Drug Evaluation

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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.

KEYWORDS: cardiovascular disease n dyslipidemia n hydroxymethylglutaryl coA Leiv Ose reductase inhibitor n pitavastatin n primary hypercholesterolemia Consultant, Medical Department, Medical Director, Lipid Clinic, Rikshospitalet, Oslo University Cardiovascular disease (CVD) is a major con- mean LDL‑C reduction following 1 year of Hospital, Oslo N-0027, Norway tributor to global morbidity, mortality and statin treatment varied from 0.35 to 1.77 mmol/l Tel.: +47 23 075 614 Fax: +47 23 075 610 disability. Indeed, the WHO estimates that (mean: 1.09). All-cause and coronary mortality [email protected] CVD accounted for 29% of global mortality declined by 12 and 19%, respectively, for each during 2004 [101]. Numerous mutually rein- mmol/l reduction in LDL‑C concentrations. forcing factors, including dyslipidemia, con- Furthermore, each mmol/l decline in LDL‑C tribute to CVD. A recent paper analyzed data level was associated with a risk reduction for from 302,430 people without vascular disease myocardial infarction or coronary death of 23%, at baseline in 68 long-term prospective studies. coronary revascularization of 24% and fatal or Coronary heart disease (CHD) rates per 1000 nonfatal stroke of 17%. Combining these end person-years in the bottom and top thirds of points, each mmol/l decline in LDL‑C concentra- baseline lipids were 2.6 and 6.2, respectively, tion was associated with a reduction in total risk for triglycerides, 6.4 and 2.4, respectively, for of major vascular events of 21%. The reduced risk HDL‑C and 2.3 and 6.7, respectively, for non- attained statistical significance within the first HDL‑C. Adjusted hazard ratios for CHD com- year and the size of the benefit increased subse- paring the bottom and top tertiles were 0.99, quently. Overall, 48 and 25 fewer participants 0.78 and 1.50, respectively. CHD hazard ratios with and without CHD, respectively, at baseline were 1.50 comparing the bottom and top ter- would experience major vascular events for every tiles for non-HDL‑C:HDL‑C ratio, 1.49 for 1000 people treated with statins [1]. ApoB:ApoA1 ratio and 1.38 for LDL‑C. Hazard Despite this clinical efficacy, current statins ratios for ischemic stroke were 1.02 comparing have limitations. First, for example, there are the bottom and top thirds for triglycerides, adverse events associated with statins, includ- 0.93 for HDL‑C and 1.12 for non-HDL‑C [1]. ing myopathy, gastrointestinal disturbances, Clearly, managing dyslipidemia is critical to altered liver function tests, sleep disturbances, reduce the human, clinical and societal burdens headache, paresthesia and hypersensitivity reac- imposed by CVD. tions [102]. The risk of rhabdomyolysis (which, HMG‑CoA reductase inhibitors (statins) are while rare, remains possibly the most serious the mainstay of dyslipidemia management. A adverse event associated with statins) is 0.44 meta-ana­lysis of 14 studies estimated that the per 10,000 treatment-years for simvastatin,

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atorvastatin and pravastatin. The risk reached As these limitations suggest, there is still a 5.34 per 10,000 treatment-years with ceriva­ need for new agents to manage dyslipidemia. statin [2], which was withdrawn from the market. This review examines pitavastatin, a novel statin Several factors contribute to the risk of that potentially represents an important addi- develop­ing myopathy during statin treatment. tion to the cardiovascular armamentarium. For example, the risk of developing muscular Kowa launched pitavastatin in Japan during disorders with statins is sixfold higher among September 2003 for hypercholesterolemia and patients taking concurrent drugs that inhibit familial hypercholesterolemia after complet- CYP3A4 compared with controls [3]. CYP3A4 ing a Japanese development program. In June metabolizes lovastatin, simvastatin and atorvas- 2008, Kowa launched pitavastatin in Korea and tatin [4]. As discussed later, statins that act as a Thailand [10]. Regulatory submissions have been substrate for CYP3A4 potentially cause clinically made in a number of additional countries follow- significant interactions with concurrent medica- ing the completion of a European and American tions and dietary components m­etabolized by development program. The US FDA approved this isoenzyme. pitavastatin doses of 1–4 mg in August 2009, In fully adherent patients, statins poten- and pitavastatin is currently under evaluation in tially reduce LDL‑C concentrations by at least Europe. The review summarizes the evidence that 1.5 mmol/l and, therefore, the risk of major pitavastatin is efficacious and well tolerated in a vascular events by approximately a third [5]. broad range of patients and offers a distinctive However, considerable residual risk (approxi- pharmacodynamic and pharmacokinetic profile. mately two-thirds) remains in patients in whom statins reduce LDL‑C levels to target values. Introduction to pitavastatin Therefore, innovative treatments for dyslipid- & experimental data emia need to address a wider range of risk fac- HMG‑CoA reductase catalyzes mevalonate tors than LDL‑C alone, including increased production from HMG‑CoA. Pitavastatin is triglyceride concentrations, reduced HDL‑C a synthetic HMG‑CoA reductase inhibitor concentrations and increased ApoB:ApoA1 ratio. with a novel cyclopropyl moiety. This struc- For example, among statin-treated patients with tural innovation means that pitavastatin binds known CHD, the ApoB:ApoA1 ratio predicts avidly to and potently inhibits, HMG‑CoA clinical outcomes after correcting for standard reductase. The structural similarity of statins to risk factors. The corrected LDL‑C:HDL‑C ratio HMG‑CoA, the precursor for cholesterol syn- did not show this correlation [6]. An increased thesis, translates into an affinity for the enzyme’s ApoB:ApoA1 ratio may offer a marker for early catalytic pocket that is at least 1000-fold higher atherosclerosis as well as unstable plaques that than the affinity of HMG‑CoA reductase for the produce weak ultrasound signals [7]. Such asso- endogenous substrate [11,12]. ciations might underlie the prognostic value Despite certain structural similarities, some offered by the ApoB:ApoA1 ratio in addition to physicochemical profiles (notably lipo­philicity) conventional risk factors. vary markedly between statins (Figure 1). Finally, many patients at high-risk of develop- The ability of statins to inhibit HMG‑CoA ing CVD, or with overt disease, have LDL‑C reductase is largely independent of the drug’s levels that exceed those recommended in primary physico­chemical properties. However, mem- and secondary prevention guidelines, even when branes of the endoplasmic reticulum express taking statin therapy. In one study, approximately HMG‑CoA reductase. Physiochemical proper- half of patients did not achieve LDL‑C targets ties may influence both of the routes statins use with their initial statin dose. Of these, 86% had to cross plasma membranes. First, statins diffuse not reached the LDL‑C target after 6 months, passively from intracellular fluid, across plasma despite dose titration and receiving the clinician’s membranes and into the cytosol. The rate and statin of choice [8]. In another study, 34.7 and extent of passive diffusion is, partly, a function 27.4% of general practice patients in the UK did of lipophilicity [13]. not attain the total cholesterol and LDL‑C goals, Second, an active transporter translocates respectively, set by Joint British guidelines within statins into hepatocytes. Statins’ physico­chemical 1 year of starting statins. Furthermore, 68.2 and properties partly determine the affinity for this 57.6% of subjects failed to attain optimal lev- active transport system for the drug [13]. As dis- els of HDL‑C and triglycerides, respectively, as cussed later, pitavastatin is a substrate of organic defined in European management guidelines [9]. anion-transporting polypeptide 1B (OATP1B).

