Pitavastatin: a Distinctive Lipid-Lowering Drug
Addressing dyslipidemia is crucial to reducing the burden imposed by cardiovascular disease. However, many current statins have major limitations. Moreover, innovative treatments need to address non-LDL-C residual risk (which may be marked by high triglycerides, low HDL-C concentrations or raised ApoB:ApoA1 ratio) and increase the proportion of patients attaining treatment targets. Pitavastatin is a novel statin that induces plaque regression and is non-inferior to atorvastatin and, on some measures, superior to simvastatin and to pravastatin in the elderly. Pitavastatin addresses non-LDL-C risk factors, including producing reproducible and sustained increases in HDL-C levels. Both the pitavastatin molecule and the lactone metabolite undergo very little metabolism by CYP3A4 and, therefore, unlike some other statins, does not interact with CYP3A4 substrates. Pitavastatin is well tolerated. As such, pitavastatin shows distinctive pharmacokinetic and clinical profiles that should help a greater proportion of dyslipidemic patients attain their treatment goals.
Cardiovascular disease (CVD) is a major contributor to global morbidity, mortality and disability. Indeed, the WHO estimates that CVD accounted for 29% of global mortality during 2004. Numerous mutually reinforcing factors, including dyslipidemia, contribute to CVD. A recent paper analyzed data from 302,430 people without vascular disease at baseline in 68 long-term prospective studies. Coronary heart disease (CHD) rates per 1000 person-years in the bottom and top thirds of baseline lipids were 2.6 and 6.2, respectively, for triglycerides, 6.4 and 2.4, respectively, for HDL-C and 2.3 and 6.7, respectively, for non-HDL-C. Adjusted hazard ratios for CHD comparing the bottom and top tertiles were 0.99, 0.78 and 1.50, respectively. CHD hazard ratios were 1.50 comparing the bottom and top tertiles for non-HDL-C:HDL-C ratio, 1.49 for ApoB:ApoA1 ratio and 1.38 for LDL-C. Hazard ratios for ischemic stroke were 1.02 comparing the bottom and top thirds for triglycerides, 0.93 for HDL-C and 1.12 for non-HDL-C. Clearly, managing dyslipidemia is critical to reduce the human, clinical and societal burdens imposed by CVD.
HMG-CoA reductase inhibitors (statins) are the mainstay of dyslipidemia management. A meta-analysis of 14 studies estimated that the mean LDL-C reduction following 1 year of statin treatment varied from 0.35 to 1.77 mmol/l (mean: 1.09). All-cause and coronary mortality declined by 12 and 19%, respectively, for each mmol/l reduction in LDL-C concentrations. Furthermore, each mmol/l decline in LDL-C level was associated with a risk reduction for myocardial infarction or coronary death of 23%, coronary revascularization of 24% and fatal or nonfatal stroke of 17%. Combining these end points, each mmol/l decline in LDL-C concentration was associated with a reduction in total risk of major vascular events of 21%. The reduced risk attained statistical significance within the first year and the size of the benefit increased subsequently. Overall, 48 and 25 fewer participants with and without CHD, respectively, at baseline would experience major vascular events for every 1000 people treated with statins.
Despite this clinical efficacy, current statins have limitations. First, for example, there are adverse events associated with statins, including myopathy, gastrointestinal disturbances, altered liver function tests, sleep disturbances, headache, paresthesia and hypersensitivity reactions. The risk of rhabdomyolysis (which, while rare, remains possibly the most serious adverse event associated with statins) is 0.44 per 10,000 treatment-years for simvastatin, atorvastatin and pravastatin. The risk reached 5.34 per 10,000 treatment-years with cerivastatin, which was withdrawn from the market.
Several factors contribute to the risk of developing myopathy during statin treatment. For example, the risk of developing muscular disorders with statins is sixfold higher among patients taking concurrent drugs that inhibit CYP3A4 compared with controls. CYP3A4 metabolizes lovastatin, simvastatin and atorvastatin. As discussed later, statins that act as a substrate for CYP3A4 potentially cause clinically significant interactions with concurrent medications and dietary components metabolized by this isoenzyme.
