Pitavastatin: An overview
Yasushi Saito*
President, Chiba University, Chiba, Japan

Compared to other statins, pitavastatin is a highly potent 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor and an efficient hepatocyte low-density lipoprotein-cholesterol (LDL-C) receptor inducer. Its characteristic structure (heptenoate as the basic structure, a core quinoline ring and side chains that include fluorophenyl and cyclopropyl moieties) provides improved pharmacokinetics and significant LDL-C-lowering efficacy at low doses. Unlike other statins, the cyclopropyl group on the pitavastatin molecule appears to divert the drug away from metabolism by cytochrome P450 (CYP) 3A4 and allows only a small degree of clinically insignificant metabolism by CYP2C9. As a result, pitavastatin is minimally metabolized; most of the bioavailable fraction of an oral dose is excreted unchanged in the bile and is reabsorbed by the small intestine ready for entero-hepatic recirculation. This process probably accounts for pitavastatin’s increased bioavailability relative to most other statins and contributes to its prolonged duration of action.
In addition to its potent LDL-C-lowering efficacy, a number of pleiotropic benefits that might lead to a reduction in residual risk have been suggested in vitro. These include beneficial effects on endothelial function, stabilisation of the coronary plaque, anti-inflammatory effects and anti-oxidation. With regard to the clinical safety and efficacy of pitavastatin, the Phase IV Collaborative study of Hypercholesterolemia drug Intervention and their Benefits for Atherosclerosis prevention (CHIBA study) showed similar changes in lipid profile with pitavastatin and atorvastatin in Japanese patients with hypercholesterolemia. However, a subgroup analysis of the CHIBA study showed that pitavastatin produced more significant changes from baseline in LDL-C, TG, and HDL-C in patients with hypercholesterolemia and metabolic syndrome. The clinical usefulness of pitavastatin has been further demonstrated in a number of Japanese patient groups with hypercholesterolemia, including those with insulin resistance, low levels of high-density lipoprotein-cholesterol (HDL-C), high levels of C-reactive protein, and chronic kidney disease. Finally, the Japan Assessment of Pitavastatin and AtorvastatiN in Acute Coronary Syndrome (JAPAN-ACS) study showed that pitavastatin induces plaque regression in patients with ACS, which suggests potential benefits for pitavastatin in reducing CV risk.
© 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Pitavastatin; Hypercholesterolemia; Statin; Pleiotropic

⦁ Introduction
Pitavastatin (LIVALO™) is a new member of the 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reductase in- hibitor (statin) family. It was first introduced in Japan in 2003 for the treatment of primary hyperlipidemia or mixed dyslipidemia and has since been licensed for use in Korea (2005), Thailand (2008), China (2009), the USA (2010) and Lebanon (2010). Pitavastatin has recently been approved for use in the European Union and is under regulatory review in Australia.

⦁ Pitavastatin: Relationship between structure and action
Statins have a structure similar to that of HMG-CoA and generally bind HMG-CoA reductase with a several

* Correspondence: Yasushi Saito. 1-33 Yayoi-cho, inage-ku, Chiba, 263-8522, Japan. Tel.: +81 43 290 2000; fax: +81 43 290 2107.
E-mail address: [email protected]fice.chiba-u.jp (Y. Saito).
thousand-fold greater affinity [1]. This inhibits mevalonate production from HMG-CoA and reduces the level of intracellular cholesterol, thereby stimulating low-density lipoprotein (LDL) receptor activity and increasing the uptake of non-high-density lipoprotein (non-HDL) particles from the systemic circulation.
Pitavastatin calcium (NK-104) was designed as a novel statin with a synthetic cyclopropyl side group (Fig. 1). This

Fig. 1. Chemical structure of pitavastatin. Reproduced from Saito (2009)
[2] with permission from Dove Medical Press Ltd.

