Drugs 36 (Suppl. 3): 87-92 (1988) 0012-6667/88/0300-0087/$3.00/0 © ADIS Press Limited All rights reserved.

Clinical Experience with Simvastatin Compared with Cholestyramine D. W. Erkelens', M.G.A. Baggen/, J.J. Van Doormaal', M. Kettner', J.e. Koningsberger' and M.J.T.M. Mof5 I 2 3 4 5

Summary

Department of Internal Department of Internal Department of Internal Department of Internal Department of Internal The Netherlands

Medicine, Medicine, Medicine, Med icine, Medicine,

University Hospital Utrecht, The Netherlands University Hospital 'Dijkzigt', The Netherlands University Hospital Groningen, The Netherlands Gasthuis Middleburg, The Netherlands University Hospital St Radboud, Nijmegen ,

Simvastatin (MK733). derived from lovastatin by substitut ing CH] for H at the 2' position. is a potent hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor. Its cholesterol-lowering effect in 40 patients with heterozygous familial hypercholesterolaemia was more pronounced (an LDL-cholesterol reduction of 43%) than that of cholestyramine monotherapy in a matched group of 20 patients (30% reduction). The combination ofthe 2 drugs for 50 patients who tolerated cholestyramine was even more effective (a 54% reduction ofLDL-cholesterol). The other changes were as follows: total cholesterol (simvastatin IS; -36%, cholestyramine ICj -23%, both drugs in combination IS+Cj -45%): HDL-cholesterol (S +16%. C +9%, S+C +20%); triglyceride (S ,....21%. C +11%. S+C -17%); and the apolipoprotein Brapolipoprotein A ratio (S -51%. C -39%. S+C -67%). Cholestyramine caused more gastrointestinal adverse effects (/2 of 20 patients). whereas a transaminase increase was seen both with cholestyramine (2 of 20 patients) and sim vastatin (3 of 40 patients) and with the combination (6 of50 patients). Treatment with simvastatin decreases the atherogenic potential of plasma more than cholestyramine monotherapy and causes fewer adverse effects. For those patients who tolerate cholestyramine, the combination of the drugs is even more potent.

Patients with familial hypercholesterolaemia are at an exceptionally high risk of atherosclerosis (Goldstein & Brown 1983), and reduction of hypercholesterolaemia is accompanied by a reduction in the incidence of myocardial infarction (Lipid Research Clinics Program 1984). It is fitting, therefore, to search for the most potent cholesterol-lowering medication. Since the introduction (Alberts et al. 1980) of a new class of cholesterol-lowering drugs, the hydroxyrnethylglutaryl coenzyme A (HMO CoA) reductase inhibi-

tors, these agents have been shown to be effective both as monotherapy (Havel et al. 1987) and in combination with other cholesterol-lowering drugs (Malloy et al. 1987). In this study, simvastatin I (Mol et al. 1987), the most potent HMG CoA reductase inhibitor known today, and the combina1 To prevent confusion in nomenclature. old and new names are MK733 (old synvinolin, new simvastatin), MK803 (old mevinolin , new lovastatin), ML236 (old compactin, new mevastatin), SQ3 1.000 (pravastatin),

88

Clinical Experience with Simvastatin

Table I. Demographic and clinical data of treatment groups

Number of patients Male/female Age (years) [range 24-701 Angina pectoris (no. of patients) Myocardial infarction (no. of patients) Coronary bypass (no. of patients) Serum lipid concentrations Cholesterol (mmol/l) lDl-cholesterol (mmol/l) HDl-cholesterol (mmol/l) Triglyceride (mmol/L) Apo A (% of normal) Apo B (% of normal) Apo B/Apo A

Cholestyramine

Simvastatin

20 10/10 49.1

40 19/21 49.5

5 5

5

4

5

12.1 ± 2.0 10.2 ± 2.0 1.1 ± 0.2 1.7 ± 0.6 101 ± 18 293 ± 130 1.52 ± 0.58

11.8 ± 2.4 9.8 ± 2.5 1.1 ± 0.3 1.9 ± 1.1 96 ± 17 314 ± 136 1.66 ± 0.42

tion of simvastatin and cholestyram ine are compared with cholestyramine, the drug used in the Lipid Research Clinics trial (Lipid Research Clinics Program 1984).

