Figure 1. Relationship (r = 0.86; p<0.001) between changes of LDL-cholesterol and skeletal muscle lipoprotein lipase activity (mU/g) after cessation of gemfibrozil treatment.

Table 3

Blood glucose concentration, intravenous (i.v.) glucose tolerance and serum insulin concentration before and after i.v. glucose injection, during gemfibrozil treatment and following gemfibrozil termination (mean ± SEM; n = 16)

=

KIVGTT fractional removal rate (K) during the i.v. glucose tolerance test Insulin index = peak serum insulin (mean of determinations at 4 and 6 min) divided by the fasting insulin concentration

Effects on plasma lipid ester fatty acid composition

There were no major changes in plasma lipid ester fatty acid composition after termination of gemfibrozil treatment (Table 2). There were slight but significant increases of the relative content of di-homo-y linolenic acid (20:3 w-6) in cholesterol

Gemfibrozil lipoproteins and fatty acids

7

esters and phospholipids. In the latter fraction there was also a reduction of the mean content of arachidonic acid (20:4 w-6) while docosa-penta-enoic acid (22:5 w-3) increased slightly. Some additional minor changes were also seen in plasma triglycerides.

Effects on blood glucose, glucose tolerance and serum insulin concentrations

There were no significant changes in fasting blood glucose concentrations or in intravenous glucose tolerance after termination of gemfibrozil treatment (Table 3), nor were there any significant changes in serum insulin concentrations during fasting or after an intravenous glucose load.

Discussion

The effects of termination of gemfibrozil treatment on lipoprotein and glucose metabolism were studied in 17 patients who had been on long-term treatment with gemfibrozil. As expected, there were rather pronounced effects on the serum lipoprotein lipid and apolipoprotein concentrations (Table 1). The changes recorded are in accordance with earlier findings, showing reductions of triglyceride concentrations and increased HDL-cholesterol concentrations during gemfibrozil treatment (Nikkilä et al. 1976, Olsson et al. 1976, Vessby et al. 1976). Changes in serum apolipoprotein concentrations were also as expected (Børresen et al. 1981, Kaukola et al. 1981, Vessby and Lithell 1983) with a more pronounced increase in apo A-II than in apo A-I during treatment. This is compatible with a more pronounced effect of gemfibrozil on HDL, than on HDL2.

With regard to the mechanisms behind the triglyceride reduction, studies by Kesäniemi and Grundy (1984) have indicated that gemfibrozil both decreases the production of VLDL triglyceride and enhances its clearance. Nikkilä et al. (1976) reported an increased post-heparin lipoprotein lipase activity, as well as hepatic lipase activity, during treatment with gemfibrozil. The increased post-heparin lipoprotein lipase activity is compatible with the present finding of an increased fractional catabolic rate following the IVFTT.

The reductions in lipoprotein lipase activity in adipose tissue (significant in females) and in skeletal muscle (significant in males) may explain earlier findings of an increase in post-heparin lipoprotein lipase activity and contribute to the increased fractional removal rate during IVFTT. Thus, the present study supports the hypothesis that at least part of the triglyceride lowering effect by gemfibrozil is due to an enhanced triglyceride clearance. In an earlier study (Vessby et al. 1976) we could not demonstrate any significant increase of adipose tissue lipoprotein lipase activity during gemfibrozil treatment. However, among the 28 patients studied at that time, there were only a few women. It is possible that gemfibrozil in males mainly affects lipoprotein lipase activity in skeletal muscle, as does clofibrate (Lithell et al. 1978) and bezafibrate (Vessby et al. 1982).

The positive relationship between changes in skeletal muscle lipoprotein lipase on the one hand and those of LDL-cholesterol (Fig. 1) and the serum apo B concentration on the other, is compatible with the assumption of a key role for skeletal muscle

8

B Vessby et al.

lipoprotein lipase in the conversion of VLDL to LDL. When the lipase activity increases there is more rapid VLDL triglyceride hydrolysis, which may result in a more rapid conversion of VLDL to LDL and thus to an increasing LDL-cholesterol and serum apolipoprotein B concentration. Positive relationships between the changes in skeletal muscle lipoprotein lipase and LDL-cholesterol concentration have also been observed in obese patients with Type 2 diabetes during body weight reduction (Vessby and Lithell, in press).

An additional question addressed in the present study was whether gemfibrozil significantly affects the plasma lipid ester fatty acid compositions. Two other derivatives of fibric acid, clofibrate (Vessby et al. 1980a,b) and bezafibrate (Vessby et al. 1980a,b), have both been shown to change the plasma lipid fatty acid composition, mainly by an increase in mono-unsaturated fatty acids with a concomitant and significant decrease in the content of linoleate. However, after terminating gemfibrozil treatment, only very slight changes were seen in the plasma lipid ester fatty acid composition (Table 2). In particular, there was no fall in the content of linoleic acid and no increase in mono-unsaturated fatty acids as would be expected if gemfibrozil affected the fatty acid composition. It can therefore be concluded that differences exist between gemfibrozil and clofibrate or bezafibrate with regard to possible influences on plasma fatty acid composition though the mechanisms involved, as well as the significance of these changes, are at present obscure.

Gemfibrozil also seems to differ from clofibrate with regard to effects on carbohydrate metabolism. During clofibrate treatment, reductions of fasting blood glucose concentrations as well as of fasting serum insulin concentrations, have been reported (Lithell et al. 1977) with an increased K value during the intravenous glucose tolerance test (Lithell et al. 1982). No changes in blood glucose concentrations, glucose tolerance or serum insulin concentration before or after administration of intravenous glucose were seen following the termination of gemfibrozil treatment (Table 3). This finding is also in accordance with the results of earlier studies (Vessby et al. 1976). In conclusion, the present study has verified the fact that gemfibrozil is an effective triglyceride lowering agent. This action seems, at least partly, to be mediated by an increased clearance of triglycerides resulting from an increase in lipoprotein lipase activity. Other studies have also shown that gemfibrozil seems to be more effective in decreasing the production of VLDL than is clofibrate. The present investigation also found other metabolic differences between the two drugs, with regard both to effects on the fatty acid composition of plasma lipid esters and to influences on glucose metabolism.

Acknowledgments

We are indebted to Dr Ingemar Selinus who performed the statistical calculations. Financial support from the Swedish Medical Research Council (Grant no. 5446) is also gratefully acknowledged.

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