Atorvastatin monotherapy vs. combination therapy in the management of patients with combined hyperlipidemia

European Journal of Internal Medicine 19 (2008) 203 – 208 www.elsevier.com/locate/ejim

Original article

Atorvastatin monotherapy vs. combination therapy in the management of patients with combined hyperlipidemia Inbal Avisar, J. Gerald Brook, Efrat Wolfovitz ⁎ Bnai Zion Medical Center, Rambam Medical Center and the Technion Faculty of Medicine, Haifa, Israel Received 20 March 2007; received in revised form 4 July 2007; accepted 27 September 2007 Available online 31 October 2007

Abstract Background: Mixed hyperlipidemia is a common disorder characterized by elevated VLDL and LDL levels. Patients with this syndrome usually are in need of combination therapy, comprising a fibric acid derivate with a statin drug in order to achieve LDL and triglyceride target values. Atorvastatin is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor demonstrated to be effective in reducing both cholesterol (CHOL) and triglyceride (TG) levels in humans. We examined the efficacy of atorvastatin as monotherapy in achieving a better or the same lipid profile in patients with mixed hyperlipidemia treated with combination therapy. Design: We compared atorvastatin with a combination of a fibric acid derivate and a statin drug (other than atorvastatin) in a 24-week, prospective randomized, open-label study of 27 patients with mixed hyperlipidemia. Methods: All 27 patients had been treated with statin–fibrate therapy in different regimens for at least a year. Atorvastatin at a daily dose of 20 mg was substituted for statin–fibrate therapy. Lipid and safety profiles were assessed. Results: Atorvastatin significantly reduced total cholesterol, LDL-C, and HDL-C compared to statin–fibrate therapy. In contrast, TG and glucose levels were significantly elevated with atorvastatin. Target LDL-C and TG was achieved in 10 patients with the single therapy of atorvastatin vs. 6 patients under statin–fibrate. In 16 patients, atorvastatin was at least as effective as, or better than, the combination therapy, and was recommended for continuation of treatment. Conclusion: Atorvastatin is an adequate monotherapy for many mixed hyperlipidemia patients. We recommend atorvastatin be considered for every patient suffering from mixed hyperlipidemia. © 2007 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Mixed hyperlipidemia; Atorvastatin; Statin–fibrate combinations

1. Introduction Mixed hyperlipidemia is a common disorder characterized by elevated VLDL and LDL levels. Affected individuals have elevated plasma levels of total cholesterol (250–500 mg/dL) and TG (N 250 mg/dL). Among the different phenotypes comprising mixed hyperlipidemia, familial combined hyper-

⁎ Corresponding author. Department Medicine C, Bnai Zion Medical Center, 47 Golumb St. Haifa, 31500, Israel. Tel.: +972 4 835 9131; fax: +972 4 835 9115. E-mail address: [email protected] (E. Wolfovitz).

lipoproteinemia is the most common and is associated with an increased risk for atherosclerosis and coronary heart disease. Diet modifications and exercise are usually not sufficient for treatment and pharmacotherapy is often required [1]. The European Atherosclerosis Society and the National Cholesterol Education Program (NCEP) consider fibric acid derivates (fibrates) and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors to be effective therapy for familial combined hyperlipoproteinemia [2]. The majority of available statins, e.g. lovastatin, pravastatin, simvastatin and fluvastatin, reduce LDL-C and total cholesterol (TC) levels (up to 48% and 36%, respectively) in a dose-dependent manner, but have a modest effect only on plasma triglycerides

