Long-term use of lovastatin in different types of hyperlipidaemia

Atherosclerosis, 91 (1992) S21432 0 1992 ElsevierScientificPublishersIreland,Ltd. All rights reserved. 0021-9150/92/%05.00

s21

Printed and Published in Ireland

ATHERO 04906

Long-term use of lovastatin in different types of hyperlipidaemia Matti J. Tikkanena, Jukka-Pekka

Ojalab and Eero Helveb

‘First and bThird Departments of Medicine, Helsinki University Central Hospital, Helsinki (Finland)

Summary Groups of patients with various forms of familial or non-familial hypercholesterolaemia who had participated in short-term trials comparing lovastatin and probucol, entered an open 5-year follow-up study during which they received lovastatin alone or in combination with colestipol. The results indicated that the total and low density lipoprotein (LDL)-cholesterol lowering effect of lovastatin was maintained and, to some degree, improved during prolonged administration. Moreover, in all patient groups the increments in high density lipoprotein (HDL)-cholesterol were higher after 5 years than after short-term studies. Equal reductions in LDL-cholesterol were produced in familial hypercholesterolaemia, non-familial hypercholesterolaemia and mixed hyperlipidaemia. Although treatment goals were met in the majority of patients, further development of drug regimens is needed for certain subgroups of patients: that is, familial hypercholesterolaemia patients with very high serum cholesterol levels and patients with mixed hyperlipidaemia.

Key words: HMG-CoA reductase inhibitors; Hypercholesterolaemia;

Introduction Several /3-hydroxy-/3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are now internationally accepted as treatments for hyperlipidaemias. There remains a need, however, to define the patient groups that would most benefit from treatment with these lipid-lowering agents. According to the updated version of the 1988 European treatment guidelines [l] currently in the process of publication, three therapeutic classes Correspondence to: Matti J. Tikkanen, M.D., First Department of Medicine, Helsinki University Central Hospital, 00290 Helsinki, Finland.

Mixed (combined) hyperlipidaemia

will be recognized: hypercholesterolaemia, mixed (combined) hyperlipidaemia and hypertriglyceridaemia [2]. Patients with hypercholesterolaemia and mixed hyperlipidaemia may benefit from treatment with HMG-CoA reductase inhibitors. Lovastatin is the most widely used reductase inhibitor and experience with this drug is well documented. Centres in Finland participated in some of the early treatment trials that compared lovastatin with other lipid-lowering agents already on the market [3-91. Some of the patients participating in these trials have now been followed up for 5 years and the results of this long-term investigation have been summarized. This paper also discusses the role of lovastatin in the treatment of

S28

various forms of hypercholesterolaemia hyperlipidaemia.

and mixed

Patients and methods Clinical protocol

Patient groups and methodology have been defined in previous reports describing short-term studies [3,9]. The results discussed below were obtained in a 5-year follow-up of patients participating in a double-blind comparison between lovastatin and probucol [3]. After this 1Cweek comparison study, 57 patients (33 with familial hypercholesterolaemia (FI-I), 24 with non-familial hypercholesterolaemia (non-FH)) continued on lovastatin treatment in an open-label extension (long-term follow-up) study [9]. All patients started the extension study on lovastatin, 20 mg once daily. The dose was doubled every 4 weeks up to a maximum of 40 mg twice daily, or until low density lipoprotein (LDL)-cholesterol fell below 3.1 mmol/l in patients with coronary heart disease (CHD), or below 3.7 mmoyl in patients without CHD. If these target levels could not be reached with lovastatin alone, gradually increasing doses of colestipol were added to the treatment regimen, in most cases starting with an initial dose of 5 g/day in week 20 of the long-term follow-up study. The colestipol dose was increased until either the target level of LDL-cholesterol, or the maximum readily tolerated colestipol dose, was reached. Apart from three non-FH patients who received lovastatin, 40 mg once daily, all patients received lovastatin, 40 mg twice daily. The addition of colestipol was needed in all except one of the FH patients, but in only two of the non-FH patients. Results and discussion Familial hypercholesterolaemia

