A comparison of cholestyramine and probucol in the treatment of familial hypercholesterolaemia

Atherosclerosis, 53 (1984) l-l Elsevier Scientific Publishers Ireland, Ltd

1

ATH 03526

A Comparison of Cholestyramine and Probucol in the Treatment of Familial Hypercholesterolaemia D.B. Jones

‘, H.C.R.

Simpson ‘, P. Slaughter r, S. Lousley S.M. Cobbe 3 and J.I. Mann 1,2

’Diabetes Research Laboratories, Infirmary,

and ’Department

‘, R.D.

Carter

‘,

’Department of Community Medicine and General Practice, Radcliffe of Cardiology, John Radcliffe Hospital, Oxford (Great Britain) (Received 25 November, 1983) (Accepted 15 March, 1984)

Summary Twelve patients with familial hypercholesterolaemia (FH) who had not achieved satisfactory cholesterol levels on dietary advice alone were treated with cholestyramine for 6 months and probucol for 6 months in a randomised cross-over study to compare the relative effectiveness of the two drugs. Over the 6-month period, mean total cholesterol fell by 16.4% on cholestyramine and 12.7% on probucol. Cholestyramine produced a 17.4% fall in low density lipoprotein (LDL) cholesterol, no significant changes in very low density lipoprotein (VLDL) cholesterol or high density lipoprotein (HDL) cholesterol, a 21.4% increase in HDL cholesterol subfraction HDL, and a 24.1% increase in the HDL/LDL cholesterol ratio. Triglyceride levels rose by 29.6% but remained within the normal range. Probucol produced a 11.7% fall in LDL cholesterol, a 9.9% fall in VLDL cholesterol, a 10% fall in total HDL cholesterol, a 37% fall in HDL cholesterol subfraction HDL, and no change in the HDL/LDL cholesterol ratio. Triglyceride levels fell by 14%. The mean corrected QT interval increased from 0.418 to 0.434 s (P c 0.01) on probucol but did not change significantly on cholestyramine (from 0.405 to 0.41 s). The two drugs have different metabolic effects on FH. Cholestyramine has a more marked effect on LDL cholesterol, favourably influences the HDL/LDL cholesterol ratio and is therefore considered to be the drug of choice.

This work was supported financially by the Simon Broome Heart Research Trust and Merrel Pharmaceuticals, Ltd. Correspondence to: Dr. J.I. Mann, Gibson Laboratories Building, Radcliffe Infirmary, Oxford OX2 6HE, Great Britain. 0021-9150/84/$03.00

0 1984 Elsevier Scientific Publishers Ireland, Ltd.

2

Probucol may be beneficial cholesterol levels. Key words:

in patients

who additionally

Cholesterol - Cholestyramine - Familial proteins - Probucol - Triglycerides

have elevated

hypercholesterolaemia

VLDL

- Lipo-

Introduction While the controversy concerning the optimal serum cholesterol and the most appropriate means of achieving this continues [l] there is little dispute that FH warrants energetic therapy. This autosomal dominant condition is associated with a greatly increased risk of ischaemic heart disease and is characterised by markedly elevated LDL cholesterol levels and the presence of tendon xanthomas [2]. Dietary modification alone seldom results in satisfactory cholesterol levels. Cholestyramine has long been regarded as the mainstay of the treatment [3]: it is an effective cholesterol-lowering drug, but some patients find the powder form inconvenient and occasionally it produces unacceptable gastrointestinal side-effects. Probucol is a recently introduced alternative in tablet form. No direct comparison has been previously made between the two as first line treatment in the management of FH. We report here a randomised cross-over study in which the effects of the two drugs on total cholesterol, cholesterol in the lipoprotein fractions, HDL cholesterol subfractions and total triglycerides are compared in patients with FH. Patients and methods Twenty patients with FH were recruited into the study. All had tendon xanthomas, pretreatment total cholesterol levels greater than 7.5 mmol/l (mean 10.2 mmol/l) and a clear family history of premature (below the age of 55) coronary heart disease and/or raised cholesterol levels. All were heterozygotes. They were initially recommended a cholesterol lowering diet which was low in fat (less than 35% of total energy), high in fibre-rich carbohydrate (55% of total energy), with a polyunsaturated to saturated fatty acid ratio of between 0.7 and 1.0 containing no more than 300 mg dietary cholesterol each day. After 3-6 months of dietary advice, 16 patients had total cholesterol levels persistently greater than 7.0 mmol/l and they were randomised to receive either cholestyramine (8 g twice daily) or probucol (500 mg twice daily). The full dose of cholestyramine was achieved after 2 weeks by gradually increasing from one sachet daily. At the end of 6 months, drug treatment was discontinued for one month and the patients were then given the alternative drug treatment for a further 6 months. Eight patients were given cholestyramine first and 8 started on probucol. All patients were seen monthly and fasting blood samples taken to determine total cholesterol and triglycerides, cholesterol in the lipoprotein fractions and HDL subfractions HDL, and HDL,. Blood glucose, full blood count, liver function tests, electrolytes and serum creatinine were measured every 3 months.