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(12% to 17% reduction) [3]. While fibrates effectively reduce TG levels (ranging from 18% to 54%), they do not consistently reduce LDL-C and TC (7% to 22%) [4]. Patients suffering from mixed hyperlipidemia usually need the combination of a fibric acid derivate with a statin drug in order to achieve target values of LDL and triglycerides. It is recognized that administering both drugs, while synergistic in their actions, decreases the safety profile of this mode of therapy. Side effects such as impairment of liver function and increase in CPK levels and more serious complications such as myositis and rhabdomyolysis are more frequent when both drugs are used [5–7]. Combination therapy is often recommended but less often used due to concerns with cost, tolerability and compliance. The advantage of a single drug that is capable of safely lowering both cholesterol and TG effectively is evident. The availability of atorvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor (statin) with the capability of lowering LDL-C by 41%–61%, in a dosedependent manner, and also lowering triglycerides by up to 50%, might allow a significant number of patients to achieve the desired therapeutic goals of both LDL and triglycerides with only one drug [8,9]. To our knowledge, few studies have attempted to compare the efficiency of atorvastatin to other combinations of statins and fibrate acid derivates in the treatment of mixed hyperlipidemia [10,11]. We examined the efficacy of atorvastatin as monotherapy in achieving a better or at least the same lipid profile in patients with mixed hyperlipidemia treated with combination therapy. Certainly, the safety profile would be improved by employing this statin alone since atorvastatin has a safety profile similar to other statin drugs [12]. It would also be far less expensive to prescribe one rather than two drugs, and the patients' compliance would be expected to increase. We used a drug regimen in which 20 mg atorvastatin replaced the most common combination treatment used in the clinic for patients with combined hyperlipidemia. This comprised a statin plus a fibric acid derivate in different dose combinations. The patients were recruited after follow-up of at least 1 year in our clinic during which they were following a diet and receiving combination therapy. Each patient was a control for himself in that each received both regimens of treatments, and comparisons were made between the results while on one regimen compared to the other. Our aim was to test the hypothesis that it is worth considering monotherapy with atorvastatin in every patient with combined hyperlipidemia treated with combination therapy. 2. Methods This study was designed as an outpatient study to evaluate the response to therapy under free living conditions and implemented at the outpatient Lipid Clinic of the Rambam Medical Center in Haifa. It is a prospective, randomized, open-label study which received ethical approval.

2.1. Patients We recruited 28 outpatients known to have the phenotype type IIb hyperlipoproteinemia and had been treated with a combination of statin and fibrate during at least 1 year of follow-up in our clinic. Signed informed consent was obtained from each patient. Patients with known CAD or peripheral vascular disease were not excluded from the study; however, patients must not have undergone a major cardiovascular event resulting in hospitalization during the 3 months preceding study entry. 2.2. Study design All patients were randomly allocated into two treatment groups. The first (group A) continued current medication for 12 weeks (period 1) which was then replaced with atorvastatin 20 mg for another 12 weeks (period 2). The second (group B) started with atorvastatin 20 mg for 12 weeks (period 2) and then returned to their previous combination therapy for another 12 weeks (period 1). 2.3. Laboratory investigations Fasting blood samples were obtained for CBC, glucose, lipid profile, liver function tests and CPK (creatinine phosphokinase) blood level which were repeated at 4-week intervals: 0, 4, 8, 12, 16, 20, 24 weeks. The mean lipid values of weeks 4, 8 and 12 were compared with those at 16, 20 and 24 weeks and, on this basis, changes in the lipid profile were determined. Patients were asked to report their assessment of side effects during the study. A full physical examination was carried out for each participant. The safety profile comprised assessment of liver function tests: alanine transaminase (ALT), gamma-glutamyl transferase (GGT), and the muscle enzyme creatinine kinase. Patients whose ALT or AST was consistently greater than three times the upper limit of normal or CPK levels greater than 10 times the upper limit of normal were required to discontinue study medication. Glucose levels were analyzed every visit in order to test the relationship with triglyceride values. All chemical analyses were performed using standard commercial kits at Rambam chemical laboratory, under strict procedures of quality control. 2.4. Data analysis The two groups of patients were compared in regard to individual, demographic, and disease characteristics. Results were analyzed by χ2 test or paired t-test for normally distributed variables across the population. Each group was analyzed by Mann–Whitney test for the mean percent change with atorvastatin therapy from baseline to the final treatment values for the following parameters: TC, LDL-C, HDL-C, TG and glucose. The comparison for interaction

I. Avisar et al. / European Journal of Internal Medicine 19 (2008) 203–208 Table 1 Demographics and baseline characteristic of patients

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3. Results

Characteristic

Group A (n = 14) Group B (n = 13)

