Comparative effects of gemfibrozil and clofibrate in type III hyperlipoproteinemia

ATHEROSCLEROSIS ELSFVIER SCIENCE IRELAND

Atherosclerosis 106 (1994) 235-240

Comparative effects of gemfibrozil and clofibrate in type III hyperlipoproteinemia M. Lytken LarsenT, D. Roger Illingworth*, Jean P. O’Malley Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine-L465. Portland, OR 97201-3098, USA

(Received 16 August 1993; revision received 20 December

1993; accepted

Oregon Health Sciences University,

20 December

1993)

Abstract Type III hyperlipoproteinemia (dysbetalipoproteinemia) is characterized by elevated concentrations of plasma cholesterol and triglycerides due to an increase in very low density lipoprotein (VLDL) remnant lipoproteins. In a retrospective analysis we observed that in 12 patients with this disorder, gemfibrozil reduced concentrations of total cholesterol, VLDL cholesterol and triglycerides by 48%, 72% and 68X, respectively. These changes were greater than those reported in a similar number of patients treated with clofibrate. Comparative data on the efficacy of different fibrates in this disorder are very limited; to assess this further we have compared the hypolipidemic effects of gemfibrozil (600 mg twice daily) and clofibrate (1 g twice daily) in six patients with well-characterized type III hyperlipoproteinemia. Baseline values were obtained after at least 8 weeks on diet and treatment values were obtained after 6 and 8 weeks of treatment with each drug. Treatment with clofibrate and gemlibrozil both resulted in significant reductions in the plasma concentrations of total cholesterol (40% and 54%), VLDL cholesterol (59% and 79%) and total triglycerides (48% and 70%), as well as a significant increase in HDL cholesterol (9% and 7%). Gemtibrozil was, however, significantly (P < 0.05) more effective in reducing plasma concentrations of total cholesterol, VLDL choles-

terol and triglycerides

than was clofibrate,

Key words: Gemfibrozil;

Clotibrate; tein; Low density lipoprotein

in the same patients.

Hypolipidemic

agents; Type III hyperlipoproteinemia;

1. Introduction

Type III hyperlipoproteinemia (dysbetalipoproteinemia) is characterized by elevated concentra* Corresponding author. tpresent address: Department of Cardiology Amtssygehus, Tage-Hansens Gade 2, DK-5000 Denmark.

A, Aarhus Odense C,

tions of plasma cholesterol and triglycerides due to an increase in very low density lipoprotein (VLDL) remnant lipoproteins; most patients are homozygous for apolipoprotein E2 [l]. Although uncommon, patients with this disorder are at substantially increased risk for the premature development of both coronary and peripheral vascular disease and frequently develop characteristic palmar and tuberous xanthomas which regress in

C@2t-9150/94/%07.00 @ 1994 Elsevier Science Ireland Ltd. All rights reserved. SSDI 002 I-9 150(94)05204-V

Very low density lipopro-

236

M. L. Larsen

response to effective hypolipidemic therapy [ 1,2]. Fibrate drugs are extremely effective in the therapy of those patients with type III hyperlipoproteinemia who remain significantly hyperlipidemic following the correction of secondary factors and maximal dietary therapy [2]. However, data on the comparative efficacy of different fibrates in this disorder are limited to a single report which included 4 patients [3]. In a retrospective analysis we have observed that gemlibrozil reduced plasma concentrations of total cholesterol, VLDL-cholesterol and triglycerides more than seen in a similar number of patients with type III hyperlipoproteinemia treated with clofibrate; this conclusion is also supported by data from previously published but noncomparative studies [4-B]. In the present report we have directly compared the hypolipidemic effects of gemfibrozil and clofibrate in 6 adult patients with well-characterized type III hyperlipoproteinemia.

et al. /Atherosclerosis

106 (1994)

235-240

A retrospective analysis to assess the efficacy of gemlibrozil in the treatment of type III hyperlipidemia was performed in 12 patients with this disorder who had been treated with gemtibrozil (Lopid@ >at a dose of 600 mg twice daily. Baseline values for calculation of eflicacy used two measurements from a steady state period after at least 8 weeks on a low fat (< 30% calories), low cholesterol (< 300 mgday) diet alone. The treatment values on gemfibrozil were calculated as the mean of two separate values obtained after 4-6 and B-10 weeks of treatment with gemfibrozil. Dietary stability was assessed by verbal discussion with a dietitian but was not quantitatively evaluated. The patients consisted of 7 men and 5 women with a mean age of 53 years (range 32-70 years). The diagnosis of type III hyperlipidemia was based on the presence of cholesterol-enriched VLDL particles in plasma (a VLDL cholesterol/total plasma triglycerides ratio greater than 0.30); all patients were homozygous for apolipoprotein E2.

