Pitavastatin in cardiometabolic disease: therapeutic profile

Statins effectively lower low-density lipoprotein-cholesterol (LDL-C) and reduce cardiovascular risk in people with dyslipidemia and cardiometabolic diseases such as Metabolic syndrome (MetS) or type 2 diabetes (T2D). In addition to elevated levels of LDL-C, people with these conditions often have other lipid-related risk factors, such as high levels of triglycerides, low levels of high-density lipoprotein-cholesterol (HDL-C), and a preponderance of highly atherogenic, small, dense low-density lipoprotein particles. The optimal management of dyslipidemia in people with MetS or T2D should therefore address each of these risk factors in addition to LDL-C. Although statins typically have similar effects on LDL-C levels, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects, adverse event profiles and drug-drug interactions. The choice of statin should therefore depend on the characteristics and needs of the individual patient. Compared with other statins, pitavastatin has distinct pharmacological features that translate into a broad range of actions on both apolipoprotein-B-containing and apolipoprotein-A-containing lipoproteins. Studies show that pitavastatin 1 to 4 mg is well tolerated and significantly improves LDL-C and triglyceride levels to a similar or greater degree than comparable doses of atorvastatin, simvastatin or pravastatin, irrespective of diabetic status. Moreover, whereas most statins show inconsistent effects on HDL-C levels, pitavastatin-treated patients routinely experience clinically significant elevations in HDL-C that are maintained and even increased over the long term. In addition to increasing high-density lipoprotein quantity, pitavastatin appears to improve high-density lipoprotein function and to slow the progression of atherosclerotic plaques by modifying high-density lipoprotein-related inflammation and oxidation, both of which are common in patients with MetS and T2D. When choosing a statin, it is important to note that patients with MetS have an increased risk of developing T2D and that some statins can exacerbate this risk via adverse effects on glucose regulation. Unlike many statins, pitavastatin appears to have a neutral and even beneficial effect on glucose regulation, making it a useful treatment option in this high-risk group of patients. Together with pitavastatin’s beneficial effects on the cardiometabolic lipid profile and its low potential for drug-drug interactions, this suggests that pitavastatin might be a useful lipid-lowering option for people with cardiometabolic disease.

additional therapy, and poor persistence with medications due to cost, adverse events and/or drug-drug interactions (DDIs) [8]. If LDL-C-target attainment rates are to be improved, these problems must be avoided. It is therefore important to tailor the choice of fi rst-line lipidlowering agent according to a patient's individual clinical profi le and therapeutic need.
Although LDL-C-lowering is important for the reduction of CV risk, studies have shown that the risk of CV events in patients that fully attain their recommended LDL-C-target is only reduced by about one-third [9], leaving substantial residual risk. In addition to elevated levels of LDL-C, people with MetS and T2D often have other lipid-related risk factors, such as high levels of triglycerides, low levels of high-density lipoproteincholesterol (HDL-C), and a preponderance of highly athero genic, small, dense low-density lipoprotein particles [10][11][12]. Th e optimal management of dyslipidemia in people with these conditions should therefore address each of these risk factors in addition to LDL-C. However, further studies are required to fully understand the therapeutic benefi ts of the various lipid-lowering drugs for the reduction of residual risk and to better defi ne nonlow-density lipoprotein treatment targets.

Pitavastatin
Pitavastatin is a relatively new member of the statin family. Pitavastatin was fi rst introduced in Japan in 2003 for the treatment of primary hyperlipidemia or mixed dyslipidemia and has since been licensed for use in 13 countries worldwide, including the USA, Japan, China, Germany and Spain. Pitavastatin has recently been approved for use in 20 additional countries, including the UK, Australia, and France, and is pending approval in a further 12 countries. Compared with other statins, pitava statin has a unique structure that contributes to a number of pharmacological benefi ts, including increased systemic bioavailability [13], a high level of oral absorption [14,15] and potent eff ects on LDL-C and HDL-C [16][17][18][19]. Th is review will discuss the potential benefi ts for pitavastatin in the treatment of patients with MetS or T2D, focusing on its benefi cial eff ects on the atherogenic lipid triad, its neutral eff ects on glycemic control and its reduced potential for DDIs.