Sex, n(%) mean Age, year; mean Age distribution, n(%) b70 years Body mass index, kg/m2; mean ± sem LDL-C, mg/dL; mean ± sem TC, mg/dL; mean ± sem HDL-C, mg/dL; mean ± sem TG, mg/dL; mean ± sem GLU, mg/dL; mean ± sem

7(50) 55.6 11 (79%) 28.21 ± 1.19 119 ± 9.62 202.21 ± 39.93 41.5 ± 2.90 208.64 ± 16.83 127.28 ± 10.31

10(76) 57 12 (92%) 28.15 ± 0.77 130 ± 8.99 214.23 ± 12.17 43.76 ± 1.61 201.85 ± 25.19 118.54 ± 11.1

between each group was analyzed by ANOVA test. Comparisons for changes in the lipid values between the two treatment modalities were performed by paired Wilcoxon signed ranks test. We defined success as the achievement of target levels of TG, and LDL-C compared to current therapy. Target levels were those defined by the NCEP and EAS with respect to the different lipid risk factors. We also determined the linear regression of TG corresponding to glucose with and without atorvastatin.

3.1. Demographics Twenty-eight patients with mixed hyperlipidemia (type IIb phenotype) were assigned randomly to either commence treatment with atorvastatin at the beginning of our study (group A, 13 patients) or after 12 weeks (group B, 15 patients). Of these, 27 patients completed the 24-week study (13 and 14, respectively). The mean age was 56 ± 17 years and 63% were male. In group A, 3/13 (23%) and, in group B, 4/14 (29%) had coronary heart disease (or stroke before age 70). In group A, 8/13 (62%) and, in group B, 10/14 (66%) had diabetes. In the initial analysis, no significant differences were found between the two groups with respect to their basic lipid profile. Group A had lower TC, LDL-C and HDL-C values and higher TG and glucose values than group B, but these differences were not statistically significant (Table 1). 3.2. Drug therapy All patients had been treated with a combination of statin: 52% simvastatin, 26% lovastatin, 22% pravastatin with

Fig. 1. Levels of triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol and glucose under combination therapy (statin + fibrate) compared to monotherapy (lipitor).

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bezafibrate 400 mg daily. Atorvastatin was prescribed at doses of 20 mg daily. 3.3. Lipid profile We have shown that the mean values of all parameters measured prior to the study and after the first period (treatment with statin–fibrate) for both treatment groups were comparable (p b 0.05). By Mann–Whitney–ANOVA analysis, we proved that the mean values of both periods and the pattern of the changes in the lipid profile were not different for the two groups, and, as a result, all subjects could be combined for the subsequent composition analysis. Data from all patients were included independently of their group since there was neither a “group effect” nor changes in the interaction between them. The statistical significance of the changes was assessed by the Wilcoxon test. Compared to baseline levels (while on combination therapy), atorvastatin reduced patients' total cholesterol and LDL-C from 217.24 to 191.45 mg/dL (p = 0.037 and p = 0.002, respectively). It also resulted in an increase in plasma glucose (from 125.25 to 134.15 mg/dL) and triglycerides (from 227.1 to 266.99 mg/dL) (p = 0.009 and p = 0.022, respectively) and a significant lowering of HDL from 43.4 to 40.14 mg/dL (p = 0.013) (Fig. 1). Over the course of the study period, mean TG and glucose levels showed a trend towards an increase in values over time. Interestingly, on the basis of the linear regression test, the increase in plasma TG with atorvastatin therapy was not significantly correlated with elevation in plasma glucose. We concluded that the rise in TG levels was due either to a direct effect of the atorvastatin therapy and/or the withdrawal of fibrate therapy. Indeed, we observed an increase in TG levels in 17 patients, although only 11 had levels above 250 mg/dL. When treatment success was defined as: TG level reduced or remaining unchanged with a plasma TG level of less than 250 mg/dL, 16 patients were considered as having a successful outcome (59.3%) and 11 patients as failures with atorvastatin therapy, in respect to their TG levels only. LDL-C levels were significantly modified by atorvastatin therapy. When on combination therapy, 15 patients had levels above 130 mg/dL, while on 20 mg atorvastatin daily, 12 of these 15 patients had LDL-C levels of less than 130 mg/dL, and only 3 patients remained above 130 mg/dL. Therefore, 89% of patients achieved LDL-C levels of less than 130 mg/dL. Moreover, with statin–fibrate therapy, 5 patients had LDL-C levels of less than 100 mg/dL, while with atorvastatin therapy, 14 patients (52%) achieved these levels. After 12 weeks of therapy with atorvastatin, 10 patients (37%) achieved the LDL-C target goal and triglyceride desired levels, while only 7 patients (26%) achieved these levels with statin–fibrate therapy. Moreover, 6 patients (22%) achieved lower LDL-C and TG levels with atorvastatin therapy compared to lipid levels while on combination