1567-5688/ $ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.

unique structure contributes to a number of pharmacological benefits compared to other statins. For example, in vitro studies show that pitavastatin binds to HMG-CoA reductase with a 1.6- and 3.5-fold greater affinity than simvastatin or pravastatin, respectively [3], and that it inhibits HMG-CoA reductase in a competitive, concentration-dependent manner that is 2.4 times more potent than simvastatin and 6.8 times more potent than pravastatin [3]. Moreover, it enhances LDL-receptor binding and LDL-internalisation in a dose- dependent manner [4] and is associated with a significantly greater increase in LDL-receptor mRNA expression in vitro than either atorvastatin or simvastatin (P < 0.01 for both) [5]. Thus, pitavastatin effectively reduces LDL-C levels at lower doses than other statins [6−14].

⦁ Pharmacokinetic profile of pitavastatin
The pharmacokinetic profiles of statins vary from drug to drug [15]. Pitavastatin’s oral absorption is, at 80%, second only to fluvastatin and its level of protein binding is also among the highest (>95% for pitavastatin, simvas- tatin, atorvastatin and lovastatin vs. 50% for pravastatin) [16,17]. Whereas lovastatin, simvastatin and atorvastatin
inhibit monocyte–endothelium adhesion, reduce foam cell formation and cholesterol accumulation, improve plaque stabilisation, inhibit thrombosis formation, and reduce levels of inflammatory markers and oxidation [2].

⦁ Endothelial function
Endothelial dysfunction is an early marker for athero- sclerosis and is predictive of future CV events [20]. It is often seen in patients with hypercholesterolemia, coronary artery disease and type 2 diabetes and is characterised by reduced levels of endothelium-derived nitric oxide (eNO) and increased levels of endothelin-1 (ET-1). To evaluate the effects of pitavastatin on endothelial function, Morikawa et al. [21] carried out a DNA microarray analysis on cultured human umbilical vein endothelial cells (HUVEC) incubated with or without pitavastatin. After 8 hours, pitavastatin increased the mRNA levels of nitric oxide synthase-3 (eNOS) and reduced mRNA levels of ET-1 (Fig. 2). These effects are likely to increase vascular relaxation and inhibit platelet aggregation, vascular smooth muscle cell proliferation, and endothelium–leukocyte inter- actions, thereby leading to improved endothelial function.

Average difference
are metabolised predominantly by CYP3A4 and fluvastatin and rosuvastatin are metabolised by CYP2C9, pitavastatin’s cyclopropyl group diverts the drug away from metabolism by CYP3A4 and allows only a small amount of clinically insignificant metabolism by CYP2C9. As a result, most of the bioavailable fraction of an oral dose of pitavastatin is excreted unchanged in the bile and is then ready for entero- hepatic circulation by reabsorption in the small bowel. Less than 5% of a dose of pitavastatin is excreted in the urine. Moreover, studies in human hepatic microsomes have shown that, whereas the lactone metabolites of other statins





8 hours 24 hours






8 hours 24 hours

are rapidly eliminated by CYP isoenzymes, both pitavastatin
Pitavastatin 1.1 μM

acid and lactone undergo limited metabolism [18]. Thus, pitavastatin has a unique metabolic profile compared to other statins that contributes to an increased bioavailability, a longer duration of action and a lower probability of drug– food or drug–drug interactions.

⦁ Pleiotropic effects
Phase III and IV clinical trials have shown that pitavastatin is well tolerated and beneficially modifies lipid profile with a similar or greater efficacy to comparable doses of other statins [6−13,19]. Moreover, like other statins, pitavastatin has a number of pleiotropic effects beyond lipid-lowering that are expected to contribute to a reduction in residual CV risk. For example, pitavastatin can improve endothe- lial function, reduce monocyte activation and migration,
Fig. 2. Pitavastatin enhances eNOS mRNA expression and down- regulates ET-1 mRNA expression in human umbilical vein endothelial cells. Reproduced from Morikawa et al. (2002) [21] with permission from the Japan Atherosclerosis Society. eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; mRNA, messenger ribonucleic acid.