1. Patients and Methods In the Dutch section of an international study by 19 investigators in 9 countries, 60 patients (29 male, 31 female) aged between 24 and 70 years, with heterozygous familial hypercholesterolaemia, were maintained on a lipid-lowering diet and all lipid-lowering drug therapy was withheld 6 weeks before the study. Antihypertensive, anticoagulant and antiaggregatory therapies were not discontinued . After a placebo run-in period of 4 weeks, the patients were randomised to receive either cholestyramine (8 to 16g in a divided dosage; n = 20) for 12 weeks or simvastatin 20mg for 6 weeks then 40mg for a further 6 weeks (n = 40). At the end of 12 weeks, all 20 patients on cholestyram ine also received simvastatin 40mg, and 30 of the 40 patients on simvastatin, who could tolerate cholestyramine, received 8 to 16gfor 8 weeks. At both the beginning and end of the study, the

10

patients had a complete physical and ophthalmological examination. Efficacy and safety were checked at regular intervals by a short physical examination , questions about adverse effects and a complete set of laboratory investigations (lipids, complete blood count , blood chemistry, urinalysis, prothrombin and partial thromboplastin time). Total cholesterol and triglyceride concentrations were determined by use of enzymatic methods, and high density lipoprotein (HDL)-cholesterol concentrations were determined after precipitation of lipoproteins containing B apoproteins. Low densit y lipoprotein (LDL)-cholesterol was calculated by the Friedewald formula: LDLcholesterol = total cholesterol - HDL-cholesterol - 0.45 triglyceride. Apolipoproteins (apo) A and B were measured in 3 of 5 clinics by radial immunodiffusion or immunoturbidimetry. To circumvent interclinical methodological differences, apolipoprotein levels are expressed as percentages of the mean normal levels for each clinic. Statistical evaluation was done by analysis of variance, multiple regression analysis and Student's t-test. Values are given as mean ± standard deviation ; when a difference is cited, 2-sided p < 0.05.

Clinical Experience with Simvastatin

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Fig. 1. Effect of medication on total and LDL-cholesterol in heterozygous familial hypercholesterolaemia. From weeks -4 to 0 a placebo was given . At week 0 patients were randomised to receive simvastatin (--) 20mg for 6 weeks and 40mg for a further 6 weeks (n = 40), or cholestyramine (•••••) 8 to 16g for 12 weeks (n = 20). From weeks 12 to 20, 50 patients (20 from the cholestyramine group, 30 from the simvastatin group) received the 2 drugs in combination.

2. Results The results of randomisation are given in table I. Except for a statistically significant but clinically unimportant difference in baseline triglyceride, randomisation was successful.

Total cholesterol and LDL-cholesterol decreased more with simvastatin 20 and 40mg than with cholestyramine (fig. I). It appeared that cholesterol levels were not yet stable after 6 weeks of treatment with simvastatin 40mg. With the combination of the 2 drugs, a further reduction in cholesterol was reached after 4 weeks, and the levels remained stable after 8 weeks. There was no difference in final cholesterol concentrations between the patients who initially received either therapy. HDL-cholesterol tended to rise more with simvastatin than with cholestyramine (fig. 2), but effects on triglyceride differed between the treatments; there was a rise in triglyceride concentrations with

Table II. Baseline blood lipid concentrations (mmoI/L) and apolipoprotein levels (% of normal), and percentage change in patients with familial hypercholesterolaemia treated with simvastatin, cholestyramine and the combination of these 2 drugs . All changes were different from baseline (p < 0.01) and among each of the 3 treatments (p < 0.05)

Baseline Simvastatin Cholestyramine Combination

No. of patients

Total chol.

