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Effect of colestipol and clofibrate, singly and in combination, on plasma lipid and lipoproteins in Type IIb hyperlipoproteinemia
Effect of Colestipol and Clofibrate, Singly and in Combination, Plasma Lipid and Lipoproteins in Type IIb Hyperlipoproteinemia Donald B. Hunninghake,
Catherine
on
Bell, and Linda Olson
The effect of colestipol, clofibrate and a combination of these two drugs on plasma lipid and lipoprotein levels was evaluated in 14 adult male patients with Type Ilb hyperlipoproteinemia. A crossover design with each patient receiving all three treatments was utilized. Twenty g of colestipol per day reduced total and LDL cholesterol by 39.1 and 51.5 mg/dl, respectively (p < 0.001). There was an associated rise in total triglycerides of 63.5 mg/dl (p < 0.01) with no significant change in HDL cholesterol. Clofibrate, 2.0 g per day, did not significantly lower either total (- 7.9 mg/dl) or LDL cholesterol (+8.7 mg/dl). There was marked interpatient variability in terms of the LDL cholesterol response to clofibrate, but the majority of patients demonstrated an increase. HDL cholesterol levels increased by 6.7 mg/dl (p < 0.01) and total triglycerides were reduced by 94.6 mg/dl (p < O.OOll. Utilizing the same dosages of both drugs, the combination of colestipol and clofibrate was less effective in lowering total and LDL cholesterol than colestipol therapy alone, and increases in HDL cholesterol and decreases in triglycerides similar to those obtained with clofibrate were observed.
T
HE CURRENT STUDY was designed to evaluate the effect of two drugs, colestipol and clofibrate, with different mechanisms of action in the treatment of Type IIb hyperlipoproteinemia (HLP). The drugs were evaluated with a crossover design, and each patient received both drugs, individually and in combination. The preceding paper in this symposium included the rationale for the necessity of including lipoprotein determinations in the evaluation of any form of hypolipidemic drug therapy and the necessity for doing such studies in specific lipoprotein disorders.’ This is especially true in patients with Type IIb HLP where controlled studies to evaluate the efficacy of drug therapy, especially studies which include lipoprotein determinations, are extremely rare. The efficacy of clofibrate in Type IIb HLP has not been clearly defined. Although clofibrate is more effective in lowering triglycerides (TGG) than total plasma cholesterol (TPC),’ it is frequently assumed that clofibrate is effective in Type IIb HLP, a ondition with elevated TGG. Uncontrolled studies which were done either in a small number of subject? or report the cumulative experience of multiple investigators4 suggest that clofibrate effectively lowers TPC and TGG. A study reported by Davignon et al. indicated that clofibrate was more likely to reduce serum
From the Departments of Pharmacology and Medicine, University of Minnesota,Minneapolis, Minnesota. Receivedfor publication May 28, 1980. Supported in part by Grant from Upjohn Company and NHLBI Contract #NOI HV 2-2195-L. Presented at Brooke Lodge Symposium, September 24, 25. 1979; sponsored by Upjohn Company. Address reprint requests to Donald B. Hunninghake. M.D., University of Minnesota, Department of Pharmacology, 3-260 Millard Hall. 435 Delaware Street S.E.. Minneapolis, Minnesota 55455. 0 1981 by Grune & Stratton, Inc. 0026-0495/81/3006-0016$01.00/O
610
cholesterol in patients with Type IIa than those with Type IIb HLP.’ After the present study was initiated, Fellin et al. reported that clofibrate increased TPC levels in patients who were already receiving colesti~01.~ Their study was not a controlled one and did not include lipoprotein determinations. Colestipol is generally reported to be effective in reducing the TPC and low-density lipoprotein cholesterol (LDL-C) in Type IIb,6.7.8.9 but the number of subjects studied is small. The current report is a preliminary one from an on going study, and includes the data obtained from the first 14 patients who have completed this study. MATERIALS
AND
METHODS
Adult male patients ranging in age from 35-60 yr (mean 51.7) with suspected Type Ilb HLP were screened for possible eligibility in the study depicted in Fig. 1. Written consent was obtained and patients were seen at 4 wk intervals throughout the study. At visit -3 subjects were instructed on a diet approximating a P/S ratio of 0.8 and a cholesterol intake of 350 mg/day plus carbohydrate restriction. Subjects who were on more restrictive diets were advised to continue them during the study. Patients with a history of 10 or more alcoholic drinks/week at the screening visit were excluded from the study. Some subjects were also instructed on caloric restriction. Dietary evaluations and reinforcement continued at each visit throughout the study. The subjects had not been on any lipid lowering drug for at least three months and the majority had not been previously treated with hypolipidemic drugs. No patient was selected for previous known response to a medication. Secondary causes of hyperlipoproteinemia including liver disease, renal impairment, hypothyroidism, gross obesity and a history of excess ethanol intake were excluded. Patients with diabetes mellitus requiring hypolycemic agents were also excluded. Two patients were each chronically receiving one other medication-phenytoin and cholorothiazide. Plasma lipid and lipoprotein concentrations were determined at each visit according to the methods described in the Lipid Research Clinic’s Program.” Blood samples were collected in a sitting position with minimal hemostasis after 12 hr fast and instructions to abstain from ethanol for 24 hr. The plasma lipid and lipoprotein criteria for entry into the study were LDL-C 2 190 mg/dl prior to diet and ~175 mg/dl after diet. Triglyceride values after diet were required to be 2200 mg/dl. Patients who were losing weight or making other major adjustments in diet were not randomized until their weight and plasma lipid and
Metabolism, Vol. 30. No. 6 (June), 1981
COLESTIPOL AND CLOFIBRATE IN TYPE Ilb HLP
611
STUDY DESIGN Diet Evaluation and Reinforcement
Diet Instruction
Stable Weight 6 Lipoprotein _Ccncentrations
I 1 Clofibrate
’ I I
Clofibrate
i
Screening Adult
LDL 2 TGG 2
190 200
LDLL 175 TGG Z 200 -
Viai;
-3
Viai;
Colestipol
plus Colestiwl
clofibrate
-2
Males
I
Colestipol
I ;
;
i2
i6
Fig. 1
lipoprotein
levels were stable.
Summary
of important
Visit -I was simply repeated
features
until we
had this documentation. Clofibrate (Atromid-S) was administered in a dosage regimen of I .O g twice daily. Colestipol (Colestid) was administered in a dosage regimen of 10 g twice daily. Subjects were instructed to use Hz0 or an unsweetened juice as the vehicle for mixing with the resin. Twelve of the 14 subjects used H,O as their vehicle. The same dosage regimens were utilized when the subjects took the combination of the two drugs. Each subject received all three treatments in a crossover design and was randomized to one of the three regimens as illustrated in Fig. I. Adherence to the medication was determined by pill and/or packet counts of dispensed and returned medication at each visit. Weight was determined at each visit. The paired t test was used for statistical
20
;4
;S
;2
36
;O
;4 .
