Gemfibrozil in Type Ila and FH

Table 4

19

Effect of duration of gemfibrozil treatment on plasma cholesterol concentration (mmol/l

***p<0·05, 0·025 and 0·01 respectively compared to the values obtained after 8 weeks of treatment with gemfibrozil (1200 mg/day) by paired comparison.

intake of 0.8 and 1·6g, and the values obtained at these two dosage levels were virtually identical. The lack of effect of daily intake of 1.2 g should probably not therefore be ascribed to an inadequate dose, but rather be taken as an indication that 8 weeks of treatment is too short a period, regardless of dose, to obtain substantial effects on plasma cholesterol levels.

Three patients out of 20 showed no decrease in LDL-cholesterol, and three others showed no increase in HDL-cholesterol.

The effects on cholesterol levels observed in the patients with familial hypercholesterolaemia were similar, and possibly greater, than those observed in the entire group (Table 2). The average maximum decrease in LDL-cholesterol was about 11 per cent, and the increase in HDL-cholesterol was 28 per cent, compared to placebo values. The corresponding decrease in average LDL-C/HDL-C ratio was about 32 per cent, from 7.15 to 4.90.

Table 3 shows that gemfibrozil treatment reduced total triglyceride levels, as well as those of the various lipoprotein fractions. In contrast to its effects on cholesterol, 1.2 g of gemfibrozil a day was as efficient in lowering the triglyceride values as were the other two dose levels. LDL-triglycerides were the least sensitive to treatment, and in the patients with familial hypercholesterolaemia this effect never achieved statistical significance.

The relation of treatment duration to cholesterol effects, regardless of dose levels, is shown in Table 4. It is apparent, both in the total group and in the subgroup with familial hypercholesterolaemia, that there was a continuing drop in LDL-cholesterol throughout the entire treatment period, although the major portion of that reduction occurred during the initial 16 weeks of treatment. Such a finding suggests that this relatively short-term study may not have been of sufficient duration to reveal maximal achievable reductions in LDL-cholesterol levels.

No serious adverse effects were observed. Two patients experienced weight gain and acne, problems they had encountered previously and which may have been drugrelated. One complained of loss of hair, and another had more frequent bowel movements than usual. There was no evidence of drug toxicity in haematological, urinary or biochemical parameters.

20

Discussion

H. Meinertz

The generally accepted treatment of primary Type IIa hyperlipoproteinaemia is an LDLlowering diet, supplemented by drugs when necessary. The most effective medications are the bile-acid sequestering resins and nicotinic acid (Levi 1980) separately, or, more particularly when combined (Kane et al. 1981). Since many patients find the resins unpalable in long-term use and nicotinic acid preparations often have severe cutaneous and gastric side-effects, there is a need for other, less troublesome drugs.

Gemfibrozil appears to have a number of advantages over currently available alternative preparations. Although the immediate effect on LDL-cholesterol is limited to about a 10 per cent reduction, longer term studies, in agreement with the trends presented here, have shown that LDL-cholesterol in Type IIa patients is lowered by about 25 per cent (Samuel 1983). In addition, gemfibrozil produces a substantial increase in HDL-cholesterol, due mainly to an increase in the HDL2 sub-fraction (Manninen 1983). Although the benefit of an increase in HDL and particularly HDL2 is unproven, current opinion considers therapy for lipoprotein disturbances that increases HDL-cholesterol to be superior to those treatments that lower it. Two other drugs, probucol and neomycin sulphate, produce effects on LDL-cholesterol similar to those obtained with gemfibrozil, but both lower HDL-cholesterol substantially (Mellies et al. 1980, Kesäniemi and Grundy 1984a). The effects of clofibrate on LDL and HDL in Type II hyperlipoproteinaemia are generally not pronounced, and, except for an occasional individual who responds extraordinarily well, this drug is not usually recommended for treatment of Type II patients. It must be borne in mind, however, that although gemfibrozil in long-term treatment has favourable effects on both LDL and HDL in Type II hyperlipoproteinaemia, no study thus far published has proven its efficacy in preventing ischaemic heart disease, nor demonstrated its long-term safety.