Theoretically, HMG-CoA reductase inhibitors are ideal drugs for the treatment of FH. FH is a genetic disorder in which the heterozygous patient inherits one abnormal gene coding for the LDL receptor and, as a result, only half the usual number of functioning LDL receptors are expressed. Consequently, patients have a serum cholesterol level of approximately twice normal. By

reducing hepatocellular cholesterol synthesis, HMG-CoA reductase inhibitors stimulate the normal LDL receptor gene to produce more LDL receptors and, possibly, normalize their number. The European Atherosclerosis Society have defined the treatment goals for total and LDLcholesterol as 5.2 mmol/l and 3.5 mmol/l, respectively [ 11.In most studies, lovastatin treatment has reduced serum cholesterol by 30% and LDLcholesterol by 40%. However, if the initial cholesterol levels on dietary treatment alone were very high, lovastatin treatment, even at the maximum dose of 40 mg twice daily, did not reduce cholesterol to the required levels (< 5.2 mmol/l). For example, before treatment, the average serum cholesterol level of the Finnish patients with FH [9] was 11.9 mmol/l and the LDL-cholesterol level was 10.2 mmol/l. The maximum dose of lovastatin given alone reduced these levels by 35% and 42%, respectively, to 7.7 mmol/l and 5.9 rnmol/l (data not shown in the original article [3]). It was, therefore, necessary to add colestipol, a bile acid sequestrant, to the treatment regimen [9]. During the first year of combination therapy, it became evident that, due to gastrointestinal side-effects, patients could tolerate only lo-15 g of colestipol per day. At the end of the 5-year follow-up, the mean dose of colestipol was 12 g daily; serum cholesterol was reduced by 46% and LDLcholesterol by 56% (Table 1). High density (HDL)cholesterol was increased by 25%: a larger elevation than expected. Serum triglyceride levels remained unchanged because the initial reduction by lovastatin alone was neutralized by the opposing effect of colestipol [9]. Primary hypercholesterolaemia

(non-FH)

Patients with primary hypercholesterolaemia (non-FH) comprise a heterogeneous group in which elevated cholesterol levels may arise for a variety of reasons. Increased production or decreased removal of LDL may be the cause. The underlying mechanisms are not known, but genetic variation at several gene loci, such as the apo B and apo E ‘genes, may contribute. In many patients, dietary and genetic influences apparently interact to produce hypercholesterolaemia. At present, however, it is not usually possible to distinguish the various conditions causing primary

S29 TABLE 1 EFFECTS OF LONG-TERM COMBINATION THERAPY USING LOVASTATIN, 40 mg TWICE DAILY, AND COLESTIPOL, 12 g/day (AVERAGE DOSES) IN PATIENTS WITH FAMILIAL HYPERCHOLESTEROLAEMIA (n = 32) All changes between baseline and 5 years were significant (P < O.Ol), except for triglyceride. The percentages in parentheses were calculated as averages of percentage changes from baseline. Lipid levels (mmol/l)

Total cholesterol LDL-cholesterol HDL-cholesterol Triglyceride

Baseline

1 year

5 years

11.9 f 10.2 f 1.14 zt 1.34 *

6.4 + 1.0 4.6 f 1.0 1.35 f 0.33 1.15 ?? 0.50

6.4 f 1.2 4.4 zt 1. I 1.42 ?? 0.37 1.19 ?? 0.51

1.8 1.7 0.27 0.47

non-FH hypercholesterolaemia, and the physician must base treatment on the serum lipid phenotype, the family history and other concomitant risk factors. Fortunately, there is now evidence that HMG-CoA reductase inhibitors are effective in lowering serum cholesterol in patients with these poorly defined forms of hypercholesterolaemia. Primary non-FH hypercholesterolaemia is usually characterized by moderately elevated serum cholesterol levels (6.5-7.8 mmol/l). As a result, monotherapy with an HMG-CoA reductase inhibitor is usually adequate. For example, in the non-FH patients participating in the present 5year follow-up, the average serum total and LDLcholesterol levels before the study were 8.1 mmoY1 and 6.2 mmol/l, respectively. After the dose titration of lovastatin was completed at week 20 (see Clinical protocol), total and LDL-cholesterol levels had fallen to 5.3 mmoY1 (-35%) and 3.3 mmoY1 (-47%), respectively (data not shown).

(-46%) (-56%) (25%) (0%)

Although these averages were close to target levels, many patients’ cholesterol levels still slightly exceeded the treatment goals. As most of these patients remained on lovastatin monotherapy (see Clinical protocol), it is interesting to examine the results of the 5-year follow-up in these individuals (Table 2). Prolonged therapy with lovastatin produced some improvement, with the mean serum cholesterol being reduced to 5.0 mmol/l and the LDL-cholesterol to 3.0 mmohl, indicating achievement of treatment goals in the majority of patients. Moreover, HDL-cholesterol was increased by 21%, much more than during short-term trials [3,4], and the significant reduction in serum triglyceride levels was maintained (-22% after 5 years of follow-up; Table 2). Despite the efficacy of HMG-CoA reductase inhibitors, marked interindividual variation in treatment response has been observed in both short-term and long-term trials [7,9]. Initial efforts