;S
Weeks
Randomization Visit = Visit 0
analyses. RESULTS
The mean TPC, TGG, LDL-C, high-density lipoprotein cholesterol (HDL-C), weight and adherence values for the control and the three treatment periods are illustrated in Table 1. The control values represent the mean of the randomization visit plus the two immediate preceding visits as described in the Methods. The mean TPC and LDL values for these three visits were 296.1, 294.2, 295.3 mg/dl and 197.5, 196.1, 196.4 mg/dl, respectively, and suggest that a stable diet effect had been achieved. The values recorded for the three treatment periods represent the mean of the four values obtained for each patient during each treatment period. A mean reduction in TPC from baseline values of 13.3% or 39.1 mg/dl was noted with colestipol (p < 0.001). The mean reduction of 51.5 mg/ml or 26.2% in LDL-C with colestipol was also significant (p < 0.001). The absolute and percent reductions in LDL-C
of the study design described
in Methods.
are greater than those observed for TPC with colestipal. Colestipol treatment was associated with a mean increase in TGG of 63.5 mg/dl (p cy 0.01). If one uses the formula triglycerides + 5 to estimate VLDL cholesterol (VLDL-C),” this would mean that VLDLC was increased by approximately 12.7 mg/dl. This increase in VLDL-C is primarily responsible for the fact that coiestipol does not lower TPC as much as LDL-C. There was no significant change in mean HDL-C levels or weight with colestipol. One subject tolerated colestipol poorly and his mean adherence was 30%. This primarily accounts for the slight difference in adherence between colestipol and clofibrate noted in this study. Clofibrate treatment was associated with a mean decrease of 94.6 mg/dl in TGG (p < 0.001) and a mean increase in HDL-C of 6.7 mg/dl (p X<0.01). The mean TPC and LDL-C values during clofibrate treatment were not significantly different from baseline values, but a mean increase in LDL-C of 8.7 mgfdl was noted with clofibrate. The mean weight during the clofibrate treatment period was 2.5 lb greater than that observed in the control period. This was not a significant increase and the change is not of sufficient magnitude to account for the alteration in plasma lipid and lipoprotein values seen with clofibrate treatment. The combination of colestipol and clofibrate produced significant decreases of 32. I mg/dl in TPC (p < 0.001) and 24.4 mg/dl in LDL-C (p < 0.01). The greater reduction in TPC appears to be related primarily to the reduction in VLDL-C. The 61.3 mg/dl decrease in TGG with the combination of the
HUNNINGHAKE,
612
Table 1. Mean Plasma Lipids, Lipoproteins, Dief Control TPC
295.1
Colestipol
256.0
Mg/dl 196.7
Mg/dl 38.8
287.2
k 4.4
* 5.0
263.0
f 4.5
-7.9
-32.1t
-13.3
-2.7
- 10.9
+ 3.4
205.4
-+ 5.1
172.3
+ 4.3
-51.5j
t8.7
- 24.4$
-26.2
f4.4
- 12.4
+ 1.4 40.6
Mean Rx value Change from control
?r 1.0 +1.8
Mgldl Percent 286.8
45.5
k 1.5
48.4
f6.7$
+4.6
+17.3
t 1.6
+9.6t f24.7
+ 11.3 350.3
Mean Rx value Change from control
* 16.8
192.2
+ 8.8
Mg/dl
+63.5$
-94.6t
Percent
+22.1
-33.0
177.5
175.6 f 2.8
Weight (lb) Adherence (%)
Combtinatlon
-39.1t
145.2
TGG-
Clofibrate
k 3.6
Mean Rx value Change from control Percent HDL-C
and Adherence
+ 3.4’
Mean Rx value Change from control
Percent LDL-C
Weight
BELL, AND OLSON
-
178.1
2 1.4 87.9
224.9
* 10.5
-61.9t -21.6
+ 2.1
177.8
+ 1.6 87.3s
94.0
*Mean value in mg/dl for period r SEM. tp =
adherence was 87.1 for colestipol and 87.5 for clofibrate.
two drugs was also significant (p < 0.001). A significant increase in HDL-C of 8.4 mg/dl was also noted (p < 0.001). The increase in weight of 2.2 lb noted during this treatment period was not significant. Adherence to the two drugs in the combination treatment period was similar to that noted when each drug was used individually. The mean plasma lipid and lipoprotein values during the three treatment periods are again illustrated in Table 2 to facilitate comparisons. The differences between the three treatment periods are shown in the lower half of Table 2. Colestipol was much more
effective in lowering TPC and LDL-C than was clofibrate. Colestipol treatment resulted in 31.2 and 60.2 mg/dl greater mean reductions in TPC and LDL-C, respectively, than did clofibrate treatment (p < 0.001). Mean HDL-C levels were 4.9 mg/dl higher with clofibrate than with colestipol treatment (p < 0.001) and the mean TGG levels were 192.2 mg/dl lower with clofibrate treatment (p < 0.001). Colestipol was also more effective in lowering LDLC levels than was the combination of colestipol and clofibrate. The difference of 27.1 mg/dl was significant (p < 0.001). HDL-C levels were 7.8 mg/dl higher
Table 2. Mean Plasma Lipid and Lipoprotein
Values and Treatment
Differences
Mean TreatmentValues TPC
LDL-C
HDL-C
TGG
Colestipol
256.0
of:4.4
145.2
+ 3.4
40.6
-e 1.0
350.3
+ 16.8
Clofibrate
287.2
+ 5.0
205.4
+ 5.1
45.5
k 1.5
192.2
+ 8.8
Combination
263.0
+ 4.5
172.3
+ 4.3
48.4
f 1.6
224.9
+ 10.5
Mean Treatment Difference Colestipol minus clofibrate Mgidl difference p value Colestipol minus combination Mg/dl difference p value
158.1
-60.2
-4.9
-c0.001
-7.0 N.S.
