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Treatment of hypercholesterolemia with Secholex A long-term clinical trial and comparison with cholestyramine
401
Atherosclerosis, 24 (1976) 407-419 0 Elsevier Scientific Publishing Company,
TREATMENT
Amsterdam
OF HYPERCHOLESTEROLEMIA
A LONG-TERM CLINICAL CHOLESTYRAMINE
ESKO A. NIKKILA,
- Printed
in The Netherlands
WITH SECHOLEX
TRIAL AND COMPARISON
TATU A. MIETTINEN
WITH
and ;iKE LANNER
Third Department of Medicine, University of Helsinki (Finland) and Clinical Research Department of Pharmacia AB, Uppsala (Sweden) (Received (Revised, (Accepted
4th November, 1975) received 17th December, 18th December, 1975)
1975)
Summary gel, Secholex, as a hypocholesterolemic The efficacy of an anion-exchange agent was assessed in 46 patients in 4 different studies and the effects were compared with those of cholestyramine. All patients had severe Type 11-a or II-b hyperlipoproteinemia. In short-term metabolic studies Secholex (15 g/day) and cholestyramine (16 g/day) decreased serum cholesterol levels and increased total fecal sterol output and serum methyl sterol concentration to a similar extent, but cholestyramine was more effective than Secholex in increasing fecal bile acid excretion. In crossover studies, the two drugs appeared to be equally effective in lowering serum cholesterol levels but the patients mostly preferred Secholex. Twenty patients were treated with Secholex over a two-year period. The average decrease in serum cholesterol levels from the mean pretreatment value of 406 mg/lOO ml was 15% during the first year, and 13% during the second year. In 5 patients the serum cholesterol was permanently lowered by more than 20% (good responders), while in 7 patients the average reduction of serum cholesterol level during Secholex administration was less than 10% (non-responders). The serum triglyceride level was slightly decreased by Secholex in Type 11-b patients but was unaltered in Type 11-a patients. At the end of the treatment period, serum iron and vitamin Blz levels were normal but the serum folic acid concentration was reduced in eight of 20 patients. A dose-response study indicated that a similar cholesterol-lowering effect was obtained with daily doses’of 9 and 15 g of Secholex. It is concluded that Secholex is a relatively safe drug which effectively reduces serum cholesterol levels in two-thirds of patients with severe hypercholesterolemia. _
408
Key words:
Anion exchange resin - Cholestyramine -Serum cholesterol
- Hypercholesterolemia
- Polydexide
Introduction Bile acid sequestrants have been found to be most effective in the treatment of hypercholesterolemia [l-4]. These compounds are insoluble anion-exchange resins which bind bile acids, thus preventing their absorption from the gut. The enhanced fecal excretion of bile acids is accompanied by a proportional decrease in serum cholesterol levels [ 51 as a result of an increased hepatic conversion of cholesterol to bile acids [ 61, by increased cholesterol production [ 7,8] and by an accelerated fractional turnover rate of serum and liver cholesterol [8] and serum LDL apoprotein [9]. The exact mechanism of the serum cholesterol-lowering action of these drugs is still somewhat obscure. Two anion-exchange resins, cholestyramine and colestipol, have been extensively tested in different forms of hypercholesterolemia and found to possess comparable but not completely identical cholesterol-lowering effects [3,10]. Another compound which effectively binds bile acids [ 111 is a diethyl aminoethyl-substituted dextran derivative, polydexide, Secholex@ *. In experimental and clinical studies this anion-exchange gel has been shown to decrease serum cholesterol levels [ 12-151. In the present study the effectiveness of Secholex in treating Type 11-aand 11-b hypercholesterolemia was determined over a two-year clinical trial period. A comparison was also made between the effects of Secholex and cholestyr,amine ** on sterol metabolism and serum cholesterol and trigyceride levels. Material and Methods This paper presents the results of 4 separate studies, the details of which are described below. Patients from the Lipid Clinic at the Third Department of Medicine, University of Helsinki, who had been previously treated by low fat diet without effective lowering of serum cholesterol, were selected for this study. All patients were informed as to the purpose and design of the study, and had given their consent before onset of treatment. Study I.
This short-term experiment compared the effects of cholestyramine with those of Secholex on serum cholesterol and methyl sterol levels and fecal sterol output. Ten patients (4 males and 6 females), heterozygous for classical familial hypercholesterolemia (II-a), were selected and metabolic studies were carried out under strictly standardized conditions for a period of 30 days. The diet was isocaloric and contained 120 mg of cholesterol per 2000 kcal; 50% of calories * Manufactured by Pharmacia AB. Uppsala. Sweden. ** Cuemid@, manufactured by Merck. Sharp and Dohme,
NJ.,
U.S.A.
409
were in the form of carbohydrate, 30% were fat and 20% were protein. No drugs were administered during the first 10 days; during the second and third lo-day periods, patients were given (in random order) either cholestyramine 4 g q.i.d. or Secholex 5 g t.i.d. with meals. Cr,O, and /3-sitosterol were fed as markers throughout the experimental period. Serum cholesterol and methyl sterols were determined at three-day intervals. During the last 3 days of each period, stools were collected and quantitatively assayed for neutral sterols and bile acids. Study II This study consisted of 2 crossover experiments comparing the hypocholesterolemic effect of Secholex with that of cholestyramine. The first of these (II-l) 10 patients (4 male and 6 female, aged 25 to 60 years), heterozygous for familial hypercholesterolemia (Type II-a), underwent a 12-week pretreatment period without any drugs, after which they were given 4 g cholestyramine 4 times daily for a period of 24 weeks, then 5 g Secholex 3 times daily for a further 24 weeks. During the whole 60-week experimental period, each patient attended hospital at 4-week intervals for blood sampling and clinical check-up. Three patients (2 during the first 4 weeks and 1 during the 8th week of cholestyramine administration) discontinued treatment because of nausea and constipation. Thus, only 7 subjects completed the whole study. In the second crossover study (I&2), 9 of the patients in the long-term trial (Study III, see below) were selected after treatment with Secholex for 36 weeks. This selection was carried out on the basis of pretreatment serum cholesterol levels, so that the subjects in Study II-2 had a similar initial mean serum cholesterol level to the patients in the other crossover study (II-l). Subjects were given 4 g cholestyramine 4 times daily over 2 four-week periods (weeks 37-44), after which they were put back on Secholex, as indicated in Study-III. Serum lipids were analyzed after 4 and 8 weeks on cholestyramine, and these values were compared to those obtained with Secholex immediately preceding and following the cholestyramine treatment. Study III This study was a long-term clinical trial which investigated the effectiveness of Secholex in the treatment of moderate or severe hypercholesterolemia. Twenty-eight subjects, 14 female and 14 male, were initially recruited for the study. Their age ranged from 22 to 58 years, with a mean of 44 years. Seventeen were heterozygous members of families with known Type II-a hypercholesterolemia. The remaining 12 patients had a Type II-b (combined) hyperlipoproteinemia, with a verified familial background (multiple-type hyperlipoproteinemia) [ 161 in 9 of them. All patients had serum cholesterol levels in excess of 320 mg/lOO ml (8.3 mmoles/l). Patients with Type II-a hypercholesterolemia had serum triglyceride levels below 1.80 mmoles/l. Four subjects had a relative body weight +15% above that of normal. None were suffering from clinical diabetes. The study was initiated by a control (pretreatment) period a minimum of 6 weeks after cessation of all previous drugs; 2 records of each variable were made at 4-week intervals. Thereafter Secholex was administered (5 g t.i.d.) for