LDL

60 40 20 50

12.0 -36 -23 -45

10.0

HDL

rn-

Apo A

Apo B

99 +21 +9 +15

303 -47 -32 -64

glyceride

-43 -30 -54

1.11 +16 +9 +20

1.85 -21 +11

-17

90

Clinical Experience with Simvastatin

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Fig. 3. Changes in apo S and in apo S/apo A ratio (see fig . 1 legend for protocol) with simvastatin ( - ) and cholestyramine (-----).

cholestyramine versus a decrease with simvastatin. Triglyceride concentrations always fell when the drugs were used in combination. Both drugs alone, and in combination, produced decreases in apo B concentrations which were consistent with the changes in LDL- and HDL-cholesterol (fig. 3). Since apo A concentrations increased slightly during

treatment (table II), the result was a substantial decrease in the apo B/apo A ratio in each treatment group (fig. 3). A summary of results is provided in table II. Clinical and laboratory adverse experiences (table III) were mostly as expected. Gastrointestinal symptoms, including abdominal discomfort, constipation, diarrhoea, flatulence, anorexia, nausea and heartburn, were prevalent in the cholestyramine group and resulted in the withdrawal of I patient from the study. Ten patients who were randomised to initial therapy with simvastatin could not tolerate cholestyramine when they entered the combination therapy stage of the protocol. Transaminase increases were observed with both drugs and creatine phosphokinase (CPK) increases occurred in the simvastatin group only. Two of the 3 patients who exhibited a CPK increase had performed strenuous exercise. Minimal lens sclerosis was seen in 2 patients on simvastatin, but this did not require discontinuation of the drug.

3. Discussion The results of this study show that simvastatin is a more potent cholesterol-lowering agent than cholestyramine in familial hypercholesterolaemia and that the combination of the 2 drugs has an additive effect. This may be expected, since the mode of action of the 2 drugs is completely different. Simvastatin is a potent inhibitor of HMG CoA, which catalyses the rate-limiting step in cholesterol synthesis (Alberts et al. 1980). The intracellular mechanisms of the liver, which maintain

Table III. Clinical and laboratory adverse effects in patients with familial hypercholesterolaemia treated with simvastatin. cholestyramine or the combination of both drugs Treatment

Incidence of effects (no. of patients) GI

Simvastatin (n = 40) Cholestyramine (n = 20) Comb ination (n = 50)

1 12 10

Opht

ALT

CPK

3

3

2 2

6

Abbreviations: GI = gastrointestinal; Opht = minor lens opacities; ALT = alanine aminotransferase (elevation to less than twice the upper limit of normal) ; CPK = creatine phosphokinase (elevation to less than 5 times the upper limit of normal) .

Clinical Experience with Simvastatin

an adequate and constant cholesterol level inside the hepatocyte, compensate for this decreased cholesterol synthesis by increasing the number of LDL (cholesterol) receptors (Goldstein & Brown 1983). Cholestyramine acts by binding and preventing ileal reabsorption of bile salts, interrupting the enterohepatic cycle and thereby stimulating the liver to use more cholesterol for bile salt synthesis; this cholesterol is obtained from LDL receptor activity and an enhanced local cholesterol synthesis. The latter effect explains both the triglyceride increase seen in this study - a consequence of an increased VLDL (very low density lipoprotein) secretion and the synergistic effect of cholestyramine and simvastatin. When the 2 drugs are combined, the liver is totally dependent on LDL-cholesterol uptake for maintaining intracellular cholesterol homeostasis, since both recirculation from the gut and local synthesis are inhibited. The dramatic decrease in apo B with simvastatin demonstrates the decreased secretion from the liver and the enhanced removal of the atherogenic apo B-carrying lipoproteins. The fall in triglyceride and increase in HDL-cholesterol suggests that this not only holds for LDL but for VLDL and IDL (intermediate density lipoprotein) as well. This will need substantiation by the study of the effects of simvastatin in patients with combined hyperlipidaemia and dysbetalipoproteinaemia (type III). The reason for the HDL-cholesterol increase with simvastatin is not immediately apparent. It may be that the decrease in apo B-carrying lipoproteins (VLDL, IDL, LDL) restricts the available lipoprotein space for cholesterol ester transfer from HDL to these particles (Dullaart et al. 1987). When it is comb ined with the LDL and apo B decrease, the increase in HDL-cholesterol would certainly diminish the atherogenic potential of plasma. The results reported in the study are comparable to those with lovastatin (Havel et al. 1987; Hoeg et al. 1986; Illingworth & Sexton 1984), although it appears that double- and triple-drug combinations with both VLDL-synthesis inhibitors (niacin) and bile acid binding resins (colestipol) are even more potent (Blankenhorn et al. 1987; Malloy