⦁ Plaque stabilisation
It is widely accepted that the incidence of secondary CV events can be significantly reduced by intensive statin therapy in patients with acute coronary syndrome (ACS) [22,23]. In addition to lowering the concentration of LDL-C, statins are thought to reduce the risk of coronary events by improving the composition and stability of the vulnerable plaque. The beneficial effects of pitavastatin on the coronary plaque were demonstrated in WHHL rabbits treated with pitavastatin 0.5 mg/kg for 16 weeks [24]. In this study, pitavastatin reduced plasma lipid levels and

decreased the area of the aortic lesion by 39%, reduced the macrophage-positive area in the aortic plaque by 39%, increased the areas occupied by collagen and a-SMA by 66% and 92%, respectively, increased the average thickness of a-SMA in the plaque by 97% and reduced the vulnerabil- ity index by 76%. Other changes included reductions in the positive area of monocyte chemoattractant protein-1 (39%) and in matrix metalloproteinase-3 (41%) and -9 (52%). Although studies have yet to confirm whether pitavastatin reduces CV risk in humans, the Japan Assessment of Pitavastatin and AtorvastatiN in Acute Coronary Syndrome (JAPAN-ACS) study showed that pitavastatin induced a 17% reduction in plaque volume in patients with ACS [25]. Together, these results suggest that pitavastatin has the potential to reduce CV risk in people with ACS by improving the composition of the atherosclerotic plaque and reversing stenosis.

⦁ Inflammation
Inflammation plays a pivotal role in all stages of athero- genesis, from the formation of foam cells and plaque enlargement, to plaque rupture and thrombosis [26]. Thus patients with chronic, low-grade inflammatory states, such as those with metabolic syndrome, are at particularly high risk of developing an ACS.
In vitro studies have shown that the level of inflammation determines the severity of neointimal thickness in injured vessels and therefore plays a critical role in restenosis after stenting. A study in porcine coronary vessels after stenting showed that administration of pitavastatin 40 mg QD 7 days before stenting until 3 or 28 days after stenting inhibited the early inflammatory response in the injured coronary artery [27]. Scanning electron microscopy showed significantly reduced levels of inflammatory cell infiltration in the treated vs. untreated vessels (Fig. 3). On Day 28, intravascular ultrasound and histopathological assessment showed that the neointimal area was significantly smaller at the stent site in animals treated with pitavastatin vs. placebo (2.16±0.13 mm2 vs. 2.88±0.25 mm2; P = 0.029). These
results suggest that pitavastatin inhibited neointimal hyper- plasia after stenting by reducing the inflammatory reaction.
Low-grade chronic inflammation can also be measured using hsCRP, high levels of which are independent risk factors for ACS. Several studies in humans have shown that hsCRP levels can be significantly reduced using statins [19,28,29]. In the Kansai Investigation of Statin for Hyperlipidemic Intervention in Metabolism and En- docrinology (KISHIMEN) study, for example, 12 months’ treatment with pitavastatin 1−2 mg QD resulted in a significant 34.8% decrease in serum hsCRP levels (P < 0.01 vs baseline) in Japanese patients with hypercholesterolemia

Fig. 3. Scanning electron microscope images showing lymphocyte production during the early inflammatory response in porcine coronary arteries after stenting after treatment with (A) Control and (B) Pitavastatin. Reproduced from Yokoyama et al. (2004) [27] with permission from Elsevier.

(58% with type 2 diabetes) [19]. This suggests that pitavas- tatin can reduce the pro-inflammatory response in people with atherosclerosis, an effect that is likely to reduce residual risk.