410
96 weeks (with the exception of the 9 patients participating in Study II-2 during weeks 37-44). The drug period was followed by another control (pretreatment) period of 8 weeks, during which no lipid-lowering drugs were given (weeks 97104). Serum cholesterol and triglyceride levels, body weight and blood pressure were recorded at 4-week intervals. Hematological data, serum iron, bilirubin, glutamic oxalacetic transaminase (SGOT) glutamic pyruvic transaminase (SGPT), prothrombin activity (P+P) and triiodothyronine uptake were measured at 0,24, 56 and 96 weeks. Serum vitamin B12 and folic acid content were analyzed at the end of the experiment and the values compared to those of the controls (i.e. untreated hypercholesterolemic patients). Twenty of the initial 28 patients completed the whole study. Six patients discontinued treatment due to serious side effects (see p. 416) and two were excluded from the study because of excessive alcohol intake and irregular attendance. Study IV This study was designed to assess the dose-response relationship of serum cholesterol and Secholex. Nine subjects with serum cholesterol levels in excess of 350 mg/lOO ml (9.0 mmoles/l) but with normal serum triglyceride levels were given different dosages - either 9, 12 or 15 g Secholex (t.i.d.) daily -for 3 successive 8-week periods. The periods were in random order, so as to eliminate the effect of seasonal variation in serum cholesterol. Analytical procedures All serum analyses were made from samples taken in the morning after a 12-h fasting period. Serum cholesterol was measured according to Huang et al. [ 171 and serum triglycerides by an automatic method [18]. Two control sera taken from the same initial pool were always run simultaneously, and the results corrected if both gave a paraliel deviation which exceeded 5%. Serum methyl sterols were measured after separation by thin layer chromatography [19]. Serum vitamin B , 2 was analyzed by Phadebas Blz Test (Radiosorbent test from Pharmacia AB, Uppsala, Sweden). All other assays were made by routine laboratory methods. Fecal collections and bile acid and neutral sterol assays were performed as described by Miettinen et al. [19]. CrzO, and /3-sitosterol were used to correct for uneven fecal output and for cholesterol loss during intestinal passage, respectively. Results Comparison of the effects of Secholex and cholestyramine on fecal sterol excretion and serum methyl sterols (Study I) The results of this experiment are presented in Table 1. During the lo-day treatment period both Secholex and cholestyramine brought about a significant decrease in serum cholesterol levels in the 10 hypercholesterolemic patients. The effect of the two drugs on serum cholesterol values was essentially identical. In all subjects both drugs caused an increase in fecal bile acid (Fig. 1) and
411 TABLE 1 COMPARISON OF THE EFFECTS OF CUEMID AND SECHOLEX ON SERUM CHOLESTEROL, TRIGLYCERIDE, AND METHYL STEROL LEVELS AND ON FECAL EXCRETION OF BILE ACIDS AND NEUTRAL
STEROIDS
DURING
IO-DAY
TREATMENT
PERIODS
(N = lo), mean + SD.
Serum cholesterol (mg/lOO ml) Serum triglyceride (mmol/l) Serum methyl sterols (&mg free cholesterol) Fecal bile acids
No drugs
Secholex
Cuemid
Difference Secholex-Cuemid
438 f 26
347 + 27 **
332 2 22 **
+15 (N.S.)
2.06 i 0.27
2.14 f 0.27
2.16 t 0.28
-0.02
1.42 + 1.05
3.58 + 2.32 **
3.28 f 2.10 **
+30 (N.S.)
(N.S.)
212 * 24
677 f 79 **
872?111***
-195
(me/day) Fecal neutral steroids
755 + 79
791 f 109
728 ?: 142
+63 (N.S.)
(mg/day) Fecal total steroids
967 f 89
1468+138**
1599 t 210 **
-131
(p < 0.05)
(N.S.)
(me/day) ** P < 0.01,
*** P < 0.001
for the difference from no-drug period, N.S. = not significant
total steroid excretion, but they did not significantly alter the fecal output of neutral steroids. In all cases, bile acid excretion was higher during cholestyramine than during Secholex treatment (Fig. l), the average increment in bile acid output during the administration of the latter being 30% less than that in cholestyramine (P < 0.05). The increase in fecal bile acids as a result of cholestyramine was positively correlated with the pretreatment bile acid excretion (r 1400
NO DRUGS
SECHOLEX
CUEMID
Fig. 1. Increase in fecal excretion of bile acids after Secholex gel and cholestyramine resin (Cuemid) treatment in patients with familial hypercholesterolemia. The duration of each period was 10 days, and feces were collected during the last three days of each period.
TABLE
2
1.34 + 0.42
408 r 76
Initial level
+5 -15
-27 -22
4
~____
++ **
-5 -15
-16 -20
8
* ***
-16 +6
-22 -18
12
** **
16
-15 -20
-24 -23
20
PATIENTS
*** ***
*0 -26 **
-24 -23
IN HYPERCHOLESTEROLEMIC
Number of weeks on drug
LEVELS
* = P < 0.05, * * = P < 0.01. * * * = P < 0.001 for the difference from pretreatment value.
Cuemid, % change Secholex. % change
Triglyceride (mmol/l)
Cuemid, % change Secholex, % change
(mg/lOO ml)
Cholesterol
(N = 7)
SERUM CHOLESTEROL AND TRIGLYCERIDE SECHOLEX FOR 24 WEEKS EACH
* *
*** ***
24
-11 -19
WITH
CUEMID
-8 -22
-22 -21
*
(1.24 * 0.15) (1.04 t 0.20)
** (319 f 51) ** (322 t 58)
Average during treatment period A% (mean C_SD)
SEQUENTIALLY
-18 ** _21***
TREATED
AND
413
= +0.72), but this correlation was not apparent during Secholex tretament (r = +0.21). No correlation was present between the increment in bile acid or total steroid output and the decrease in serum cholesterol levels during administration of either drug. Serum methyl sterols, which are precursors of cholesterol and which in many conditions reflect the overall rate of cholesterol synthesis [19] increased in all patients during Secholex and cholestyramine treatment. The mean concentration of these sterols in plasma was approximately doubled during the lo-day treatment period with both drugs, and there was no significant difference in the response to the two treatments (Table 1). The most consistent increase occurred in diunsaturated dimethyl sterol. These results indicate that in a short-term experiment, Secholex and cholestyramine were equally effective in reducing the serum cholesterol level of patients with familial hypercholesterolemia; but in the doses compared, cholestyramine was slightly more potent than Secholex in increasing the fecal bile acid output. Comparison of Secholex and cholestyramine in crossover experiments In an open crossover experiment (Study II-l) 7 hypercholesterolemic patients received cholestyramine (16 g daily) for 24 weeks and then Secholex (15 g daily) for a further 24 weeks. The results are shown in Table 2. Both drugs brought about a similar and sustained reduction in serum cholesterol levels in all subjects. The individual average reductions in serum cholesterol during the treatment periods varied from 14 to 32% with cholestyramine and from 15 to 29% with Secholex. Serum triglyceride levels showed no consistent change during either treatment, but the mean of all values taken during the Secholex period was slightly lower than the pretreatment level (Table 2). In the second crossover experiment (Study II-2), 9 patients who had been treated with Secholex for 36 weeks were given cholestyramine for 8 weeks and then put back on Secholex. The serum lipid values can be seen in Table 3. Cholestyramine caused no further alteration in levels of either serum cholesterol or triglyceride from those reached during the preceding Secholex treatment period. After the second Secholex treatment, cholesterol decreased further, and the
TABLI?