2. Methods

The effects of gemlibrozil and clolibrate were compared directly in 6 patients with type III hyperlipoproteinemia; all of these patients were included in the larger group of 12 patients studied in the retrospective analysis of response to gemlibrozil alone (Table 1). The patients were all homozygous for apolipoprotein E2 and had normal tests of thyroid, renal, and hepatic function; one had well-controlled non-insulin dependent

2.1. Patients The patients included in this study were all adults who had been referred to the Lipid Disorders Clinic at Oregon Health Sciences University for evaluation and treatment of combined hyperlipidemia. With the exception of type II diabetes (2 patients) no secondary causes of hyperlipidemia were present.

Table 1 Characteristics of the 6 patients with type III hyperlipidemia Patient no.

I 2 3 4 5

6

Age (years)/sex

40/M 63/F 67/F 46/M 44/M 41/M

BMI

27.1 30.4 29.6 23.0 30.6 24.5

Palmar/ tendon xanthomas

CAD

PVD

Lipoprotein cholesterol concentration (mg/dU

Plasma TmGp/do

Total

VLDL

LDL

HDL

477 379 411

215 180 260

205 92 93

53 31 42

355 532 753

+I+/+/-

+ + +

+

-l-

-

-

380

186

145

29

634

-l-

-

-

490 478

350 268

120 172

48 52

712 825

-l-

BMI, body mass index (kg/m*); CAD, coronary artery disease; HDL, high density lipoproteins; LDL, low density lipoproteins; PVD, peripheral vascular disease; TG, triglycerides; VLDL, very low density lipoproteins.

M.L. Larsen et al. /Atherosclerosis

231

106 (1994) 235-240

diabetes and the others all had normal fasting blood glucose values. Prior to drug therapy all patients were given dietary counseling and were habituated to a low fat, low cholesterol diet [9]. The patients were seen on an outpatient basis in the Lipid Disorders Clinic and Clinical Research Center at Oregon Health Sciences University. Baseline lipid and lipoprotein determinations were obtained after at least 8 weeks on diet alone and mean values were based on two separate measurements obtained over a 4 week interval. Treatment values were also calculated as the mean of two measurements obtained after 6 and 8 weeks of treatment with gemfibrozil (Lopid@), 600 mg twice daily, or clolibrate (Atromid So), 1 g twice daily. Dietary compliance was assessed by verbal questions; body weights remained stable. The patients were treated with either clofibrate or gemlibrozil for the first of these two periods without any wash out between treatments; the assignment of initial treatment was random but we did not use a specific randomization code. Patients 1, 5 and 6 received gemtibrozil first whereas patients 2, 3 and 4 were initially treated with clotibrate. The study was not blinded to either the patients or the investigators. 2.2. Assay methods Blood samples for lipid and lipoprotein analysis were obtained in tubes containing 1 mg/ml EDTA (final concentration), and the plasma was separated at 4°C. Total concentrations of plasma cholesterol and triglycerides were determined by

Table 2 The hypolipidemic

effects of gemfibrozil Plasma

in 12 patients

lipoprotein

enzymatic calorimetric methods using an Abbott VP autoanalyzer (Abbott Laboratories, Abbott Park, IL), and lipoproteins were separated by preparative ultracentrifugation and precipitation techniques [ 10,111. Lipid determinations were standardized with samples of known composition obtained from the Centers for Disease Control, Atlanta, GA. Apolipoprotein E phenotypes were determined using a modification of the slab gel isoelectric focusing method of Assmann et al. [ 121 as previously described from our laboratory [6]. All the statistical comparisons were performed using paired t-tests and the normality of the data sets was tested by the Kolmogorov-Smirnov test (with Lilliefor’s correction). 3. Results The effects of gemtibrozil on plasma lipids and lipoproteins in 12 patients with type III hyperlipidemia are given in Table 2. A significant decrease (P < 0.001) was observed in the concentrations of total cholesterol (-47%) (P < O.OOl), VLDL-cholesterol (-73%) (P < 0.005), and triglycerides (-67%) (P < 0.001) together with a signiticant rise (P < 0.005) in HDL-cholesterol concentrations (+ 16%). Six patients were treated sequentially with both gemfibrozil (600 mg twice daily) and clofibrate (1 g twice daily). In comparison with diet alone, treatment with either gemtibrozil or clotibrate significantly reduced serum concentrations of total cholesterol, VLDL-cholesterol and triglycerides

with type III hyperlipoproteinemia

cholesterol

concentration

(mgidl)