Th e Japanese long-term prospective post-marketing surveillance LIVALO Eff ectiveness and Safety (LIVES) Study (n = 20,279) [33] and the JAPAN-ACS study [27] a prospective, randomized, open-label study in patients with hypercholesterolemia and acute coronary syndrome (ACS) (n = 251) -showed that the LDL-C-lowering effi cacy of pitavastatin was similar among patients with and without T2D (-27.3% vs. -29.7%, respectively, in the LIVES study, and -35.7% vs. 36.4% in the JAPAN-ACS study). Furthermore, a subgroup analysis of the 12-week, randomized, open-label CHIBA study (n = 53) showed that the percentage reduction from baseline in LDL-C was signifi cantly greater with pitavastatin than with atorvastatin in patients with MetS (45.8% vs. 39.1%; P = 0.0495) [23]. Th e CHIBA study was carried out in a relatively small population and results should therefore be treated with caution. However, the authors suggest that this diff erence may be due to the relationship between statin effi cacy and obesity. Whereas the LDL-Clowering effi cacy of atorvastatin was attenuated by increased waist circumference, body weight and BMI, pitavastatin's effi cacy was unaff ected by obesity-related parameters. Together these results suggest that pita vastatin might be useful for the reduction of LDL-C in people with MetS or T2D, many of whom are overweight or obese. triglycerides [10,11]. A subanalysis of the J-LIT study showed that a 2.6 mmol/l (10 mg/dl) increase in HDL-C was associated with a 34.9% reduction in the risk of coronary events in patients with T2D [34]. Moreover, studies have shown that increasing HDL-C levels using statins can signifi cantly reduce the progression of atherosclerosis and reduce CV and cerebrovascular risk in people with dyslipidemia irrespective of LDL-C levels [35][36][37][38][39].
Although most statins increase HDL-C levels to some extent, effi cacy varies from statin to statin and eff ects are not always consistent between trials [39][40][41]. For example, the VOYAGER study -a meta-analysis of data from 32,258 high-risk individuals in 37 randomized clinical trials -showed dose-dependent increases in HDL-C ranging from 5.5 to 7.9% with rosuvastatin 5 to 40 mg and from 4.2 to 5.3% with simvastatin 10 to 80 mg, whereas the increases observed with atorvastatin were inversely related to the dose, falling from 4.5% with 10 mg to 2.3% with 80 mg [40]. In contrast, pitavastatin-treated patients routinely experience clinically signifi cant, reproducible elevations in HDL-C [22,[42][43][44].
In the pivotal phase III studies, 12-week treatment with pitavastatin 2 to 4 mg/day increased HDL-C levels by 4 to 6% -an eff ect that was similar among patients treated with simvastatin and atorvastatin [20,21]. However, the longer-term (52 week) Eff ects of Pitavastatin and Atorvastatin on HDL-cholesterol Levels in Patients with Hyper-LDL Cholesterolemia and Glucose Intolerance (PIAT) study showed that pitavastatin 2 mg/day was associated with signifi cant increases in HDL-C compared with atorva statin 10 mg/day (8.2% vs. 2.9%; P = 0.031), an eff ect that was refl ected by increasing levels of apolipoprotein A-1 (5.1% with pitavastatin vs. 0.6% with atorvastatin; P = 0.019) ( Figure 1) [24].
In another long-term trial -the 70-month retro spective, single-center, observational CIRCLE study -HDL-C levels were increased by 13.4% with pitavastatin compared with only 7.0% with atorvastatin in patients with percutaneous coronary intervention (n = 743) (P = 0.029) [44]. Th ese data suggest that the high-density lipoprotein (HDL)-elevating eff ect of pitavastatin might increase over time. Consistent with this observation, an extension of the pivotal phase III studies showed that pitavastatinmediated elevations in HDL levels ultimately increased from 4% to 6% after 12 weeks to 14.3% after 60 weeks [22].
As for other statins [39], the degree of pitavastatin's HDL-C-elevating effi cacy appears to be related to serum concentrations of HDL-C at baseline. For example, the PATROL study showed that neither pitavastatin nor atorvastatin had a signifi cant eff ect on HDL-C levels in patients with hypercholesterolemia and high baseline levels of HDL-C (~1.55 mmol/l; 60 mg/dl) [30]. In contrast, the KISHIMEN study in 178 Japanese subjects with hypercholesterolemia (58% with T2D) demonstrated signifi cant pitavastatin-mediated elevations in HDL-C after 6 months ranging from 5.9% in the general cohort to 22.4% in patients with low baseline HDL-C (<1 mmol/l; 40 mg/dl) [45]. Similarly, the increase in HDL-C achieved with pitavastatin in the CIRCLE study was 21.3% among patients with a low baseline HDL-C level (≤1.17 mmol/l; 45 mg/dl) compared with 13.4% in the general population [44]. A subanalysis of the 2-year LIVES study showed that pitavastatin 1 to 4 mg/day signifi cantly increased HDL-C levels by 5.9% in all subjects (n = 631) and by 24.6% (P <0.0001) in those with a low baseline HDL-C (<1 mmol/l; 40 mg/dl) (n = 86) ( Figure 2) [46]. Moreover, HDL-C levels rose by 15.8% after patients with persistently low levels of HDL-C despite previous statin treatment switched to pitavastatin [42]. Th is observation suggests that patients might benefi t from pitavastatin therapy if HDL-C remains unacceptably low on other treatments.