3
SERUM
LIPID
SECHOLEX
LEVELS
IN HYPERCHOLESTEROLEMIC
CROSSOVER
PATIENTS
DURING
SECHOLEX-CUEMID-
TRIAL
(N = 9)
No
drugs
408
+ 43
Secholex
I
Cuemid
Secholex
11
Cholesterol Mean
i
SD
(mg/lOO
ml)
o/o change
350 -14.6
+ 43 ***
358
* 53
-12.3
**
1.58
+ 0.64
327 -20.3
***
‘I’riplycerides Mean
? SD
-~
?+achange -.
**
=
P < 0.01.
(mmol/l)
1.68
+ 0.56
1.56 -7.0
***
= P < 0.001.
+ 0.58
-6.0
1.47 -12.5
i 0.54
414
mean value obtained during the next 3 four-week periods was significantly lower than the average serum cholesterol level during the previous Secholex (P < 0.05) or cholestyramine treatment period (P < 0.01) (Table 3). Serum triglyceride concentrations did not alter markedly during any of the treatment periods (Table 3). The preference for either drug was recorded after both crossover experiments. Of the total of 16 subjects, 11 preferred Secholex, 4 had no opinion and 1 preferred cholestyramine because in his case it was more effective in lowering serum cholesterol. Fourteen patients complained of the unpleasant smell and taste of cholestyramine, the absence of which was their main reason for preferring Secholex. Long-term effect of Secholex on hypercholesterolemia
Twenty-eight patients were recruited for this study and 20 of them completed the two-year trial period, which included 96 treatment weeks, and 8 posttreatment “off-drug” weeks. Only the results from these 20 patients have been used for the statistical calculations. Serum cholesterol
The mean serum cholesterol response to Secholex is presented in Fig. 2. The
I
0
l-24
25-49
49-72
73-96
104
WEEKS Fig. 2. Effect tients treated
of Secholex gel on serum cholesterol and triglyceride levels in 20 hypercholesterolemic pafora period of 96 weeks. Each point represents a mean of 6 values taken at 4-week intervals.
415
mg/lOOml
d
mmolli
120
-
3.0
-
6 L:
0
loo-
0
= z
0. 8O-
2.0-
0
u $
0
.
8 0
/ 0
60-
: 9 8
4O-
l.O-
x 5 g
r = 0.50 20-
L,
‘1
300
7.0
8.0
1
I
I
I
350
400
450
500
9.0
10.0
INITIAL
11.0
SERUM
Fig. 3. Correlation of pretreatment ment. 0 = Type II-a, 0 = Type II-b.
12.0
mg/iOOml
13.0
mmol
/I
CHOLESTEROL
serum cholesterol
and average cholesterol
response
to Secholex
treat-
drug caused a significant decrease in serum cholesterol throughout the entire treatment period of 96 weeks. After discontinuation of Secholex, cholesterol values returned to pretreatment levels. The mean decrease varied from 6.8 to 24.4%, being on average 15.0% during the first year of treatment and 13.0% during the second year. With few exceptions, mean cholesterol was maintained by Secholex at a level which was 12-18% lower than the value obtained with diet only. There was no significant difference in the mean cholesterol response of Type II-a and II-b patients. The steady-state serum cholesterol level was reached in all patients during the first 8 weeks of treatment. The individual serum cholesterol responses to Secholex treatment in relation to initial serum cholesterol are shown in Fig. 3. The mean cholesterol was lowered to below the “off-drug” level in all patients, but the average response was less than 10% in 7 patients. An adequate result (average cholesterol reduction TABLE
4
AVERAGE SECHOLEX
DECREASE
OF
SERUM
The per cent change is calculated Decrease in serum cholesterol
5-10% 11--~20% 221%
CHOLESTEROL
IN
20
PATIENTS
from the mean of pre- and posttreatment
Number
DURING
96
WEEKS
ON
values.
of patients
Type 11-a
Type 11-b
Total
3 4 3
4 4 2
7 (35%) 8 (40%) 5 (25%)
_
416
of ll-20%)
was obtained in 8 patients, and a good response (average decrease
of cholesterol >21%) in 5 cases (Table 4). A normal cholesterol mmol/l) was reached and maintained in five patients.
level (<7.5
Serum triglyceride
The average serum triglyceride concentration did not show any consistent changes during Secholex treatment (Fig. 2). The mean values were either equal to or slightly below the pretreatment mean level, and none of the patients showed a systematic rise or decrease in serum triglyceride levels during administration of Secholex. There was no significant difference in the effect of Secholex on serum triglyceride in Type 11-aand 11-b patients (Fig. 2). Body weight and blood pressure.
The average body weight of the patients before trial was 72.3 f 18.1 kg (+105% of normal) and 71.3 + 18.4 kg at the end of the Secholex period. A weight gain of over 10% occurred in 3 patients, and a weight reduction of 11% in 1 patient. Systolic and diastolic blood pressure remained unchanged in all cases throughout the experimental period. Hema tological data
The average hematocrit, hemoglobin and white blood cell count remained unchanged during the trial period. At the end of the treatment period the hematocrit, hemoglobin and white blood cells of 1 patient were seen to be slightly below the normal range, whereas no deviations from normal occurred in the remaining 19 cases. Serum iron, vitamin B12 and folic acid levels
Average serum iron was normal and remained unchanged during the trial. Subnormal levels found in some of the 3 samples taken during Secholex treatment were observed in 3 subjects, but by the end of the experiment only 1 of these showed signs of slight hypoferremia.
TABLE 5 SERUM VITAMIN Bl2 AND FOLK ACID LEVELS IN PATIENTS TREATED FOR 96 WEEKS WITH SECHOLEX, AND IN UNTREATED HYPERCHOLESTEROLEMIC CONTROL SUBJECTS Vitamin B 12 (pg/ml)
Meal-l SD Y Number of cases Within normal range a Above normal Borderline a Normal range Borderline
Folic acid @g/ml)
Secholex
Control
632 111
650 171
4.30 2.10
7.11 3.05
19 18 1 0 300-1000
Control
Secholex
pglml
21 13 0 8
19 19 0 0 3.1-15.0 2.1-3.0
nglml ng/ml
417
Vitamin B12 ‘and folic acid concentrations were only analyzed at the end of the trial (96th week), and the values were compared with those taken from randomly selected untreated hypercholesterolemic Type II patients. The results are presented in Table 5. The average vitamin B1* concentration in the serum of Secholex-treated patients was significantly higher, and that of folic acid lower than the corresponding mean values in the control group. Three Secholex-treated patients had serum Blz values that were above the normal limits and eight (40%) had slightly reduced serum folic acid levels. Liver function tests.