Plasma

TG

(mgdl)

Diet (baseline) Diet plus gemfibrozil

Total

VLDL

LDL

HDL

384 f 78 201 f 46+

206 * 65 57 f 24**

118 f 41 100 f 26

45 f 51 f

14 14**

627 f 176 203 f 57*

Results are the mean f SD. of two separate determinations on diet alone and then during treatment with gemfibrozil at a dose of 600 mg twice daily. HDL, high density lipoprotein; LDL, low density lipoprotein; TG, triglycerides. VLDL, very low density lipoprotein. ?? P < 0.001 vs. baseline

values,

**P < 0.005 (repeated

measures

f-test).

M.L. Larsen et al. /Atherosclerosis

238

Table 3 Comparative

effects of gemfibrozil Plasma

A. Baseline B. Clotibrate C. Gemfibrozil

Statistical A vs. B A vs. C B vs. C

significance

and clotibrate lipoprotein

in patients

cholesterol

106 (1994) 235-240

with type III hyperlipidemia

concentration

(mgdl)

Plasma TG (mgdl)

T-CHOL

VLDL

LDL

HDL

435 f 52 262 * 35 (-40%) 199 Zk 37 (-54%)

243 f 64 99 f 39 (-59%) 52* 11 (-79%)

138 f 45 I21 f I5 (-12%) 107 ?? 22 (-22%)

43 f II 47* II (+9%) 46* II (+7%)

635 f 170 341 f I25 (-48%) 189 f 45 (-70%)

<0.05 <0.05 N.S.


of differences
as measured

N.S., non-significant, T-CHOL, total cholesterol; tage change is indicated in parentheses.

by a repeated
measures

other abbreviations

(P < 0.01). These changes were accompanied by a rise in HDL-cholesterol (P < 0.05); no significant changes were seen in the concentrations of LDLcholesterol. When compared in the same patients (Table 3), gemfibrozil was significantly (P < 0.05) more effective than clofibrate in reducing plasma concentrations of total cholesterol, VLDL-cholester01 and triglycerides; individual patient data for the last two parameters are shown in Fig. 1.

t-test N.S. N.S. N.S.

as in Tables 1 and 2. Results are the mean f S.D. The percen-

4. Discussion

Our study confirms previous reports on the efficacy of gemlibrozil and clofibrate in the treatment of adult patients with type III hyperlipidemia (Table 4), but provides new comparative data on the relative efficacy of these two drugs in this disorder.

A

VLDL-

500r

cholesterol

(me/dl) 400

triglycerides

I

(w/dl) 800 I 600 t

gemfibrozil

clafibrate

diet

Treatment

Fig. 1. Changes

sequential

therapy

Treatment

phase

in the concentrations of VLDL cholesterol during

clofibrate

diet

with clotibrate

(A) and plasma triglycerides

(B) in 6 patients

(1 g twice daily) and gemtibrozil

gemfibrazil

phase

with type III hyperlipidemia

(600 mg twice daily).

M. L. Larsen et al. /Atherosclerosis Table 4 Literature

reports on the hypolipidemic

Lipid or Lipoprotein

Percentage

239

106 (1994) 235-240

change

effects of gemtibrozil

and cloftbrate

with type III hyperlipidemia

with drug treatment

Gemlibrozil” (n = 12)

Gemlibrozil (n = 8)

T-CHOL VLDL-CHOL

-48X* -72x**

-4&S* -46’S**

LDL-CHOL HDL-CHOL TG

- 15% +13’S** -68%*

-4 I “/;I* + 54”/“’* -65%~~

b

GemlibrozilC (n= 13)

Clofibrated (n = 12)

Clofibratee (n = 7)

Clolibrate’ (n = 26)

-4o’%,*

-4o%*** -61”/;,***

-II”/;, -5I”/u**

-1% +31’%*** -52X***

-6% +24%** -4o”/;,**

-28%** -51x** 0% +12”/1** -4&**

+45x* -70%’

Gemlibrozil was given at a dose of 600 mg twice daily and clolibrate “Present study; bRef. 4; ‘Ref. 5: dRef. 6; eRef. 7; ‘Ref. 8. *P < 0.001; **p <

in patients

at a dose of I g twice daily. Abbreviations

as in Tables

1-3.