310 Clin. Lipidol. (2010) 5(3) future science group Pitavastatin: a distinctive lipid-lowering drug | Drug Evaluation

O O HMG-CoA Simvastatin HO Lovastatin HO O HO O- O O

H2O H H

S-CoA H H H3C H3C CH3 CH3 CH3

H3C H3C

O O O HO O- HO O- HO O-

Pravastatin Fluvastatin Cerivastatin OH OH OH O

O CH H F 3 F CH3 H C 3 CH3 N CH CH3 3 O N OH H2O

CH H3C 3

O O O - - HO O HO O HO O-

Atorvastatin Rosuvastatin Pitavastatin OH OH OH

F CH F 3 F CH3

N CH CH 3 N 3 N N O O H C HN 3 N S CH3

O

Figure 1. Pitavastatin and other statins with the moiety similar to HMG‑CoA highlighted.

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Several tissues, including hepatic sinusoidal The study also examined expression of Rho membranes, express members belonging to and Rho kinase, which are proteins that con- the OATP1B superfamily. OATP1B1 medi- tribute to intracellular signaling pathways. Rho ates translocation of pitavastatin, rosuvas- and Rho kinase inhibitors (C3T and Y27632) tatin, pravastatin, atorvastatin, fluvastatin and increased ApoA1 production in HepG2 cells. p­robably lovastatin [14–16]. Taken together, these results suggest that Against this background, in vitro stud- pitavastatin may promote ApoA1 production ies indicate that pitavastatin potently inhibits by three inter-related actions. First, pitavastatin HMG‑CoA reductase. Indeed, in cell culture, inhibits HMG‑CoA reductase and, second, sup- pitavastatin competitively inhibits HMG‑CoA presses Rho activity. Third, pitavastatin seems reductase 2.4- and 6.8‑times more potently than to protect ApoA1 from catabolism by inducing simvastatin and pravastatin, respectively [17]. In ABCA1 and augmenting lipidation (covalent a human cell line (HepG2), pitavastatin inhib- binding of lipids to peptides) of ApoA1 [20]. ited cholesterol synthesis 2.9- and 5.7‑times more potently than simvastatin and atorvas- Pharmacokinetics tatin, respectively [18]. Furthermore, Saiki and Statins show several clinically significant colleagues examined lipoprotein lipase expres- pharmaco­kinetic differences. For example, sys- sion in 3T3‑L1 preadipocytes following expo- temic bioavailability ranges from 5% with sim- sure to pravastatin, simvastatin, atorvastatin and vastatin, lovastatin and fluvastatin to more than pitavastatin (1 µM for 3 days) [19]. Pitavastatin 50% with pitavastatin (Table 1). The extent of increased lipoprotein lipase activity by 30%; a first-pass metabolism and variations in the activ- greater increase than that produced by the other ity of intestinal and hepatic transport proteins statins. Pitavastatin also induced strong expres- apparently contribute to these differences in bio- sion of lipoprotein lipase and its mRNA. Adding availability. Furthermore, protein binding varies mevalonate (10 µM for 3 days) weakened lipo- from more than 95% for pitavastatin, simvas- protein lipase activity. Thus, pitavastatin’s effects tatin, atorva­statin and lovastatin, to 50% for on triglycerides as observed in clinical studies pravastatin [21,22]. (vide infra) may arise from increased lipoprotein Nevertheless, the most clinically significant lipase production in adipocytes. pharmacokinetic differences arise from varia- In clinical studies, pitavastatin consistently tions in the metabolic and excretory pathways. produces a marked and sustained increase in Most of the bioavailable fraction of an oral dose HDL‑C concentrations. Indeed, pitavastatin’s of pitavastatin is excreted unchanged in the ability to elevate HDL‑C levels is one factor dif- bile and pitavastatin undergoes enterohepatic ferentiating it from other statins. ApoA1 is the circulation. Less than 5% of a dose of pitavas- main protein component of HDL‑C. Therefore, tatin is excreted in the urine [22]. This pathway secretion of ApoA1 is a rate-determining step in contrasts with those statins that undergo exten- HDL production. In HepG2 cells, pitavastatin sive metabolism by CYP450 isoenzymes. For is especially potent at inducing ApoA1 (3 µM) example, lovastatin, simvastatin and atorvastatin compared with both simvastatin (10 µM) are substrates for CYP3A4, and fluvastatin and and atorvastatin (30 µM). Adding mevalon- rosuvastatin are metabolized by CYP2C9 [22]. ate prevented ApoA1 induction by statins. The first-pass hepatic metabolism of fluvastatin This s­uggests that a statin’s action on ApoA1 varies from 50% (40 mg) to 80% (2–5 mg) secretion depends on inhibition of HMG‑CoA [23]. Furthermore, a study using human hepatic reductase [20]. microsomes suggested that rosuvastatin reduced However, other actions may contribute to the the activity of CYP2C9 by 10% [24]. The cyclo- increase in HDL‑C levels produced by pitava­ propyl group on the pitavastatin molecule, statin. For example, in HepG2 cells, pitavas- which accounts for the potency of the molecule tatin increased expression of mRNA encoding appears to ‘protect’ pitavastatin from metabo- the ATP-binding cassette transporter ABCA1, lism by CYP3A4. Therefore, pitavastatin appears also known as the cholesterol efflux regulatory to have less potential for interactions compared protein (CERP). ABCA1 controls the export of with statins extensively biotransformed by cholesterol and phospholipids, which incorpo- CYP3A4 (vide infra) [22]. rate into ApoA1 and ApoE. Again, increased In common with most statins, pitavastatin ABCA1 expression depended on HMG‑CoA is administered orally as an active acidic form. reductase inhibition [20]. Glucuronosyltransferase (UGT) biotransforms