-27.1
-7.8
125.4
24.2
33.1 to.001
2.9
-31.2
10.00
Clofibrate minus combination Mg/dl difference p value
-32.7
1
613
COLESTIPOL AND CLOFIBRATE IN TYPE Ilb HLP
during combination therapy and were significantly different from the colestipol treatment period (p < 0.001). The combination of the two drugs also produced a 125.4 mg/dl greater decrease in TGG than was noted during colestipol treatment (p < 0.001). The 7.0 mg/dl greater decrease in TPC with colestipol was not significantly different from the combination. The disparity between the reductions in TPC and LDL-C for colestipol versus combination therapy is primarily due to the fact that the combination treatment period would have a calculated 25 mg/dl greater decrease in VLDL-C. The combination of the two drugs resulted in greater reductions in TPC of 24.2 mg/dl and LDL-C of 33.1 mg/dl than did clofibrate treatment (p < 0.001). The greater increase in HDL-C of 2.9 mg/dl with combination therapy was also significant (p < 0.01). Clofibrate produced a 32.7 mg/dl greater decrease in TGG (p < 0.01). The individual mean changes in LDL-C and HDLC levels from diet control values for each patient are illustrated in Table 3 for each treatment period. The subjects were arbitrarily ranked according to the LDL-C response during clofibrate treatment. There is tremendous variability between subjects in terms of clofibrate’s effect on LDL-C levels ranging from a decrease of 62.0 mg/dl to an increase of 67.0 mg/dl. Eight of the 14 subjects in this study had a mean increase in LDL-C levels during clofibrate treatment. There was no significant correlation between LDL-C and HDL-C changes with clofibrate treatment, but the data suggests that those subjects having the greatest reduction in LDL-C tend to have greater increases in HDL-C. In general, the changes in LDL-C levels during combination therapy tended to parallel those observed Table 3. Mean Changes in LDL-C and HDL-C Levels for Individual Subjects by Treatment Groups Combtnation
Clofibrata
Colestipol
HDLC
HDL-C
LDL-C
HDL-C
LDL-C
-62.0’
+ 16.1
-76.5
+24.1
-31.5
-1.9
0
-21.2
f8.0
-62.5
f9.4
- 75.8
+4.7
C
- 18.7
+11.2
D
- 17.2
E
Subject A
LDL-C
- 76.0
f 13.8
-62.8
- 1.5
+9.3
-49.0
+9.0
-47.2
+3.0
~ 16.7
+9.J
- 13.5
+ 12.0
-39.7
-0.5
F
-1.0
+0.4
- 16.8
-0.6
- 16.5
-2.5
G
+ 1.5
+18.0
- 17.8
+20.5
-42.3
+6.0
Ii
+ 16.8
-3.3
-34.3
+3.7
-62.7
-3.0
I J
+21.6 +30.8
i4.0 +5.2
to.6 - 18.2
+9.0
-54.2
+3.8
+8.2
-45.5
+ 1.4
K
+34.2
+2.3
+ 4.0
-0.2
-44.0
L
+43.2
f7.6
-11.8
+9.8
-50.8
+6.1
M
+43.8
f5.2
-3.0
+8.6
-93.5
-14.2
N
+67.0
+0.2
+20.5
f4.5
-30.3
+6.2
lmg/di
mean changes from diet control values.
0.0
during clofibrate treatment. Subjects with the greatest reductions in LDL-C during clofibrate treatment tended to have the greater decreases in LDL-C during the combination treatment period. Colestipol treatment was associated with a more uniform effect on LDL-C levels with all 14 subjects showing mean decreases in LDL-C levels ranging from 16.5-93.5 mg/dl. Colestipol’s effect on HDL-C levels was inconsistent with 8 subjects having an increase and 6 subjects having no change or a slight decrease. DISCUSSION
The effect of colestipol on plasma lipids and lipoprotein levels noted in this study are consistent with other reported studies in Type II HLP.‘.6.7.“,9 The reductions in LDL-C levels of 48 mg/dl or 24% noted with 20 g of colestipol in this study is highly significant (p < O.OOl), and somewhat greater than that observed with the same dose in our Type Ila study.’ The reduction in TPC with colestipol is not as great as that observed for LDL-C, primarily because the resin increases TGG and there is an associated increase in VLDL-C. The reported effects of colestipol on HDL-C levels are generally minimal, ranging from slight increases to slight decreases,‘*‘2 and no significant effect was noted in this study. In males, TGG do not appear to be an independent risk factor for the development of coronary artery diseaseI and the small increase noted with colestipol in this study is not of major concern. Previous studies have shown either no change or small increases in TGG.‘*7.8.9 The subjects used water as the vehicle for colestipol administration and there was an insignificant mean increase in weight of 1.9 lb (individual changes ranged from - 1.5 to + 5.1 lb). There was no significant correlation between changes in weight and TGG values. Thus these two parameters cannot explain the increase in TGG. Previous observations which could be important include the fact that any form of treatment which lowers LDL levels has a tendency to increase TGG:14 bile acid sequestering agents increase the apparent biosynthesis and fractional turnover rate for TGG.” or they may alter the composition of individual lipoproteins.‘2 The increase in VLDL-C and TGG may be greater in patients with Type Ilb than those with Type 1Ia HLP and may be correlated with pretreatment VLDL-C levels.16 Clofibrate produced only a modest decrease in TPC of 8 mg/dl in this study, which was primarily due to a reduction in VLDL-C. Clofibrate’s ability to lower TGG and VLDL fraction is generally accepted and was again confirmed in this study. Moderate increases in HDL have been previously reported.‘*‘7.‘8 There was no consistent effect of clofibrate on LDL-C levels and
HUNNINGHAKE.