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A chest X-ray and an electrocardiogram were performed at the beginning and end of the treatment phases. Side-effects from the drugs were assessed by questionnaire during and at the end of the treatment phases. Informed consent was obtained from all patients. Six of the remaining 16 patients were male and 10 were female. Mean age was 48.7 years and the mean percentage ideal body weight at the beginning of the study was 112.3%. There were no significant changes in body weight during the course of the study (mean weight during cholestyramine treatment: 65.9 kg and during probucol treatment: 65.7 kg). Cholesterol was measured by a Technicon Autoanalyzer using the Liebermann Burchard reaction, cholesterol in the lipoprotein fractions and the HDL subfractions were measured by precipitation [4-61. Triglycerides were measured spectrophotometrically after enzymatic hydrolysis [7]. The QT interval was measured from multichannel ECG recordings using the lead in which the end of the T wave was most clearly defined (usually V3). The same lead was used for each measurement in an individual patient. A mean value was obtained from 5 consecutive beats. QT interval was corrected for heart rate (QTc) using the Bazett formula [8]. The measurements were made without knowledge of treatment group. The significance of differences was assessed by paired t-test. Results Two of the 16 patients who entered into the drug phase of the protocol found cholestyramine unacceptable, one because of unpalatability and the other because of diarrhoea. Two patients discontinued probucol, one because of diarrhoea and the other because of paraesthesiae affecting the left arm for which no cause could be found. The other patients developed no side-effects on either drug. Hence, 12 patients completed the 6 months on both drugs. The mean total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, HDL, and total triglycerides were not significantly different at the beginning of the two treatment phases following discontinuation of all treatment for 1 month between the two periods. The results are expressed as the mean change over the 6 months as a percentage of the initial value. The mean level of total cholesterol fell on both drugs. The percentage fall on cholestyramine was 16.4% and was 12.7% on probucol (see Fig. 1). However, the mean total cholesterol during the 6-month period was significantly lower on cholestyramine (6.74 mmol/l) than on probucol (7.62 mmol/l; P < 0.0001). LDL cholesterol fell by 17.4% during treatment with cholestyramine and by 11.7% on probucol. Neither the percentage fall nor the absolute fall from pretreatment levels differed significantly on the 2 treatments, but mean LDL cholesterol levels were significantly lower on cholestyramine (4.38 mmol/l) than on probucol(S.71 mmol/l; P < 0.0001). VLDL cholesterol fell by 9.9% on probucol but showed no significant change on cholestyramine. Mean VLDL levels were not significantly different during the 6-month periods. Mean total triglyceride levels fell by 14.8% on probucol and

4

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**

25-

,” I

,

I

I

I

I

1

2

3

a

5

6

TIME

Fig. 1. Mean percentage (O-----O).

fall monthly

rose by 29.6% on cholestyramine. on cholestyramine (1.4 mmol/l)

I monlhnb

in total cholesterol

on cholestyramine

Mean triglyceride than on probucol

(O-

0) and probucol

levels were significantly greater (1.04 mmol/l; P < 0.01) (Table

1). Total HDL levels showed no change on cholestyramine but a fall of 16.8% on probucol. Mean total HDL cholesterol was significantly lower on probucol (1.19 P < 0.0001). However, HDL, rose mmol/l) than on cholestyramine (1.55 mmol/l; by 21.4% on cholestyramine but fell by 32.6% on probucol. Mean HDL, levels were significantly lower on probucol(O.29 mmol/l) than on cholestyramine (0.51 mmol/l; P < 0.0001). The HDL/LDL cholesterol ratio increased by 24.1% on cholestyramine but fell slightly (4.6%) on probucol (Table 2). Changes in lipid levels occurred by the end of the first month and were sustained during the rest of the study. No changes occurred in blood glucose, haemoglobin . TABLE

1

Cholestyramine

Probucol

Pre-treatment

Mean over 6 mths

% Change over 6 mths

Pre-treatment

Mean over 6 mths

% Change over 6 mths

Total cholesterol mean f SD (mmol/l)

8.06 f 0.93

6.74+ 1.11

- 16.4%

8.74+ 1.39

7.62* 1.18

- 12.8%

LDL cholesterol mean f SD (mmol/l)