Pitavastatin-mediated high-density lipoprotein elevation has the potential to reduce residual risk via a number of mechanisms HDL particles are central to the reverse cholesterol transport pathway, a process in which excess cholesterol is removed from peripheral cells and transported to the liver for excretion into bile [11]. Th e suggestion has therefore been made that elevations in HDL-C might slow the formation of atherosclerotic plaques and may reduce the residual CV risk by increasing the rate of cholesterol effl ux from cells. A post hoc analysis of intravascular ultrasono graphy data from four prospective randomized clinical trials (n = 1455) showed that statintreated patients with angiographic CHD experienced ≥5% reduction in the coronary atheroma volume when LDL-C levels were sub stantially decreased to <2.21 mmol/l (87.5 mg/dl) and HDL-C levels were increased by >7.5% [36]. However, a recent review of the literature suggests that, whilst the plaque volume change induced by a 1% reduction in LDL-C showed little diff erence using diff erent statins (ator va statin, pravastatin, pitavastatin, rosuvastatin, simva statin), pitavastatin delivered the greatest reduction in plaque volume per 1% increase in HDL-C ( Figure 3) [37]. Pitavastatin probably therefore benefi cially modifi es HDL function as well as quantity.
In addition to their role in reverse cholesterol transport, normal HDL particles can inhibit some of the atherogenic processes that occur in people with MetS and T2D, including increased oxidation [47][48][49], vascular infl ammation [50,51], thrombosis [52], endothelial dysfunc tion [53], and reduced insulin sensitivity [54][55][56]. A 12-week, open-label multicenter study performed among 103 consecutive patients with hypercholesterolemia showed that patients with MetS (n = 69) had signifi cantly higher mean levels of plasma high-sensitivity C-reactive protein and signifi cantly lower mean levels of highmolecular-weight adiponectin than their counterparts without MetS (n = 34) [51]. In this study, a signifi cant correlation was observed between baseline highmolecular-weight adiponectin levels and HDL-C values in patients with MetS (r = 0.318; P = 0.01) but not in those without. Moreover, an eff ectiveness analysis including 62 patients with MetS and 32 patients without showed that the level of high-sensitivity C-reactive protein was signifi cantly decreased in MetS patients during pitavastatin treatment, whereas high-molecularweight adiponectin levels did not change. When patients were grouped according to their percentage change in HDL-C, signifi cantly greater pitavastatin-mediated increases in high-molecular-weight adiponectin were observed in patients with versus patients without HDL elevations ≥10% (P = 0.009) (Figure 4). Th is observation suggests that pitavastatin might slow the progression of coronary atheromas by modifying HDL-related eff ects on infl ammation and oxidation, both of which are common in people with MetS and T2D.

Pitavastatin has a neutral eff ect on glucose control
A number of clinical trials have highlighted a potential association between statin therapy and an increased risk of developing T2D [57][58][59][60]. For example, the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study (n = 17,802) showed a signifi cant 3.0% versus 2.4% increase in incident T2D among healthy adults treated with rosuvastatin 20 mg/day versus placebo for 1.9 years (P = 0.01) [61]. Similarly, a meta-analysis of 13 statin trials including 91,140 patients without T2D showed that statin therapy (atorvastatin 10 mg, pravastatin 40 mg, simvastatin 40 mg or rosuvastatin 20 mg) was associated with a 9% increased risk for T2D over 4 years (odds ratio = 1.09; 95% confi dence interval = 1.02 to 1.17) [58]. Values are mean ± standard deviation. ANOVA, analysis of variance. Adapted from [46]. Figure 3. Pitavastatin induced greater plaque volume reduction by high-density lipoprotein cholesterol unit increase. Compared with other statins, pitavastatin is associated with the greatest reduction in plaque volume per 1% increase in high-density lipoprotein-cholesterol (HDL-C) (KISHIMEN study). Adapted from [37].
Masana Cardiovascular Diabetology 2013, 12(Suppl 1):S2 http://www.cardiab.com/supplements/12/S1/S2 Th e mechanisms by which statins might cause this eff ect are unclear. A recent study carried out in 27 patients with well-controlled T2D suggests that the potential diabetogenic eff ects of simvastatin and rosuvastatin are not driven by a detrimental eff ect on insulin sensitivity, but rather by a deterioration of insulin secretion [62]. In this study, patients were randomly assigned to receive either rosuvastatin 20 mg/day or simvastatin 20 mg/day for 6 months followed by the other treatment for a further 6 months. Both strategies were associated with a similar 0.8 to 0.9% increase in hemoglobin A1c levels after 12 months (P <0.001 vs. baseline for both) and similar trends in fasting plasma glucose levels. No changes in insulin sensitivity were detected throughout the study, whereas HOMAβ levels were significantly decreased in both groups.