TABLE 2 EFFECTS OF LONG-TERM TREATMENT OF PATIENTS WITH NON-FAMILIAL HYPERCHOLESTEROLAEMIA USING LOVASTATIN, 40 mg TWICE DAILY (n = 17) AND 40 mg ONCE DAILY (n = 3) All changes between baseline and 5 years were significant (P < 0.001 for cholesterol and P < 0.005 for triglyceride). The percentages in parentheses were calculated as averages of percentage changes from baseline. Lipid levels (mmol/l)

Total cholesterol LDL-cholesterol HDL-cholesterol Triglyceride

Baseline

1 year

5 years

8.1 f 0.9 6.2 ziz 1.0 1.02 f 0.21 1.84 f 0.73

5.1 ?? 0.9 3.2 zt 0.7 1.40 * 0.34 1.30 f 0.50

5.0 zt 0.8 3.0 ztz0.7 1.30 ze 0.52 1.44 ?? 0.51

(-38%) (-52%) (21%) (-22%)

s30

to explore the underlying genetic causes of this variation have not, however, been successful. Studies of the possible effects of the apo E or apo B XbaI genotype on the treatment response in Finnish patients [8], or of apo E in other populations [lO,l 11, did not reveal clinically significant differences between genotypes.

tients with primary mixed hyperlipidaemia (type IIb) (Table 3). All the patients received lovastatin, 40 mg twice daily, except for three who received 40 mg once daily with their evening meal. No other lipid-lowering agents were co-administered during the 5-year period and patients with FH were excluded. At the end of the follow-up, reductions in total cholesterol and LDL-cholesterol of 37-41% and 51%, respectively, were observed in both groups, indicating no difference in treatment response (Table 3). Although serum triglyceride levels were reduced by 33% from baseline in patients with mixed hyperlipidaemia compared with 8% in those with pure hypercholesterolaemia, the difference between phenotypes was of only borderline significance (P = 0.052). Nevertheless, this finding is in line with previous studies, indicating that lovastatin causes a greater reduction in triglycerides in those patients who presented with elevated levels [IS]. The increases in HDLcholesterol in patients with type IIa and IIb were 26% and 20%, respectively.

Primary mixed hyperlipidaemia

Most patients in this group have mild or moderate elevations in both serum cholesterol (5.2-7.8 mmol/l) and triglyceride (2.3-4.5 mmol/l) levels. Many patients have familial combined hyperlipidaemia (FCHL), which is characterized by increased production of apo B-containing lipoproteins [ 121.In some patients with FCHL, genetic factors have been suggested to contribute to the disorder, including heterozygous lipoprotein lipase deficiency [ 131 and genetic variation at the apo AI-CIII-AIV locus 1141.At present, however, no useful markers are available for the practising physician to distinguish between patients with different types of mixed hyperlipidaemia, and treatment decisions are made on the basis of the serum lipid phenotype, other CHD risk factors and family history. A group of patients with pure cholesterol elevation (type IIa) was compared with a group of pa-

Side-effects during long-term therapy

Treatment regimens were generally well tolerated; however, four patients did not complete the 5-year follow-up. One patient with FH receiving lovastatin monotherapy discontinued the study

TABLE 3 EFFECTS OF LONG-TERM TREATMENT OF PATIENTS WITH NON-FAMILIAL HYPERCHOLESTEROLAEMIA TYPE Ha PHENOTYPE (n = 13) OR TYPE IIb PHENOTYPE (n = 7) USING LOVASTATIN

WITH

None of the differences between treatment-induced changes in type Ha and IIb after 5 years were statistically significant. The percentages in parentheses were calculated as averages of percentage changes from baseline. Lipid level (mmoliI) Baseline Total cholesterol Type Ha Type IIb LDL-cholesterol Type Ha Type IIb HDL-cholesterol Type Ha Type IIb Triglyceride Type Ha Type IIb

1 year

5 years

8.2 zt 1.1 7.7 ?? 0.3

5.1 f 0.7 5.1 * 0.7

5.1 ?? 0.8 (-37%) 4.6 zt 0.6 (-41%)

6.4 f 1.1 5.6 t 0.3

3.1 +z 0.8 3.3 ?? 0.5

3.1 f 0.8 (-51%) 2.7 ?? 0.5 (-51%)

1.15 f 0.18 0.88 f 0.14

1.53 f 0.31 1.11 ?? 0.22

1.43 zt 0.30 (26%) 1.05 * 0.15 (20%)

