Effects of gemfibrozil on plasma lipoproteins, plasma activities of hepatic enzymes, and hemostatic variables in hypertriglyceridemic patients

CURRENT THERAPEUTIC RESEARCH® VOL.56, NO. 6, JUNE 1995 E F F E C T S OF GEMFIBROZIL ON PLASMA LTPOPROTEINS, PLASMA ACTIVITIES OF HEPATIC ENZYMES, AND HEMOSTATIC VARIABLES IN HYPERTRIGLYCERIDEMIC P A T I E N T S FRANCIS ROBERT HEI,I,ER, 1'2 ALEXPARFONRY,t OLIVIERDESCA.MPS, 1'2 JEAN-PIERRE DESAGER,8 AND CARLHARVENGTs 1Groupe d'Etude du M~tabolisme Tumoral, 2Service de Medecine Interne, HOpital de Jolimont, Haine St. Paul, and 3Laboratoire de Pharmacotherapls, Universit~ Catholique de Louvain, Brussels, Belgium

ABSTRACT In 15 patients with hypertriglyceridemia defined as plasma trigiyceride (TG) concentration >250 mg/dL--gemfibrozi1600 mg given twice daily for 4 months significantly reduced the mean plasma concentration of total cholesterol (TC) (-15%) and TG (-61%). In the lowdensity lipoprotein (LDL) fraction, the TC concentration was un. changed but the TG concentration was decreased. As the apoprotein B concentration also decreased, it is likely that the LDL particles were not only enriched with TC but also reduced in number. The increase in high-density lipoprotein cholesterol (HDL-C) was accounted for by an increase in the TC content of HDL3. Most of these changes can be considered beneficial in terms of protection against atherosclerosis. The plasma activities of lecithin-cholesterol acyltransferase and hepatic lipase were not changed significantly by the drug, while that of lipoprotein lipase increased significantly (44.1%, P < 0.05). Thus the mechanism of action of gemfibrozil appears to mainly involve an increased catabolism of TG-rich lipoproteins, although the correlations between lipoprotein lipaso and lipoprotein concentrations were only marginally significant. As significant correlations were found between hepatic lipase and HDL-C, gemfibrozil appears to also have some impact on hepatic lipase. Finally, gemfibrozil did not change the activity of the fibrinolytic system, while the fibrinogen concentration and the platelet count increased. The significance of the latter changes is unclear. INTRODUCTION Gemfibrozil, a fibric acid derivative, lowers plasma total cholesterol (TC) and triglycerides (TG) and significantly reduces t he incidence of coronary h e a r t disease in dyslipidemic middle-aged men. 1 In normolipidemic subjects, t h e effects of gemfibrozil on plasma lipids are believed to be seconda r y to a reduction in t he production of very-low-density lipoprotein (VLDL) Address correspondenceto: F. R. Heller,Grouped'Etudedu M6tabolismeTumoral,H0pitalde Jolimont, 7100-HaineSt. Paul, Belgium. Received~orpubtication on February16,1995. Printed in the U.S.A. Reproductionin wholeor part is not permitted. 597

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GEMFIBROZIL IN HYPERTRIGLYCERIDEMIC PATIENTS

associated with enhancement of the activity of both lipoprotein lipase and hepatic lipase.2 Moreover, hypercoagulability and reduced fibrinolytic activity risk factors for coronary heart disease are well established and are associated with hypertriglyceridemia.3'4 The aim of the present open-label study was to evaluate the effects of gemfibrozil on plasma lipids and the post-heparin lipolytic activity of lipoprotein lipase and hepatic lipase in hypertriglyceridemic patients. The effects of gemfibrozil on hemostatic variables associated with hypertriglyceridemia were also examined. PATIENTS AND METHODS

