Acta Med Scand 200: 55-58, 1976

Clofibrate in Type I1 Hyperlipoproteinemia

Jsrn Ditzel and Hans Olaf Bang

From the Departments of Medicine and Clinical Chemistry, Alborg Regional Hospital, Alborg, Denmarh

ABSTRACT. As part of a double-blind randomized study, the safety and the lipid- and uric acid-lowering effect of clofibrate have been evaluated in 28 patients with type I1 hyperlipoproteinemia (HLP). A highly significant reduction of serum cholesterol occurred in type I1 a and of serum triglyceride and cholesterol in type I1 b HLP throughout the 60-week observation period @<0.01). Of the patients with types IIa and IIb HLP, 65% had at least a 25% reduction of serum cholesterol. Uric acid was significantly re- duced only during the first period of treatment ecO.05). In the laboratory measurements concern- ing safety, a persistent, slight reduction was ob- served in Hb, hematocrit and alkaline phosphatase. No significant clinical side-effects were noted. Clo- fibrate is considered effective as a lipid-lowering agent in many cases of type I1 HLP.

Although the lipid-lowering effect of clofibrate has been repeatedly demonstrated in hyperlipoprotein- emias (HLP), it is not infrequently maintained that the serum cholesterol levels in patients with type I1 HLP (essential cholesterolemia, hyper-P-lipo- proteinemia) respond poorly to clofibrate therapy (12, 13, 14, 20). The result of the present double- blind randomized study supports the contention that clofibrate is also effective in the majority of cases of type I1 HLP.

MATERIAL AND METHODS After a thorough discussion of the purpose and procedure of the investigation, patient volunteers, ranging in age from 44 to 65 years (mean 5 9 , with type I1 HLP and persistent elevation of serum cholesterol (>280 mgl100 mi) were selected for this double-blind study (clofibrate and an unregistered hypolipoproteinemic drug). Patients with secondary causes of HLP were excluded. Twenty of the patients had atherosclerotic complications. All pa-

tients had been on appropriate dietary therapy prior to the study: when P-lipoprotein was high, a low saturated, high polyunsaturated diet low in cholesterol was pre- scribed; patients with high pre-@lipoproteins as well, were instructed to moderate their sugar intake and lose weight. They were told to continue on the same diet and to avoid excessive alcohol intake throughout the study. When the code was broken, clofibrate had been given to 10 male and 18 female patients, of whom 8 had type I I a and 20 type I Ib HLP according to Fredrickson’s classification (7, 8).

The investigation period was divided into a placebo period of 8 weeks and 5 treatment periods, each lasting 12 weeks. Blood determinations were made initially, every 4 weeks during the placebo period and the first treatment period and once during each of the subsequent 4 treatment periods. All patients were given placebo or clofibrate (2 g daily) in the form of two 500 mg capsules twice daily.

Blood for lipid analyses was drawn at each visit to the clinic after an overnight fast. Cholesterol was deter- mined by the method of Runde (16), plasma triglyceride by the method of Eggstein and Kreutz (6) and the typing of HPL was made by Lipoprotein electrophoresis (5 ) . Serum uric acid, Hb, hematocrit, W C , platelets, fasting blood sugar, serum creatinine, serum bilirubin, serum alkaline phosphatase and SGPT were determined by routine laboratory procedures.

Wilcoxon’s rank test and Student’s t-test for paired data were used for statistical analyses.

RESULTS

Cholesterol and triglycerides The lipid-lowering effect of clofibrate is shown in Table I. The mean cholesterol reduction in both types I1 a and I1 b was approximately 20% (varia- tions 0 4 0 % ) . At least a 25% reduction of serum cholesterol was found in 65% of the patients. The mean reduction of plasma triglycerides in type 11 b was approximately 30% (variations 0-75 %). At least a 30% reduction of plasma triglycerides was found in 65 % of the patients. No significant change

Acta Med Scand 200

56 J . Ditzel and H . 0. Bang

Table I . Effect of clofibrute on serum cholesterol, plasma triglycerides und uric acid (meun+S.E.M.)