⦁ Anti-oxidation
The accumulation of oxidized LDL (Ox-LDL) in foam cells is central to the formation of atherosclerotic plaques [30]. Studies have shown that HDL particles can protect LDL against oxidation via the action of human serum para- oxonase 1 (PON1), an intrinsic component of HDL. To investigate the effects of statins on PON1 levels in vitro, a gene reporter assay was used to measure PON1 gene transcription in human hepatoma HepG2 cells and human embryonic kidney (HEK) 293 cells [31]. Pitavastatin, simvastatin, and atorvastatin each significantly increased PON1 promoter activity. However, pitavastatin- mediated transactivation was abrogated by mevalonic acid and farnesyl pyrophosphate (FPP) but not by geranyl- geranyl pyrophosphate. Furthermore, PON1 promoter ac- tivity was enhanced by farnesyl transferase inhibitor, but not by geranylgeranyl transferase inhibitor. Studies have demonstrated that PON1 gene transcription is dependent on Sp1 [32]. In this study, pitavastatin-mediated PON1 transactivation was abrogated by mithramycin (an inhibitor of Sp1) suggesting that pitavastatin activates transcription of the PON1 gene through the FPP pathway. These results demonstrate that, in addition to increasing the concentration of HDL, pitavastatin exerts anti-atherosclerotic effects by improving HDL functionality.

⦁ Tolerability and efficacy of pitavastatin: Phase IV trials
Pitavastatin’s long-term safety and efficacy have been estab- lished over a period of more than 60,000 patient-years in the Japanese long-term prospective post-marketing surveillance

% change from baseline to 12 weeks
LIVALO Effectiveness and Safety (LIVES) Study [13,33]. Moreover, the tolerability and lipid-lowering efficacy of pitavastatin compared to that of other statins have been clearly demonstrated in a number of Phase III [6−10,34] and IV [11,12,19,25] clinical trials in a wide range of patients with hypercholesterolemia.

⦁ Modifying lipid profile in Japanese subjects with hypercholesterolemia: Pitavastatin was non-inferior to atorvastatin
The Collaborative study of Hypercholesterolemia drug Intervention and their Benefits for Atherosclerosis pre- vention (CHIBA) study was a multicenter, open label, active control trial designed to assess the non-inferiority of pitavastatin 2 mg vs. atorvastatin 10 mg in 251 Japanese

Fig. 4.

Percent change from baseline in lipid profile after 12 weeks’

subjects with hypercholesterolemia (total cholesterol [TC]
>220 mg/dL) [11]. The mean age of the population at baseline was 61.5 years and 33% were male. After 12 weeks of treatment, non-HDL-C was reduced by 39.0% with pitavastatin and 40.3% with atorvastatin (P = 0.456). Both pitavastatin and atorvastatin significantly reduced LDL-C (by 42.6% and 44.1%), TC (by 29.7% and 31.1%),
and TG (by 17.3% and 10.7%, respectively), with no significant differences between treatments. HDL-C showed a significant increase at 12 weeks with pitavastatin (3.2%, P = 0.033 vs. baseline) but not with atorvastatin (1.7%, P = 0.221 vs. baseline).

⦁ Modifying lipid profile in Japanese subjects with hypercholesterolemia and cardiometabolic disease: Pitavastatin was generally better than atorvastatin
A subgroup analysis of CHIBA patients with metabolic syndrome (n = 53) showed that the percent reduction from baseline in LDL-C was significantly greater with pitavas- tatin than with atorvastatin (45.8% vs. 39.1%; P = 0.0495) (Fig. 4). Although the differences between pitavastatin and atorvastatin in TG and HDL-C were not significant, the re- duction in TG and the increase in HDL-C vs. baseline were only significant with pitavastatin (25.2%; P < 0.001 and 6.7%; P = 0.019, respectively). The increase in efficacy that was observed with pitavastatin vs. atorvastatin in patients with vs. without metabolic syndrome might be explained by the relationship between statin efficacy and obesity. Further analysis of CHIBA data showed that atorvastatin’s non-HDL-C-lowering efficacy was significantly reduced as waist circumference, body weight and BMI increased, whereas pitavastatin demonstrated consistent efficacy ir- respective of obesity-related parameters [11]. Pitavastatin might therefore be a useful treatment option for people with hypercholesterolemia and metabolic syndrome or diabetes,
treatment with atorvastatin or pitavastatin in CHIBA patients with metabolic syndrome [11]. Numbers in parentheses are numbers of subjects;
*P < 0.05, **P < 0.01, ***P < 0.001 (vs Week 0) by one sample t-test;
†P < 0.05 (vs. atorvastatin) by Wilcoxon t-test.