Patients Blood samples were obtained from 15 patients (7 w o m e n and 8 men, mean - S D age 55 -+ 14 years) with hypertriglyceridemia (TG > 250 mg/dL). Hypertriglyceridemia associated with hypercholesterolemia (TC > 250 mg/dL) was found in 13 patients, and hypertriglyceridemia alone was found in the other two patients. All patients adhered to a low-fat, lowcholesterol diet for at least 5 weeks before starting gemfibrozil, and none were taking hypolipidemic drugs. Most patients were obese, with a body mass index of 29.4 -+ 3.2 kg/m 2 (extreme values, 25.2 and 39.0 kg/m2). Non-insulin-dependent diabetes mellitus was present in two patients and was treated by the use of diet in one and by the use of diet and metformin in the other. Their diabetes was well equilibrated (glycated hemoglobin A1c level less than 6.5%). Eight patients had arterial hypertension and two patients had cerebrovascular diseases. Five patients were treated with beta-blockers (atenolol in 3, pindolol in 1, bisoprolol in 1), 1 patient with nifedipine, and 1 with enalapril. All drugs were maintained at the same dosages throughout the study. One patient was a cigarette smoker. None of the patients reportedly drank more than 15 g/d of alcohol. The patients received 600 m g gemfibrozil twice daily for 4 months. All patients provided informed consent before participating in the study.

Effectiveness and Safety Parameters Samples of venous blood were collected before and at 2 and 4 months of gemfibrozil treatment after a 12-hour fast.T C and T G were measured by using an automated enzymatic method (Boehringer-Mannheim, Mannheim, Germany). High-density lipoprotein cholesterol (HDL-C) concentration was determined after sodium phosphotungstate/magnesium chloride precipitation. 5 Density gradient ultracentrifugation was performed 598

F. R. HELLER ET AL.

according to the method described by Chapman et al e to isolate VLDL, low-density lipoprotein (LDL), HDL2, and H D L 3 in an L 8-70 M ultracentrifuge using an SW4i rotor (Beckman Instruments, Inc., Palo Alto, California), and TC and TG were then measured in each fraction. Plasma apoproteins (apo) A-I, A-II, and B were measured via laser immunonephelometry using polyclonal antibodies. Plasma lipoprotein(a) (Lp[a]) levels were determined using a commercial kit (TintElizeTM, Biopool, Umea, Sweden). Lipoprotein lipase and hepatic lipase activities were assayed according to the Nillsson-Ehle and Ekman method in post-heparin venous plasma taken 10 minutes after injection of heparin 100 IV/kg. 7 Lecithincholesterol acyltransferase activity expressed as the fractional esterification rate (LCAT-FER) was determined by using a radioenzymatic method, s The following hemostatic variables were measured: plasma fibrinogen (Fibrinomat, Biomerieux, Marcy L'Etoile, France), plasminogen (Chremostrate plasminogen assay, Organon-Teknika, Boxtel, Holland), tissue activator of plasminogen (tPA; Asserachrom tPA, Diagnostica Stago, Asniere, France), inhibitor of tPA (PAI; Coatest PAI, Chromogenix, M61ndal, Sweden), and platelet count. To monitor patient health, the following were also determined by using routine clinical laboratory methods: sedimentation rate, complete blood counts, serum creatinine, creatine kinase, aminotransferases, gamma-glutamyltransferase, and alkaline phosphatase.

Statistical Analysis The paired Student's t test was used only to compare the values of the laboratory findings before and after 2 and 4 months of gemfibrozil treatment. A linear regression model was used to determine correlation coefficients for the association of lipoprotein lipase and hepatic lipase activities, on one hand, and lipid and lipoprotein concentrations, on the other. RESULTS

Lipids and Lipoproteins Compared with pretreatment values, a significant decrease in plasma TG was observed at 2 months ( - 63.1%, P < 0.001) and 4 months ( - 60.9%, P < 0.001) and of TC at 2 ( - 17.3%, P < 0.01) and 4 months ( - 14.6%, P 0.05) (Table I). Apo B levels decreased with gemfibrozil at 2 ( - 26.4%, P 0.001) and 4 months (-27.4%, P < 0.001). Lp(a) levels did not change significantly. HDL-C was higher at 2 (34.3%, P < 0.01) and 4 months (26.3%, P < 0.01). Plasma apo A-I levels remained almost unchanged, while plasma apo A-H levels increased at 2 (17.4%, P ~ 0.001) and 4 months (12.2%, P ~ 0.05). 599

GEMFIBROZIL IN HYPERTRIGLYCERIDEMIC PATIENTS

Table I. Plasma lipids and apoprotein concentrations (mean -+ SD) before and after treatment with gendibrozil 600 mg twice daily in 15 hypertriglyceridemic patients. Pretreatment Total cholesterol (mg/dL) Triglyceddes (mg/dL) HDL cholesterol (mg/dL) Lp(a) (mg/dL) Apo A-I (mg/dL) Apo A-II (mg/dL) Apo B (mg/dL)