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Table 1. Pharmacokinetics of HMG‑CoA reductase inhibitors. Parameter Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin extended release Fraction absorbed (%) 30 98 30 75 34 50 60–80 tmax (h) 2–3 4 2–4 1.2 0.9 –1.6 3 1.3–2.4

Cmax (ng/ml) 27–66 55 10–20 18.2 45–55 37 10–34 Bioavailability (%) 12 6 5 60–80 18 20 5 Effect of food on ↓13 0 ↑­50 0 ↓30 ↑­20 0 bioavailability (%) Lipophilicity Yes Yes Yes Yes No No Yes Transporter substrate Yes Yes Yes Yes Yes Yes Yes Protein binding (%) >98 >99 >95 >99 43–55 88 94–98 Hepatic extraction (%) >70 >68 >70 Unknown 46–66 63 78–87 Systemic metabolites Active Inactive Active Inactive Inactive Active (minor) Active Systemic clearance (ml/min) 2916 4433 303–1166 1341–50,166 945 805 525 Renal clearance (ml/min) >400 226 t1/2 (h) 15–30 4.7 2.9 13 1.3–2.8 20.8 2–3 Fecal excretion (%) 70 90 83 ? 71 90 58 Urinary excretion (%) 2 6 10 <4 20 10 13 Based on a 40 mg oral dose with the exception of fluvastatin extended release (80 mg) and pitavastatin 2 mg. Data from [11,13,21,22,59,60]. open acid forms of statins. The products of UGT biotransformation of the acid form of these statins biotransformation are very unstable and rapidly [22]. By contrast, after administration of 2 mg/day convert to the lactone metabolite. The lactone pitavastatin in humans for 5 days, the parent com- form of many statins then undergoes rapid pound and the lactone metabolite are the major metabolism by CYP450 isoenzymes (Table 2). plasma components, suggesting that the lactone For example, the metabolic clearance catalyzed form does not undergo further metabolism [25]. by CYP3A4 of the lactone metabolites of ator- Transporter molecules also contribute to vastatin, simvastatin, cerivastatin and rosuv- statins’ pharmacokinetic profile. For example, astatin is between 30- and 71-fold higher than p‑glycoprotein shares several substrates with

Table 2. Enzymatic pathways involved in the pharmacokinetics of lipid-lowering agents. Statins Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin extended release CYP-mediated CYP3A4 CYP2C9 CYP3A4 Biliary, CYP2C9/2C8 Sulphonation Biliary, CYP2C9, 2C19 CYP3A4 metabolism (minor) (minor) UGTA1/1A3- + + + + + + + mediated metabolism Transporter Yes Yes Yes Yes Yes Yes Yes proteins OATP1B1 + + + + + + + OATP1B3 NA + NA + + + + OATP1A2 NA NA + NA NA + NA OATP2B1 + + NA + + + NA OAT3 NA + + NA + NA + BCRP + + NA NA + + NA MDR1/P-gp + - + + + - + MRP2 + NA NA NA + NA NA BESP ? + ? NA + ? ? +: Yes; ?: Unknown; NA: Not available. Data from [21,35,59,61].

