32 B. Ek et al. mechanisms (Stanley et al. 1979, Kay 1980, Burton and Manninen 1982). Gemfibrozil is a newer lipid-modulating drug. It decreases total cholesterol, LDL-cholesterol and triglycerides, whereas HDL-cholesterol is increased (Manninen et al. 1982, Manninen 1983). Like many other metabolically active drugs, its precise mechanism of action is not fully understood. The present study was designed to assess the antidyslipoproteinaemic properties of fibre and gemfibrozil, when given either alone or in combination. Methods Eight outpatients (mean age ±SD: 47±7 years) with Type II dyslipidaemia volunteered for the study. For inclusion the patients had to be otherwise healthy but have either total cholesterol or cholesterol and triglyceride levels above the upper limits of normal (7.5 mmol/l for cholesterol; 2.0 mmol/l for triglycerides). There were two females and six males. All were of normal weight. None had previously been treated for dyslipidaemia. Blood lipids were measured at 2 week intervals from entry to ensure stability of the measurements. The means of these values were used as the initial control pretrial levels. Thereafter the patients were to receive gemfibrozil (Parke Davis & Co. Pontypool, UK) 600 mg twice daily for 16 veeks. At 8 weeks, a psyllium-based fibre preparation (Vi-Siblin®) was added at a daily dose of 18 g (9 g twice daily for 16 weeks). The patients received combination therapy for 8 weeks and fibre alone for 8 weeks, followed by an 8 week post-treatment follow-up. They visited the clinic at 4 week intervals during the active treatment period. For each period, results are given at 8 weeks of treatment. Routine clinical laboratory methods were used for monitoring haematology, liver and renal function and blood chemistry. Conventional ultracentrifugation was used for separation of LDL and HDL. The manganese-heparin precipitation technique yielded consistent results for HDL. The ferric chloride method was used for cholesterol determinations. Enzymatic methods (Boehringer reagent kits) were used in measuring triglyceride values. Paired t-tests were used to evaluate the changes on treatment in each group, compared to the pre-treatment period. Results The results are summarized in Fig. 1. Gemfibrozil significantly decreased total cholesterol (-16.7 per cent), LDL-cholesterol (12.5 per cent) and triglycerides (-46.5 per cent) whereas HDL-cholesterol was increased (+25·5 per cent). Decreases in total cholesterol and LDL-cholesterol were significantly greater after adding the fibre to the treatment regimen. The net decline was 25·1 per cent in total cholesterol and 29.1 per cent in LDL-cholesterol. Fibre slightly attenuated the gemfibrozilaugmenting effect on HDL-cholesterol. Fibre alone had a significant but small effect in lowering total and LDL-cholesterol, -6.1 per cent and -9.6 per cent respectively. HDL-cholesterol did not differ from control values during the fibre period. Triglycerides were decreased by 46.5 per cent, both during gemfibrozil and gemfibrozil plus fibre combination therapy. Fibre alone was less effective (−29.5 per cent) in decreasing triglycerides. During the wash-out follow-up period, all measured variables returned to initial pre-trial levels. Figure 1. Changes in plasma total cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride pretreatment values (mean; n=8) resulting from the use of gemfibrozil alone, gemfibrozil plus fibre, fibre alone, and post-trial findings ***p<0.05, 0.01 and 0.001 respectively compared to pre-treatment values. Bars below the gemfibrozil, gemfibrozil plus fibre and fibre alone columns show percentage change from control values (open bars show percentage decrease, solid bars show percentage increase). The patients' weights remained unchanged during the study and no abnormal values were seen in blood chemistry, liver or renal function or haematology. Discussion This study confirms previous results on the lipid-modulating profile of both gemfibrozil and psyllium-based fibre. The most significant new finding was the clearcut augmentation of LDL lowering during concurrent administration of gemfibrozil and fibre. The fibre also attenuated the gemfibrozil-augmenting effect on HDLcholesterol. The effect of gemfibrozil on plasma lipoproteins reached its maximum in 4 weeks and so the maximum gemfibrozil effect was observed during this study. During the wash-out period, most of the effects also disappear within 4 weeks (Manninen et al. 1982). Thus, these individual drug effects should not be influenced by other treatments. In the absence of detailed information about the precise effects of gemfibrozil and fibre on blood lipoproteins it is not possible fully to explain the present findings. In rats, gemfibrozil alters sterol handling and excretion (Maxwell et al. 1983). Gemfibrozil may also enhance sterol excretion in man and thus render more cholesterol available to be bound by the fibre. Enhanced excretion may result in lowered levels of LDL. If fibre acts like cholestyramine, increased activity of the LDL-receptors may also be involved (Shepherd et al. 1980). 33 34 B. Ek et al. Cholestyramine is effective in the management of hyperlipoproteinaemia but its use is limited, mainly because of its side-effects. Combination therapy with compounds having additive effects is warranted in patients who either have a poor response to one agent alone, or those at high risk because of exceptionally high LDL-cholesterol levels. References Burton, R. and Manninen, V. (1982). Influence of a psyllium-based fibre preparation on faecal and serum parameters. Acta Medica Scandinavica (Suppl. 