331 413 31 21 147 40 213

-+ 91 -+ 200 -+ 9 -+ 23 -+ 25 -+ 7 -+ 52

2 Months

4 Months

263 139 39 28 149 48 152

269 148 37 19 144 44 147

-+ 48* -+ 59¢ -+ 11" -+ 37 -+ 27 -+ 9~: + 32$

-+ 42t -+ 67 -+ 10 -+ 20 -+ 21 ÷ 6t -~ 45~;

HDL = high-density lipoprotein; Lp(a) = lipoprotein(a); apo = apoprotein. * P < 0.01 versus pretreatment. I P < 0.05 versus pretreatment. P < 0.001 versus prstrestment.

P l a s m a lipoprotein c o n s t i t u e n t s a n a l y z e d a f t e r u l t r a c e n t r i f u g a t i o n w e r e m e a s u r e d before a n d a f t e r 4 m o n t h s of gemfibrozil t r e a t m e n t (Table II). In t h e V L D L fraction, TC a n d T G d e c r e a s e d ( - 36.2%, P < 0.01, a n d - 55.9%, P < 0.001, respectively). In t h e L D L fraction, TC did not c h a n g e significantly b u t T G d e c r e a s e d ( - 36.1%, P < 0.001). In t h e HDL2 fraction, t h e T G c o n c e n t r a t i o n was lower w i t h gemfibrozil ( - 4 3 . 3 % , P < 0.001), w h i l e t h e TC c o n t e n t was not s u b s t a n t i a l l y modified. In t h e HDL3 fraction,

Table II. Plasma cholesterol and triglyceride concentrations in lipoprotein fractions and activities of lipolytic enzymes (mean -+ SD) before and after treatment with gemfibrozil 600 mg twice daily in 15 hypertriglyceridemic patients. Pretreatment VLDL Total cholesterol (mg/dL) LTriglycerides (mg/dL) Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL2 Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL3 Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL3-cholesterol:HDL~-cholesterol HDL~-trtglyceddes:HD~-triglycerides Lecithin-cholesterol acy]transferaseactivity (%/h) Lipoprotein lipcse activity (mU/mL) Hepatic lipase activity (mU/mL)

4 Months

107 -+ 58 257 -+ 153

57 -+ 18" 102 -+ 56t

110 -+ 47 26 -+ 7

119 -+ 31 16 -+ 6t

13-+5 7_+2

12-+4 4_+2t

18-+4 13 ± 5 1.56 -+ 0.55 1.91 -+ 0.40 7.4 -+ 1.5 201 -+ 108 527 -+ 220

22-+5 * 9 -+ 4* 1.90 -+ 0.55¢ 3.00 -+ 1.84¢ 7.5 -+ 1.2 268 -+ 113~:§ 550 -+ 231§

VLDL = very-low-density lipoprotein; LDL = low-density lipoprotein; HDL = high-density lipoprotein. * P < 0.01 versus pretreatment. i P < 0.001 versus pretreatment. P < 0.05 versus pretreatment. Analysisperformed in 14 patients. In one patient, lipoprotein lipase and hepatic lipase activities could not e obtained.

600

F. R. HELI,RR ] ~ AL.

the concentration of TC increased (27.7%, P < 0.01), while that of TG decreased ( - 25.5%, P < 0.01). The ratio of HDL3-C:HDL2-C increased by 29% (P < 0.05) and that of HDL3-TG/HDL2-TG increased by 60% (P <

0.05). Plasma LCAT-FER, lipoprotein lipase, and hepatic lipase activities were measured before and after 4 months of gemfibrezil treatment, except in one patient in whom the lipoprotein lipase and hepatic lipase activities could not be obtained during treatment. No significant change was observed in LCAT-FER activity. Lipoprotein lipase activity increased significantly with gemfibrozil (44.1%, P < 0.05), while hepatic lipase activity was not significantly changed. A marginally significant (P = 0.06) correlation was found between changes in lipoprotein lipase activity and changes in the TC (r = -.453) and TG (r = -.475) contents of VLDL. Significant correlations were found between individual changes in hepatic lipase activity, on one hand, and individual changes in HDL2-C (r = - .57, P < 0.05) and the I-IDL3-C:HDL2-C ratio (r = .53, P < 0.05), on the ether.

