Long-term treatment with pitavastatin is effective and well tolerated by patients with primary hypercholesterolemia or combined dyslipidemia

Abstract

Objectives

The primary objective was to assess the safety and tolerability of pitavastatin 4 mg once daily during 52 weeks treatment. The secondary objectives were to assess the effect on lipid and lipoprotein fractions and ratios, and LDL-C target attainment.

Methods

Patients with primary hypercholesterolemia or combined dyslipidemia who had previously received pitavastatin, atorvastatin or simvastatin for 12 weeks during double-blind phase III studies received open-label pitavastatin 4 mg once daily for up to 52 weeks.

Results

Investigators at 72 sites enrolled 1353 patients who received at least one dose of pitavastatin 4 mg; 155 (11.5%) patients discontinued treatment during the 52-week follow up. The proportion of patients achieving NCEP and EAS LDL-C targets at week 52 was 74.0% and 73.5% respectively. The reduction in LDL-C levels seen during the double-blind studies was sustained, while HDL-C levels rose continually during follow up, ultimately increasing by 14.3% over the initial baseline. Changes in other efficacy parameters (triglycerides, total cholesterol, non-HDL-C, Apo-A1 and Apo-B, high sensitivity C-reactive protein, oxidised LDL) and ratios (total cholesterol: HDL-C, non-HDL-C:HDL-C and Apo-B:Apo-A1) were sustained during 52-weeks treatment compared with the end of the double-blind studies. Pitavastatin was well tolerated: 4.1% of patients withdrew from the study due to treatment emergent adverse events (TEAEs) and none of the serious adverse events were considered treatment-related. No clinically significant abnormalities were associated with pitavastatin in routine laboratory variables, urinalysis, vital signs or 12-lead ECG. There were no reports of myopathy, myositis or rhabdomyolysis. The most common TEAEs were: increased creatine phosphokinase (5.8%), nasopharyngitis (5.4%) and myalgia (4.1%).

Conclusion

Pitavastatin 4 mg once daily was effective and well tolerated during 52-weeks treatment in patients with primary hypercholesterolemia or combined dyslipidemia. Around three-quarters of patients achieved NCEP and EAS LDL-C targets at week 52, HDL-C levels rose continually during follow up, while changes in other efficacy parameters were sustained over the year-long study.

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.