614
the majority of patients had an increase in LDL-C. Many mechanisms of action have been proposed for clofibrate and it is probable that multiple mechanisms are responsible for its lipid altering effect.” Increases in LDL-C following clofibrate administration have been reported in Type IV HLP,‘43’s and were predicted to occur in Type IIb.14 The reason for the increase in LDL-C following clofibrate administration has not been established. Decreased plasma levels and altered pharmacokinetic properties for clofibrate have been demonstrated in patients with Type IIb HLP:’ but these observations do not explain the increase in LDL-C. It has been suggested that clofibrate increases LDL-C levels by facilitating the conversion of VLDL to LDL.” Increases in LDL occur when a significant reduction in VLDL occurs following a variety of therapeutic interventions.14 The reductions in TGG noted in this study were similar for patients having either increases or decreases in LDL-C. Patients who had decreases in LDL-C following clofibrate administration tend to have lower pretreatment relative body weights and TGG and higher HDL-C levels (some similarity to Type IIa’s). The number of patients studied to date does not permit an evaluation of potential genetic mechanisms. This study demonstrates considerable variability in LDL-C response following clofibrate, but does not provide an explanation for the mechanism involved. The variable response of the individual lipoproteins, HDL and LDL, following clofibrate administration is also of interest in view of the possible effect on atherogenic potential. The risk for developing coronary artery disease appears to be inversely correlated with HDL levels,‘4,22*23and positively correlated with LDL levels.‘4*22~23Utilizing the predictors of risk previously defined,14 the theoretical alteration in risk of coronary heart disease for individual patients in this study following clofibrate administration would be quite variable. Some subjects would have a significant decrease in risk while others would be at increased risk. It is possible that the recently completed Intervention Trials24*25 contained patients with Type IIb HLP whose risk could have been increased by clofibrate administration and this could have influenced the observed effects in terms of morbidity and mortality. We feel that patients with Type IIb HLP should be monitored with both plasma lipid and lipoprotein levels. The reduction in TPC and LDL-C observed with
BELL, AND OLSON
the combination of clofibrate and colestipol was less than that observed with colestipol alone. Increases in plasma cholesterol have been reported when clofibrate is added to the treatment regimen of patients with Type IIb HLP who are receiving colestipol.’ This study documents that both increases and decreases in TPC and LDL may occur. In contrast, patients with Type IIa HLP have similar or greater reductions in TPC and LDL-C when combination therapy is compared to resin therapy alone.‘,3,9 The reason for the decreased efficacy of combination therapy in terms of LDL-C reduction is unknown, but must include the following considerations. Colestipol does not interfere with the absorption of clofibrate,26 and the obtaining of the expected effect of clofibrate on TGG and HDL-C levels in this study negates this possibility. LDL is primarily a catabolic product of VLDL metabolism” and it has been suggested that clofibrate increases LDL levels by enhancing this mechanism.2’ Increased LDL formation could negate the effect of the bile acid sequestering agents, which increase the fractional catabolic rate of LDL.28 It is also possible that the observed LDL effects are related to opposing effects of clofibrate and colestipol on bile acid metabolism. There are very few studies of the effect of clofibrate on fecal bile acid excretion in Type IIb HLP, but clofibrate has been reported to occasionally decrease fecal bile acid excretion in Type II HLP patients who are receiving cholestyramine.29 Clofibrate does decrease fecal bile acid excretion in hypertriglyceridemic patients, primarily Type IV.*’ This study demonstrates that there is considerable interpatient variation in the effect of clofibrate, colestipol and a combination of these two drugs on plasma lipid and lipoprotein levels in patients with Type IIb HLP. The effect of colestipol is reasonably predictable, but the response of patients to clofibrate or combination therapy is quite variable. Colestipol reduced TPC and LDL-C levels in all subjects while clofibrate frequently increased them. Clofibrate increased HDL-C levels. Colestipol increases and clofibrate decreases TGG levels. Patients receiving clofibrate must be monitored with both plasma lipid and lipoprotein determinations. ACKNOWLEDGMENT The authors are indebted to Kay Posthumus for secretarial and data analysis assistance in the preparation of this manuscript, and to Kanta Kuba, M.S. and staff for assistance in analysis of lipid and lipoproteins.
REFERENCES 1. Hunninghake DB, Probstfield JL, Crow LO, et al: Effect of colestipol and clofibrate on plasma lipid and lipoproteins in Type Ila hyperlipoproteinemia. Metabolism (in press)
2. Hunninghake DB, Tucker DR. Azarnoff DL: Long-term effects of clofibrate (Atromid-S) on serum lipids in man. Circulation 39:615X%3, 1969
615
COLESTIPOL AND CLOFIBRATE IN TYPE Ilb HLP
3. Oro L, Olsson AG, Rossner S, et al: Cholestyramine, clofibrate and nicotinic acid as single or combined treatment of Type IIa and Ilb hyperlipoproteinemia. Postgrad Med J Sl(Suppl 8):76-79, 1975 4. Gustafson A: Clofibrate and related compounds in hyperlipoproteinemia. A review. Postgrad Med J 5 I (Suppl8):66-7 1, 1975 5. Davignon J, Aubry F. Noel C, et al: Heterogeneity of familial hyperlipoproteinemia Type II on the basis of the fasting plasma triglyceride/cholesterol ration and plasma cholesterol response to chlorophenoxyisobutyrate. Rev Can Biol 30:307-3 13, 197 1 6. Fellin R, Baggio G, Briani G, et al: Long-term trial with colestipol plus clofibrate in familial hypercholesteremia. Atherosclerosis 29:241- 249, 1978 7. Gundersen, Kare, Cooper, et al: Cholesterol-lowering effect of colestipol hydrochloride given twice daily in hypercholesteremic patients. Atherosclerosis 25:303-3 10, 1976 8. Mishkel MA, Crowther SA: Long-term therapy of diet resistant hypercholesteremia with colestipol. Cur Ther Res 22:398-412, 1977 9. Stein EA, Heimann KW: Colestipol, clofibrate, cholestyramine and combination therapy in the treatment of familial hyperbeta lipoproteinaemia. S Afr Med J 49: 1252-l 256, 1975 10. Manual of Laboratory Operations. Lipid Research Clinics Program. Vol. 1. Lipid and Lipoprotein Analyses. NHLBI, NIH. Bethesda, Maryland 20014 DHEW Publication No (NIH) 75-628 I 1. Friedewald WT. Levy RI, Fredrickson DS: Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499502, 1972 12. Witzum JL, Schonfeld G, Weidman SW: The effects of colestipol on the metabolism of very-low-density lipoproteins in man. J LabClin Med 88:1008-1018, 1976 13. Gordon T, Castelli WP, Hjortland MC, et al: High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 62:707-7 14, 1977 14. Wilson DE, Lees RS: Metabolic relationships among the plasma lipoproteins-reciprocal changes in the concentrations of very low and low density lipoproteins in man. J Clin Invest 51:1051-1057, 1972 15. Angelin B, Einarsson K, Hellstrom K, et al: Effect of cholestyramine and chencdeoxycholic acid on the metabolism of endogenous triglycerides. J Lipid Res 19: 101771024, 1978
16. Miller NE, Nestel PJ: Differences among hyperlipoproteinemit subjects in the response of lipoprotein lipids to resin therapy. Em J Clin Invest 5:241-247, 1975 17. Enger SC, Erikssen J, Johnson V, et al: The effect of clofibrate on high density lipoprotein and total cholesterol in patients with coronary heart disease. Artery 4:28-35, 1978 18. Strisower EH, Adamson G, Stirsower B: Treatment of hyperlipidemias. Am J Med 45488-501, 1968 19. Hunninghake DB, Probstlield JL: Drug treatment of hyperlipoproteinemia in Rifkind BM, Levy RI (eds): Hyperlipidemiadiagnosis and therapy, New York, Grune and Stratton. 1977. pp 327-362 20. Pichardo R, Boulet L, Davignon clofibrate in familial hypercholesteremia. 582, 1977
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2 I. Yeshurun D, Gotto AM: Drug treatment Am J Med 60:379-396, 1976
of hyperlipidemia.