668), 91-94. Kay, R. M. (1980). Effects of dietary fibre on serum lipid levels and fecal acid excretion. Canadian Medical Association Journal 123, 1213–1217. Levy, R. I., Brensike, J. F., Epstein, S. E. et al. (1984). The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: results of the NHLBI type II coronary intervention study. Circulation 69, 325-337. Lipid Research Clinics Program (1984). The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in the incidence of coronary heart disease. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. Journal of the American Medical Association 251, 351-364 and 365-374. Manninen, V. (1983). Clinical results with gemfibrozil and background for the Helsinki Heart Study. American Journal of Cardiology 52, 35B-38B. Manninen, V., Mälkönen, M., Eisalo, A., Virtamo, J., Tuomilehto, J. and Kuusisto, P. (1982). Gemfibrozil in the treatment of dyslipidaemia. A 5-year follow-up study. Acta Medica Scandinavica (Suppl. 668), 82-87. Maxwell, R. E., Nawrocki, J. W. and Uhlendorf, P. D. (1983). Some comparative effects of gemfibrozil, clofibrate, bezafibrate, cholestyramine and compactin on sterol metabolism in rats. Atherosclerosis 48, 195-203. Shepherd, J., Packard, C. J., Biker, S., Lawrie, T. D. V. and Morgan, H. G. (1980). Cholestyramine promotes receptors mediated low density lipoprotein catabolism. New England Journal of Medicine 302, 1219-1222. Stanley, M. M., Paul, D., Gacke, D. and Murphy, J. (1979). Effects of cholestyramine, metamucil and cellulose on fecal bile acid excretion in man. Gastroenterology 65, 889-894. Long-term treatment with gemfibrozil in male survivors of myocardial infarction SIRKKA KAUKOLA, MARJATTA MÄLKÖNEN, PEKKA KOSKINEN and VESA MANNINEN First Department of Medicine, University of Helsinki, and the Summary The efficacy and safety of gemfibrozil treatment has been investigated following longterm use over 5 years in 52 dyslipidaemic men with CHD. The daily dose of the drug was 1200 mg. During this period the level of serum total cholesterol decreased by an average of 12.1 per cent and triglycerides fell by 38.3 per cent. HDL-cholesterol increased by 20.9 per cent and the ratio of HDL-cholesterol to total cholesterol rose by 18.4 per cent. The rate of new coronary events (reinfarctions and sudden coronary deaths) was lower than the rate expected on the basis of previous population studies. Elevated serum low density lipoprotein (LDL) and very low density lipoprotein (VLDL) concentrations are positively related to the risk of coronary heart disease (CHD), whereas the concentration of high density lipoprotein (HDL)-cholesterol is inversely related. The management of lipid disorders is generally considered essential in both primary and secondary prevention of CHD, and several clinical trials designed to lower serum LDL and VLDL levels have given positive results (Rosenhamer and Carlson 1980, Hjermann et al. 1981, May et al. 1982, Lipid Research Clinics Program 1984). The elevation of HDL-cholesterol may also be beneficial in CHD prevention but its precise role in this respect is not fully understood. Dietary intervention is the preferred method of changing serum lipid patterns, but diet alone is not always sufficient and drug therapy is sometimes required. Gemfibrozil is an anti-dyslipidaemic drug, which has been shown to change the serum lipid profile in several favourable respects (Royal Society of Medicine 1976). Side-effects have been few (Hodges and Marcus 1982) and so it may be particularly appropriate for long-term use. In a double-blind, placebo-controlled trial, 60 dyslipidaemic male survivors of myocardial infarction (MI) were treated with gemfibrozil for 3 months followed by 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. 36 S. Kaukola et al. placebo for a further 3-month period. Most patients have continued the drug for 4.5 years since the end of this trial. The purpose of the present study was to investigate the efficacy of gemfibrozil in changing the lipid profile and also its safety following long-term use in dyslipidaemic subjects with CHD. Methods Patient population All 60 male volunteers (mean age 43·6±4·3 years; range 28-48) had survived a myocardial infarction occurring from 3 months to 2 years before the study, and 14 had undergone coronary by-pass operations before entry. Pre-entry serum lipid measurements demonstrated total cholesterol values >7.0 mmol/l and/or triglycerides > 1.7 mmol/l in 45 subjects and the other 15 subjects all had a low (<0·20) HDLcholesterol/total cholesterol ratio. Beta-blocking agents were used by 40 patients and diuretics by 13. There were 38 smokers, 19 ex-smokers and three non-smokers. Base-line study During an initial double-blind, placebo-controlled, cross-over phase, all subjects received either gemfibrozil or placebo for 3 months. The daily dose of gemfibrozil was 1200 mg. They were then crossed over to the alternative treatment for a second 3-month period. The results of this preliminary trial have already been reported (Kaukola et al. 1981). Long-term trial Most subjects were willing to continue on long-term medication. They visited the clinic initially at 3-monthly and later at 6-monthly intervals. At each visit body weight and blood pressure were measured and blood samples were drawn following an overnight fast for measurement of haemoglobin, white blood cell count, serum alanine aminotransferase, serum total cholesterol, HDL-cholesterol and triglycerides. Serum cholesterol was determined by the ferric chloride method (Badzio and Boczon 1966), HDL-cholesterol by the PEG-6000 method (Viikari 1976) and triglycerides according to Fletcher (1968). A resting ECG was also recorded annually. Results Drop-outs and drug compliance The cumulative percentage of drop-outs for patients during the double-blind, placebocontrolled phase of the trial was 13.3 per cent. Reasons for discontinuing either |