In fully adherent patients, statins potentially reduce LDL-C concentrations by at least 1.5 mmol/l and, therefore, the risk of major vascular events by approximately a third. However, considerable residual risk (approximately two-thirds) remains in patients in whom statins reduce LDL-C levels to target values. Therefore, innovative treatments for dyslipidemia need to address a wider range of risk factors than LDL-C alone, including increased triglyceride concentrations, reduced HDL-C concentrations and increased ApoB:ApoA1 ratio. For example, among statin-treated patients with known CHD, the ApoB:ApoA1 ratio predicts clinical outcomes after correcting for standard risk factors. The corrected LDL-C:HDL-C ratio did not show this correlation. An increased ApoB:ApoA1 ratio may offer a marker for early atherosclerosis as well as unstable plaques that produce weak ultrasound signals. Such associations might underlie the prognostic value offered by the ApoB:ApoA1 ratio in addition to conventional risk factors.
Finally, many patients at high-risk of developing CVD, or with overt disease, have LDL-C levels that exceed those recommended in primary and secondary prevention guidelines, even when taking statin therapy. In one study, approximately half of patients did not achieve LDL-C targets with their initial statin dose. Of these, 86% had not reached the LDL-C target after 6 months, despite dose titration and receiving the clinician's statin of choice. In another study, 34.7 and 27.4% of general practice patients in the UK did not attain the total cholesterol and LDL-C goals, respectively, set by Joint British guidelines within 1 year of starting statins. Furthermore, 68.2 and 57.6% of subjects failed to attain optimal levels of HDL-C and triglycerides, respectively, as defined in European management guidelines.
As these limitations suggest, there is still a need for new agents to manage dyslipidemia. This review examines pitavastatin, a novel statin that potentially represents an important addition to the cardiovascular armamentarium. Kowa launched pitavastatin in Japan during September 2003 for hypercholesterolemia and familial hypercholesterolemia after completing a Japanese development program. In June 2008, Kowa launched pitavastatin in Korea and Thailand. Regulatory submissions have been made in a number of additional countries following the completion of a European and American development program. The US FDA approved pitavastatin doses of 1–4 mg in August 2009, and pitavastatin is currently under evaluation in Europe. The review summarizes the evidence that pitavastatin is efficacious and well tolerated in a broad range of patients and offers a distinctive pharmacodynamic and pharmacokinetic profile.
Abstract and Introduction
Abstract
Addressing dyslipidemia is crucial to reducing the burden imposed by cardiovascular disease. However, many current statins have major limitations. Moreover, innovative treatments need to address non-LDL-C residual risk (which may be marked by high triglycerides, low HDL-C concentrations or raised ApoB:ApoA1 ratio) and increase the proportion of patients attaining treatment targets. Pitavastatin is a novel statin that induces plaque regression and is non-inferior to atorvastatin and, on some measures, superior to simvastatin and to pravastatin in the elderly. Pitavastatin addresses non-LDL-C risk factors, including producing reproducible and sustained increases in HDL-C levels. Both the pitavastatin molecule and the lactone metabolite undergo very little metabolism by CYP3A4 and, therefore, unlike some other statins, does not interact with CYP3A4 substrates. Pitavastatin is well tolerated. As such, pitavastatin shows distinctive pharmacokinetic and clinical profiles that should help a greater proportion of dyslipidemic patients attain their treatment goals.
Introduction
Cardiovascular disease (CVD) is a major contributor to global morbidity, mortality and disability. Indeed, the WHO estimates that CVD accounted for 29% of global mortality during 2004. Numerous mutually reinforcing factors, including dyslipidemia, contribute to CVD. A recent paper analyzed data from 302,430 people without vascular disease at baseline in 68 long-term prospective studies. Coronary heart disease (CHD) rates per 1000 person-years in the bottom and top thirds of baseline lipids were 2.6 and 6.2, respectively, for triglycerides, 6.4 and 2.4, respectively, for HDL-C and 2.3 and 6.7, respectively, for non-HDL-C. Adjusted hazard ratios for CHD comparing the bottom and top tertiles were 0.99, 0.78 and 1.50, respectively. CHD hazard ratios were 1.50 comparing the bottom and top tertiles for non-HDL-C:HDL-C ratio, 1.49 for ApoB:ApoA1 ratio and 1.38 for LDL-C. Hazard ratios for ischemic stroke were 1.02 comparing the bottom and top thirds for triglycerides, 0.93 for HDL-C and 1.12 for non-HDL-C. Clearly, managing dyslipidemia is critical to reduce the human, clinical and societal burdens imposed by CVD.
