Figure 1. The relation between HDL-cholesterol and apoprotein A-l concentrations in 17 subjects during the first placebo period (r= +0·71, p<0.01) and after gemfibrozil treatment for 4 months (r= +0·85, p<0·001). = before gemfibrozil, = after gemfibrozil. A symbol in parentheses indicates the corresponding regression line.

Figure 2. The relation between HDL-cholesterol and apoprotein A-Il concentrations in 17 subjects during the first placebo period (r = +0.42, NS) and after gemfibrozil treatment for 4 months (r = +0·83, p<0·001). ○ = before gemfibrozil, = after gemfibrozil. A symbol in parentheses indicates the corresponding regression line.

Gemfibrozil, HDL and apolipoproteins

27

HDL-cholesterol concentration was correlated with the apoprotein A-I level both before and after gemfibrozil treatment (Fig. 1). The correlation between HDLcholesterol and apoprotein A-II was not significant before, but was significant after gemfibrozil (p<0·001; Fig. 2) falling to +0.59 (p<0·05) 2 months after withdrawal of the drug. The ratio of HDL-cholesterol to both apoproteins A-I and A-II increased significantly during gemfibrozil treatment. The former rose from 30.4±5.8 (mean ± SD) to 32·5±5·5 (p<0·05); the latter from 55.7±13·8 to 61·1 ± 11·4 (p<0.001), indicating an increased transport of cholesterol by HDL.

Discussion

The serum lipid changes observed during gemfibrozil treatment in this study are similar to previous findings (Rhoads et al. 1976, Gordon et al. 1977, Miller et al. 1977). The significant increase in HDL-cholesterol and the marked decrease observed in serum total cholesterol and triglyceride levels, are generally believed to protect against the appearance or progression of ischaemic heart disease. In addition, the ratio of HDLcholesterol/total cholesterol increased from 15 per cent to 20 per cent, which may be even more important than individual changes in HDL and LDL concentrations with regard to prevention (Robinson et al. 1979).

The increase in HDL-cholesterol was especially prominent throughout the study, whereas total cholesterol and triglyceride levels showed more fluctuation during gemfibrozil treatment. However, this may reflect a seasonal variation in LDL- and VLDL-cholesterol levels (Paloheimo 1961, Bortz 1974), because the initial gemfibrozil period occurred during the summer, whilst the second period of administration took place in the winter.

The mechanism by which gemfibrozil alters serum lipid and lipoprotein patterns has not been fully established. There is some evidence that the drug may reduce hepatic triglyceride synthesis (Kissebah et al. 1976) but this seems unlikely in the light of what is known about VLDL metabolism and the changes in lipoprotein pattern caused by gemfibrozil. On the other hand, there are data to suggest that gemfibrozil stimulates lipoprotein lipase activity which is able to raise HDL by increasing the rate of VLDLtriglyceride removal (Nikkilä et al. 1976). Increased catabolism of VLDL is generally considered to lead to the elevation of HDL-cholesterol levels (Nikkilä 1978). However, some subjects may respond to gemfibrozil, but not to clofibrate, which is also known to increase lipoprotein lipase activity.

Previous findings indicate that gemfibrozil increases HDL-cholesterol more effectively than does clofibrate (Nash 1980, Nye et al. 1980). In this study, changes observed in HDL-cholesterol and triglyceride concentrations were unrelated, although they showed, respectively, a significant increase and decrease during gemfibrozil treatment. Thus, increased catabolism of VLDL seems unlikely to account exclusively for the rise of HDL-cholesterol. Nor does it seem likely that gemfibrozil is an inducer of liver enzymes which are able to increase HDL-cholesterol, because it has not been found to elevate y-glutamyl transferase activity (Miller et al. 1977).