22. Castelli WP, Doyle JT, Gordon T, et al: HDL cholesterol and other lipids in coronary heart disease. Circulation 55:767-782, 1977 23. Rhoads GG, Gulbrandsen CL, Kagan A: Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men. N Engl J Med 294:293-298, 1976 24. A co-operative trial in the primary prevention of ischemic heart disease using clofibrate. Report from the Committee of Principal Investigators. Br Heart J 40:1069-l 118, 1978 25. Clofibrate and niacin in coronary heart disease. The Coronary Drug Project Research Group. JAMA 23 1:36&38 I, 1975 26. DeSante KA, DiSanto AR, Albert KS, et al: The effect of colestipol hydrochloride and cholestyramine on the bioavailability and pharmacokinetics of clofibrate. Clin Pharmacol Ther 23:l 12, I978 27. Eisenberg S, Bilheimer DW, Levy RI, et al: On the metabolic conversion of human plasma very low density lipoprotein to low density lipoprotein. Biochim Biophys Acta 326:361-377, 1973 28. Levy RI, Langer T: Hypolipidemic drugs and lipoprotein metabolism. Adv Exp Med Bio126: I 55-l 63, 1976 29. Grundy SM. Ahrens EH, Salen G, et al: Mechanisms of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia. J Lipid Res l3:53 l--551, 1972
Catherine
on
Bell, and Linda Olson
The effect of colestipol, clofibrate and a combination of these two drugs on plasma lipid and lipoprotein levels was evaluated in 14 adult male patients with Type Ilb hyperlipoproteinemia. A crossover design with each patient receiving all three treatments was utilized. Twenty g of colestipol per day reduced total and LDL cholesterol by 39.1 and 51.5 mg/dl, respectively (p < 0.001). There was an associated rise in total triglycerides of 63.5 mg/dl (p < 0.01) with no significant change in HDL cholesterol. Clofibrate, 2.0 g per day, did not significantly lower either total (- 7.9 mg/dl) or LDL cholesterol (+8.7 mg/dl). There was marked interpatient variability in terms of the LDL cholesterol response to clofibrate, but the majority of patients demonstrated an increase. HDL cholesterol levels increased by 6.7 mg/dl (p < 0.01) and total triglycerides were reduced by 94.6 mg/dl (p < O.OOll. Utilizing the same dosages of both drugs, the combination of colestipol and clofibrate was less effective in lowering total and LDL cholesterol than colestipol therapy alone, and increases in HDL cholesterol and decreases in triglycerides similar to those obtained with clofibrate were observed.
T
HE CURRENT STUDY was designed to evaluate the effect of two drugs, colestipol and clofibrate, with different mechanisms of action in the treatment of Type IIb hyperlipoproteinemia (HLP). The drugs were evaluated with a crossover design, and each patient received both drugs, individually and in combination. The preceding paper in this symposium included the rationale for the necessity of including lipoprotein determinations in the evaluation of any form of hypolipidemic drug therapy and the necessity for doing such studies in specific lipoprotein disorders.’ This is especially true in patients with Type IIb HLP where controlled studies to evaluate the efficacy of drug therapy, especially studies which include lipoprotein determinations, are extremely rare. The efficacy of clofibrate in Type IIb HLP has not been clearly defined. Although clofibrate is more effective in lowering triglycerides (TGG) than total plasma cholesterol (TPC),’ it is frequently assumed that clofibrate is effective in Type IIb HLP, a ondition with elevated TGG. Uncontrolled studies which were done either in a small number of subject? or report the cumulative experience of multiple investigators4 suggest that clofibrate effectively lowers TPC and TGG. A study reported by Davignon et al. indicated that clofibrate was more likely to reduce serum
From the Departments of Pharmacology and Medicine, University of Minnesota,Minneapolis, Minnesota. Receivedfor publication May 28, 1980. Supported in part by Grant from Upjohn Company and NHLBI Contract #NOI HV 2-2195-L. Presented at Brooke Lodge Symposium, September 24, 25. 1979; sponsored by Upjohn Company. Address reprint requests to Donald B. Hunninghake. M.D., University of Minnesota, Department of Pharmacology, 3-260 Millard Hall. 435 Delaware Street S.E.. Minneapolis, Minnesota 55455. 0 1981 by Grune & Stratton, Inc. 0026-0495/81/3006-0016$01.00/O
610
cholesterol in patients with Type IIa than those with Type IIb HLP.’ After the present study was initiated, Fellin et al. reported that clofibrate increased TPC levels in patients who were already receiving colesti~01.~ Their study was not a controlled one and did not include lipoprotein determinations. Colestipol is generally reported to be effective in reducing the TPC and low-density lipoprotein cholesterol (LDL-C) in Type IIb,6.7.8.9 but the number of subjects studied is small. The current report is a preliminary one from an on going study, and includes the data obtained from the first 14 patients who have completed this study. MATERIALS
AND
METHODS
Adult male patients ranging in age from 35-60 yr (mean 51.7) with suspected Type Ilb HLP were screened for possible eligibility in the study depicted in Fig. 1. Written consent was obtained and patients were seen at 4 wk intervals throughout the study. At visit -3 subjects were instructed on a diet approximating a P/S ratio of 0.8 and a cholesterol intake of 350 mg/day plus carbohydrate restriction. Subjects who were on more restrictive diets were advised to continue them during the study. Patients with a history of 10 or more alcoholic drinks/week at the screening visit were excluded from the study. Some subjects were also instructed on caloric restriction. Dietary evaluations and reinforcement continued at each visit throughout the study. The subjects had not been on any lipid lowering drug for at least three months and the majority had not been previously treated with hypolipidemic drugs. No patient was selected for previous known response to a medication. Secondary causes of hyperlipoproteinemia including liver disease, renal impairment, hypothyroidism, gross obesity and a history of excess ethanol intake were excluded. Patients with diabetes mellitus requiring hypolycemic agents were also excluded. Two patients were each chronically receiving one other medication-phenytoin and cholorothiazide. Plasma lipid and lipoprotein concentrations were determined at each visit according to the methods described in the Lipid Research Clinic’s Program.” Blood samples were collected in a sitting position with minimal hemostasis after 12 hr fast and instructions to abstain from ethanol for 24 hr. The plasma lipid and lipoprotein criteria for entry into the study were LDL-C 2 190 mg/dl prior to diet and ~175 mg/dl after diet. Triglyceride values after diet were required to be 2200 mg/dl. Patients who were losing weight or making other major adjustments in diet were not randomized until their weight and plasma lipid and
Metabolism, Vol. 30. No. 6 (June), 1981
COLESTIPOL AND CLOFIBRATE IN TYPE Ilb HLP
611
STUDY DESIGN Diet Evaluation and Reinforcement
Diet Instruction
Stable Weight 6 Lipoprotein _Ccncentrations
I 1 Clofibrate
’ I I
Clofibrate
i
Screening Adult
LDL 2 TGG 2
190 200
LDLL 175 TGG Z 200 -
Viai;
-3
Viai;
Colestipol
plus Colestiwl
clofibrate
-2
Males
I
Colestipol
I ;
;
i2
i6
Fig. 1
lipoprotein
levels were stable.