Serum bilirubin remained within normal limits in all patients. SGOT rose to above 20 units (21-41) in 5 patients by the end of the experiment. One of them already showed elevated levels at the initial examination. After 96 weeks on Secholex, elevated SGPT values were also seen in 5 patients. Four of these already had elevated SGPT at the initial examination. Prothrombin activity was normal in all subjects throughout the duration of the study. Side effects and subjects excluded from the study Of the 28 patients initially included in the trial 6 (21%) discontinued
Secholex treatment because of side-effects. Three of these complained of nausea, and 3 of constipation, which was being inadequately treated with laxatives. Two patients were excluded before completion of the study because of irreg ular intake of the drug. Of the 20 patients completing the whole trial period, 3 had occasional constipation particularly during the first weeks of the study, but this was adequately treated by drugs. No other side-effects were recorded. Effect of different doses of Secholex on serum cholesterol
The results of the dose-response study in the 8 patients who underwent all 3 dose sequences are given in Table 6. The mean decreases of serum cholesterol obtained with daily doses of 9,12 and 15 g of Secholex were 11.5% (P < O.OOl), 11.5% (P < 0.01) and 14.6% (P< O.OOl), respectively. Although the highest dose resulted in lowest average serum cholesterol level, there was no significant difference between the hypocholesteremic effect of the three doses.
TABLE 6 SERUM CHOLESTEROL
RESPONSE TO DIFFERENT
DOSES OF SECHOLEX
Serum cholesterol (mgl100
ml)
Mean
SD
Max
Min
Pretreatment
374
34
456
347
Secholex 9 g/day Secholex 12 g/day Secholex 15 g/day
332 332 320
46 62 31
432 475 362
282 282 293
Period
N
a Difference between Secholex > 0.10.
and pretreatment
Mean % change
-11.5 -11.5 -14.6
pa ____~~___
periods. all differences between Secholex dose levels
418
Discussion The present results show that Secholex gel is as effective as cholestyramine in reducing the serum cholesterol level of patients with severe hypercholesterolemia. This result was sustained for at least 2 years in those patients who responded to the therapy. The effect of Secholex on serum cholesterol and the patient’s tolerance to the drug could be assessed in all cases within 8 weeks from onset treatment, and no secondary failures were observed. Of the 26 patients who participated in the chronic trial, 6 were excluded because of poor tolerance to the drug and it was found that 7 were resistant to the cholesterollowering action of Secholex. In the remaining 13 cases, the average sustained fall of serum cholesterol was 18%. On the basis of these figures, Secholex can be expected to bring about a satisfactory reduction in serum cholesterol levels in one-half of cases with severe hypercholesterolemia. These results are comparable to previously published studies on the use of Secholex in the treatment of hypercholesterolemia. In a limited number of patients with mild Type II hyperlipoproteinemia, Howard and co-workers observed that Secholex effected a reduction in serum cholesterol levels of 12-20% [13,14], whilst Gustafson and Lanner noted an average reduction of 16% in 11 patients with severe hypercholesterolemia [15]. A similar result has been recently reported by Ritland and co-workers [ 201. Cholestyramine increased fecal bile acid output slightly more than Secholex but in spite of this, both drugs lowered serum cholesterol level to a similar extent. This observation suggests that the mechanism of action of these two bile acid sequestrants is not completely identical. In fact, Borgstrom has shown that the capacity of Secholex to bind free bile salts in vitro is lower than that of cholestyramine [ 111. On the other hand, Secholex does bind free fatty acids in aqueous solution and interacts with the breakdown of triglycerides by pancreatic lipase [ll]. It is therefore possible that Secholex decreases the intestinal absorption of cholesterol, in addition to that of bile acids. This hypothesis is supported by the higher fecal neutral steroid/bile acid ratio observed in the present study during Secholex as compared to cholestyramine treatment. In many previous studies, both cholestyramine [21] and colestipol [3] have been reported to increase serum triglyceride and VLDL levels. This change was not observed during Secholex administration, which if anything had a slight triglyceride-lowering effect. Attention has been recently drawn to the possibility that oral anion-exchangers might inhibit the intestinal absorption of vitamins and iron, and in chronic use might cause an increase in the deficiency of these substances. In animal experiments, large doses of cholestyramine actually inhibit absorption of iron [22], vitamin A [23] and vitamin Blz [24] and deplete the tissue stores of these compounds [ 221. Secholex in the dosage used in the present trial did not lead to decreased serum iron or vitamin B12 levels in patients treated over a two-year period. On the other hand, several patients receiving Secholex had marginal or sub-normal serum folic acid values. Similar observations have been made by Ritland et al. [20], and it seems to be advisable to check serum folic acid biannually in patients under chronic treatment with bile acid sequestrants.
419
References 1 Grundy,
SM.,
Treatment
Int. Med., 130 (1972)
of hypercholesterolemia
by interference
with bile acid metabolism,
Arch.
638.
2 Levy, R.I. and Rifkind, B.M., Lipid-lowering drugs and hyperlipidaemia, Drugs, 6 (1973) 12. 3 Glueck, C.J., Ford, Jr.. S., Scheel, D. and Steiner, P.. Colestipol and cholestyramine resin - Comparative effects in familial type II hyperhpoproteinemia, J. Amer. Med. Ass.. 222 (1972) 676. 4 Miller, N.E.. Clifton-B&h, P.. Nest+ P.J. and Whyte. H.M., Controlled clinical trial of a new bile acid-sequestering resin, colestipol, in the treatment of hypercholesterolaemia, Med. J. Aust, 1 (1973) 1223. 5 Miettinen. T.A., Effect of drugs on bile acid and cholesterol excretion. In: D.W.K. Cotton (Ed.), Lipid Metabolism and Atherosclerosis (International Congress Series, No. 283). Excerpta Medica. Amsterdam, 1973, p. 77. 6 Moore, R.B., Crane, C.A. and Frantz, Jr., I.D., Effect of cholestyramine on the fecal excretion of intravenously administered cholesterol-4-14C and its degradation products in hypercholesterolemic patients, J. CIin. Invest. 47 (1968) 1664. 7 Huff, J.W.. Gilfillan. J.L. and Hunt, V.M.. Effect of cholestyramine. a bile acid-binding polymer on plasma cholesterol and fecal bile acid excretion in the rat, Proc. Sot. Exp. Biol. Med., 114 (1963) 532. 8 Goodman, D.S.. Noble, R.P. and Dell. R.B., The effects of colestipol resin and of colestipol PIUS clofibrate on the turnover of plasma cholesterol in man, J. Clin. Invest., 52 (1973) 2646. 9 Langer, T., Strober. W. and Levy, R.I., The metabolism of low density lipoprotein in familial type II hyperhpoproteinemia. J. CIin. Invest., 51 (1972) 1528. 10 Parkinson, T.M.. Gundersen. K. and Nelson. N.A., Effects of colestipol (U-26, 597), a new bile acid sequestrant, on serum lipids in experimental animals and man, Atherosclerosis, 11 (1970) 531. 