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CYP3A4, including several statins. While, the cyclopropyl group of pitavastatin protects p‑glycoprotein does not contribute to the bioe- against metabolism by CYP3A4. Combined limination of pitavastatin, it is (as discussed with the inactivity of the lactone form, pitava­ p­reviously) a substrate of OATP1B. statin does not show clinically significant inter- Hepatocytes express efflux transporters, such actions with CYP3A4 inhibitors. For example, as breast cancer resistance protein (BCRP), concurrent grapefruit juice (a CYP3A4 inhibi- which contribute to the biliary excretion of tor) increased the mean area under the concen-

pitavastatin (Figure 2) [26]. BCRP is respon- tration–time curve (AUC0–24) of atorvastatin by sible for the efflux of several statins, including 83%. By contrast, concurrent grapefruit juice

unchanged pitavastatin and rosuvastatin. A increased the mean AUC0–24 of pitavastatin by study with rosuvastatin suggests that reduced 13% [28]. Similarly, coadministration of itracon- BCRP activity due to polymorphism may be azole (a CYP3A4 inhibitor) produced no clini- associated with enhanced lipid-lowering effi- cally relevant effect on the pharmacokinetics of cacy; variability in statin efficacy with rosu­ pitavastatin or the lactone metabolite [29]. vastatin, but not simvastatin, is related to BCRP Turning to other lipid-lowering medications, p­olymorphism [27]. These pharmacokinetic dif- pitavastatin does not show clinically signifi- ferences influence the risk of drug–drug and cant interactions with bezafibrate or ezetimibe. drug–diet interactions. Fenofibrate increased pitavastatin’s steady state

AUC0–24 by 18%. Gemfibrozil increased pitava­

Drug–drug & drug–diet interactions statin’s steady state mean AUC0–24 and Cmax by 45 Pitavastatin is eliminated from the liver in an and 31%, respectively, and decreased steady state

unchanged form and is an important underlying mean AUC0–24 and Cmax for the lactone meta­bolite reason for the low potential of drug–drug inter- by 15 and 28%, respectively. However, concur- actions. As described earlier, pitavastatin’s major rent administration of pitavastatin and either route of biotransformation is lactionization to fenofibrate or gemfibrozil was safe and well toler- an inactive metabolite. In contrast to statins ated, suggesting the changes in p­harmacokinetics such as simvastatin, lovastatin and atorvastatin, were not clinically significant [30].

Digoxin Atazanavir Enalapril Blood flow Erythromycin Ciclosporin OATPIB1 OATPIB3 NTCP Gemfibrozil

Fenofibrate warfarin Hepatocyte M-3 CYP2CP Pitavastatin

Intermediate Gemfibrozil UGT Atazanavir CYP2D6

M-13 CYP3A4 Lactone Glucuronide

Itraconazole Grapefruit juice MDR1 BCRP Erthrymycin Ciclosporin

Bile duct Digoxin Ciclosporin

Figure 2. Mechanisms of possible drug–drug interaction. Mode of different statin bioelimination by Phase I metabolism (CYP isoenzymes), Phase II metabolism (transpherases) or Phase III metabolism (influx/efflux transporters). The influence of drug–drug interactions and pharmacogenetic factors are depicted. BCRP: Breast cancer resistance protein; MDR: Multidrug resistance associated protein; NTCP: Sodium taurocholate cotransporting polypeptide; OATP: Organic anion transporting polypeptide.