While the mechanism determining the triglyceride-lowering effect of gemfibrozil is understood to some extent, there is no certainty about how the drug affects LDL and HDL levels. Gemfibrozil both lowers production and increases clearance of VLDL (Kesäniemi and Grundy 1984b). The reduction of plasma triglycerides and VLDL may in part explain the increase in HDL-cholesterol through the inverse relationship between VLDL-triglyceride and HDL-cholesterol due to the lipid exchange proteins in plasma. But since gemfibrozil also increases the major protein component of HDL, apo A-I (Børresen et al. 1981), additional mechanisms must be involved. The lowering of LDL may also, in part, be due to reduced VLDL production, since VLDL is a precursor of LDL. But since LDL reduction is a much slower process than the reduction of VLDL, gemfibrozil probably lowers LDL by other mechanisms as well. Gemfibrozil does not increase total faecal steroid excretion (Kesäniemi and Grundy 1984b). It may however reduce cholesterol synthesis, as its chemical analogue clofibrate appears to do (Grundy et al. 1972). If that is the case, then gemfibrozil may increase hepatic LDL-receptor activity and thereby contribute to the lowering of plasma LDL levels.

Acknowledgments

This work was supported by the Danish Heart Foundation. Thanks are due to Ms Irma Stannius for expert technical assistance and to Ms Hanne Merete Olsen for help in preparation of the tables. I appreciate the assistance I have received from Ms J. Garcia Perez and Dr D. P. Evans of Warner-Lambert/Parke-Davis.

Gemfibrozil in Type Ila and FH

References

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Abell, L. L., Levy, B. B., Brodie, B. B. and Kendall, F. E. (1952). A simplified method for the estimation of total cholesterol in serum and demonstration of its specificity. Journal of Biological Chemistry 195, 357–366.

Børresen, A. L., Berg, K., Dahlen, G., Gillnäs, T. and Ericson, C. (1981). The effect of gemfibrozil on human serum lipoproteins and on serum reserve binding

capacity (SRCBC). Artery 9, 77-86.

Burstein, M. and Samaille, J. (1960). Sur un dosage rapide du cholesterol lié aux a- et aux B-lipoproteins du sérum. Clinica Chimica Acta 5, 609.

Goldstein, J. L. (1983). In: The Metabolic Basis of Inherited Disease (Ed J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. L. Goldstein and M. S. Brown) pp. 672-712. New York.

Grundy, G. M., Ahrens, E. J. Jr., Salen, G., Schreibman, P. H. and Nestel, P. J. (1972). Mechanisms of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia. Journal of Lipid Research 13, 531-535.

Holme, I. (1982). On the separation of the intervention effects of diet and antismoking advice on the incidence of major coronary events in coronary high risk men. The Oslo Study. Journal of the Oslo City Hospital 32, 31–54.

Kane, J. P., Malloy, M. J., Tun, P., Phillips, N. R., Freedman, D. D., Williams, M. L., Rowe, J. S. and Havel, R. J. (1981). Normalization of low density lipoprotein

levels in heterozygous familial hypercholesterolaemia with a combined drug regimen. New England Journal of Medicine 304, 251-256.

Kesäniemi, Y. A. and Grundy, S. M. (1984a). Turnover of low density lipoproteins during inhibition of cholesterol absorption by neomycin. Arteriosclerosis 4, 41-48. Kesäniemi, Y. A. and Grundy, S. M. (1984b). Influence of gemfibrozil and clofibrate on metabolism of cholesterol and plasma triglycerides in man. Journal of the American Medical Association 251, 2241-2246.

Levi, R. I. (1980). In: The Pharmacological Basis of Therapeutics. (Eds A. G. Gilman, L. S. Goodman and A. Gilman) pp. 834-844. McMillan, New York.

Lipid Research Clinics Program (1984). The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationship of reduction in incidence of

coronary heart disease to cholesterol lowering. Journal of the American Medical Association 251, 365-374.

Manninen, V. (1983). Clinical results with gemfibrozil and the background to the Helsinki Heart Study. American Journal of Cardiology 52, 35A-38A.

Mellies, M. J., Gartside, P. S., Glatfelter, L., Vink, P., Guy, G., Schonfeld, G. and Gleuck, C. J. (1980). Effect of probucol on plasma cholesterol, high and low density lipoprotein cholesterol, and apo-lipoproteins A1 and A2 in adults with primary familial hypercholesterolaemia. Metabolism 29, 956–964. National Institutes of Health (1973). US Department of Health, Education and Welfare Publication No. 73-110. National Institutes of Health, Bethesda, Maryland, USA.

Samuel, P. (1983). Effects of gemfibrozil on serum lipids. American Journal of Medicine 74 (5A) 23-27.

Soloni, F. G. (1971). Simplified manual micro method for determination of serum triglycerides. Clinical Chemistry 17, 529-534.