0.005; ***p < 0.01.

In contrast to the greater efficacy of the secondgeneration fibrates (bezafibrate, fenofibrate and ciprofibrate) as compared with clolibrate or gemIibrozil to reduce concentrations of LDL-cholester01 in patients with combined hyperlipidemia, all of the fibrate drugs have been felt to be equally effective in the treatment of patients with type III hyperlipidemia (2,13,14). At the present time, however, we are aware of only one study in which a direct comparison of different librate drugs in the treatment of patients with type III hyperlipidemia has been reported [3]. In this study the eflicacy of clolibrate (1.0 g twice daily) and gemfibrozil (600 mg twice daily) were compared in 4 patients with type III hyperlipidemia, only 2 of whom had the apo E2iE2 phenotype. Both treatments resulted in a significant change in the plasma concentrations of total cholesterol, HDLcholesterol and total triglycerides, whereas the observed reduction in mean VLDL-cholesterol did not reach statistical significance; no changes in LDL-cholesterol were observed. The slightly larger percentage reduction in plasma triglycerides with gemfibrozil (-56%) than with clofibrate (-44%) was not statistically significant. Subjects with the apo E2iE2 phenotype seemed to have a better response to drug treatment than subjects with other apolipoprotein E phenotypes, but the number of patients studied was small. Nonetheless, this conclusion is in agreement with recent findings by Zhao et al. [ 151, who suggested that the marked interindividual variability in serum choles-

terol and triglyceride concentrations observed in patients with type III hyperlipidemia is mainly due to variations in the concentrations of VLDLl and VLDL2, and that in most patients with type III hyperlipidemia the clinical expression of this disorder requires the combined presence of homozygosity for apolipoprotein E2 and an inherent increase in VLDL production. The precise cellular mechanism(s) responsible for the hypolipidemic effects of Iibrate drugs have not been fully clarified, but include: activation of lipoprotein lipase, suppression of free fatty acid release from adipose tissue, inhibition of hepatic triglyceride synthesis, and increased secretion of cholesterol into bile. We propose that the greater hypolipidemic effects of gemlibrozil as compared with clolibrate found in the present study may be attributable to a greater inhibition of VLDL triglyceride synthesis by gemfibrozil. In support of this, Kesaniemi and Grundy [16] examined VLDL triglyceride kinetics in hypertriglyceridemic patients during treatment with gemfibrozil and documented that this drug decreased the synthesis of VLDL triglycerides and concurrently increased the rate of VLDL catabolism. In contrast, therapy with clolibrate did not significantly reduce the rate of synthesis of VLDL triglycerides, but such treatment was associated with an increase in the rate of catabolism of VLDL particles. These results indicate that gemfibrozil reduces triglyceride synthesis more effectively than does clotibrate, but that both drugs enhance the rate of catabolism of

240

hf. L. Larsen et al. / Aiherosclerosis 106 (1994) 235-240

triglyceride-rich lipoproteins. In addition to their influence on triglyceride metabolism, librates have also been reported to influence the synthesis and excretion of cholesterol. Clofibrate has been shown to reduce the activity of hepatic 3-hydroxy3-methylglutaryl coenzyme A (HMG CoA) reductase [ 171,whereas an increase in hepatic sterol biosynthesis has been observed in rats treated with gemlibrozil 1181. Whether this difference is attributable to different mechanisms of action of these two drugs on cholesterol metabolism remains unclear. In conclusion, patients with type III hyperlipoproteinemia exhibit a marked interindividual variability in plasma cholesterol and triglyceride concentrations; this variability also extends to their response to therapy and makes it difficult to assess the comparative efficacy of different treatments in this disorder. In a direct comparison of gemlibrozil and clolibrate in the treatment of six patients with type III hyperlipoproteinemia, we confirmed the well-known efficacy of these two drugs, but found that gemfibrozil was more effective in reducing plasma concentrations of total cholesterol, VLDL-cholesterol and triglycerides.