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Pitavastatin undergoes only a small degree of potential for interactions and associated adverse metabolism by CYP2C9 and almost negligible events compared with those statins extensively transformation by CYP2C8 (Table 2) [31]. Drugs metabolized by CYP3A4, such as lovastatin, that inhibit CYP2C9 and either inhibit or com- simvastatin or atorvastatin [22,39]. pete for p‑glycoprotein do not significantly inter- act with pitavastatin [21]. For example, digoxin Clinical data is a substrate for p‑glycoprotein. There is, there- A large and growing number of studies show fore, a risk of interaction between digoxin and that pitavastatin is clinically efficacious in the p‑glycoprotein inhibitors, which could com- management of primary hyper­cholesterolemia plicate management of atrial fibrillation, atrial or combined dyslipidemia in a wide range of flutter and heart failure. Interactions mediated patients. For example, in Japanese patients, by p‑glycoprotein could be responsible for the pitavastatin (2 mg/day) and pravastatin increased risk of rhabdomyolysis observed among (10 mg/day) reduced LDL‑C levels by 38 and people taking combinations of some statins and 18%, respectively, over 12 weeks [40]. This sec- digoxin. Both simvastatin and a­torvastatin tion focuses on clinical studies performed in potentially interact with digoxin [32,33]. Caucasian patients to support the FDA and This metabolic pathway means that pitava­ European license applications. Doses of compar- statin is relatively devoid of drug–drug inter- ators selected in these studies were in the ranges actions. However, there is a theoretical risk of recommended by their respective manufacturers interaction between pitavastatin and established and clinical data, although the authors accept OATP1B1 inhibitors. Gemfibrozil, which inhib- that maximal doses are also available [41]. its OATP1B1, increases the AUC of cerivastatin One of these studies demonstrated that 5.6-fold, lovastatin 3.8-fold, simvastatin acid pitavastatin was non-inferior to atorvastatin at 2.9-fold, pravastatin 2.2-fold and rosuvastatin reducing LDL‑C concentrations [42]. The study 1.9-fold [34]. However, the AUC for pitavastatin enrolled 821 patients with primary hyper­ increased 1.4-fold with concurrent gemfibro- cholesterolemia or combined dyslipidemia. After zil [35], suggesting that pitavastatin is not as a 6–8‑week dietary lead-in period, randomized dependent on OATP1B1 transportation as other patients received one of four treatment regimens statins. On the other hand, coadministration of for 12 weeks. Two groups received pitavastatin pitavastatin and ciclosporin increased mean Cmax (2 mg/day) or atorvastatin (10 mg/day), and and AUC0–24 of pitavastatin 6.6- and 4.6-fold, two groups received pitavastatin (2 mg/day) or respectively [36]. Concurrent treatment was well atorvastatin (10 mg/day) for 4 weeks followed tolerated by healthy adults [36]. by forced titration to pitavastatin (4 mg/day) or However, ciclosporin inhibits several members atorvastatin (20 mg/day). of the OATP family as well as other transport- Over 12 weeks, pitavastatin produced a non- ers, such as p‑glycoprotein [37,38].Further studies inferior reduction in LDL‑C concentrations need to investigate whether these various actions from baseline to end point (week 12 or last obser- account for greater interaction between ciclo- vation carried forward) compared with atorvas- sporin and pitavastatin than observed between tatin. The mean change was -37.9 and -37.8% pitavastatin and other OATP inhibitors, such for pitavastatin 2 mg/day and atorvastatin as fenofibrate and gemfibrozil [30]. While the 10 mg/day, respectively, and ‑44.6 and ‑43.5% pharma­cokinetic interaction between ciclospo- for pitavastatin 4 mg/day and atorvastatin 20 mg/ rin and pitavastatin is less marked than with day, respectively. Most patients reached National some other statins, there are not enough clinical Cholesterol Education Program (NCEP) LDL‑C data to define the safety of the coadministration targets: pitavastatin 4 mg, 77.9%; atorvastatin of the two drugs. Therefore, concomitant use is 20 mg, 70.6%; pitavastatin 2 mg, 56.8%; and currently contraindicated. atorvastatin 10 mg, 65.7%. The proportion Overall, the most significant pharmacokinetic attaining European Atherosclerosis Society differences between the statins are due to differ- (EAS) targets showed a similar pattern: pitavas- ences in metabolism and excretion. Pitavastatin tatin 4 mg, 78.5%; atorvastatin 20 mg, 76.5%; has a relatively low drug–drug interaction pitavastatin 2 mg, 56.8%; and atorvastatin profile, although there is a speculative risk of 10 mg, 59.8%. HDL‑C levels increased from interactions between pitavastatin and estab- baseline by 4 and 5% with pitavastatin 2 and lished OATP1B1 inhibitors, such as ciclospo- 4 mg, respectively, compared with 3 and 2.5% rin. Nonetheless, pitavastatin may present less with atorvastatin 10 and 20 mg, respectively [42].

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A second study compared pitavastatin and However, HDL‑C concentrations increased simvastatin in 857 patients with either primary steadily during long-term treatment with hypercholesterolemia or combined dyslipid- pitavastatin, at least d­oubling initial baseline emia [43]. Patients received pitavastatin 2 mg/day levels after 52 weeks. or simvastatin 20 mg/day, with forced titration to pitavastatin 4 mg/day or simvastatin 40 mg/day Plaque regression in a similar manner to the study detailed above. Studies have yet to show that pitavastatin Pitavastatin 2 mg reduced concentrations of reduces CVD and all-cause mortality or mor- LDL‑C, non-HDL‑C and total cholesterol more bidity. However, pitavastatin induces plaque than simvastatin 20 mg. Furthermore, a greater regression through changes in lipid profile, proportion of patients treated with pitavastatin pleiotropic effects or both. The JAPAN-ACS 2 mg achieved the EAS LDL‑C target than with study compared 8–12 months treatment with simvastatin 20 mg: 59.6 and 48.6% respectively, 4 mg/day pitavastatin or 20 mg/day atorvastatin. a statistically significant difference. For example, Researchers measured coronary plaque volume pitavastatin 2 mg and simvastatin 20 mg reduced in 252 patients undergoing percutaneous coro- LDL‑C levels by 39.0 and 35.0%, respectively; nary intervention for acute coronary syndrome another statistically significant difference. guided by intravascular ultrasound. LDL‑C Pitavastatin 4 mg was non-inferior to simvastatin concentrations decreased by 38 and 37% from 40 mg. The reductions in LDL‑C concentra- baseline, respectively. Pitavastatin and atorva­ tions were 44.0 and 42.8%, respectively, while statin reduced the volumes of nonculprit plaques 75.2 and 75.5%, respectively, attained the EAS by 16.9 and 18.1%, respectively. In both cases, LDL‑C target. HDL‑C concentrations were plaque regression was associated with negative increased from baseline to a similar extent by vessel remodeling (113.0–105.4 mm3). The both treatments: 6.0 and 6.2% with pitavastatin upper limit of 95% confidence interval of the 2 and 4 mg, respectively; and 5.0 and 6.8% with mean difference in percentage change in plaque simvastatin 20 and 40 mg, respectively. volume between pitavastatin and atorvastatin Of the volunteers who completed one of these (1.11%) after adjusting for sex, diabetes and studies, 1353 patients elected to receive open- total cholesterol levels, did not exceed the 5% label pitavastatin 4 mg once daily for up to predefined non-inferiority margin [45]. 52 weeks. The proportion of patients achieving In another recent Japanese study, the plaque NCEP and EAS LDL‑C targets at week 52 was volume index declined by 2.6% in patients 74.0 and 73.5%, respectively. Pitavastatin main- with acute coronary syndrome treated with tained the reduction in LDL‑C that emerged 80 mg/daily pitavastatin compared with a 0.2% during the double-blind studies. Changes in increase in those receiving 80 mg/daily atorvas- other efficacy parameters (triglycerides, total tatin for 2–3 weeks [46]. The early benefit seen cholesterol, non-HDL‑C, ApoA1 and ApoB, with pitavastatin may reflect a greater affinity for high-sensitivity C‑reactive protein, oxidized fibrofat than atorvastatin. LDL) and ratios (total cholesterol:HDL‑C, In part, the discordance between these stud- non-HDL‑C:HDL‑C and ApoB:ApoA1) were ies reflects differences in the cohorts enrolled sustained over 52 weeks compared with the and intravascular ultrasound techniques. The end of the double-blind studies. HDL‑C levels Japanese study enrolled patients with acute coro- rose continually during follow-up, ultimately nary syndrome, while REVERSAL assessed the i­ncreasing by 14.3% over the initial baseline [44]. regression of stable coronary artery disease [45]. Overall, although these pitavastatin clinical In the JAPAN-ACS study, intravascular ultra- studies demonstrate, at the least, achievement sound measurement was performed in an area of non-inferiority criteria for LDL‑C reduc- adjacent to where percutaneous coronary inter- tions versus simvastatin and atorvastatin, the vention was performed. In REVERSAL, intra- clinical efficacy of pitavastatin is clearly dem- vascular ultrasound measurement was taken onstrated in attainment of EAS and NCEP from vessels where percutaneous coronary inter- targets. Patients receiving the higher dose over vention had not been performed. Further stud- the 52-week, open-label interval maintained the ies must examine this hypothesis and determine benefits observed in the shorter-term studies. whether plaques regress in other patient popula- Short-term treatment with pitavastatin was not tions. However, the results are consistent with associated with increases in HDL‑C levels that the meta-ana­lysis demonstrating that 48 and were signifi­cantly different from comparators. 25 fewer participants with and without CHD,