5.30 + 2.04

4.38 f 1.47

- 17.4%

6.47+1.57

5.71 f 1.38

- 11.8%

VLDL cholesterol mean + SD (mmol/l)

0.63 +0.37

0.62 f 0.44

- 1.6%

0.81+ 0.50

0.73 *0.44

Triglycerides mean f SD (mmol/l)

1.08 + 0.22

1.40 f 0.64

+ 29.6%

1.22kO.63

1.04* 0.54

- 9.9%

- 14.8%

TABLE

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Cholestyramine

Probucol

Pre-treatment

Mean over 6 mths

% Change over 6 mths

Pre-treatment

Mean over 6 mths

W Change over 6 mths

HDL cholesterol (total) mean k SD (mmol/I)

1.55 + 0.22

1.55 * 0.34

0%

1.43 + 0.26

1.19kO.28

-16.8%

HDL subfraction I1 mean f SD (mmol/l)

0.42 + 0.20

0.51 kO.24

+21.4%

0.43 f 0.20

0.29kO.18

-32.6%

HDL subfraction III mean f SD (mmol/I)

1.13 f 0.28

1.03 f 0.35

0.90 * 0.34

0.92kO.24

+2.2%

HDL/LDL

0.29

0.36

0.22

0.21

- 4.6%

levels, X-ray ucol, while

ratio mean

- 8.9% + 24.1%

white blood count, renal function, liver enzymes, electrolytes or in the chest appearances during the two treatment phases. During treatment with probthe QTc increased significantly from a mean of 0.418 to 0.434 s (P < 0.01) on cholestyramine the mean QTc did not change significantly (0.405-0.410 s).

Discussion Our results show that in FH, cholestyramine produces a greater degree of lowering of total and LDL cholesterol than probucol although probucol also produces a clinically useful fall in total cholesterol. The initial total cholesterol value was slightly higher before probucol treatment than before cholestyramine treatment but the mean values over a 6-month period were lower on cholestyramine and are the most powerful indicators of comparative effectiveness. They represent the mean of 6 values whereas there is only one measurement for each patient immediately before starting a treatment period. Fifty-two percent of patients with familial hypercho!esterolaemia suffer a myocardial infarction by the age of 50 years and half of these episodes are likely to be fatal. This compares with 12.7% in normal controls by the same age [9,10]. There is, therefore, little doubt that energetic treatment is warranted. Few patients respond to dietary measures alone and the careful choice of drug therapy is particularly important because treatment is usually continued indefinitely. Clofibrate (and its newer analogues), nicotinic acid and cholestyramine have been amongst the most widely used drugs. The WHO Clofibrate Study suggested an increase in non-cardiovascular mortality in patients treated with the drug [ll] and its use has declined as a result. Nicotinic acid has not gained widespread acceptance because of frequent autonomic side-effects such as severe cutaneous flushing. Cholestyramine has been used for many years with few side-effects and is regarded by many as the treatment of choice in FH. The development of probucol, an encouraging lipid-lowering drug available in tablet form prompted a comparison with cholestyramine.

An elevated LDL cholesterol level is the feature of FH which is most implicated in determining the cardiovascular complications [12]. Both drugs are effective in lowering total cholesterol but cholestyramine produces a greater degree of lowering of both total and LDL cholesterol. In normal individuals, HDL probably facilitates the uptake and transport of cholesterol from peripheral tissues to the liver [13]. A low plasma HDL cholesterol is associated with ischaemic heart disease and high levels may be protective [14]. HDL, is thought to be the most important determinant within the HDL cholesterol group of subfractions [6]. Other authorities suggest that the ratio of HDL cholesterol to LDL cholesterol is an indicator of ischaemic heart disease risk [15]. If these associations are true of patients with FH there are further indications from total HDL cholesterol, HDL, and the HDL/LDL cholesterol ratio to suggest that cholestyramine has advantages over probucol. The increases in the duration of the QTc interval have been previously reported in patients on probucol [16,17] and were a cause of concern but no cardiovascular symptoms or events could be related to this during the study. The changes may represent a proarrythmic effect or type III antiarrythmic effect [18], but no firm conclusions can be drawn. Although probucol may be beneficial to patients in whom VLDL cholesterol is also raised, cholestyramine appears to be the treatment of choice in familial hypercholesterolaemia. The use of the two drugs together may be appropriate for some patients [19]. Acknowledgements We thank Mrs. K. Fisher and Mr. R. Jelfs for technical Reeve for typing the manuscript.

assistance

and Mrs. Anne

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