Dodge, H.T. Treatment of type III hyperlipoproteinemia with gemfibrozil to retard progression of coronary artery disease, Am. Heart J., 6 (1988) 85. Houlston, R., Quiney, J., Watts, G.F. and Lewis, B. Gemfibrozil in the treatment of resistant familial hypercholesterolemia and type III hyperlipoproteinemia, J. R. Sot. Med., 81 (1988) 274. Illingworth, D.R. and O’Malley, J.P. The hypolipidemic effects of lovastatin and clolibrate alone and in combination in patients with type III hyperlipoproteinemia, Metabolism, 39 (1990) 403. Hoogwerf, B.J., Peters, J.R., Frantz, I.D., Jr. and Hunninghake, D.B. Effect of clolibrate and colestipol singly and in combination on plasma lipids and lipoproteins in type III hyperlipoproteinemia, Metabolism, 34 (1985) 978. Brewer, H.B., Jr., Zech, L.A., Gregg, R.E., Schwartz, D. and Schaefer, E.J., Type III hyperlipoproteinemia: diagnosis, molecular defects, pathology, and treatment, Ann. Intern. Med., 98 (1983) 623. National Cholesterol Education Program, Report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults, Arch. Intern. Med., 148 (1988) 36. Lipid Research Clinics Program, Manual of Laboratory Operations, Lipids and Lipoprotein Analysis, DHEW Publication (NIH) 75-628, 1974, pp. l-74. Friedwald, W.T., Levy, R.I. and Fredrickson, D.S., Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge, Clin. Chem., 18 (1972) 499. Assmann, G., Schmidt, G., Menzel, H.G. et al., Apolipoprotein E polymorphism and hyperlipidemia, Clin. Chem., 30 (1984) 641. Fruchart, J.C., Davignon, J., Bard, J.M., Grothe, A.M., Richard, A. and Fievet, C. Effect of fenolibrate treatment on type III hyperlipoproteinemia, Am. J. Med., 83, Suppl. 5B (1987) 71. Klosiewicz-Latoszek, L., Nowicka, G., Szostak, W.B. and Naruszewicz, M., Influence of bezatibrate and colestipol on LDL cholesterol, LDL apolipoprotein B and HDL cholesterol in hyperlipoproteinemia, Atherosclerosis, 63 (1987) 203. Zhao, S.-P., Smelt, A.H.M., Leuven, J.A.G., van den Maagdenberg, A.M.J.M., van der Laarse, A. and van’t Hooft, F., Lipoproteins in familial dysbetalipoproteinemia, Arteriosclerosis Thromb., I3 (1993) 3 16. Kesaniemi, Y.A. and Grundy, SM., Influence of gemfibrozil and clotibrate on the metabolism of cholesterol and plasma triglycerides in man, J. Am. Med. Assoc., 251 (1984) 2241. Berndt, J., Gaumert, R. and Still, J., Mode of action of lipid lowering agents clotibrate and BM15075 on cholesterol biosynthesis in rat liver, Atherosclerosis, 30 (1978) 147. Maxwell, R.E., Nawrocki, J.W. and Uhlendorf, P.D., Some comparative effects of gemlibrozil, clotibrate, bezalibrate, cholestyramine and compactin on sterol metabolism in rats, Atherosclerosis, 48 (1983) 195.

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II

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5. Acknowledgements We are grateful to the patients involved in this study for their interest, time commitment and cooperation and to Paula Bisaccio for preparation of the manuscript. This work was supported in part by the General Clinical Research Centers Program (RR334), National Institutes of Health and by a grant from the Danish Heart Foundation.

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6. References Mahley, R.W. and Rail, S.C., Jr., Type III hyperlipoproteinemia. In: The Metabolic Basis of Inherited Disease, 6th Edn., McGraw-Hill Book Co., New York, 1989, pp. 1195-1214. Illingworth, D.R., Fibric acid derivatives. In: Rifkind, B.M. (Ed.), Drug Treatment of Hyperlipidemia, Marcel Dekker, Inc., New York, 1991, pp. 103-138. Hoogwerf, B.J., Bantle, J.P., Kuba, K., Fran@ I.D., Jr., and Hunninghake, D.B., Treatment of type III hyperlipoproteinemia with four different treatment regimens, Atherosclerosis, 51 (1984) 251. Kuo, P.T., Wilson, A.C., Kostis, J.B., Moreyra, A.B. and

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