11 Borgstrom. B., Effect of ion-exchange substances on the Iipolysis catalybed by pancreatic lipase, Stand. J. Gastroent., 5 (1970) 549. 12 Parkinson, T.M., Hypolipidemic effects of orally administered dextran and cellulose anion exchangers in cockerels and dogs, J. Lipid Res., 8 (1967) 24. 13 Howard, A.N. and Hyams, D.E., Combined use of clofibrate and cholestyramine or DEAE Sephadex in hypercholesterolaemia, Brit. Med. J.. 3 (1971) 25. clofibrate and taurine in hyperlipidaemia, 14 Howard, A.N. and Courtenay Evans, R.J., Secholex@, Atherosclerosis, 20 (1974) 105. 15 Gustafson, A. and Lamer, A., Treatment of hyperlipoproteinaemia type HA with a new anion exchange resin Secholex @, Europ. J. CIin. Pharmacol., 7 (1974) 65. 16 Nikkihi, E.A. and Are, A., Family study of serum lipids and lipoproteins in coronary heart disease, Lance& 1(1973) 954. 17 Huang, T.C.. Chen, C.P., Wefler. V. and Raftery, A., A stable reagent for the Liebermann-Burchard reaction. Application to rapid serum-cholesterol determination. Anal. Chem., 33 (1961) 1405. 18 Kessler, G. and Lederer, H.. Fluorometric measurement of triglycerides. In: L.T. Skeggs (Ed.), Automation in Analytical Chemistry, Mediad. New York, N.Y.. 1966, p. 341. 19 Miettinen, T.A., Cholesterol production in obesity, Circulation, 44 (1971) 842. 20 Ritland, S.. Fausa, 0.. Gjone, E.. Blomhoff, J.P., Skrede, S. and Lanner, A., Effect of treatment with a bile sequestering resin (Secholex@) on plasma lipids, intestinal absorption and duodenal bile acids, Scan. J. Gastroenterol., 10 (1975) 791. 21
Levy, R.I., Fredrickson, D.S.. Stone, N.J.. BiIheimer, D.W.. Brown, W.V., Glueck. C.J., Gotto, A.M., Herbert, P.N., Kwiterovich, P.O., Langer. T.. LaRosa. J., Lux, S.E., Rider, A.K., Shulman, R.S. and Sloan, H.R., Cholestyramine in type II hyperlipoproteinemia - A double-blind trial, Ann. Int. Med., 79 (1973) 51. 22 Thomas, C.B., Salsburey. D. and Greenberger, N.J.. Inhibition of iron absorption by cholestyramine Demonstration of diminished iron stores following prolonged administration, Amer. J. Digest. Dis., 17 (1972) 263. 23 Thompson, W.G. and Thompson, G.R.. Effect of cholestyramine on the absorption of vitamins D3 and calcium, Gut, 10 (1969) 717. 24 Coronato, A. and Glass, G.B.J.. Depression of the intestinal uptake of radio-vitamin Bi2 by cholestyramine, Proc. Sot. EXP. Biol. Med.. 142 (1973) 1341.
Atherosclerosis, 24 (1976) 407-419 0 Elsevier Scientific Publishing Company,
TREATMENT
Amsterdam
OF HYPERCHOLESTEROLEMIA
A LONG-TERM CLINICAL CHOLESTYRAMINE
ESKO A. NIKKILA,
- Printed
in The Netherlands
WITH SECHOLEX
TRIAL AND COMPARISON
TATU A. MIETTINEN
WITH
and ;iKE LANNER
Third Department of Medicine, University of Helsinki (Finland) and Clinical Research Department of Pharmacia AB, Uppsala (Sweden) (Received (Revised, (Accepted
4th November, 1975) received 17th December, 18th December, 1975)
1975)
Summary gel, Secholex, as a hypocholesterolemic The efficacy of an anion-exchange agent was assessed in 46 patients in 4 different studies and the effects were compared with those of cholestyramine. All patients had severe Type 11-a or II-b hyperlipoproteinemia. In short-term metabolic studies Secholex (15 g/day) and cholestyramine (16 g/day) decreased serum cholesterol levels and increased total fecal sterol output and serum methyl sterol concentration to a similar extent, but cholestyramine was more effective than Secholex in increasing fecal bile acid excretion. In crossover studies, the two drugs appeared to be equally effective in lowering serum cholesterol levels but the patients mostly preferred Secholex. Twenty patients were treated with Secholex over a two-year period. The average decrease in serum cholesterol levels from the mean pretreatment value of 406 mg/lOO ml was 15% during the first year, and 13% during the second year. In 5 patients the serum cholesterol was permanently lowered by more than 20% (good responders), while in 7 patients the average reduction of serum cholesterol level during Secholex administration was less than 10% (non-responders). The serum triglyceride level was slightly decreased by Secholex in Type 11-b patients but was unaltered in Type 11-a patients. At the end of the treatment period, serum iron and vitamin Blz levels were normal but the serum folic acid concentration was reduced in eight of 20 patients. A dose-response study indicated that a similar cholesterol-lowering effect was obtained with daily doses’of 9 and 15 g of Secholex. It is concluded that Secholex is a relatively safe drug which effectively reduces serum cholesterol levels in two-thirds of patients with severe hypercholesterolemia. _
408
Key words:
Anion exchange resin - Cholestyramine -Serum cholesterol
- Hypercholesterolemia
- Polydexide
Introduction Bile acid sequestrants have been found to be most effective in the treatment of hypercholesterolemia [l-4]. These compounds are insoluble anion-exchange resins which bind bile acids, thus preventing their absorption from the gut. The enhanced fecal excretion of bile acids is accompanied by a proportional decrease in serum cholesterol levels [ 51 as a result of an increased hepatic conversion of cholesterol to bile acids [ 61, by increased cholesterol production [ 7,8] and by an accelerated fractional turnover rate of serum and liver cholesterol [8] and serum LDL apoprotein [9]. The exact mechanism of the serum cholesterol-lowering action of these drugs is still somewhat obscure. Two anion-exchange resins, cholestyramine and colestipol, have been extensively tested in different forms of hypercholesterolemia and found to possess comparable but not completely identical cholesterol-lowering effects [3,10]. Another compound which effectively binds bile acids [ 111 is a diethyl aminoethyl-substituted dextran derivative, polydexide, Secholex@ *. In experimental and clinical studies this anion-exchange gel has been shown to decrease serum cholesterol levels [ 12-151. In the present study the effectiveness of Secholex in treating Type 11-aand 11-b hypercholesterolemia was determined over a two-year clinical trial period. A comparison was also made between the effects of Secholex and cholestyr,amine ** on sterol metabolism and serum cholesterol and trigyceride levels. Material and Methods This paper presents the results of 4 separate studies, the details of which are described below. Patients from the Lipid Clinic at the Third Department of Medicine, University of Helsinki, who had been previously treated by low fat diet without effective lowering of serum cholesterol, were selected for this study. All patients were informed as to the purpose and design of the study, and had given their consent before onset of treatment. Study I.
This short-term experiment compared the effects of cholestyramine with those of Secholex on serum cholesterol and methyl sterol levels and fecal sterol output. Ten patients (4 males and 6 females), heterozygous for classical familial hypercholesterolemia (II-a), were selected and metabolic studies were carried out under strictly standardized conditions for a period of 30 days. The diet was isocaloric and contained 120 mg of cholesterol per 2000 kcal; 50% of calories * Manufactured by Pharmacia AB. Uppsala. Sweden. ** Cuemid@, manufactured by Merck. Sharp and Dohme,
NJ.,
U.S.A.