91

et al. 1987). The fibrates (gemfibrozil, fenofibrate and bezafibrate) generally have a more pronounced triglyceride-lowering effect and a less potent LDLcholesterol-loweringeffect (Brown et al. 1987; Frick et al. 1987; Schulzeck et al. 1988). Their use seems to be indicated in familial combined hyperlipidaemia and familial dysbetalipoproteinaemia (type III) but not in hypercholesterolaemia. It is concluded that , in the treatment offamilial hypercholesterolaemia, simvastatin monotherapy is not only more potent than cholestyramine, the present drug of choice in Europe, but is also better tolerated and exhibits fewer adverse effects. The safety oflong term treatment needs to be examined in further studies. The combination of simvastatin as a cholesterol-synthesis inhibitor with bile acid binding resins can bring the cholesterol close to 'ideal' levels, even in heterozygous familial hypercholesterolaemia.

References Alberts AW, Chen J, Kuron G, Hunt V, Huff J, et al. Mevinolin : a highly potent competitive inhibitor of hydroxy-methylglutaryl-coenzyme A reductase and a cholesterol lowering agent. Proceedings of the National Academy of Sciences of the USA 77: 3957-3961, 1980 Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, et al. Beneficial effectsof combined colestipol-niacin therapy on coronary atheroscl erosis and corona ry venous bypass grafts. Journal of the American Medical Association 257: 3233-3240, 1987 Brown WV, Dujovne CA, Farquhar JW, et al. Effects of fenofibrate on plasma lipids. Arterioscleros is 6: 670-678, 1986 Dullaart RPF, Groener JEM , Erkelens OW. Effect of the composit ion of very low and low density lipoproteins on the rate of cholesterylester transfer from high dens ity lipoproteins in man , studied in vitro. European Journal of Clinical Investigation 17: 241-248, 1987 Frick MH , Elo 0, Haapa K, et al. Helsinki heart study primary prevention trial with gemfibrozil in middle aged men with dys1ipidemia. New England Journal of Medicine 317: 1237-1255, 1987 Goldstein JL, Brown MS. Familial hypercholesterolemia. In Stanbury JB, et al. (Eds) Metabo lic base of inherited disease, pp. 672-712, McGraw Hill, New York, 1983 Havel RJ, Hunn inghake DB, Illingworth DR, et al. Lovastat in (me vinolin) in the treatment of heterozygous fam ilial hypercholesterolemia. Annals ofInternal Medicine 107: 609-615, 1987 Hoeg JM , Maher MB, Zech LA, Bailey KR, Gregg RE, et al. Effectiveness of mevinolin on plasma lipoprotein concentrations in type II hyperlipoproteinem ia. American Journal of Card iology 57: 933-939, 1986 Illingworth DR, Sexton GJ. Hypocholesterolemic effects of rnevinolin in pat ients with heterozygous familial hypercholesterolemia . Journal of Clinical Investigation 74: 1972-1978, 1984 Lipid Research Clinics Program. The Lipid Research Clinics coronary prima ry prevent ion trial results: I. Reduct ion in incidence of coronary heart disease. Journal of the American Medical Association 251: 351-364, 1984

Clinical Experience with Simvastatin

Malloy MJ. Kane JP. Kunitake ST, Tun P. Complementarity of colestipol, niacin. and lovastatin in treatment of severe familial hypercholesterolemia. Annals of Internal Medicine 107: 616-623. 1987 Mol MJTM. Erkelens DW, Gevers Leuven JA, Schouten JA. Stalenhoef AFM. Simvastatin (MK-733): a potent cholesterol synthesis inhibitor in heterozygous familial hypercholesterolaemia. Atherosclerosis 69: 131-137. 1987 Schulzack P, Bojanovski M, Jochim A, et at. Comparison be-

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tween sirnvastatin and bezafibrate in effect on plasma lipoprote ins and apolipoproteinsin primary hypercholesterolemia. Lancet I: 611-613, 1988 Author's address: Prof. Dr D. W. Erkelens, Department of Internal Medicine. University Hospital Utrecht . Catharijnesingel 101. 3511 GV Utrecht (The Netherlands) .