in whom the incidence of obesity is high and HDL-C levels are likely to be low.
Further evidence for the HDL-elevating benefits of pitavastatin vs. atorvastatin in people with, or at risk of developing, diabetes was obtained from the Effects of Pitavastatin and ATorvastatin on HDL-Cholesterol Levels in Patients with Hyper-LDL Cholesterolemia and Glu- cose Intolerance (PIAT) study [12] and the KISHIMEN study [19]. In the multicentre, open-label parallel-group PIAT trial [12], pitavastatin 2 mg QD was compared with atorvastatin 10 mg QD in 207 Japanese patients with LDL-C
140 mg/dL and glucose intolerance. The mean age of the population at baseline was 63 years, 38% were male, and there were no significant between-group differences in mean LDL-C (163.7 mg/dL in the pitavastatin group vs.
161.9 mg/dL with atorvastatin), fasting blood glucose (134.8 mg/dL vs. 131.7 mg/dL) or HbA1c (6.5% vs. 6.4%). After 52 weeks, HDL-C (8.2% vs. 2.9%; P = 0.031) and apolipoprotein A1 (apo A1) levels (5.1 vs. 0.6; P = 0.019) were increased significantly more with pitavastatin vs. atorvastatin. Although the reductions in LDL-C (40.1% vs. 33.0%; P = 0.002), non-HDL-C (37.4 vs. 31.1; P = 0.004), apo B (35.1 vs. 28.2; P < 0.001), and apo E (28.1 vs. 17.8; P < 0.001) were greater with atorvastatin vs. pitavastatin, reductions vs. baseline were significant for both treatment groups.
In the KISHIMEN study [19], pitavastatin demonstrated significant reductions in serum LDL-C (30.3%) and RLP-C levels (22.8%) in 178 Japanese subjects with hyper- cholesterolemia, including 58% with type 2 diabetes. TG levels were decreased by 15.9% in subjects with high

baseline TG (>50 mg/dL) and serum HDL-C levels were significantly increased by up to 5.9% in the general cohort and by up to 22.4% in patients with low baseline HDL-C (<40 mg/dL). No serious adverse events were observed and there were no significant changes in glycosylated hemoglobin levels in diabetic patients. Overall, the results from Phase IV studies suggest that pitavastatin is a well-tolerated and effective treatment for improving lipid profile − in particular HDL-C levels − in patients with hypercholesterolemia with or without cardiometabolic dis- ease. Compared to atorvastatin, pitavastatin offers particular benefits for obese patients and for those with low levels of HDL-C.

⦁ Conclusions
Pitavastatin’s novel structure contributes to a number of pharmacological benefits compared to other statins, including inhibition of cholesterol synthesis at low doses, minimal metabolism leading to increased bioavailability and an extended duration of action, and a unique metabolic profile that reduces the risk of drug–food and drug– drug interactions [2]. Phase III and IV clinical trials show that pitavastatin has robust LDL-C-lowering efficacy at lower doses than other statins and has significant HDL-C- elevating activity that is sustained and even increased over time [6−13,19,25,33−35]. Unlike atorvastatin, pitavastatin’s efficacy is not reduced by obesity-related parameters, making it an ideal treatment choice for people with cardiometabolic diseases, in whom obesity rates are high and HDL levels are likely to be low. In addition to its effects on lipid profile, pitavastatin has a number of pleiotropic benefits that have the potential to reduce residual CV risk. These include effects that improve endothelial function, reduce monocyte activation and mi- gration, inhibit monocyte–endothelium adhesion, reduce foam cell formation and cholesterol accumulation, improve plaque stabilisation, and reduce levels of inflammatory markers and oxidation [2]. Overall, pitavastatin is a well- tolerated and effective alternative treatment for patients with hypercholesterolemia and may be particularly beneficial for those with obesity and/or low HDL-C.