Hemostatic Variables Serum fibrinogen levels increased significantly at 2 months (56.9%, P < 0.01) and at 4 months (53.4%, P < 0.05) (Table HI). No significant changes were seen in plasminogen, tPA, or PAI. Platelet counts increased at 2 and 4 months (15.4%, P < 0.001, and 19.4%, P < 0.001, respectively).

Safety Parameters A significant increase in the sedimentation rate was observed at 2 and 4 months (85.4%, P < 0.05, and 36.7%, P < 0.05, respectively) (Table IV). A small but significant decrease in hemoglobin levels ( - 4.9%, P < 0.01) TableM. Hemostaticvariables(mean-+SD)beforeand aftertreatmentwith gemfibrozi1600 mg twice daily in hypertriglyceridemicpatients. Numberof patients analyzedis given in parentheses.* Prelxeatment

Fibrinogen (mg/dL) Plasminogen (%) Tissue plasminogen activator (ng/mL) Inhibitor of tissue plasminogen activator (AU/mL) Platelets (/nL)

125 -+ 22

2 Months

120 _ 27

13 -+ 5 (14) 254 _+ 66

12 __ 7

131 -+ 15 (15)

288 _+ 68§

i ln somepatients, the blood sample volume was not sufficient for measurement. P < 0.01versus pretreatment. P < 0.05 versus baseline. P < 0.001 versus baseline. 601

4 Months

12 -+ 5 297 -+ 80~

(15)

GEMFIBROZIL IN HYPERTRIGLYCERIDEMICPATIENTS

Table IV. Safety parameters (mean +- SD) before and after treatment with gemfibrozil600 mg twice dally in hypertriglyceridemicpatients. Number of patients analyzed is given in parentheses.* Pretreatment

Sedimentation rata (mm/h)

15 _ 13

(15)

Hemoglobin(g/&)

13.8 _ 1.0

(15)

Hematocrtt(%) Red blood cells (/nL) White blood cells (/nL) Glucose (mg/dL) Creattnine (mg/dL) Total bilirubin (mg/dL) Creatine kinase (mU/dL) Aspartate aminotrsnsfersse (mU/mL) . Alanine aminotransTerase (mU/mL) Alkaline phosphatase(mU/mL) Gamma-glutamyltransferase (mU/mL)

42_+3 (15) 4613 _+ 345 (15) 5332 _ 1217 (15) 99 _+ 11 (15) 1.1 -- 0.3 (15) 0.6 -+ 0,2 (13) 117 ÷ 72 (14)

2 Months

4 Months

22 - 171" (15) 13.3 - 1.0

(15)

4 0 - + 3 5 (15) 4535 _+ 329 (15) 4888 _+ 1297 (15) 103 -+ 11 (15) 1.2 _+ 0.2 (14) 0.5 -+ 0.2 (15) 147 _+ 104 (15)

19 __ 141" (15) 13.2 - 1.45 (15)

39_+~ 4699 _+ 5191 -7 99 -+ 13 1.1 +- 0.2 0.5 -+ 0.2 126 +_ 111

Iiil (15) (15) (15) (14)

22 +- 6

(15)

24 -+ 10

(15)

21 -+ 10

(15)

25-+ 11 91 -+ 19

II~l

26-14 89 -+ 17

11551

24-+ 11 89 +- 19

I~l

42 _+ 34

(14)

27 -+ 141" (13)

24 -+ 155 (15)

* In some patienta, the blood sample volume was not sufficient for measurement.

1"P < 0.05 versus pretreatment.