Placebo Active treatment periods (weeks) period (0-8 weeks) 1st (8-20) 2nd (20-32) 3rd (3244) 4th (44-56) 5th (56-68)

Type I l a HLP No. of pats. Serum cholesterol (mg/100 ml)

Reduction (%) P-value

Type I1 b H L P No. of pats. Serum cholesterol (mg/100 ml)

Reduction (%)

No. of pats. with 3 15 % reduction

P-value Plasma triglycerides (mg/100 ml)

Reduction (%) P-value No. of pats. Plasma uric acid

P-value (mg/100 ml)

8 8

292f19.6 20.8f 3.0

<O.oOI

8

305 f26.5 17.82 3.9

<O.oOI

5

311k31.4 15.6f 6.5

<0.01

368f 19.4 - -

20

403+ 16.0 -

20

315k 15.5 2 2 . l t 2.8

19

3 l 9 k 14.5 19.6k 3.1

I I

296 f20.8 25.5k 4.2

7 7

285k 15.6 29.5k 4.8

287f14.8 26.0f 5.7

14 <O.oOI

11 <0.001

9 <0.001

6 <0.01

7 CO.01

3 13k32.6 - -

18

4.9 -

202k 16.2 31.9k 4.1

<O.oOl 18

4.4 ~ 0 . 0 5

203k24.2 32.3k 5.1

<0.001

17

4.9 ns.

175k19.7 33.7f 6.4

<O.oOl 9

5 . 5 n.s.

179k3 1.1 36.7f 8.1

<0.01 -

1751f.2 I .9 39.7f 5.5

<0.01 -

n.s . =non-significant .

in plasma triglyceride levels, which were within the normal range prior to clofibrate treatment, was observed in type I1 a.

Uric acid A significant reduction of mean uric acid, from 4.9 to 4.2 mg/100 ml, was present only in the first clo- fibrate period @<0.05) (Table I).

data Table I1 summarizes the safety laboratory meas- urements, showing the significance of the changes between the placebo period and each active period.

Hb and hematocrit were slightly reduced in all three treatment periods @<0.01). Total WBC was slightly reduced during the first and second active medication period @ < O . O I ) . Fasting blood sugar

Table 11. Effects of clojibrate on safety measurements ~~

Active treatment periods (weeks)

1st 2nd 3rd Placebo period (n ) (Mean) n Mean n Mean n Mean

Hb (g/100 ml) Hematocrit (%) WBC (1 OOo/ml) Platelets (1 OOo/ml) Fasting blood sugar (mg/100 ml) Serum creatinine (mg/100 ml) Serum bilirubin (mg/100 ml) Serum alkaline phosphatase (U/I) SGPT (U/I)

18 14.9 18 18 45.3 18 18 8.18 18 18 244.3 18 18 87.5 18 18 0.97 18 18 0.48 18 18 34.6 18 18 7.6 18

14.3** 43.4***

7.28**

79.4*** 1.03* 0.39**

21.1*** 8.9

259.1

13.9*** 43.6***

6.44* * * 265. I 80.2** 0.98 0.40*

15.9*** 8.9

14.0*** 43.94 7. I6

233.9 89.4 0.99 0.39

18.9*** 11.9

17 17 17 17 17 17 17 17 17

16 16 14 14 14 14 14 14 14

Significant difference from mean placebo values: *p<0.05, **p<O.Ol, ***p<O.001.

Acta Med Scand 200

Clofibrute in type I1 hyperlipoproteinemiu 57

and serum bilirubin were significantly reduced dur- ing the first and second medication period, as was serum alkaline phosphatase during all medication periods @ < O . O O I ) . No significance was found for changes in SGPT.

Adverse reuctions

A clinical adverse reaction was suspected in only one patient, who complained of worsening of her spastic colitis during the first month of clofibrate treatment.