1.37 f 0.25 2.70 f 0.48

1.16 f 0.46 1.57 * 0.48

1.27 zt 0.43 (-8%) 1.77 ?? 0.50 (-33%)

s31

after 3 years due to a rash that was considered to be drug-related. The three other discontinuations were considered not to be drug-related: one patient died from a myocardial infarction, one emigrated and one received another investigational drug causing withdrawal from the follow-up. Laboratory safety data were analysed after 3 years of treatment and slight, but significant, increases (within the normal range) were seen in the average serum alanine aminotransferase and aspartate aminotransferase levels [9]. Nonsignificant increases were observed in the average serum creatine phosphokinase activities, but treatment was not discontinued in any of the patients because of elevated serum enzyme levels. The gain in body weight observed in non-FH patients after 3 years was no longer significant after 5 years (76.8 f 9.6 kg vs. 76.0 f 9.4 kg at baseline), but there was a weight gain in FH patients (73.2 f 11.8 kg vs. 71.9 f 10.6 kg at baseline (P < 0.05)) [9]. The lack of a control group, however, makes it difficult to evaluate the relevance of any weight change over a period of 5 years. Ophthalmologic examination did not reveal any untoward effects 191. Conclusion Short-term and long-term studies using lovastatin, either as a single lipid-lowering agent or in combination with bile acid sequestrants, have demonstrated its value in treating different forms of hypercholesterolaemia and mixed hyperlipidaemia. The rationale for using HMG-CoA reductase inhibitors in FH is clear: these agents stimulate the production of functioning LDL receptors. However, the other types of hyperlipidaemias are caused by a variety of genetic and dietary factors. Regardless of the type and origin of these lipid disorders, HMG-CoA reductase inhibitors produce, on average, similar percentage reductions in LDL-cholesterol levels [3,4,6]. Moreover, the recently described genetic form of hypercholesterolaemia, familial defective apo B100 (FDB) [16], responds to treatment with a HMG-CoA reductase inhibitor in the same way as FH [ 171. However, FDB has not yet been detected in Finland [18].

The 5-year data presented here indicate that the LDL-cholesterol lowering effect of HMG-CoA reductase inhibitors can be maintained and, to some degree, improved. Moreover, in all patient groups, the increments in HDL-cholesterol were higher after 5 years than after the initial short-term studies: the mechanism behind this phenomenon is not apparent. The results indicate that ideal cholesterol and LDL-cholesterol levels could not be achieved in all patients with FH despite the marked reductions from baseline (-56% for LDL cholesterol). This was due to the extremely high levels of cholesterol prior to drug treatment and the poor patient compliance during therapy with bile acid sequestrants. A possible way of overcoming this problem might be to develop more palatable and better tolerated bile acid sequestrants. In non-FH, lovastatin monotherapy reduced LDL-cholesterol to below 3.5 mmol/l in most patients, a level that meets current recomrnendations [l]. In some of the patients with mixed hyperlipidaemia, the serum triglyceride level remained elevated, though the average level was reduced to below 2 mmol/l. Theoretically, the ideal treatment for these patients should be combination therapy with HMG-CoA reductase inhibitors and triglyceride-lowering agents, such as tibrates and nicotinic acid. However, the suitability of this combination therapy remains undetermined because it may, in rare instances, be associated with myopathy [19,20]. The side-effect profile for lovastatin during long-term treatment [9,2 l] remained similar to that described in short-term studies. At present, it would appear that HMG-CoA reductase inhibitors offer the most promising approach to the treatment of various forms of elevated serum cholesterol. This is based on several considerations: these drugs are more effective than previously used agents [3-5,22-241, they produce equal percentage reductions in LDLcholesterol in patients with FH, non-FH and mixed hyperlipidaemia, and the treatment response can be maintained over long periods of time because of good patient compliance. In some types of hyperlipidaemia (e.g. FH patients with very high serum cholesterol and patients with mixed hyperlipidaemia), there is a need for further development of combined drug regimens.

S32

Acknowledgements The authors have received support from the Academy of Finland, The University of Helsinki and the Sigrid Juselius Foundation. The skillful technical assistance of Ms. Terhi Hakala and PBivi Ruha is appreciated. References 1