:[: P < 0.01 versus pretreatment.

was observed at 4 months and in hematecrit at 2 and 4 months ( -4.5%, P < 0.01 and -6.3%, P < 0.01, respectively). No significant change was observed in serum creatinine, glucose, aminotransferases, alkaline phosphatase, or creatine kinase. Serum g-mma-glutamyltransferase activities were significantly decreased at 2 ( - 18%, P < 0.05) and 4 months ( - 17.3%, P < 0.01). There was no significant change in body weight, and no abnormal signs or symptoms were reported. DISCUSSION Gemfibrozil at a dose of 600 mg twice daily significantly reduced the plasma concentrations of TC ( - 15%) and TG ( - 61%) in hypertriglyceridemic patients. The approximately 30% increase in HDL-C concentration was explained by an increase in the HDL3-C concentration. Previous studies 9-12 have shown t h a t gemfibrozil affects HDLs-C r a t h e r t h a n HDL2-C in dyslipidemic patients. The apo A-H concentration increased, however, and t h a t increase was associated with minor ch-nges in apo A-I. Similar findings have been reported by Kahri et al,11 Miller et al,12 and Zhao et al.13 Although the H L D 2 and LpA-I particles are thought to be protective factors against atherosclerosis, a recent study 14 indicates t h a t the HDLs-C concentration m a y be the most potent inverse predictor of myocardial infarction. In the St. Thomas's Atherosclerosis Regression Study, 15 the positive correlations found between changes in coronary luminal dimensions and HDL3-C concentration in patients receiving hypolipidemic therapy was of borderline significance (P = 0.066). In the latter study, no correla602

F. R. HELLER ET AL.

tion was found with HDL2-C concentration. On the other hand, in vitro studies have shown that HDL3, rather than HDL2, le and LpA-II, like LpA-I and LpA-I/LpA-H,17 are effective promoters of cholesterol effiux from bovine heart mitochondrial membranes and from fbroblasts and aortic endothelial cells. The increase in the HDL-C concentration with gemfibrozil has recently been attributed to the lowering effect of this drug on the transfer of esterified cholesterol from HDL to VLDL and LDL. is In the LDL fraction, the TC concentration remained unchanged; this is the usual finding in hypertriglyceridemic patients treated with fibrates and gemfibrozil. In such patients, LDL-C levels are usually low before treatment and rise slightly with hypolipidemic drugs. 12'13 As the apo B concentration is decreased by gemfibrozil, it is likely that the number of LDL particles is reduced. Therefore, compared with the pretreatment state, the LDL particles appear to be less numerous but are relatively enriched with TC and depleted in TG. This change in lipid composition is usually associated with an increaseof the apparent size of LDL. 13 Because TG-rich, small LDL particles are associated with a high risk of coronary heart disease, 19 the changes in LDL observed during gemfibrozil treatment can be considered benefcial. As with other fibrates, 2° lipoprotein lipase activity is increased by gemfibrozil; this increased activity was demonstrated in normolipidemic subjects 2 and may explain the decrease in VLDL concentration. However, in the present study, the coefficient correlation between these two parameters was found to be only marginally significant. Moreover, in a recent study, 21 no increase in the adipose tissue and muscle LPL activity was seen in hypertriglyceridemicpatients treated with gemfibrozil for 6 weeks. The authors concluded that gemfibrozil predominantly decreases hepatic VLDL secretion. Hepatic lipase activity has been found to be increased by gemfibrozil in normolipidemic s u b j e c t s 2'22 and in patients with n o n - i n s u l i n dependent diabetes mellitus. 11 Gemfibrozil is the only available fibrate that has this effect. 20 In the present study, hepatic lipase was not significantly changed by gemfibrozil. Nevertheless, a significant correlation was found between individual changes in hepatic lipase and individual changes in the TC concentrations in HDL 2 and in HDL3, suggesting that the drug may influence this lipolytic activity. From this perspective, it is noteworthy that we found an increase in the apo A-II concentration. It has been suggested that apo A-II is an activator for hepatic lipase. 23 A significant increase in fibrinogen levels and sedimentation rate was found during gemfibrozil treatment. The changes in fibrinogen levels with gemfibrozil have been found to vary greatly from one study to another: they were unchanged in two studies, 24'25 decreased by 10%, 26 marginally increased, 27 ol, significantly increased by 5.3%2s and by 19%.29 The increase in platelet counts seen in the present study were also noted in three 603

GEMFIBROZILIN HYPERTRIGLYCERIDEMICPATIENTS

We have no explanation for these findings; however, it has been suggested that the increase in fibrinogen and platelets may reflect a reduction in consumption as thrombi generation is decreased by gemfibrozil therapy. 2s In vitro, gemfibrozil decreases the secretion of PAL1 by a human hepatoma cell line, Hep G2 .32 Gemfibrozil was not found to have an effect on PAI in the present study. Concerning safety parameters, we were unable to explain the slight decrease in the hemoglobin concentrations and hematocrit. There was no evidence of blood loss in the patients treated with gemfibrozil. Gammaglutamyltransferase activities were decreased by gemfibrozil, another unexplained but well-known effect of f i b r a t e s . 33 p r e v i o u s s t u d i e s . 2s'30'31