Summary
of important
Visit -I was simply repeated
features
until we
had this documentation. Clofibrate (Atromid-S) was administered in a dosage regimen of I .O g twice daily. Colestipol (Colestid) was administered in a dosage regimen of 10 g twice daily. Subjects were instructed to use Hz0 or an unsweetened juice as the vehicle for mixing with the resin. Twelve of the 14 subjects used H,O as their vehicle. The same dosage regimens were utilized when the subjects took the combination of the two drugs. Each subject received all three treatments in a crossover design and was randomized to one of the three regimens as illustrated in Fig. I. Adherence to the medication was determined by pill and/or packet counts of dispensed and returned medication at each visit. Weight was determined at each visit. The paired t test was used for statistical
20
;4
;S
;2
36
;O
;4 .
;S
Weeks
Randomization Visit = Visit 0
analyses. RESULTS
The mean TPC, TGG, LDL-C, high-density lipoprotein cholesterol (HDL-C), weight and adherence values for the control and the three treatment periods are illustrated in Table 1. The control values represent the mean of the randomization visit plus the two immediate preceding visits as described in the Methods. The mean TPC and LDL values for these three visits were 296.1, 294.2, 295.3 mg/dl and 197.5, 196.1, 196.4 mg/dl, respectively, and suggest that a stable diet effect had been achieved. The values recorded for the three treatment periods represent the mean of the four values obtained for each patient during each treatment period. A mean reduction in TPC from baseline values of 13.3% or 39.1 mg/dl was noted with colestipol (p < 0.001). The mean reduction of 51.5 mg/ml or 26.2% in LDL-C with colestipol was also significant (p < 0.001). The absolute and percent reductions in LDL-C
of the study design described
in Methods.
are greater than those observed for TPC with colestipal. Colestipol treatment was associated with a mean increase in TGG of 63.5 mg/dl (p cy 0.01). If one uses the formula triglycerides + 5 to estimate VLDL cholesterol (VLDL-C),” this would mean that VLDLC was increased by approximately 12.7 mg/dl. This increase in VLDL-C is primarily responsible for the fact that coiestipol does not lower TPC as much as LDL-C. There was no significant change in mean HDL-C levels or weight with colestipol. One subject tolerated colestipol poorly and his mean adherence was 30%. This primarily accounts for the slight difference in adherence between colestipol and clofibrate noted in this study. Clofibrate treatment was associated with a mean decrease of 94.6 mg/dl in TGG (p < 0.001) and a mean increase in HDL-C of 6.7 mg/dl (p X<0.01). The mean TPC and LDL-C values during clofibrate treatment were not significantly different from baseline values, but a mean increase in LDL-C of 8.7 mgfdl was noted with clofibrate. The mean weight during the clofibrate treatment period was 2.5 lb greater than that observed in the control period. This was not a significant increase and the change is not of sufficient magnitude to account for the alteration in plasma lipid and lipoprotein values seen with clofibrate treatment. The combination of colestipol and clofibrate produced significant decreases of 32. I mg/dl in TPC (p < 0.001) and 24.4 mg/dl in LDL-C (p < 0.01). The greater reduction in TPC appears to be related primarily to the reduction in VLDL-C. The 61.3 mg/dl decrease in TGG with the combination of the
HUNNINGHAKE,
612
Table 1. Mean Plasma Lipids, Lipoproteins, Dief Control TPC
295.1
Colestipol
256.0
Mg/dl 196.7
Mg/dl 38.8
287.2
k 4.4
* 5.0
263.0
f 4.5
-7.9
-32.1t
-13.3
-2.7
- 10.9
+ 3.4
205.4
-+ 5.1
172.3
+ 4.3
-51.5j
t8.7
- 24.4$
-26.2
f4.4
- 12.4
+ 1.4 40.6
Mean Rx value Change from control
?r 1.0 +1.8
Mgldl Percent 286.8
45.5
k 1.5
48.4
f6.7$
+4.6
+17.3
t 1.6
+9.6t f24.7
+ 11.3 350.3
Mean Rx value Change from control
* 16.8
192.2
+ 8.8
Mg/dl
+63.5$
-94.6t
Percent
+22.1
-33.0
177.5
175.6 f 2.8
Weight (lb) Adherence (%)
Combtinatlon
-39.1t
145.2
TGG-
Clofibrate
k 3.6
Mean Rx value Change from control Percent HDL-C
and Adherence
+ 3.4’
Mean Rx value Change from control
Percent LDL-C
Weight
BELL, AND OLSON
-
178.1
2 1.4 87.9
224.9
* 10.5
-61.9t -21.6
+ 2.1
177.8
+ 1.6 87.3s
94.0
*Mean value in mg/dl for period r SEM. tp =
adherence was 87.1 for colestipol and 87.5 for clofibrate.
two drugs was also significant (p < 0.001). A significant increase in HDL-C of 8.4 mg/dl was also noted (p < 0.001). The increase in weight of 2.2 lb noted during this treatment period was not significant. Adherence to the two drugs in the combination treatment period was similar to that noted when each drug was used individually. The mean plasma lipid and lipoprotein values during the three treatment periods are again illustrated in Table 2 to facilitate comparisons. The differences between the three treatment periods are shown in the lower half of Table 2. Colestipol was much more
effective in lowering TPC and LDL-C than was clofibrate. Colestipol treatment resulted in 31.2 and 60.2 mg/dl greater mean reductions in TPC and LDL-C, respectively, than did clofibrate treatment (p < 0.001). Mean HDL-C levels were 4.9 mg/dl higher with clofibrate than with colestipol treatment (p < 0.001) and the mean TGG levels were 192.2 mg/dl lower with clofibrate treatment (p < 0.001). Colestipol was also more effective in lowering LDLC levels than was the combination of colestipol and clofibrate. The difference of 27.1 mg/dl was significant (p < 0.001). HDL-C levels were 7.8 mg/dl higher
Table 2. Mean Plasma Lipid and Lipoprotein
Values and Treatment
Differences
Mean TreatmentValues TPC
LDL-C
HDL-C
TGG
Colestipol
256.0
of:4.4
145.2
+ 3.4
40.6
-e 1.0
350.3
+ 16.8
Clofibrate
287.2
+ 5.0
205.4
+ 5.1
45.5
k 1.5
192.2
+ 8.8
Combination
263.0
+ 4.5
172.3
+ 4.3
48.4
f 1.6
224.9
+ 10.5
Mean Treatment Difference Colestipol minus clofibrate Mgidl difference p value Colestipol minus combination Mg/dl difference p value
158.1
-60.2
-4.9
-c0.001
-7.0 N.S.
