, D.L.. Colestipol and clofihrate in hypercholesterolemia, Clin. Pharmacol. Ther., 16 (1974) 291. 15 Glueck, C.J., Ford, S., Scheel. D. and Steiner, P., Colestipol and cholestyramine resin, J. Amer. Med. Ass., 222 (1972) 676. 16 Stamler. J. (Chrmn), The coronary drug project - Clofibrate and niacin in coronary heart disease, J. Amer. Med. Ass., 231 (1975) 360.