2

3

4

5

6

7

8

9

10

11

European Atherosclerosis Society Study Group, The recognition and management of hyperlipidaemia in adults: a policy statement of the European Atherosclerosis Society, Eur. Heart J., 9 (1988) 571. Lewis, B., Second generation recommendations for prevention of cardiovascular disease: considerations in evolving updated guidelines, Nutr. Metab. Cardiovasc. Dis., 1 (1991) 46. Helve, E. and Tikkanen, M.J., Comparison of lovastatin and probucol in treatment of familial and non-familial hypercholesterolemia: different effects on lipoprotein protiles, Atherosclerosis, 72 (1988) 189. Tikkanen, M.J., Helve, E., Jgiittelii, A. et al., Comparison between lovastatin and gemfbrozil in the treatment of primary hypercholesterolemia: The Finnish Multicenter Study, Am. J. Cardiol., 62 (1988) 355. The Lovastatin Study Group IV, A multicenter comparison of lovastatin and probucol for treatment of severe primary hypercholesterolemia, Am. J. Cardiol., 66 (1990) 22B. Ojala, J.-P., Helve, E., Tikkanen, M.J. et al., Switch from gemtibrozil to lovastatin (mevinohn) therapy in patients with primary hypercholesterolemia: a multicentre study, Drug Invest., 2 (Suppl.) (1990) 40. Ojala, J.-P., Helve, E. and Tikkanen, M.J., Treatment of combined hyperlipidemia with lovastatin versus gemfibrozil: a comparison study, Cardiology, 77 Suppl. 4 (1990) 39. Ojala, J.-P., Helve, O., Ehnholm, C. et al., Effect of apolipoprotein E polymorphism and XbaI polymorphism of apolipoprotein B on response to lovastatin treatment in familial and non-familial hypercholesterolemia, J. Intern. Med., 230 (1991) 397. Ojala, J.-P., Helve, E., Karjalainen, K. et al., Long-term maintenance of therapeutic response to lovastatin in patients with familial and non-familial hypercholesterolemia: a 3-year follow-up, Atherosclerosis, 82 (1990) 85. O’Malley, J.P. and Illingworth, D.R., The influence of apolipoprotein E phenotype on the response to lovastatin therapy in patients with heterozygous familial hypercholesterolemia, Metabolism, 39 (1990) 150. De Kniff, P., Stalenhoef, A.F.H., Mol, M.J.T.M. et al.,

12

13

14

15

16

17

18

19

20 21

22

23 24

Influence of apoE polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia, Atherosclerosis, 83 (1990) 89. Arad, Y., Ramakrishnan, R. and Ginsberg, H.N., Lovastatin therapy reduces low density lipoprotein apoB levels in subjects with combined hyperlipidaemia by reducing the production of apoB-containing lipoproteins: implications for the pathophysiology of apoB production, J. Lipid Res., 30 (1990) 567. Babirak, S.P., Iverius, P.-H., Fujimoto, W.Y. and Bnmzell, J.D., Detection and characterization of the heterozygote state for lipoprotein lipase deficiency, Arteriosclerosis, 9 (1989) 326. Wojchiechowski, A.P., Farrall, M., Cullen, P. et al., Familial combined hyperlipidaemia linked to the apolipoprotein AI-CIII-AIV gene cluster on chromosome llq23-q24, Nature, 349 (1991) 161. Garg, A. and Grundy, S.M., Lovastatin for lowering cholesterol levels in non-insulin-dependent diabetes mellitus, N. Engl. J. Med., 318 (1988) 81. Innerarity, T.L., Mahley, R.W., Weisgraber, K.H. et al., Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia, J. Lipid Res., 31 (1990) 1337. Illingworth, D.R., Vakar, F., Mahley, R.W. and Weisgraber, K.H., Hypocholesterolaemic effects of lovastatin in familial defective apolipoprotein B-100, Lancet, 339 (1992) 596. HHm%liIinen, T., Palotie, A., Aalto-Setllii, K. et al., Absence of familial defective apolipoprotein B-100 in Finnish patients with elevated serum cholesterol, Atherosclerosis, 82 (1990) 177. Pierce, L.R., Wysowski, D.K. and Gross, T.P., Myopathy with lovastatinand rhabdomyolysis associated gemtibrozil combination therapy, J. Am. Med. Assoc., 264, (1990) 71. Tobert, J.A., Efficacy and long term adverse effect pattern of lovastatin, Am. J. Cardiol., 62 (1988) 285. Bradford, R.H., Shear, CL., Chremos, A.N. et al., Expanded clinical evaluation of lovastatin (EXCEL) study results I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia, Arch. Intern. Med., 151 (1991) 43. Tikkanen, M.J., Bocanegra, T.S., Walker, F. et al., Comparison of low-dose simvastatin and gemfibrozil in the treatment of elevated plasma cholesterol: a multicenter study, Am. J. Med., 87 (1989) 47s. Tikkanen, M.J., Practical drug therapy for common hyperlipidaemias, Clin. Endocrinol. Metab., 4 (1990) 719. The Lovastatin Study Group III. A multicenter comparison of lovastatin and cholestyramine therapy for severe primary hypercholesterolemia, J. Am. Med. Assoc., 260 (1988) 359.