therapy. Altogether, 16 patients (60%) benefited from monotherapy with atorvastatin. No patient had to be withdrawn due to increased CPK or elevated liver transaminase levels. No adverse events considered to be associated with treatment were reported. 4. Discussion HMG-CoA reductase inhibitors (the statin group of drugs) constitute a class of compounds that are very effective in reducing plasma concentrations of TC and LDL-C. In addition, modest reductions in TG (10%–20%) and a potential for increasing HDL levels have been reported [3]. Atorvastatin has been very effective in reducing both TG and TC in patients with mixed hyperlipidemia and in other hyperlipidemic patients [8,9]. Mean reductions of TG of 27%–45% have been observed after 6 weeks therapy on either 10, 20, 40 or 80 mg atorvastatin per day in a dose-dependent manner [12]. With regard to cholesterol-lowering, atorvastatin has been shown to be more effective than other statins [13], with reductions in total cholesterol of up to 46% and in LDL-C of up to 61%. Again there was a dose-dependent effect and the safety profile was similar to the other statin drugs when administered to subjects with hypercholesterolemia [14–17]. The mechanisms whereby atorvastatin induced reduction in atherogenic lipoprotein levels (mostly LDL-C) in patients with Familial Combined Hyperlipidemia were elaborated by Maryse Guerin et al. [18] as: 1. A significant degree of normalization of circulatory levels and composition of key LDL precursors, i.e. the various VLDL particle subclasses. 2. Up-regulation of hepatic LDL receptors with consequent enhanced catabolism of the major LDL particle subclasses. Atorvastatin also appears unique in its ability to preferentially lower those components most elevated with each dyslipidemic situation; the LDL-C when there is pure hypercholesterolemia, triglycerides and VLDL-C when high triglycerides are prominent and all three in patients with mixed hyperlipidemia [19]. In view of the claimed concomitant reduction of both cholesterol and triglycerides we were interested in comparing the effect of this drug to that of a combination therapy comprising a statin and fibric acid derivate in patients with mixed hyperlipidemia. With few exceptions, prior studies that tested the atorvastatin effect on the lipid/lipoprotein profile have been limited to comparisons with other single drugs. In a 24-week study, 84 patients with mixed hyperlipidemia were randomized to receive atorvastatin at both 10 mg and 20 mg doses or fenofibrate 300 mg daily. Atorvastatin resulted in significantly greater reductions in TC and LDL-C. Whereas atorvastatin caused significant reductions in triglyceride and increases in HDL levels, fenofibrate was more effective in altering these parameters. However, at the 20 mg dose level