409
were in the form of carbohydrate, 30% were fat and 20% were protein. No drugs were administered during the first 10 days; during the second and third lo-day periods, patients were given (in random order) either cholestyramine 4 g q.i.d. or Secholex 5 g t.i.d. with meals. Cr,O, and /3-sitosterol were fed as markers throughout the experimental period. Serum cholesterol and methyl sterols were determined at three-day intervals. During the last 3 days of each period, stools were collected and quantitatively assayed for neutral sterols and bile acids. Study II This study consisted of 2 crossover experiments comparing the hypocholesterolemic effect of Secholex with that of cholestyramine. The first of these (II-l) 10 patients (4 male and 6 female, aged 25 to 60 years), heterozygous for familial hypercholesterolemia (Type II-a), underwent a 12-week pretreatment period without any drugs, after which they were given 4 g cholestyramine 4 times daily for a period of 24 weeks, then 5 g Secholex 3 times daily for a further 24 weeks. During the whole 60-week experimental period, each patient attended hospital at 4-week intervals for blood sampling and clinical check-up. Three patients (2 during the first 4 weeks and 1 during the 8th week of cholestyramine administration) discontinued treatment because of nausea and constipation. Thus, only 7 subjects completed the whole study. In the second crossover study (I&2), 9 of the patients in the long-term trial (Study III, see below) were selected after treatment with Secholex for 36 weeks. This selection was carried out on the basis of pretreatment serum cholesterol levels, so that the subjects in Study II-2 had a similar initial mean serum cholesterol level to the patients in the other crossover study (II-l). Subjects were given 4 g cholestyramine 4 times daily over 2 four-week periods (weeks 37-44), after which they were put back on Secholex, as indicated in Study-III. Serum lipids were analyzed after 4 and 8 weeks on cholestyramine, and these values were compared to those obtained with Secholex immediately preceding and following the cholestyramine treatment. Study III This study was a long-term clinical trial which investigated the effectiveness of Secholex in the treatment of moderate or severe hypercholesterolemia. Twenty-eight subjects, 14 female and 14 male, were initially recruited for the study. Their age ranged from 22 to 58 years, with a mean of 44 years. Seventeen were heterozygous members of families with known Type II-a hypercholesterolemia. The remaining 12 patients had a Type II-b (combined) hyperlipoproteinemia, with a verified familial background (multiple-type hyperlipoproteinemia) [ 161 in 9 of them. All patients had serum cholesterol levels in excess of 320 mg/lOO ml (8.3 mmoles/l). Patients with Type II-a hypercholesterolemia had serum triglyceride levels below 1.80 mmoles/l. Four subjects had a relative body weight +15% above that of normal. None were suffering from clinical diabetes. The study was initiated by a control (pretreatment) period a minimum of 6 weeks after cessation of all previous drugs; 2 records of each variable were made at 4-week intervals. Thereafter Secholex was administered (5 g t.i.d.) for
410
96 weeks (with the exception of the 9 patients participating in Study II-2 during weeks 37-44). The drug period was followed by another control (pretreatment) period of 8 weeks, during which no lipid-lowering drugs were given (weeks 97104). Serum cholesterol and triglyceride levels, body weight and blood pressure were recorded at 4-week intervals. Hematological data, serum iron, bilirubin, glutamic oxalacetic transaminase (SGOT) glutamic pyruvic transaminase (SGPT), prothrombin activity (P+P) and triiodothyronine uptake were measured at 0,24, 56 and 96 weeks. Serum vitamin B12 and folic acid content were analyzed at the end of the experiment and the values compared to those of the controls (i.e. untreated hypercholesterolemic patients). Twenty of the initial 28 patients completed the whole study. Six patients discontinued treatment due to serious side effects (see p. 416) and two were excluded from the study because of excessive alcohol intake and irregular attendance. Study IV This study was designed to assess the dose-response relationship of serum cholesterol and Secholex. Nine subjects with serum cholesterol levels in excess of 350 mg/lOO ml (9.0 mmoles/l) but with normal serum triglyceride levels were given different dosages - either 9, 12 or 15 g Secholex (t.i.d.) daily -for 3 successive 8-week periods. The periods were in random order, so as to eliminate the effect of seasonal variation in serum cholesterol. Analytical procedures All serum analyses were made from samples taken in the morning after a 12-h fasting period. Serum cholesterol was measured according to Huang et al. [ 171 and serum triglycerides by an automatic method [18]. Two control sera taken from the same initial pool were always run simultaneously, and the results corrected if both gave a paraliel deviation which exceeded 5%. Serum methyl sterols were measured after separation by thin layer chromatography [19]. Serum vitamin B , 2 was analyzed by Phadebas Blz Test (Radiosorbent test from Pharmacia AB, Uppsala, Sweden). All other assays were made by routine laboratory methods. Fecal collections and bile acid and neutral sterol assays were performed as described by Miettinen et al. [19]. CrzO, and /3-sitosterol were used to correct for uneven fecal output and for cholesterol loss during intestinal passage, respectively. Results Comparison of the effects of Secholex and cholestyramine on fecal sterol excretion and serum methyl sterols (Study I) The results of this experiment are presented in Table 1. During the lo-day treatment period both Secholex and cholestyramine brought about a significant decrease in serum cholesterol levels in the 10 hypercholesterolemic patients. The effect of the two drugs on serum cholesterol values was essentially identical. In all subjects both drugs caused an increase in fecal bile acid (Fig. 1) and
411 TABLE 1 COMPARISON OF THE EFFECTS OF CUEMID AND SECHOLEX ON SERUM CHOLESTEROL, TRIGLYCERIDE, AND METHYL STEROL LEVELS AND ON FECAL EXCRETION OF BILE ACIDS AND NEUTRAL
STEROIDS
DURING
IO-DAY
TREATMENT
PERIODS
(N = lo), mean + SD.
Serum cholesterol (mg/lOO ml) Serum triglyceride (mmol/l) Serum methyl sterols (&mg free cholesterol) Fecal bile acids
No drugs
Secholex
Cuemid
Difference Secholex-Cuemid
438 f 26
347 + 27 **
332 2 22 **
+15 (N.S.)
2.06 i 0.27
2.14 f 0.27
2.16 t 0.28
-0.02
1.42 + 1.05
3.58 + 2.32 **
3.28 f 2.10 **
+30 (N.S.)
(N.S.)
212 * 24
677 f 79 **
872?111***
-195
(me/day) Fecal neutral steroids
755 + 79
791 f 109
728 ?: 142
+63 (N.S.)
(mg/day) Fecal total steroids
967 f 89
1468+138**
1599 t 210 **
-131
(p < 0.05)
(N.S.)
(me/day) ** P < 0.01,
*** P < 0.001
for the difference from no-drug period, N.S. = not significant
total steroid excretion, but they did not significantly alter the fecal output of neutral steroids. In all cases, bile acid excretion was higher during cholestyramine than during Secholex treatment (Fig. l), the average increment in bile acid output during the administration of the latter being 30% less than that in cholestyramine (P < 0.05). The increase in fecal bile acids as a result of cholestyramine was positively correlated with the pretreatment bile acid excretion (r 1400
NO DRUGS
SECHOLEX
CUEMID
Fig. 1. Increase in fecal excretion of bile acids after Secholex gel and cholestyramine resin (Cuemid) treatment in patients with familial hypercholesterolemia. The duration of each period was 10 days, and feces were collected during the last three days of each period.