-27.1
-7.8
125.4
24.2
33.1 to.001
2.9
-31.2
10.00
Clofibrate minus combination Mg/dl difference p value
-32.7
1
613
COLESTIPOL AND CLOFIBRATE IN TYPE Ilb HLP
during combination therapy and were significantly different from the colestipol treatment period (p < 0.001). The combination of the two drugs also produced a 125.4 mg/dl greater decrease in TGG than was noted during colestipol treatment (p < 0.001). The 7.0 mg/dl greater decrease in TPC with colestipol was not significantly different from the combination. The disparity between the reductions in TPC and LDL-C for colestipol versus combination therapy is primarily due to the fact that the combination treatment period would have a calculated 25 mg/dl greater decrease in VLDL-C. The combination of the two drugs resulted in greater reductions in TPC of 24.2 mg/dl and LDL-C of 33.1 mg/dl than did clofibrate treatment (p < 0.001). The greater increase in HDL-C of 2.9 mg/dl with combination therapy was also significant (p < 0.01). Clofibrate produced a 32.7 mg/dl greater decrease in TGG (p < 0.01). The individual mean changes in LDL-C and HDLC levels from diet control values for each patient are illustrated in Table 3 for each treatment period. The subjects were arbitrarily ranked according to the LDL-C response during clofibrate treatment. There is tremendous variability between subjects in terms of clofibrate’s effect on LDL-C levels ranging from a decrease of 62.0 mg/dl to an increase of 67.0 mg/dl. Eight of the 14 subjects in this study had a mean increase in LDL-C levels during clofibrate treatment. There was no significant correlation between LDL-C and HDL-C changes with clofibrate treatment, but the data suggests that those subjects having the greatest reduction in LDL-C tend to have greater increases in HDL-C. In general, the changes in LDL-C levels during combination therapy tended to parallel those observed Table 3. Mean Changes in LDL-C and HDL-C Levels for Individual Subjects by Treatment Groups Combtnation
Clofibrata
Colestipol
HDLC
HDL-C
LDL-C
HDL-C
LDL-C
-62.0’
+ 16.1
-76.5
+24.1
-31.5
-1.9
0
-21.2
f8.0
-62.5
f9.4
- 75.8
+4.7
C
- 18.7
+11.2
D
- 17.2
E
Subject A
LDL-C
- 76.0
f 13.8
-62.8
- 1.5
+9.3
-49.0
+9.0
-47.2
+3.0
~ 16.7
+9.J
- 13.5
+ 12.0
-39.7
-0.5
F
-1.0
+0.4
- 16.8
-0.6
- 16.5
-2.5
G
+ 1.5
+18.0
- 17.8
+20.5
-42.3
+6.0
Ii
+ 16.8
-3.3
-34.3
+3.7
-62.7
-3.0
I J
+21.6 +30.8
i4.0 +5.2
to.6 - 18.2
+9.0
-54.2
+3.8
+8.2
-45.5
+ 1.4
K
+34.2
+2.3
+ 4.0
-0.2
-44.0
L
+43.2
f7.6
-11.8
+9.8
-50.8
+6.1
M
+43.8
f5.2
-3.0
+8.6
-93.5
-14.2
N
+67.0
+0.2
+20.5
f4.5
-30.3
+6.2
lmg/di
mean changes from diet control values.
0.0
during clofibrate treatment. Subjects with the greatest reductions in LDL-C during clofibrate treatment tended to have the greater decreases in LDL-C during the combination treatment period. Colestipol treatment was associated with a more uniform effect on LDL-C levels with all 14 subjects showing mean decreases in LDL-C levels ranging from 16.5-93.5 mg/dl. Colestipol’s effect on HDL-C levels was inconsistent with 8 subjects having an increase and 6 subjects having no change or a slight decrease. DISCUSSION
The effect of colestipol on plasma lipids and lipoprotein levels noted in this study are consistent with other reported studies in Type II HLP.‘.6.7.“,9 The reductions in LDL-C levels of 48 mg/dl or 24% noted with 20 g of colestipol in this study is highly significant (p < O.OOl), and somewhat greater than that observed with the same dose in our Type Ila study.’ The reduction in TPC with colestipol is not as great as that observed for LDL-C, primarily because the resin increases TGG and there is an associated increase in VLDL-C. The reported effects of colestipol on HDL-C levels are generally minimal, ranging from slight increases to slight decreases,‘*‘2 and no significant effect was noted in this study. In males, TGG do not appear to be an independent risk factor for the development of coronary artery diseaseI and the small increase noted with colestipol in this study is not of major concern. Previous studies have shown either no change or small increases in TGG.‘*7.8.9 The subjects used water as the vehicle for colestipol administration and there was an insignificant mean increase in weight of 1.9 lb (individual changes ranged from - 1.5 to + 5.1 lb). There was no significant correlation between changes in weight and TGG values. Thus these two parameters cannot explain the increase in TGG. Previous observations which could be important include the fact that any form of treatment which lowers LDL levels has a tendency to increase TGG:14 bile acid sequestering agents increase the apparent biosynthesis and fractional turnover rate for TGG.” or they may alter the composition of individual lipoproteins.‘2 The increase in VLDL-C and TGG may be greater in patients with Type Ilb than those with Type 1Ia HLP and may be correlated with pretreatment VLDL-C levels.16 Clofibrate produced only a modest decrease in TPC of 8 mg/dl in this study, which was primarily due to a reduction in VLDL-C. Clofibrate’s ability to lower TGG and VLDL fraction is generally accepted and was again confirmed in this study. Moderate increases in HDL have been previously reported.‘*‘7.‘8 There was no consistent effect of clofibrate on LDL-C levels and
HUNNINGHAKE.