HMG-CoA reductase inhibitors (statins) are the mainstay of dyslipidemia management. A meta-analysis of 14 studies estimated that the mean LDL-C reduction following 1 year of statin treatment varied from 0.35 to 1.77 mmol/l (mean: 1.09). All-cause and coronary mortality declined by 12 and 19%, respectively, for each mmol/l reduction in LDL-C concentrations. Furthermore, each mmol/l decline in LDL-C level was associated with a risk reduction for myocardial infarction or coronary death of 23%, coronary revascularization of 24% and fatal or nonfatal stroke of 17%. Combining these end points, each mmol/l decline in LDL-C concentration was associated with a reduction in total risk of major vascular events of 21%. The reduced risk attained statistical significance within the first year and the size of the benefit increased subsequently. Overall, 48 and 25 fewer participants with and without CHD, respectively, at baseline would experience major vascular events for every 1000 people treated with statins.
Despite this clinical efficacy, current statins have limitations. First, for example, there are adverse events associated with statins, including myopathy, gastrointestinal disturbances, altered liver function tests, sleep disturbances, headache, paresthesia and hypersensitivity reactions. The risk of rhabdomyolysis (which, while rare, remains possibly the most serious adverse event associated with statins) is 0.44 per 10,000 treatment-years for simvastatin, atorvastatin and pravastatin. The risk reached 5.34 per 10,000 treatment-years with cerivastatin, which was withdrawn from the market.
Several factors contribute to the risk of developing myopathy during statin treatment. For example, the risk of developing muscular disorders with statins is sixfold higher among patients taking concurrent drugs that inhibit CYP3A4 compared with controls. CYP3A4 metabolizes lovastatin, simvastatin and atorvastatin. As discussed later, statins that act as a substrate for CYP3A4 potentially cause clinically significant interactions with concurrent medications and dietary components metabolized by this isoenzyme.
In fully adherent patients, statins potentially reduce LDL-C concentrations by at least 1.5 mmol/l and, therefore, the risk of major vascular events by approximately a third. However, considerable residual risk (approximately two-thirds) remains in patients in whom statins reduce LDL-C levels to target values. Therefore, innovative treatments for dyslipidemia need to address a wider range of risk factors than LDL-C alone, including increased triglyceride concentrations, reduced HDL-C concentrations and increased ApoB:ApoA1 ratio. For example, among statin-treated patients with known CHD, the ApoB:ApoA1 ratio predicts clinical outcomes after correcting for standard risk factors. The corrected LDL-C:HDL-C ratio did not show this correlation. An increased ApoB:ApoA1 ratio may offer a marker for early atherosclerosis as well as unstable plaques that produce weak ultrasound signals. Such associations might underlie the prognostic value offered by the ApoB:ApoA1 ratio in addition to conventional risk factors.
Finally, many patients at high-risk of developing CVD, or with overt disease, have LDL-C levels that exceed those recommended in primary and secondary prevention guidelines, even when taking statin therapy. In one study, approximately half of patients did not achieve LDL-C targets with their initial statin dose. Of these, 86% had not reached the LDL-C target after 6 months, despite dose titration and receiving the clinician's statin of choice. In another study, 34.7 and 27.4% of general practice patients in the UK did not attain the total cholesterol and LDL-C goals, respectively, set by Joint British guidelines within 1 year of starting statins. Furthermore, 68.2 and 57.6% of subjects failed to attain optimal levels of HDL-C and triglycerides, respectively, as defined in European management guidelines.
As these limitations suggest, there is still a need for new agents to manage dyslipidemia. This review examines pitavastatin, a novel statin that potentially represents an important addition to the cardiovascular armamentarium. Kowa launched pitavastatin in Japan during September 2003 for hypercholesterolemia and familial hypercholesterolemia after completing a Japanese development program. In June 2008, Kowa launched pitavastatin in Korea and Thailand. Regulatory submissions have been made in a number of additional countries following the completion of a European and American development program. The US FDA approved pitavastatin doses of 1–4 mg in August 2009, and pitavastatin is currently under evaluation in Europe. The review summarizes the evidence that pitavastatin is efficacious and well tolerated in a broad range of patients and offers a distinctive pharmacodynamic and pharmacokinetic profile.
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