88 Proc. roy. Soc. Med. Volume 69 1976 Supplement 2

Gemfibrozil Treatment: A Comparison with Clofibrate by Dr A N Howard and Dr P Ghosh (Department of Medicine, University ofCambridge, Addenbrooke's Hospital, Cambridge, UK)

Gemfibrozil has a pronounced ability to decrease serum triglycerides in rats, mice and monkeys after oral administration, but has no effect on serum cholesterol (Parke, Davis 1973). If it is possible to extrapolate these data to man, the hyperlipoproteinemias most likely to be affected are types IIb, III, IV and V. The study reported here forms part of a larger series currently under investigation. Methods The patients were 10 type Ilb and 3 type IV with serum triglycerides greater than 160 mg/100 ml. After two months of receiving placebo, they were given 800 mg/day of gemfibrozil in two divided doses for five months. Serum cholesterol and triglycerides were estimated by conventional autoanalyser techniques; chylomicrons, VLDL and LDL by the nephelometric method of Stone et al. (1970). CHOLESTEROL

m/oomi

3(x 2

200L

Dr A N Howard

Results As shown in Fig 1, serum cholesterol and triglycerides were decreased to a minimum after three months of treatment, to values of 21 % and 45 %, respectively, below the initial baseline values. Likewise, VLDL and LDL were decreased 32.5 % and 21 % (Fig 2). Chylomicrons were initially very low but these also decreased.

Table I Effect of gemfibrozil at 800 mg/day in a type V patient

TRIGLYCERIDE

250:

Before After 16 weeks (mg/lOO ml) (mg/100 ml) 293 223 Cholesterol 230 Triglycerides 1295 13 Chylomicrons 183 2590 267 VLDL 113 408 LDL Serum

200

ISO, 4

12

8

16

20

Fig 1 Effect ofgemfibrozil (dose 2 x 400 mg/day) on serum lipids. Number ofpatients = 13 VLDL

Lipoprotein m /lOOmI

200

1001 LDL

5 50

45

401

8

12

16

20

weeks

Fig 2 Effect ofgemfibrozil (dose =2 x 400 mg/day) on serum lipoproteins. Number ofpatients= 13

In addition, 1 type V subject was investigated (Table 1). Triglycerides were markedly decreased as well as chylomicrons and VLDL. Serum cholesterol was also decreased and LDL rose, but not above normal values. Six patients in this investigation had previously been studied using clofibrate (1.5 g/day) in divided doses (Table 2). The effects on serum cholesterol and triglycerides were somewhat similar.

Discussion In our studies, gemfibrozil proved an effective drug for the reduction of serum triglycerides. The most widely used drug for the treatment of hypertriglyceridwmia is clofibrate (Howard 1975), but it has one major side effect, namely, it

Gemfibrozil Table 2 Comparison of gemfibrozil and clofibrate in type IV/IIb (mean of 6 patients, treatment for four weeks) Gemfibrozil (0.8 glday)

Clofibrate (1.5 glday)

Before

After A

Before

AJter

A

Serum cholesterol (mg/100 ml)

301

255

-46

270

236

-34

Serum triglycerides (mg/100 ml)

210

140

-70

270

144

-126

Table 3 Comparison of gemfibrozil and clofibrate in the rat Parameter Serum triglycerides Serum cholesterol Adipose tissue lipolysis Fructose hypertriglycerid3mia

Alpha-glycerophosphate dehydroge.iase Liver enlargement

Clofibrate Lowered Lowered Lowered

Gemfibrozil Lowered -

-

Lowered Lowered

Raised

-

Raised

Raised

increases the incidence of gallstones. In the Coronary Drug Project (1975), in patients with myocardial infarction, the five-year incidence of gallstones was 3%, compared with 1.3% in the control group. This was confirmed in a primary prevention trial in which the frequency of cholecystectomies was raised from 0.36% to 0.93% (Cooper et aL 1975). The widely accepted explanation for these findings is that clofibrate causes an increase in the lithogenic index of bile. The cholesterol content of bile is increased, and the ratio of biliary cholesterol to bile acid is doubled after only six days' treatment (Pertsemlidis et al. 1974).

89

Comparison of gemfibrozil and clofibrate in the rat (Parke, Davis 1973) reveals several major differences (Table 3). Thus, serum cholesterol is not affected by gemfibrozil. It is possible that biliary cholesterol is also not affected, but so far data are lacking. A study of the effect of gemfibrozil on the lithogenicity of bile would appear to be of high priority, since there is a need for a safer hypotriglycerideemic drug. The mechanism for the effect of clofibrate on serum triglycerides is speculative, but its action in raising liver alpha-glycerophosphate dehydrogenase and causing liver enlargement is thought to be of importance (Hess et al. 1965, Pereira & Holland 1970). Gemfibrozil is reported to have no effect on this enzyme, but does cause liver enlargement. Thus, the mechanism of action of the two drugs may be different. Summary Gemfibrozil was found to be an effective hypotriglyceridcmic agent in types IV, IIb and V hyperlipoproteineemia. When given at a dose level of 800 mg/day its activity was nearly of the same order of magnitude as 1.5 g/day of clofibrate. REFERENCES Cooper J, Geizerova H & Oliver M F (1975) Lancet i, 1083 Coronary Drug Project (1975) Journal of the American Medical Association 231, 360 Hess R, Staubli W & Riess W (1965) Nature, London 208,856 Howard A N (1975) Journal of Clinical Pathology 28 Suppl. 9, 106 Parke, Davis (1973) Summary for Investigators: CI-719 Research and Development. Parke, Davis, Ann Arbor, Michigan Pereira J N & Holland G F (1970) In: Proceedings of the Second International Symposium on Atherosclerosis. Ed R J Jones. Springer-Verlag, Berlin and New York; p 549 Pertsemlidis D, Panveliwalla D & Ahrens E H

(1974) Gastroenterology 66, 565 Stone M C, Thorp J M, Mills G L & Dick T B S (1970) Clinica Chimica Acta 30, 809