Conflict of interest statement
The author has no conflicts of interest to declare.

⦁ Corsini A, Bellosta S, Baetta R, et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 1999;84:413−28.
⦁ Saito Y. Critical appraisal of the role of pitavastatin in treating dyslipidemias and achieving lipid goals. Vasc Health Risk Manag 2009;5:921−36.
⦁ Aoki T, Nishimura H, Nakagawa S, et al. Pharmacological profile of a novel synthetic inhibitor of 3-hydroxy-3-methylglutaryl- coenzyme A reductase. Arzneimittelforschung 1997;47:904−9.
⦁ Tamaki T, Nakagawa S, Tanabe S. Effect of NK-104 on lipid metabolism in HepG2 cells: inhibition of cholesterol synthesis and enhancement of LDL receptor activity. Kowa Company Ltd. Tokyo Research Laboratories, Japan; 1994.
⦁ Morikawa S, Umetani M, Nakagawa S, et al. Relative induction of mRNA for HMG CoA reductase and LDL receptor by five different HMG-CoA reductase inhibitors in cultured human cells. J Atheroscler Thromb 2000;7:138−44.
⦁ Budinski D, Arneson V, Hounslow N, et al. Pitavastatin compared with atorvastatin in primary hypercholesterolemia or combined dyslipidemia. Clin Lipidol 2009;4:291–302.
⦁ Hounslow NJ, Budinski D, Eriksson M. Pitavastatin 4 mg shows comparable LDL-cholesterol and superior triglyceride reduction to simvastatin 40 mg in high-risk primary hypercholesterolemia or combined dyslipidaemia. Atheroscler Suppl 2010;11(2):188 (abstract MS389).
⦁ Ose L, Budinski D, Hounslow N, et al. Comparison of pitavastatin with simvastatin in primary hypercholesterolaemia or combined dyslipidaemia. Curr Med Res Opin 2009;25:2755−64.
⦁ Ose L, Budinski D, Hounslow N, et al. Long-term treatment with pitavastatin is effective and well tolerated by patients with primary hypercholesterolemia or combined dyslipidemia. Atherosclerosis 2010;210:202−8.
⦁ Stender S, Hounslow N. Robust efficacy of pitavastatin and comparable safety to pravastatin. Atheroscler Suppl 2009;10:P770.
⦁ Yokote K, Bujo H, Hanaoka H, et al. Multicenter collaborative randomized parallel group comparative study of pitavastatin and atorvastatin in Japanese hypercholesterolemic patients: collaborative study on hypercholesterolemia drug intervention and their benefits for atherosclerosis prevention (CHIBA study). Atherosclerosis 2008;201:345−52.
⦁ Sasaki J, Ikeda Y, Kuribayashi T, et al. A 52-week, randomized, open-label, parallel-group comparison of the tolerability and effects of pitavastatin and atorvastatin on high-density lipoprotein
cholesterol levels and glucose metabolism in Japanese patients with elevated levels of low-density lipoprotein cholesterol and glucose intolerance. Clin Ther 2008;30:1089–101.
⦁ Kurihara Y, Douzono T, Kawakita K, et al. A large-scale, long-term prospective post-marketing surveillance of pitavastatin (Livalo) − Livalo effectiveness and safety study (LIVES). Jpn Pharmacol Ther 2008;36:709−31.
⦁ Betteridge J. Pitavastatin: Results from phase III and IV trials. Atheroscler Suppl 2010;11:8−14.
⦁ Mukhtar RY, Reid J, Reckless JP. Pitavastatin. Int J Clin Pract 2005;59:239−52.
⦁ Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid- lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006;80:565−81.
⦁ Fujino H, Yamada I, Shimada S, et al. Metabolic fate of pitavastatin (NK-104), a new inhibitor of 3-hydroxy-3- methyl-glutaryl coenzyme A reductase. Effects on drug-
metabolizing systems in rats and humans. Arzneimittelforschung 2002;52:745−53.
⦁ Fujino H, Saito S, Tsunenari Y, et al. Metabolic properties of the acid and lactone forms of HMG-CoA reductase inhibitors. Xeno- biotica 2004;34:961−71.
⦁ Koshiyama H, Taniguchi A, Tanaka K, et al. Effects of pitavastatin on lipid profiles and high-sensitivity CRP in Japanese subjects with hypercholesterolemia: Kansai Investigation of
Statin for Hyperlipidemic Intervention in Metabolism and Endocrinology (KISHIMEN) investigators. J Atheroscler Thromb 2008;15:345−50.