CONCLUSION

In conclusion, in hypertriglyceridemic patients gemfibrozil induced changes in lipoprotein concentration and composition that can be considered beneficial in terms of protection against atherosclerosis. HDL-C, mainly HDL3, concentration is increased, the LDL particles are decreased in number and depleted in TG, and the VLDL particles are greatly decreased in number and depleted in TC and TG. These changes can be partially explained by an increase in lipoprotein lipase activity. Although hepatic lipase activity was not changed by the drug, the significant association found during treatment between hepatic lipase and the cholesterol content of HDL suggests that gemfibrozil affects lipolytic activity. Fibrinolytic activity was not changed but the fibrinogen concentration and platelet count increased; the significance of these findings is unknown.

Acknowledgments This work was supported by grants from Parke-Davis, Division of Warner Lambert, Brussels, Belgium, and La R6gion Wallonne, Brussels, Belgium. W e wish to thank Miss C. Vandenplas, Mr. M. Abrassart, and Mr. J. C. Hondekijn for their technical assistance, and Miss G. Luna and Miss S. De Beer for typing the manuscript. References:

1. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors and incidence of coronary heart disease. NEJM. 1987;317:1237-1245. 2. Horsmans Y, Desager JP, Harvengt C. Effects of gemfibrozil on the activities of plasma lipolytic enzymes in normolipidemic subjects. Clin Chim Acta. 1993;218:223-228. 3. Andersen P, Arnesen H, Hjermann I. Hyperlipoproteinemia and reduced fibrinolytic activity in healthy coronary high-risk men. Acta Med Scand. 1981;209:199-202. 604

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4. Simpson HCR, Meade TW, Stifling Y, et al. Hypertriglycoridemia and hypercoagulability. Lancet. 1983;1:786-790. 5. Lopes-Virella MF, Stone M, Ellis S, Colwell JA. Cholesterol determination in high density lipoproteins separated by three different methods. Clin Chem. 1977;23:882-884. 6. Chapman MJ, Goldstein S, Lagrange D, Laplaud PM. A density gradient ultracontrifugation procedure for the isolation of the major lipoprotein classes from human serum. J Lipid Res. 1981;22:339-357. 7. Nilsson-Ehle P, Ekman R. Rapid, simple and specific assays for lipoprotein lipaas and hepatic lipase. Artery. 1977;3:194-209. 8. Dobiasova M. Lecithin:cholesterol acyltransferase and the regulation of endogenous cholesterol transport. Adv Lipid Res. 1983;20:107-194.

9. Sorisky A, Ooi TC, Simo IE, et al. Change in composition of high-density lipoprotein during gemfibrozil therapy. Atherosclerosis. 1987;67:181-189. 10. Mantari M, Koskinen P, Manninen V, et al. Effect of gemfibrezil on the concentration and composition of serum lipoproteins. Atherosclerosis. 1990;81:11-17. 11. Kahri J, Vuorinen-Markkola H, Tilly-Kiesi M, et al. Effect of gemfibrozil on high density lipoprotein subspecies in non-insulin dependent diabetes mellitus. Relations to lipolytic enzymes and to the cholesteryl ester transfer protein activity. Atherosclerosis. 1993;102: 79-89. 12. Miller M, Bacherik PS, McCrindle BW, Kwiterovich PO. Effect of gemfibrozil in men with primary isolated low high-density lipoprotein chelesterel: A randomized, doubleblind, placebo-controlled, crossover study. Am J Med. 1993;94:7-12. 13. Zhao S-P, Smelt AHM, Leuven JAG, et al. Changes of lipoprotein profile in f-milial dysbetalipoproteinemia with gemfibrozil. A m J Med. 1994;96:49-56. 14. Stampfer MJ, Sacks FM, Salvini S, et al. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. NEJM. 1991;325:373-382. 15. Watts GF, Mandalia S, Brunt JNH, et al. Independent associations between plasma lipoprotein subfraction levels and the course of coronary artery disease in the St. Themas's Atherosclerosis Regression Study (STARS). Metabolism. 1993;42:1461-1467. 16. Castro Cabezas M, Van Hensden GPH, De Bruin TWA, et al. Reverse cholesterol transport: Relationship between free cholesterol uptake and HDL8 in normolipidaemic and hyperlipidaemic subjects. Eur J Clin Invest. 1993;23:122-129. 17. Oikawa S, Mendez AJ, Oram JF, et al. Effects of high-density lipoprotein particles contAinirtg apo A-I, with or without apo A-II, on intracollular cholesterol effiux. Biochim Biophys Acta Lipids Lipid Metab. 1993;1165:327-334. 18. Ponsin G, Girardot G, Berthezene F. Mechanism of the gemfibrozfl-induced decrease in the transfer of cholesterol esters from high density lipopreteins to very low and low density lipoproteins. Biochem Med Metab Biol. 1994;52:58-64. 19. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype: A proposed genetic marker for coronary heart disease risk. Circulation. 1990;82:495-506. 20. Heller F, Harvengt C. Effects of clofibrate, bezafibrate, fenofibrate and probucol on plasma lipolytic enzymes in normolipaemic subjects. Eur J Clin Pharmacol. 1983;25:5763. 605