In this study, gemfibrozil significantly raised the concentrations of both apoprotein A-I and A-II, the major protein components of HDL, while the ratio apo A-I/A-II remained unchanged. Previous studies have shown that coronary patients have low apoprotein A-I and A-II levels (Albers et al. 1978, Ishikawa et al. 1978, Avogaro et al. 1979). These observations therefore suggest that, in addition to the elevation of HDL-cholesterol, gemfibrozil may lower the risk of coronary heart disease by increasing both A-apoproteins. They also indicate that gemfibrozil facilitates the

28

S. Kaukola et al.

transfer of cholesterol by HDL, as shown by the increase in the HDLcholesterol/apoprotein A-I ratio and by the greater correlation observed between HDL-cholesterol and apoprotein A-I during drug treatment.

A low HDL-cholesterol/apoprotein A-I ratio has previously been found in association with an increased risk of coronary heart disease (Albers et al. 1976). In addition, the HDL-cholesterol/apoprotein A-II ratio has also been reported to be low in patients whose coronary heart disease was confirmed by angiography but who showed no difference in HDL-cholesterol/apoprotein A-I ratio from levels measured in healthy controls (Kladetzky et al. 1980). Gemfibrozil significantly increased this ratio and the correlation between HDL-cholesterol and apoprotein A-II, suggesting a further possible benefit for this drug in the prevention of coronary disease. The changes observed in apoprotein A-I and A-II concentrations may also relate to changes in HDL2 and HDL3 subfractions, and an investigation of these components is now in progress. Consideration of the way in which it alters serum lipid and lipoprotein patterns allows gemfibrozil to be classified as an anti-atherogenic agent. However only long-term studies will determine its value in preventing atherosclerotic vascular disease.

Acknowledgment

This study was supported in part by a grant from the Sigrid Jusélius Foundation.

References

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Albers, J. J., Cheung, M. C. and Hazzard, W. R. (1978). High-density lipoproteins in myocardial infarction survivors. Metabolism 27, 479–485.

Avogaro, P., Bittolo, Bon, G., Cazzolato, G. and Quinci, G. B. (1979). Are apolipoproteins better discriminators than lipids for atherosclerosis? Lancet 1 901-903. Badzio, T. and Boczon, H. (1966). The determination of free and esterified cholesterol in blood after separation by thin-layer chromatography. Clinica Chimica Acta 13, 794-797.

Bortz, W. M. (1974). The pathogenesis of hypercholesterolemia. Annals of Internal Medicine 80, 738-746.

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Carlson, L. A. and Böttiger, L. E. (1972). Ischaemic heart disease in relation to fasting value of plasma triglycerides and cholesterol. Lancet 1, 865-868. Dahlen, G., Gillnäs, T., Børresen, A-L, Berg, K. and Ericson, C. (1980). Effect of gemfibrozil on serum lipid levels. Artery 7, 224-231.

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Gordon, T., Castelli, W. P., Hjortland, M. C., Kannel, W. B. and Dawber, T. R. (1977). High density lipoprotein as a prospective factor against coronary heart disease. The Framingham Study. American Journal of Medicine 62, 707-714. Hodges, R. M. (1976). Gemfibrozil: a new lipid lowering agent. Proceedings of the Royal Society of Medicine 69 (Suppl. 2), 1-2.

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Huttunen, J. K., Länsimies, E., Voutilainen, E., Ehnholm, C. Hietanen, E., Penttilä, I., Siitonen, O. and Rauramaa, R. (1979). Effect of moderate physical exercise

on serum lipoproteins. A controlled clinical trial with special reference to serum high-density lipoproteins. Circulation 60, 1220-1229.

Ishikawa, T., Fidge, N., Thelle, D. S., Førde, O. H. and Miller, N. E. (1978). The Tromsø Heart Study: serum apolipoprotein A-I concentration in relation to future coronary heart disease. European Journal of Clinical Investigation 8, 179-182.

Kaukola, S., Manninen, V. and Halonen, P. I. (1980). Serum lipids with special reference to HDL cholesterol and triglycerides in young male survivors of acute myocardial infarction. Acta Medica Scandinavica 208, 41-43.