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atorvastatin resulted in greater reduction in TG, which was not significantly different from those achieved with fenofibrate [20]. A further study comparing the effect of simvastatin vs. atorvastatin on HDL and TG levels in patients with familial hyperlipidemia reported that triglyceride reduction was dose responsive with both statins but better with atorvastatin. On the contrary, HDL increases, while also being dose responsive were more pronounced with simvastatin [21]. In another study, atorvastatin, when compared with 4 statin–fibrate combinations, had a greater effect on LDL-C and Apo-B levels, but a lesser effect on HDL-C and triglycerides [10]. The basic difference between the above study and our work is that our patients were compared with each other while on each of the two therapeutic regimens. In the former study the group on atorvastatin was compared to 4 groups of other patients on different statin–fibrate combinations. This could well explain the differences observed. In a more recent study, atorvastatin alone (10 mg) was compared to combination therapy (atorvastatin + fenofibrate) and to fenofibrate alone in patients suffering from combined hyperlipidemia [11]. The main objective of this study was to compare vascular and metabolic responses to the three different drug regimens. The results of this study demonstrated reductions in triglycerides and cholesterol levels in all three groups. The difference between this study and ours (besides the higher atorvastatin dose that we used) is that the authors in the above study did not concentrate on achieving lipid level goals but discussed other parameters. In the present study, as expected, atorvastatin produced significant reductions in total cholesterol and LDL-C in our patients with mixed hyperlipidemia who had been on a statin–fibrate regimen. However, subtle modifications in triglyceride and HDL levels were apparent. An increase in the levels of the former and a reduction in the levels of the latter were found. These changes were small and in the absence of baseline levels, i.e. levels before any form of therapy was instituted, it becomes difficult to interpret their significance. They probably reflect the withdrawal of the fibrate which has a known greater effect on TG-lowering and HDL raising than the atorvastatin. Our observations are consistent with those reported by others [21–25]. It is also possible that reduced dietary compliance may have contributed to the higher triglyceride levels after atorvastatin therapy. Patients often become less compliant over a lengthy study. Moreover, the large intrapatient and interpatient variability of triglyceride levels can reduce the ability to detect associations, especially in comparison with the other less variable lipid parameters. Our study, thus, allows us to conclude that atorvastatin 20 mg daily is superior to the patients' prior therapy using combination therapy of statin and fibrate for LDL-C reduction. However, we cannot disregard the fact that a significant reduction in triglyceride levels was not demonstrated and there was an actual drop in HDL in the atorvastatin monotherapy

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arm of the study. The significance of such a fall is not known. In the VAHIT publication [26] there was a significant reduction in mortality from fibrate therapy with an associated change in HDL level of approximately 0.1 mmd/L. This is not dissimilar to the amount of HDL reduction noted in our study. Thus subtle and modest changes in HDL may be critical in the management of these patients. Further studies with clear clinical end-points are awaited to resolve this issue. Our results do suggest that 60% of the patients would definitely benefit from a switch to monotherapy with atorvastatin from the less desirable combination therapy. This figure of 60% is comparable with the results of Van Dam et al. [25] who, while treating patients with mixed hyperlipidemia, achieved desirable levels of TG and LDL-C in over 60% of their patients receiving monotherapy with atorvastatin. Athyros et al. also reported that 60% of their patients had a favorable triglyceride response to atorvastatin. Do we have sufficient evidence to determine what should be the recommended therapy for patients with mixed hyperlipidemia? Our study goes a fair way to providing an answer that monotherapy with a statin is probably sufficient. However, we admit that the study has its limitations. There was a small number of participants in each group. The study was neither blinded, nor was it powered to assess any clinically meaningful end-points. In light of the recent studies indicating that the dose of the statin is what is critical and that with aggressive cholesterol-lowering (80 mg daily of atorvastatin) significant atherosclerosis regression could be achieved [27], one possible approach would be to recommend high dose statins for all these patients. Certainly it has been demonstrated that the failure of achieving treatment goals with the use of a statin, either as monotherapy or combined with a fibrate, can be attributable to undertreatment with regard to the dose of the stain. The study patients received usual statin doses which were for the most part low doses. It is very likely that far better results could have been achieved using higher dosages of statins to meet therapeutic goals. Final recommendations for this patient cohort must await further work with hard clinical end-points. Only then can appropriate therapeutic regimens, based on sound scientific evidence, be advocated. 5. Learning points • Monotherapy with atorvastatin is an adequate and effective regimen for reducing LDL cholesterol in patients with combined hyperlipidemia. • 60% of the patients have a positive response with regard to triglyceride levels. • No serious adverse effects were detected with atorvastatin 20 mg/d therapy in this group of patients. References [1] Harrison's Principles of Internal Medicine 16th Ed., vol. 2, p. 2292–2293. [2] Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and

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