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21. Simsolo RB, Ong JM, Kern PA. Effect of gemfibrozil on adipose tissue and muscle lipoprotein lipase. Metabolism. 1993;42:1486-1491. 22. Gnasso A, Lehner B, Haberbosh W, et al. Effect of gemfibrozil on lipids, apoproteins and postheparin lipolytic activities in normolipidemic subjects. Metabolism. 1986;35:387393. 23. Jahn CE, Osborne JC, Schaefer EJ, Brewer HB. Activation of the enzymatic activity of hepatic lipase by apolipoprotein A-l'[. Characterization of a major component of high density lipoprotein as the activating plasma component in vitro. Eur J Biochem. 1983; 131:25-28. 24. O'Brien J, Etherington MD, Shuttleworth RD, et al. A pilot study of the effect of gemfibrozil on some haemostatic parameters. Thromb Res. 1982;26:275-279. 25. Laustiola K, Lassila R, Pellinen P, et al. Gemfibrozil decreases platelet reactivity in patients with hypercholesterolemia during physical stress. Clin Pharmacol Ther. 1988; 43:302-307. 26. Ciufetti G, Orecchini G, Siepi D, et al. Hemorrheological activity of gemfibrezil in primary hyperlipidemias. In: Paoletti R, Fumagalli R, Kritchevskr D, et al, eds. Drugs Affecting Lipid Metabolism. Berlin: Springer-Verlag; 1987:372-375. 27. Andersen P, Smith P, Seljeflot I, et al. Effects of gemfibrozil on lipids and haemostnsis after myocardial infarction. Thromb Haemostasis. 1990;63:174-177. 28. Wilkes HC, Meade TW, Barzegar S, et al. Gemfibrozil reduces plasma prothrombin fragment F1 + 2 concentration, a marker of coagulability, in patients with coronary heart disease. Thromb Haemostasis. 1992;67:503-506. 29. Branchi A, Rovellini A, Sommariva D, et al. Effect of three fibrate derivatives and of two HMG-CoA reductaso inhibitors on plasma fibrinogen level in patients with primary hypercholesterolemia. Thromb Haemostasis. 1993;70:241-243. 30. SchwartzkopffW, Menzel B, Stern K, KempfKU. Gemfibrozil bei patienten mit primaren hyperlipoproteinamien. Therapiewoche. 1985;35:1388-1398. 31. Stringer MD, Steadman CA, Kakkar VV. Gemfibrezil in hyperlipidaemic patients with peripheral arterial disease: Some undiscovered actions. Curr Med Res Opin. 1990;12: 207-214. 32. Fujii S, Burton ES. Direct effects of gemfibrezil on the fibrinolytic system. Diminution of synthesis of plasminogen activator inhibiter type 1. Circulation. 1992;85:1888-1893. 33. Sirtori CR, Franceschini G. Effects of fibrates on serum lipids and atheroscleresis. Pharmacol Ther. 1988;37:167-191.

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