Gemfibrozil increases HDL-cholesterol and apolipoprotein A-I and A-II concentrations in dyslipidaemic subjects

SIRKKA KAUKOLA, VESA MANNINEN, CHRISTIAN EHNHOLM and MARJATTA MÄLKÖNEN

First Department of Medicine, University of Helsinki, Wihuri Research Institute and Public Health Institute, Helsinki, Finland

Summary

A single-blind, placebo-controlled study involving 17 dyslipidaemic male subjects examined the effects of gemfibrozil on serum lipid and lipoprotein patterns. Serum total cholesterol and triglyceride levels decreased, whereas high density lipoprotein (HDL)-cholesterol and the ratio of HDL/total cholesterol increased significantly. There was also a significant increase in apolipoprotein A-I and A-II concentrations but the ratio of apoprotein A-I/A-II remained unchanged. Cholesterol transfer by HDL particles was increased by gemfibrozil, as shown by an increase in the ratio of HDL-cholesterol to apoproteins A-I and A-II. These results indicate that gemfibrozil alters the lipoprotein profile of dyslipidaemic subjects in a way which, according to current concepts, may reduce the appearance or progression of atherosclerotic vascular disease.

Lipid-lowering diets and drugs which decrease LDL-cholesterol have both been used in an attempt to prevent the development of arterial disease, but neither has proved to be completely successful. Several recent epidemiological and clinical studies have demonstrated that low levels of HDL-cholesterol may be as important as high LDLcholesterol concentrations in the development of atherosclerosis (Rhoads et al. 1976, Gordon et al. 1977, Miller et al. 1977). Raised serum triglycerides may also be of significance in this respect (Carlson 1960, Carlson and Böttiger 1972, Kaukola et al. 1980). Gemfibrozil has been shown to increase HDL-cholesterol significantly

Further Progress with Gemfibrozil, edited by C. Wood, 1986: Royal Society of Medicine Services International Congress and Symposium Series No. 87, published by Royal Society of Medicine Services Limited.

24

S. Kaukola et al.

and also to decrease both serum LDL-cholesterol and triglyceride levels (Hodges 1976, Dahlen et al. 1980, Kaukola et al. 1981). These observations have been extended in the present study of dyslipidaemic young men.

Subjects and methods

Seventeen male volunteers aged 36 to 50 years (mean ± SD: 43.6±3.9) were divided into lipoprotein phenotypes according to the World Health Organization (1970) classification. Six individuals were of Type IIa, nine of Type IIb and two of Type IV. Secondary dyslipidaemias due to other disorders, or to alcohol excess were excluded. Fasting blood glucose levels were normal in all subjects. Nine had coronary heart disease, and two in addition had arterial hypertension. Beta-blocking agents were used by six of them.

The study was a single-blind, placebo-controlled design. An initial 3-month placebo period was followed by 4 months of treatment with gemfibrozil. Thereafter, placebo was again given for 2 months and finally gemfibrozil for 6 months. Gemfibrozil (2,2 dimethyl-5(2,5 xylyloxy)-valeric acid, supplied by Parke Davis & Co., Pontypool, Gwent, UK) was administered at a dose of 600 mg twice daily. Matching placebo capsules were given in a corresponding way. The subjects were instructed to maintain their usual dietary habits.

Blood samples were collected after an overnight fast. Lipid assays were performed on fresh serum. The ferric chloride method of Badzio and Boczon (1966) was used to measure cholesterol. Triglycerides were determined as described by Fletcher (1968) and HDL-cholesterol by the PEG-6000 method (Viikari 1976). Apolipoproteins A-I and A-II determinations were performed on serum stored at -20 °C in plastic tubes using the radial immunodiffusion method (Huttunen et al. 1979).

Results

The mean body weight of subjects was 78.2±10.7 kg at the start and 78.6 ± 10.1 kg at the end of the study.

Serum lipid and lipoprotein changes observed during the 15 months of this study are shown in Table 1. HDL-cholesterol increased, while total cholesterol and triglycerides decreased significantly (p<0·001) during gemfibrozil treatment. The ratio of HDL-cholesterol/total cholesterol also showed a significant increase (p<0·001). The effect of gemfibrozil was noted within 1 month of the beginning of treatment. Thereafter it was sustained during management, though the changes were somewhat smaller during the second gemfibrozil period. The drug effect disappeared completely 2 months after its discontinuation. Neither the correlation between changes in HDLcholesterol and serum triglycerides (r = −0·14) nor that between changes in HDLcholesterol and serum total cholesterol (r = −0·17) were statistically significant. Apoliproprotein A-I and A-II levels both increased significantly (p<0·001) during gemfibrozil treatment. The effect of gemfibrozil on these parameters was also observed after 1 month of treatment. During the second placebo period, apo A-I remained at the level reached during gemfibrozil treatment, while apo A-II decreased, but not to the level observed before drug treatment. Apoprotein A-I and A-II concentrations were greatest during the second gemfibrozil period. The ratio of apolipoprotein A-I/A-II did not change significantly during the study. Values were 3.6 before and 3·7 after treatment.