316 Clin. Lipidol. (2010) 5(3) future science group Pitavastatin: a distinctive lipid-lowering drug | Drug Evaluation respectively, at baseline would experience major not meet LDL‑C targets on pitavastatin 2 mg vascular events for every 1000 people treated titrated to 4 mg. Of those on the higher dose, with statins for 1 year [5]. The plaque regres- 70% met NCEP targets at week 60. The effects sion studies suggest that pitavastatin may share of the 4 mg dose on other lipid parameters were the statins’ class effect of reducing CVD-related similar to pitavastatin 2 mg [49]. morbidity and mortality. Post-marketing surveillance study Elderly patients Clinical studies typically include a wide range Elderly people are particularly likely to develop of inclusion and exclusion criteria, which poten- CVD. Indeed, two-thirds of first major coronary tially hinder attempts to extrapolate the results to events occur in people aged 65 years or older [47]. the less-selected population encountered in clini- Vascular disease is the primary cause of mor- cal practice. However, a Japanese post-marketing tality in approximately half of this age group, surveillance study, known as LIVES, examined while 75–80% of subjects aged 80 years show this issue. LIVES assessed pitavastatin’s effec- atherosclerosis [48]. tiveness and safety in 18,031 patients who were Against this background, a non-inferiority prescribed pitavastatin and registered with study compared once-daily pitavastatin and the study team within 2 weeks. Most patients pravastatin (1 vs 10 mg; 2 vs 20 mg; and 4 vs received pitavastatin as their initial lipid-low- 40 mg) over 12 weeks in 942 patients aged ering therapy. However, 18.9% had previously 65 years or older (mean: 70; range: 65–89 years) received lipid-lowering therapy in clinical prac- with primary hypercholesterolemia or combined tice. Pitavastatin reduced LDL‑C concentra- dyslipidemia and elevated plasma LDL‑C levels tions by 29.1% within 4 weeks of the start of and triglycerides. Based on mean LDL‑C con- treatment. LDL‑C remained at this level for the centrations, pitavastatin at least met prospec- remainder of the 2‑year follow-up [10]. tive non-inferiority criteria (6% non-inferiority Serum LDL‑C levels showed similar declines limit) at all doses. Indeed, the mean decrease in in a wide variety of patients: without and with LDL‑C levels was approximately 10 percentage concomitant liver disease (29.2 and 27.7%, points greater with pitavastatin than pravastatin. respectively); without and with concomitant Furthermore, pitavastatin showed statistically renal disease (29.1 and 28.0%, respectively); significant benefits compared with pravastatin and without and with diabetes (29.7 and 27.3%, with: all doses for total cholesterol and ApoB; respectively). In patients with abnormal base- medium- and high-doses for HDL‑C; and low- line triglyceride and HDL‑C levels, p­itavastatin and high-doses for triglycerides. The proportion decreased triglyceride concentrations by 22.7% of patients that met the NCEP LDL‑C target and increased HDL‑C levels by 19.9% [10]. with pitavastatin and pravastatin, respectively, In a further ana­lysis of the LIVES database, were: low doses, 83 and 65%; medium doses, 89 c­oncentrations of total cholesterol and LDL‑C and 81%; and high doses, 91 and 88% [49]. This declined by 21.0 and 31.3%, respectively, over study suggests that in elderly patients, pitava­ 2 years of follow-up. Triglyceride levels declined statin is more effective than pravastatin using by 6.1% overall and by 24.2% in patients with doses that are as well tolerated. baseline triglyceride levels 15.8% or higher [50]. Of the volunteers that completed this double- blind study, 545 patients aged 65 years or older Consistent elevation in HDL‑C entered an open-label extension phase assessing As the aforementioned studies demonstrate, pitavastatin 2 and 4 mg once daily. During the pitavastatin consistently produces a clinically 60-week study, adverse event rates were simi- significant increase in HDL‑C levels. Other lar across the whole dose range of both drugs. statins, in contrast, show inconsistent results on After 60 weeks, pitavastatin reduced concentra- HDL‑C concentrations, with elevations ranging tions of LDL‑C and several other atherogenic from 0 to 12% [51]. Other studies confirm these lipid parameters compared with the end of the findings. For example, an ana­lysis of the LIVES double-blind comparative phase. HDL‑C con- database found that in patients with low HDL‑C centrations increased by 9.6% compared with levels (<40 mg/dl) at baseline, HDL‑C concen- the baseline for the double-blind study [49]. trations rose by 14.0 and 24.9% after 12 and After 60 weeks, 99% of patients attained 104 weeks, respectively. Indeed, HDL‑C levels NCEP targets; most patients attained LDL‑C rose by 15.8% after patients switched to pitava­ targets with pitavastatin 2 mg. Patients who did statin from other statins [50]. This suggests that

