Long-term treatment with pitavastatin is effective and well tolerated by patients with primary hypercholesterolemia or combined dyslipidemia
Introduction
Despite continual therapeutic advances, cardiovascular disease (CVD) remains a major contributor to global morbidity, mortality and disability. During 2005, the World Health Organisation estimates that CVD caused 30% of global mortality. In contrast, cancer, chronic respiratory disease and diabetes together accounted for 27% of deaths worldwide. About 80% of deaths from CVD occur in low- and middle-income countries [1].
Managing dyslipidemia is one important element in the multifaceted approach needed to reduce the global burden of CVD. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the mainstay of dyslipidemia management. A meta-analysis of 14 randomised studies of HMG-CoA reductase inhibitors that enrolled 90 056 patients showed that over a mean duration of five years each mmol/L reduction in low density lipoprotein cholesterol (LDL-C) translated into decreases of 12% and 19% in total and coronary mortality respectively [2]. However, HMG-CoA reductase inhibitors may be associated with adverse events including myopathy, gastrointestinal disturbances, altered liver function tests, sleep disturbance, headache, paraesthesia and hypersensitivity reactions [3]. The risk of rhabdomyolysis ranges from 0.44 per 10,000 treatment-years for simvastatin, atorvastatin and pravastatin, to 5.34 per 10,000 treatment-years with cerivastatin [4], which has now been withdrawn from the market.
Despite the efficacy of HMG-CoA reductase inhibitors, many patients with a history of CVD or at unacceptable cardiovascular risk still have LDL-C levels above the concentrations recommended in primary and secondary prevention guidelines, such as those published by the European Atherosclerosis Society (EAS) [5] and National Cholesterol Education Program (NCEP) [6]. For instance, in one study around half of patients did not achieve LDL-C targets with the initial dose of HMG-CoA reductase inhibitors. Of these, 86% had still not reached their LDL-C target after 6 months, despite dose titration and the use of the clinician's HMG-CoA reductase inhibitor of choice [7]. In another study, 34.7% and 27.4% of general practice patients in the United Kingdom did not attain the total cholesterol and LDL-C goals set by Joint British guidelines, respectively, within a year of starting HMG-CoA reductase inhibitors. Furthermore, 68.2% of subjects failed to attain optimal levels of high density lipoprotein cholesterol (HDL-C) and 57.6% failed to attain optimal levels of triglycerides, as defined in European guidelines [8]. There is, therefore, a crucial need for new agents to manage dyslipidemia.
Pitavastatin, a potent inhibitor of HMG-CoA reductase, was launched in 2003 in Japan, and is now available in several Asian countries. Pitavastatin is currently undergoing regulatory assessment in Europe and other western countries and was recently approved for marketing in the USA. In vitro studies have demonstrated that pitavastatin competitively inhibits HMG-CoA reductase 2.4 and 6.8 times more potently than simvastatin and pravastatin respectively [9]. In a human cell line (HepG2), pitavastatin inhibited cholesterol synthesis 2.9 and 5.7 times more potently than simvastatin and atorvastatin respectively [10].
Clinical studies confirm pitavastatin's effectiveness in controlling lipid levels. For example, in patients ≥65 years of age, pitavastatin (1, 2, 4 mg/day) produced statistically superior reductions in LDL-C (31–44%) compared with pravastatin (10, 20, 40 mg day; 22–34%) over 12 weeks [11]. Another 12-week, prospective, open-label trial found comparable reductions in LDL-C with pitavastatin (2 mg/day) and atorvastatin (10 mg/day). However, HDL-C concentrations increased with pitavastatin, but not following atorvastatin [12].
This paper reports the results of a long-term extension study of patients with primary hypercholesterolemia or combined dyslipidemia who had completed one of two double-blind phase III studies that assessed the efficacy and tolerability of pitavastatin. Results from the first study demonstrated that the efficacy of pitavastatin was non-inferior to atorvastatin in reducing LDL-C at low (2 mg/day and 10 mg/day respectively) and high doses (4 mg/day and 20 mg/day respectively) [13]. In the second study, pitavastatin was non-inferior to simvastatin at low doses (2 mg/day and 20 mg/day) and high doses (4 mg/day and 40 mg/day) [14].
The primary objective of this extension phase was to assess the long-term safety and tolerability of pitavastatin 4 mg once daily. The secondary objectives were to assess the long-term efficacy of pitavastatin 4 mg once daily on lipid and lipoprotein fractions and ratios, and, LDL-C target attainment, as defined by the EAS [5] and NCEP [6] guidelines.
Section snippets
Study design
Investigators at 72 sites in Denmark, Finland, India, Italy, Norway, Russia, and the United Kingdom enrolled male and female patients, with primary hypercholesterolemia or combined dyslipidemia: mean LDL-C ≥4.2 mmol/L (160 mg/dL) and ≤5.7 mmol/L (220 mg/dL), and triglycerides ≤4.6 mmol/L (400 mg/dL). Patients with the heterozygous component of familial hypercholesterolemia could be enrolled in the study (see supplementary information). Patients with homozygous familial hypercholesterolemia or
Patient demographics, disposition and compliance
Investigators enrolled 1353 patients who received at least one dose of pitavastatin 4 mg (the safety population). Supplementary Table 2 summarises patient demographics and disposition: 11.5% of the safety population discontinued from the study. About a third of withdrawals (4.1% of the total study population) were due to treatment emergent adverse events (TEAE). The withdrawals of consent were not drug-related. More than half of the patients were female, the average age was 58.6 years and 88.2%
Discussion
This 52-week extension of two double-blind studies [13], [14] confirmed the results of in vitro investigations [9], [10] and previous clinical studies [11], [12], [13], [14] demonstrating that pitavastatin is a potent HMG-CoA reductase inhibitor that significantly reduces LDL-C concentrations in patients with primary hypercholesterolemia or combined dyslipidemia. This study shows that pitavastatin 4 mg once daily is effective and well tolerated during long-term treatment. Pitavastatin is
Conflict of interest
Leiv Ose has disclosed that he has received research grant funding from Merck, Pfizer, Schering-Plough, Roche and Boehringer Ingelheim; that he is a consultant/advisor to Kowa; and that he has received speakers bureau fees from AstraZeneca and Kowa. Dragos Budinski and Neil Hounslow are employees of Kowa Research Europe Ltd., Valerie Arneson is an employee of PharmaNet Ltd.
Acknowledgements
The authors acknowledge the assistance of our colleagues in the 72 centres who participated in this study. Mark Greener, a medical writer, assisted with the drafting of this manuscript. However, the authors are responsible for the final document. Kowa Research Europe Ltd. funded the study and the preparation of this manuscript. The trial is registered at www.clinicaltrials.gov as NCT00325780.
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