In contrast, the CAPITAIN study in 14 healthy male adults with well-defi ned MetS showed that 6-month treatment with the highest clinically available dose of pitavastatin (4 mg/day) did not signifi cantly change mean glucose-related or insulin-related parameters, including fasting plasma glucose, the Homeostasis Model Assessment index, insulin levels, insulin/glucose ratios, or hemoglobin A1c levels, and showed that glycemic parameters were generally improved [63]. Consistent with these results, a subanalysis of LIVES study data showed a signifi cant 0.28% decrease in hemoglobin A1c levels (P <0.001) among 308 patients with T2D after 2 years of pitavastatin treatment ( Figure 5) [46]. Th ese data suggest that whereas some statins are associated with adverse eff ects on glycemic control, pitavastatin has a neutral and possibly benefi cial eff ect that is likely to be especially useful in people with, or at risk of developing, T2Dsuch as those with MetS. Defi nitive results on the impact of pitavastatin on the development of T2D are expected from the Japan Prevention Trial of Diabetes by Pitavastatin in Patients with Impaired Glucose Tolerance (J-PREDICT) study (n ~1,240) in 2015 [64].

Pitavastatin has a low potential for drug-drug interactions
People with MetS or T2D usually require multiple therapies for a range of CV risk factors. A study of  Masana Cardiovascular Diabetology 2013, 12(Suppl 1):S2 http://www.cardiab.com/supplements/12/S1/S2 >950,000 patient records from two US databases showed that 83% of patients with dyslipidemia used a CYP3A4metabolized statin and that, of these, 25 to 30% also received a CYP3A4 inhibitor [65]. Th is suggests that patients treated with statins have a particularly high risk of developing DDIs, some of which may lead to drug discontinuations owing to adverse events. Th e best way to avoid this problem is to use a statin with a low potential for DDIs.
Whereas lovastatin, simvastatin and atorvastatin are metabolized mainly by CYP3A4 and fl uvastatin and rosuvastatin are metabolized by CYP2C9, pitavastatin's cyclopropyl group diverts the drug away from meta bolism by CYP3A4 and allows only a small amount of clinically insignifi cant metabolism by CYP2C9. Moreover, studies in human hepatic micro somes have shown that, whereas the lactone metabolites of other statins are rapidly eliminated by CYP isoenzymes, both pitavastatin acid and lactone undergo limited metabolism [66]. It is not therefore surprising that the incidence of musclerelated adverse drug reactions identifi ed during a post hoc analysis of the LIVES study was unaff ected by the concomitant administration of pitavastatin with drugs known to inhibit a range of CYP isoenzymes [67]. Th ese fi ndings suggest that the pharmacokinetic data from interaction studies [68,69] are predictive of clinical experience and that pitavastatin has a low potential for DDIs. To date, the use of pitavastatin is contraindicated only in patients treated with cyclosporin or lopinavir/ ritonavir combination therapy. Administration should be temporarily sus pended in patients receiving erythromycin or fusidic acid, however, and the dosage should be limited to 2 mg in people treated with rifampicin. As for other statins, pitavastatin should be used with caution in people treated with fi brates or niacin.
Overall, studies demonstrate that statins are well tolerated and have similar eff ects on LDL-C levels in people with and without MetS or T2D. Compared with other statins, however, pitavastatin has a unique structure that contributes to a number of pharmacological benefi ts. Th ese include potent LDL-C-lowering effi cacy, clinically signifi cant, reproducible elevations in HDL-C, a neutral or benefi cial eff ect on glycemic control and a reduced potential for DDIs. Pitavastatin is therefore likely to be a useful treatment option for people with MetS or T2D.

Declaration
This article has been published as part of Cardiovascular Diabetology Volume 12 Supplement 1, 2013: Statins in cardiometabolic disease: what makes pitavastatin diff erent? The full contents of the supplement are available online at http://www.cardiab.com/supplements/12/S1. Publication of this supplement has been funded by Kowa Pharmaceutical Europe. Pitavastatin is a product marketed by the sponsor of the supplement. Articles are based on the proceedings of the World Congress for the Prevention of Diabetes. Authors received support with the preparation of their articles from GK Pharmacomm, an agency funded by the sponsor. All articles have undergone the journal's standard peer review process. The Supplement Editors declare that they have no competing interests.