⦁ Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol 2001;21:1712−9.
⦁ Morikawa S, Takabe W, Mataki C, et al. The effect of statins on mRNA levels of genes related to inflammation, coagulation, and vascular constriction in HUVEC. Human umbilical vein endothelial cells. J Atheroscler Thromb 2002;9:178−83.
⦁ Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–504.
⦁ Wiviott SD, Mohanavelu S, Raichlen JS, et al. Safety and efficacy of achieving very low low-density lipoprotein cholesterol levels with rosuvastatin 40 mg daily (from the ASTEROID Study). Am J Cardiol 2009;104:29−35.
⦁ Suzuki H, Kobayashi H, Sato F, et al. Plaque-stabilizing effect of pitavastatin in Watanabe heritable hyperlipidemic (WHHL) rabbits. J Atheroscler Thromb 2003;10:109−16.
⦁ Hiro T, Kimura T, Morimoto T, et al. Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of pitavastatin and atorvastatin in acute coronary syndrome] study). J Am Coll Cardiol 2009;54:293–302.
⦁ Libby P. Inflammation in atherosclerosis. Nature 2002;420: 868−74.
⦁ Yokoyama T, Miyauchi K, Kurata T, et al. Inhibitory efficacy of pitavastatin on the early inflammatory response and neointimal
thickening in a porcine coronary after stenting. Atherosclerosis 2004;174:253−9.
⦁ Albert MA, Danielson E, Rifai N, et al. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001;286:64−70.
⦁ Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001;344:1959−65.
⦁ Steinberg D, Witztum JL. Lipoproteins, lipoprotein oxidation, and atherogenesis. Molecular Basis of Cardiovascular Disease. Philadelphia: W.B. Saunders; 1999. p. 428−76.
⦁ Ota K, Suehiro T, Arii K, et al. Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene. Metabolism 2005;54:142−50.
⦁ Arii K, Suehiro T, Ota K, et al. Pitavastatin induces PON1 expression through p44/42 mitogen-activated protein kinase signaling cascade in Huh7 cells. Atherosclerosis 2009;202:439−45.
⦁ Teramoto T, Urashima M, Shimano H, et al. A large-scale study on cardio-cerebrovascular events during pitavastatin (LIVALO tablet) therapy in Japanese patients with hypercholesterolemia LIVES
5-year extension study. Jpn Pharmacol Ther 2011;39:789–803.
⦁ Chapman MJ. Pitavastatin: Novel effects on lipid parameters. Atheroscl Suppl 2011;12(3):277−84.
⦁ Teramoto T. Pitavastatin: Clinical effects from the LIVES Study. Atheroscl Suppl 2011;12(3):285−8.

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