TABLE
2
1.34 + 0.42
408 r 76
Initial level
+5 -15
-27 -22
4
~____
++ **
-5 -15
-16 -20
8
* ***
-16 +6
-22 -18
12
** **
16
-15 -20
-24 -23
20
PATIENTS
*** ***
*0 -26 **
-24 -23
IN HYPERCHOLESTEROLEMIC
Number of weeks on drug
LEVELS
* = P < 0.05, * * = P < 0.01. * * * = P < 0.001 for the difference from pretreatment value.
Cuemid, % change Secholex. % change
Triglyceride (mmol/l)
Cuemid, % change Secholex, % change
(mg/lOO ml)
Cholesterol
(N = 7)
SERUM CHOLESTEROL AND TRIGLYCERIDE SECHOLEX FOR 24 WEEKS EACH
* *
*** ***
24
-11 -19
WITH
CUEMID
-8 -22
-22 -21
*
(1.24 * 0.15) (1.04 t 0.20)
** (319 f 51) ** (322 t 58)
Average during treatment period A% (mean C_SD)
SEQUENTIALLY
-18 ** _21***
TREATED
AND
413
= +0.72), but this correlation was not apparent during Secholex tretament (r = +0.21). No correlation was present between the increment in bile acid or total steroid output and the decrease in serum cholesterol levels during administration of either drug. Serum methyl sterols, which are precursors of cholesterol and which in many conditions reflect the overall rate of cholesterol synthesis [19] increased in all patients during Secholex and cholestyramine treatment. The mean concentration of these sterols in plasma was approximately doubled during the lo-day treatment period with both drugs, and there was no significant difference in the response to the two treatments (Table 1). The most consistent increase occurred in diunsaturated dimethyl sterol. These results indicate that in a short-term experiment, Secholex and cholestyramine were equally effective in reducing the serum cholesterol level of patients with familial hypercholesterolemia; but in the doses compared, cholestyramine was slightly more potent than Secholex in increasing the fecal bile acid output. Comparison of Secholex and cholestyramine in crossover experiments In an open crossover experiment (Study II-l) 7 hypercholesterolemic patients received cholestyramine (16 g daily) for 24 weeks and then Secholex (15 g daily) for a further 24 weeks. The results are shown in Table 2. Both drugs brought about a similar and sustained reduction in serum cholesterol levels in all subjects. The individual average reductions in serum cholesterol during the treatment periods varied from 14 to 32% with cholestyramine and from 15 to 29% with Secholex. Serum triglyceride levels showed no consistent change during either treatment, but the mean of all values taken during the Secholex period was slightly lower than the pretreatment level (Table 2). In the second crossover experiment (Study II-2), 9 patients who had been treated with Secholex for 36 weeks were given cholestyramine for 8 weeks and then put back on Secholex. The serum lipid values can be seen in Table 3. Cholestyramine caused no further alteration in levels of either serum cholesterol or triglyceride from those reached during the preceding Secholex treatment period. After the second Secholex treatment, cholesterol decreased further, and the
TABLI?
3
SERUM
LIPID
SECHOLEX
LEVELS
IN HYPERCHOLESTEROLEMIC
CROSSOVER
PATIENTS
DURING
SECHOLEX-CUEMID-
TRIAL
(N = 9)
No
drugs
408
+ 43
Secholex
I
Cuemid
Secholex
11
Cholesterol Mean
i
SD
(mg/lOO
ml)
o/o change
350 -14.6
+ 43 ***
358
* 53
-12.3
**
1.58
+ 0.64
327 -20.3
***
‘I’riplycerides Mean
? SD
-~
?+achange -.
**
=
P < 0.01.
(mmol/l)
1.68
+ 0.56
1.56 -7.0
***
= P < 0.001.
+ 0.58
-6.0
1.47 -12.5
i 0.54
414
mean value obtained during the next 3 four-week periods was significantly lower than the average serum cholesterol level during the previous Secholex (P < 0.05) or cholestyramine treatment period (P < 0.01) (Table 3). Serum triglyceride concentrations did not alter markedly during any of the treatment periods (Table 3). The preference for either drug was recorded after both crossover experiments. Of the total of 16 subjects, 11 preferred Secholex, 4 had no opinion and 1 preferred cholestyramine because in his case it was more effective in lowering serum cholesterol. Fourteen patients complained of the unpleasant smell and taste of cholestyramine, the absence of which was their main reason for preferring Secholex. Long-term effect of Secholex on hypercholesterolemia
Twenty-eight patients were recruited for this study and 20 of them completed the two-year trial period, which included 96 treatment weeks, and 8 posttreatment “off-drug” weeks. Only the results from these 20 patients have been used for the statistical calculations. Serum cholesterol
The mean serum cholesterol response to Secholex is presented in Fig. 2. The
I
0
l-24
25-49
49-72
73-96
104
WEEKS Fig. 2. Effect tients treated
of Secholex gel on serum cholesterol and triglyceride levels in 20 hypercholesterolemic pafora period of 96 weeks. Each point represents a mean of 6 values taken at 4-week intervals.
415
mg/lOOml
d
mmolli
120
-
3.0
-
6 L:
0
loo-
0
= z
0. 8O-
2.0-
0
u $
0
.
8 0
/ 0
60-
: 9 8
4O-
l.O-
x 5 g
r = 0.50 20-
L,
‘1
300
7.0
8.0
1
I
I
I
350
400
450
500
9.0
10.0
INITIAL
11.0
SERUM
Fig. 3. Correlation of pretreatment ment. 0 = Type II-a, 0 = Type II-b.
12.0
mg/iOOml
13.0
mmol
/I
CHOLESTEROL
serum cholesterol
and average cholesterol
response
to Secholex
treat-
drug caused a significant decrease in serum cholesterol throughout the entire treatment period of 96 weeks. After discontinuation of Secholex, cholesterol values returned to pretreatment levels. The mean decrease varied from 6.8 to 24.4%, being on average 15.0% during the first year of treatment and 13.0% during the second year. With few exceptions, mean cholesterol was maintained by Secholex at a level which was 12-18% lower than the value obtained with diet only. There was no significant difference in the mean cholesterol response of Type II-a and II-b patients. The steady-state serum cholesterol level was reached in all patients during the first 8 weeks of treatment. The individual serum cholesterol responses to Secholex treatment in relation to initial serum cholesterol are shown in Fig. 3. The mean cholesterol was lowered to below the “off-drug” level in all patients, but the average response was less than 10% in 7 patients. An adequate result (average cholesterol reduction TABLE
4
AVERAGE SECHOLEX
DECREASE
OF
SERUM
The per cent change is calculated Decrease in serum cholesterol
5-10% 11--~20% 221%
CHOLESTEROL
IN
20
PATIENTS
from the mean of pre- and posttreatment
Number
DURING
96
WEEKS
ON
values.
of patients
Type 11-a
Type 11-b
Total
3 4 3
4 4 2
7 (35%) 8 (40%) 5 (25%)
_
416
of ll-20%)
was obtained in 8 patients, and a good response (average decrease
of cholesterol >21%) in 5 cases (Table 4). A normal cholesterol mmol/l) was reached and maintained in five patients.
level (<7.5
Serum triglyceride
The average serum triglyceride concentration did not show any consistent changes during Secholex treatment (Fig. 2). The mean values were either equal to or slightly below the pretreatment mean level, and none of the patients showed a systematic rise or decrease in serum triglyceride levels during administration of Secholex. There was no significant difference in the effect of Secholex on serum triglyceride in Type 11-aand 11-b patients (Fig. 2). Body weight and blood pressure.