Kaukola, S., Manninen, V., Mälkönen, M. and Ehnholm, C. (1981). Gemfibrozil in the treatment of dyslipidaemias in middle-aged male survivors of myocardial infarction. Acta Medica Scandinavica 209, 69–73.

Kissebah, A. H., Adams, P. A. and Wynn, V. (1976). Lipokinetic studies with gemfibrozil (CI-719). Proceedings of the Royal Society of Medicine 69 (Suppl. 2), 94–97. Kladetzky, R. G., Assmann, G., Walgenbach, S., Tauchert, P. and Helb, H. D. (1980). Lipoprotein and apoprotein values in coronary angiography patients. Artery 7, 191-205.

Konttinen, A., Kuisma, I., Ralli, R., Pohjola, S. and Ojala, K. (1979). The effect of gemfibrozil on serum lipids in diabetic patients. Annals of Clinical Research 11, 240–245. Miller, N. E., Førde, O. H., Thelle, D. S. and Mjøs, O. D. (1977). The Tromsø Heart Study. High-density lipoprotein and coronary heart-disease: a prospective casecontrol study. Lancet 1, 965-967.

Nash, D. T. (1980). Gemfibrozil-a new lipid lowering agent. Journal of Medicine 11, 107–116. Nikkilä, E. A. (1978). Metabolic regulation of plasma high density lipoprotein concentrations. European Journal of Clinical Investigation 8, 111-113.

Nikkilä, E. A., Ylikahri, R. and Huttunen, J. K. (1976). Gemfibrozil: effect on serum lipids, lipoproteins, postheparin plasma lipase activities and glucose tolerance in primary hypertriglyceridaemia. Proceedings of the Royal Society of Medicine 69 (Suppl. 2), 58-63.

Nye, E. R., Sutherland, W. H. F. and Temple, W. A. (1980). The treatment of hyperlipoproteinaemia with gemfibrozil compared with placebo and clofibrate. New Zealand Medical Journal 92, 345–349.

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Augmentation of gemfibrozil-induced hypolipidaemia by psyllium-based fibre

BÖRJE EK, MARJATTA MÄLKÖNEN and VESA MANNINEN

Department of Medicine, University of Umeå, Sweden and First Department of Medicine, University of Helsinki, Finland

Summary

This study assesses the efficacy of gemfibrozil and psyllium-based fibre as lipid modulating agents when given either alone or in combination to Type II dyslipidaemic subjects. In agreement with previous findings, both agents decreased total and LDLcholesterol values. Gemfibrozil also increased HDL-cholesterol, whereas fibre was without any noticeable effect. During the concurrent administration of both agents, lipid lowering efficacy was potentiated. LDL-cholesterol decreased by 12.5 per cent on gemfibrozil, 9.6 per cent on fibre and 29.1 per cent when both were given in combination. Combination therapy slightly attenuated the effect of gemfibrozil on HDL-cholesterol. Such combination therapy is therefore warranted in the management of dyslipidaemic patients with a poor response to a single agent or in those at high risk because of exceptionally high LDL-cholesterol values.

It is well established that high serum levels of low density lipoprotein (LDL)-cholesterol and low levels of high density lipoprotein (HDL)-cholesterol are associated with an increased risk of coronary heart disease (CHD). What has been lacking is any clearcut demonstration that correction of dyslipoproteinaemia will reduce the risk of CHD. Recently the Lipid Research Clinics Program (LRCP) showed that reduction of LDLcholesterol by 12.6 per cent during cholestyramine treatment resulted in a 19 per cent decline in CHD deaths or non-fatal myocardial infarctions during a 7-year followup period (Lipid Research Clinics Program, 1984, Levy et al. 1984). The results seem to indicate that anti-dyslipidaemic therapy is beneficial. However, the LRCP study was hampered because of poor compliance with the intake of cholestyramine, a subsequent high drop-out rate and a lower (12.6 per cent) than anticipated (24 per cent) decline in serum LDL-cholesterol.

Cholestyramine acts mainly by hindering reabsorption of bile acids. Several reports have indicated that fibre products have lipid-lowering effects exerted by similar

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.