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patients may benefit from switching statins to of patients withdrew due to treatment emer- pitavastatin if, ceteris paribus, HDL‑C remains gent adverse events. The investigators did not unacceptably low on the initial regimen. consider that any of the serious adverse events Indeed, pitavastatin’s ability to elevate reported during this study were related to HDL‑C levels appears to be independent of the pitavastatin. No clinically significant abnormali- efficacy on other lipid outcomes. For example, ties were associated with pitavastatin in routine a 12-week, prospective, open-label trial found laboratory variables, urinalysis, vital signs or comparable reductions in LDL‑C concentrations 12-lead ECG. Increased creatine phosphokinase with pitavastatin (2 mg/day) and atorvastatin (2.74%), nasopharyngitis (5.4%) and myal- (10 mg/day): 42.6 and 44.1%, respectively. gia (4.1%) were the most common t­reatment Pitavastatin and atorvastatin also reduced levels e­mergent adverse events [44]. of total cholesterol by 29.7 and 31.1%, respec- tively, and triglyceride concentrations by 17.3 „„Muscle toxicity and 10.7%, respectively. However, HDL‑C lev- Muscle toxicity and in particular rhabdomy- els increased significantly with pitavastatin, but olysis, is a rare but potentially serious adverse not atorvastatin: 3.2 and 1.7%, respectively [52]. event associated with statins. In a meta-ana­lysis In a separate study, Japanese patients with of 13 studies, the incidence of rhabdomyolysis LDL‑C levels 140 mg/dl or greater and glu- among statin users was 0.023%. This compared cose intolerance were randomly assigned to with 0.015% among controls. The absolute receive either pitavastatin 2 mg/day or ator­ excess risk associated with statins over 5 years vastatin 10 mg/day in a comparative 52-week, (0.01%) did not reach statistical significance[5] . open-label study. Increases in HDL‑C levels Similarly, the LIVES study suggested that myal- were significantly greater following pitava­statin gia was uncommon (1.08%) during treatment 2 mg/day, compared with atorvastatin 10 mg/ with pitavastatin. Only one patient enrolled in day: 8.2 versus 2.9%, respectively. Changes in the trial developed rhabdomyolysis with creatine ApoAI (5.1 vs 0.6%), ApoB (-35.1 vs -28.2%) phosphokinase at least ten-times the upper limit and ApoE (-28.1 vs -17.8%) also favored of normal (0.005%) [10]. Furthermore, during pitavastatin 2 mg/day versus a­torvastatin open-label treatment with pitavastatin 4 mg once 10 mg/day [53]. daily for up to 52 weeks, there were no reports of myopathy, myositis or rhabdomyolysis [44]. Safety & tolerability Taken together, these data suggest that pitava­ Pitavastatin is well tolerated. The post-marketing statin is associated with a low risk of rhabdo- LIVES study analyzed safety in 19 925 patients myolysis. However, differences in the definition receiving pitavastatin in clinical practice [10]. of rhabdomyolysis hinder comparisons between During a 2‑year follow-up, 10.4% of patients studies. Nevertheless, the dose of pitavastatin experienced adverse events, of which approxi- does not need to be adjusted in the elderly. mately 84% of side effects were mild and only approximately 1% were severe. Increases in blood Dosage & administration creatine phosphokinase (2.74%), alanine amino­ Patients swallow pitavastatin tablets whole at any transferase (1.79%), myalgia (1.08%), aspartate time of the day with or without food. Ideally, aminotransferase and g-glutamyltransferase patients should take pitavastatin at the same (1.00%) were the most common adverse events. time each day. Evening doses of statins optimizes Only 7.4% of patients discontinued pitavastatin outcomes due to the circadian rhythm of lipid after developing adverse events. metabolism [54,55]. Pitavastatin was also well tolerated in elderly The usual starting dose of pitavastatin is patients. During the 2‑year follow-up, there were 1 mg once daily. The dose should be adjusted at no differences in rates of adverse events between intervals of at least 4 weeks according to LDL‑C patients under or those 65 years of age or over. levels, the goal of therapy and patient response. In addition, regression ana­lysis demonstrated Most patients require pitavastatin 2 mg once that age (<65 vs ≥65 years) was not a signifi- daily. The maximum daily dose is 4 mg. cant factor for incidence of any adverse event or No dose adjustment is required in the myopathy-associated events [10]. elderly or in patients with impaired renal Furthermore, during a 52-week open-label function. However, clinicians should closely clinical study of pitavastatin 4 mg once daily monitor patients with moderate or severe renal (the highest recommended dose), only 4.1% impairment. Patients with mild-to-moderate