The average body weight of the patients before trial was 72.3 f 18.1 kg (+105% of normal) and 71.3 + 18.4 kg at the end of the Secholex period. A weight gain of over 10% occurred in 3 patients, and a weight reduction of 11% in 1 patient. Systolic and diastolic blood pressure remained unchanged in all cases throughout the experimental period. Hema tological data
The average hematocrit, hemoglobin and white blood cell count remained unchanged during the trial period. At the end of the treatment period the hematocrit, hemoglobin and white blood cells of 1 patient were seen to be slightly below the normal range, whereas no deviations from normal occurred in the remaining 19 cases. Serum iron, vitamin B12 and folic acid levels
Average serum iron was normal and remained unchanged during the trial. Subnormal levels found in some of the 3 samples taken during Secholex treatment were observed in 3 subjects, but by the end of the experiment only 1 of these showed signs of slight hypoferremia.
TABLE 5 SERUM VITAMIN Bl2 AND FOLK ACID LEVELS IN PATIENTS TREATED FOR 96 WEEKS WITH SECHOLEX, AND IN UNTREATED HYPERCHOLESTEROLEMIC CONTROL SUBJECTS Vitamin B 12 (pg/ml)
Meal-l SD Y Number of cases Within normal range a Above normal Borderline a Normal range Borderline
Folic acid @g/ml)
Secholex
Control
632 111
650 171
4.30 2.10
7.11 3.05
19 18 1 0 300-1000
Control
Secholex
pglml
21 13 0 8
19 19 0 0 3.1-15.0 2.1-3.0
nglml ng/ml
417
Vitamin B12 ‘and folic acid concentrations were only analyzed at the end of the trial (96th week), and the values were compared with those taken from randomly selected untreated hypercholesterolemic Type II patients. The results are presented in Table 5. The average vitamin B1* concentration in the serum of Secholex-treated patients was significantly higher, and that of folic acid lower than the corresponding mean values in the control group. Three Secholex-treated patients had serum Blz values that were above the normal limits and eight (40%) had slightly reduced serum folic acid levels. Liver function tests.
Serum bilirubin remained within normal limits in all patients. SGOT rose to above 20 units (21-41) in 5 patients by the end of the experiment. One of them already showed elevated levels at the initial examination. After 96 weeks on Secholex, elevated SGPT values were also seen in 5 patients. Four of these already had elevated SGPT at the initial examination. Prothrombin activity was normal in all subjects throughout the duration of the study. Side effects and subjects excluded from the study Of the 28 patients initially included in the trial 6 (21%) discontinued
Secholex treatment because of side-effects. Three of these complained of nausea, and 3 of constipation, which was being inadequately treated with laxatives. Two patients were excluded before completion of the study because of irreg ular intake of the drug. Of the 20 patients completing the whole trial period, 3 had occasional constipation particularly during the first weeks of the study, but this was adequately treated by drugs. No other side-effects were recorded. Effect of different doses of Secholex on serum cholesterol
The results of the dose-response study in the 8 patients who underwent all 3 dose sequences are given in Table 6. The mean decreases of serum cholesterol obtained with daily doses of 9,12 and 15 g of Secholex were 11.5% (P < O.OOl), 11.5% (P < 0.01) and 14.6% (P< O.OOl), respectively. Although the highest dose resulted in lowest average serum cholesterol level, there was no significant difference between the hypocholesteremic effect of the three doses.
TABLE 6 SERUM CHOLESTEROL
RESPONSE TO DIFFERENT
DOSES OF SECHOLEX
Serum cholesterol (mgl100
ml)
Mean
SD
Max
Min
Pretreatment
374
34
456
347
Secholex 9 g/day Secholex 12 g/day Secholex 15 g/day
332 332 320
46 62 31
432 475 362
282 282 293
Period
N
a Difference between Secholex > 0.10.
and pretreatment
Mean % change
-11.5 -11.5 -14.6
pa ____~~___
periods. all differences between Secholex dose levels
418
Discussion The present results show that Secholex gel is as effective as cholestyramine in reducing the serum cholesterol level of patients with severe hypercholesterolemia. This result was sustained for at least 2 years in those patients who responded to the therapy. The effect of Secholex on serum cholesterol and the patient’s tolerance to the drug could be assessed in all cases within 8 weeks from onset treatment, and no secondary failures were observed. Of the 26 patients who participated in the chronic trial, 6 were excluded because of poor tolerance to the drug and it was found that 7 were resistant to the cholesterollowering action of Secholex. In the remaining 13 cases, the average sustained fall of serum cholesterol was 18%. On the basis of these figures, Secholex can be expected to bring about a satisfactory reduction in serum cholesterol levels in one-half of cases with severe hypercholesterolemia. These results are comparable to previously published studies on the use of Secholex in the treatment of hypercholesterolemia. In a limited number of patients with mild Type II hyperlipoproteinemia, Howard and co-workers observed that Secholex effected a reduction in serum cholesterol levels of 12-20% [13,14], whilst Gustafson and Lanner noted an average reduction of 16% in 11 patients with severe hypercholesterolemia [15]. A similar result has been recently reported by Ritland and co-workers [ 201. Cholestyramine increased fecal bile acid output slightly more than Secholex but in spite of this, both drugs lowered serum cholesterol level to a similar extent. This observation suggests that the mechanism of action of these two bile acid sequestrants is not completely identical. In fact, Borgstrom has shown that the capacity of Secholex to bind free bile salts in vitro is lower than that of cholestyramine [ 111. On the other hand, Secholex does bind free fatty acids in aqueous solution and interacts with the breakdown of triglycerides by pancreatic lipase [ll]. It is therefore possible that Secholex decreases the intestinal absorption of cholesterol, in addition to that of bile acids. This hypothesis is supported by the higher fecal neutral steroid/bile acid ratio observed in the present study during Secholex as compared to cholestyramine treatment. In many previous studies, both cholestyramine [21] and colestipol [3] have been reported to increase serum triglyceride and VLDL levels. This change was not observed during Secholex administration, which if anything had a slight triglyceride-lowering effect. Attention has been recently drawn to the possibility that oral anion-exchangers might inhibit the intestinal absorption of vitamins and iron, and in chronic use might cause an increase in the deficiency of these substances. In animal experiments, large doses of cholestyramine actually inhibit absorption of iron [22], vitamin A [23] and vitamin Blz [24] and deplete the tissue stores of these compounds [ 221. Secholex in the dosage used in the present trial did not lead to decreased serum iron or vitamin B12 levels in patients treated over a two-year period. On the other hand, several patients receiving Secholex had marginal or sub-normal serum folic acid values. Similar observations have been made by Ritland et al. [20], and it seems to be advisable to check serum folic acid biannually in patients under chronic treatment with bile acid sequestrants.
419
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