DISCUSSION Clofibrate has been available for more than 10 years, and a number of studies have demonstrated its safety and efficiency. It is primarily a triglyceride-lowering agent and exerts its most pro- found effects in patients with type IV HLP (2, 14). Clinical experience of treatment with clofibrate in patients with type I1 HLP is limited, and there are few well conducted double-blind studies on its ability to lower serum cholesterol.

Our data show that clofibrate is a potent lipo- protein-lowering agent in many cases of type I1 HLP. As demonstrated previously ( I , 3, 1 I , 17), the lipid-lowering ability of clofibrate was pronounced in patients with type I1 b HLP; the mean decrease in triglyceride levels in such patients being more than 30% and the decrease in the cholesterol levels approximately 20%. Our results also show that a number of subjects with type I1 a HLP respond, and that the cholesterol-lowering effect is almost equivalent to that seen in type I1 b. At least a 25% reduction of serum cholesterol was observed in 65 % of our patients with types I1 a and I1 b HLP. In no case did clofibrate treatment significantly in- crease the serum cholesterol levels suggestive of a rise in P-lipoprotein (15). The side-effects were limited to minor gastrointestinal complaints in a single case.

Among the safety parameters, there was a per- sistent reduction of the slightly elevated Hb and hematocrit pretreatment values during the clo- fibrate medication. The reason for this “normaliza- tion” is not known. However, we have reported previously (4) that high plasma triglyceride levels may be associated with an increase in the oxygen affinity of whole blood. With a significant reduction of plasma triglyceride, the release of oxygen from the erythrocytes through the microcirculation may

increase, leading to a compensatory lowering of the Hb and hematocrit levels. Likewise a persistent significant reduction of serum alkaline phosphatase was found, an observation which has been reported before (10, 18). The mechanism of this reduction is not known. The addition of serum from clofibrate- treated patients to serum samples from untreated individuals did not result in any significant variation in the expected level of alkaline phosphatase in the mixtures (18). Therefore, it seems unlikely that clo- fibrate interferes with the determination of alkaline phosphatase.

The mode of action of clofibrate is still not clearly understood, although recent studies have greatly furthered our knowledge (3, 9, 19). Clofibrate ap- pears to lower plasma cholesterol by increasing the excretion of neutral steroids in the faeces, by de- creasing cholesterol synthesis, and by reducing the tissue pool of cholesterol. Whether or not this includes removal of cholesterol from the vascular walls has not been determined.

Since both hypercholesterolemia and endogenous hypertriglyceridemia are associated with increased risk of coronary heart disease, i t seems recom- mendable to treat at least severe degrees of HLP.

REFERENCES

I . Berkowitz. D.: Long-term treatment of hyper- lipidemic patients with clofibrate. J.A.M.A. 218: 1002, 1971.

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4 . Ditzel, J.: Evidence of an interference in oxygen ex- change from erythrocytes to tissues by hypertri- glyceridemia. Proceed. 1st World Congress on Micro- circulation, Toronto 1975. Plenum Press, New York. In press 1975.

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8. Fredrickson, D. S., Levy, R. J. & Lees, R. S.: Fat transport in lipoproteins. New Engl. J. Med. 276: 34, 148, 215, 273, 1%7.

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9. Grundy, S. M., Ahrens, Jr, E. H., Salen, G., Schreibman, P. H. & Nestel, P. J.: Mechanisms of action of clofibrate on cholesterol metabolism in pa- tients with hyperlipidemia. J. Lipid Res. 13: 531, 1972.

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13. Levy, R. J. & Langer, T.: Hypolipidemic drugs and lipoprotein metabolism. In: Proceedings of the 4th international symposium on drugs affecting lipid metabolism (ed. Holmes, Paoletti and Kritchevsky). Plenum Press, New York and London 1972.

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17. Sanbar, S. S. , Zweifler, A. J. & Conway, J.: Dietary fat restrictions and atromid therapy in patients with type I1 familial hyperlipoproteinemia. Mich. Med. 67: 1347, 1968.

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