614
the majority of patients had an increase in LDL-C. Many mechanisms of action have been proposed for clofibrate and it is probable that multiple mechanisms are responsible for its lipid altering effect.” Increases in LDL-C following clofibrate administration have been reported in Type IV HLP,‘43’s and were predicted to occur in Type IIb.14 The reason for the increase in LDL-C following clofibrate administration has not been established. Decreased plasma levels and altered pharmacokinetic properties for clofibrate have been demonstrated in patients with Type IIb HLP:’ but these observations do not explain the increase in LDL-C. It has been suggested that clofibrate increases LDL-C levels by facilitating the conversion of VLDL to LDL.” Increases in LDL occur when a significant reduction in VLDL occurs following a variety of therapeutic interventions.14 The reductions in TGG noted in this study were similar for patients having either increases or decreases in LDL-C. Patients who had decreases in LDL-C following clofibrate administration tend to have lower pretreatment relative body weights and TGG and higher HDL-C levels (some similarity to Type IIa’s). The number of patients studied to date does not permit an evaluation of potential genetic mechanisms. This study demonstrates considerable variability in LDL-C response following clofibrate, but does not provide an explanation for the mechanism involved. The variable response of the individual lipoproteins, HDL and LDL, following clofibrate administration is also of interest in view of the possible effect on atherogenic potential. The risk for developing coronary artery disease appears to be inversely correlated with HDL levels,‘4,22*23and positively correlated with LDL levels.‘4*22~23Utilizing the predictors of risk previously defined,14 the theoretical alteration in risk of coronary heart disease for individual patients in this study following clofibrate administration would be quite variable. Some subjects would have a significant decrease in risk while others would be at increased risk. It is possible that the recently completed Intervention Trials24*25 contained patients with Type IIb HLP whose risk could have been increased by clofibrate administration and this could have influenced the observed effects in terms of morbidity and mortality. We feel that patients with Type IIb HLP should be monitored with both plasma lipid and lipoprotein levels. The reduction in TPC and LDL-C observed with
BELL, AND OLSON
the combination of clofibrate and colestipol was less than that observed with colestipol alone. Increases in plasma cholesterol have been reported when clofibrate is added to the treatment regimen of patients with Type IIb HLP who are receiving colestipol.’ This study documents that both increases and decreases in TPC and LDL may occur. In contrast, patients with Type IIa HLP have similar or greater reductions in TPC and LDL-C when combination therapy is compared to resin therapy alone.‘,3,9 The reason for the decreased efficacy of combination therapy in terms of LDL-C reduction is unknown, but must include the following considerations. Colestipol does not interfere with the absorption of clofibrate,26 and the obtaining of the expected effect of clofibrate on TGG and HDL-C levels in this study negates this possibility. LDL is primarily a catabolic product of VLDL metabolism” and it has been suggested that clofibrate increases LDL levels by enhancing this mechanism.2’ Increased LDL formation could negate the effect of the bile acid sequestering agents, which increase the fractional catabolic rate of LDL.28 It is also possible that the observed LDL effects are related to opposing effects of clofibrate and colestipol on bile acid metabolism. There are very few studies of the effect of clofibrate on fecal bile acid excretion in Type IIb HLP, but clofibrate has been reported to occasionally decrease fecal bile acid excretion in Type II HLP patients who are receiving cholestyramine.29 Clofibrate does decrease fecal bile acid excretion in hypertriglyceridemic patients, primarily Type IV.*’ This study demonstrates that there is considerable interpatient variation in the effect of clofibrate, colestipol and a combination of these two drugs on plasma lipid and lipoprotein levels in patients with Type IIb HLP. The effect of colestipol is reasonably predictable, but the response of patients to clofibrate or combination therapy is quite variable. Colestipol reduced TPC and LDL-C levels in all subjects while clofibrate frequently increased them. Clofibrate increased HDL-C levels. Colestipol increases and clofibrate decreases TGG levels. Patients receiving clofibrate must be monitored with both plasma lipid and lipoprotein determinations. ACKNOWLEDGMENT The authors are indebted to Kay Posthumus for secretarial and data analysis assistance in the preparation of this manuscript, and to Kanta Kuba, M.S. and staff for assistance in analysis of lipid and lipoproteins.
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2. Hunninghake DB, Tucker DR. Azarnoff DL: Long-term effects of clofibrate (Atromid-S) on serum lipids in man. Circulation 39:615X%3, 1969
615
COLESTIPOL AND CLOFIBRATE IN TYPE Ilb HLP
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16. Miller NE, Nestel PJ: Differences among hyperlipoproteinemit subjects in the response of lipoprotein lipids to resin therapy. Em J Clin Invest 5:241-247, 1975 17. Enger SC, Erikssen J, Johnson V, et al: The effect of clofibrate on high density lipoprotein and total cholesterol in patients with coronary heart disease. Artery 4:28-35, 1978 18. Strisower EH, Adamson G, Stirsower B: Treatment of hyperlipidemias. Am J Med 45488-501, 1968 19. Hunninghake DB, Probstlield JL: Drug treatment of hyperlipoproteinemia in Rifkind BM, Levy RI (eds): Hyperlipidemiadiagnosis and therapy, New York, Grune and Stratton. 1977. pp 327-362 20. Pichardo R, Boulet L, Davignon clofibrate in familial hypercholesteremia. 582, 1977
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22. Castelli WP, Doyle JT, Gordon T, et al: HDL cholesterol and other lipids in coronary heart disease. Circulation 55:767-782, 1977 23. Rhoads GG, Gulbrandsen CL, Kagan A: Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men. N Engl J Med 294:293-298, 1976 24. A co-operative trial in the primary prevention of ischemic heart disease using clofibrate. Report from the Committee of Principal Investigators. Br Heart J 40:1069-l 118, 1978 25. Clofibrate and niacin in coronary heart disease. The Coronary Drug Project Research Group. JAMA 23 1:36&38 I, 1975 26. DeSante KA, DiSanto AR, Albert KS, et al: The effect of colestipol hydrochloride and cholestyramine on the bioavailability and pharmacokinetics of clofibrate. Clin Pharmacol Ther 23:l 12, I978 27. Eisenberg S, Bilheimer DW, Levy RI, et al: On the metabolic conversion of human plasma very low density lipoprotein to low density lipoprotein. Biochim Biophys Acta 326:361-377, 1973 28. Levy RI, Langer T: Hypolipidemic drugs and lipoprotein metabolism. Adv Exp Med Bio126: I 55-l 63, 1976 29. Grundy SM. Ahrens EH, Salen G, et al: Mechanisms of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia. J Lipid Res l3:53 l--551, 1972