318 Clin. Lipidol. (2010) 5(3) future science group Pitavastatin: a distinctive lipid-lowering drug | Drug Evaluation impairment of hepatic function can receive a long-term treatment (52 weeks). HDL‑C levels maximum dose of 2 mg daily with close moni- rose continually during 52 weeks of treatment toring. However, the 4 mg dose is not recom- [44].Pitavastatin and atorvastatin produce simi- mended and pitavastatin is contraindicated in lar reductions in plaque volume and negative patients with severe hepatic impairment, active vessel remodeling [45]. liver disease or unexplained persistent elevations Patients aged 65 years or older are particularly in serum transaminases that exceed three-times prone to developing CVD. In these patients, the upper limit of normal. pitavastatin reduced LDL‑C levels by approxi- mately 10% more than pravastatin. Indeed, Conclusion pitavastatin was significantly more efficacious According to the WHO, CVD accounts for than pravastatin across a range of lipid outcomes. approximately a third of global mortality [101]. A greater proportion of the elderly patients tak- Managing dyslipidemia is a central to lifting this ing pitavastatin met the EAS target compared burden; each mmol/l decline in LDL‑C reduces with the pravastatin group. During a 60-week the risk of major vascular events by approxi- open-label extension study, pitavastatin increased mately a fifth [5]. However, current statins have HDL‑C levels, reduced LDL‑C concentrations limitations that hinder statin’s full potential and more than 90% of patients attained LDL‑C from being realized in clinical practice, includ- targets. The post-marketing LIVES study sug- ing adverse events [102], residual risk from factors gests that the benefits observed in clinical studies other than LDL‑C and LDL‑C levels above tar- translate into naturalistic practice. gets recommended in guidelines [8,9]. Across the studies, pitavastatin consistently Pitavastatin potently inhibits HMG‑CoA produces a clinically significant increase in reductase, increases lipoprotein lipase expression HDL‑C. By contrast, other statins show incon- in adipocytes and promotes ApoA1 production sistent results on HDL‑C [51]. In theory, pitava­ [17,19,20]. These actions lower concentrations of statin’s effects on HDL‑C and other lipids may LDL‑C and triglycerides and increase HDL‑C offer an advantage over other statins: allowing a levels, respectively. Pitavastatin undergoes bili- greater proportion of patients to attain treatment ary excretion and enterohepatic circulation; targets. However, the size and duration makes a the latter may contribute to the drug’s phar- comparative trial needed to examine this hypoth- macodynamic profile. Pitavastatin undergoes esis impracticable. Pitavastatin is well tolerated. only a small degree of metabolism by CYP2C9 During open-label treatment with pitavastatin and almost negligible transformation by for up to 2 years, 7.4% of patients withdrew after CYP2C8 [31]. The cyclopropyl group protects developing adverse events. No clinically signifi- pitavastatin from metabolism by CYP3A4, cant abnormalities emerged in routine laboratory reducing the risk of interactions compared with variables, urinalysis, vital signs or 12-lead ECG. statins extensively biotransformed by this iso- The most common adverse events were increased enzyme [22]. OATP1B is a major transporter of creatine phosphokinase, alanine aminotrans- pitavastatin into the liver, the main site of action ferase, aspartate aminotransferase, myalgia and for statins [26]. Although pitavastatin can inter- g‑glutamyltransferase [10]. act with OATP1B1 inhibitors, the most marked interaction is with ciclosporin [30,36]. Future perspective In Caucasians, pitavastatin is non-infe- Statins are well established in the dyslipidemia rior to atorvastatin in reducing LDL‑C [42]. armamentarium. Future studies of pitavastatin Over three-quarters of patients receiving should directly compare clinical end points pitava­statin 4 mg/day attain EAS LDL‑C with other statins to define its position within targets. Pitavastatin 4 mg/day is non-infe- the armamentarium. The widening choice of rior to s­imvastatin 40 mg/day, respectively. treatments, exemplified by pitavastatin, allows Pitavastatin 2 mg reduced LDL‑C, non- clinicians to target treatment to each patient HDL‑C and total cholesterol more than simvas- with unprecedented accuracy. In the future, the tatin 20 mg. Furthermore, a greater proportion growing number of genetic polymorphisms that of patients taking pitavastatin 2 mg achieved appear to influence outcomes in CVD should the EAS LDL‑C target than those receiving f­urther hone accuracy. simvastatin 20 mg. Pitavastatin produced a sus- For example, several single nucleotide poly- tained decline in levels of LDL‑C and other morphisms (SNP) in genes encoding OATP1B lipids and maintained target attainment during may produce clinically relevant alterations in

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statin pharmacokinetics [56]. For example, be associated with a higher risk of myopa- nonsynonymous SNPs in SLCO1B1 (encoding thy and rhabdo­myolysis [57]. However, these influx system OATP1B1) and ABCC2 (encod- SNPs account for only a threefold increase in

ing efflux system MRP2) result in several AUC0–24. Each C allele increased the odds ratio clinically significant variant alleles. One SNP for myopathy by 4.5. Moreover, the CC geno- (421C/A*15/*15) produced a threefold increase type increased the risk 16.9-fold as compared

in AUC0–24 of pitavastatin compared with with TT homozygotes. Indeed, the C allele 421C/C*1b/*1b (the wild-type in Asian popula- accounted for more than 60% of myopathy tions). Another SNP (421C/C*1b/*15) doubled cases. SEARCH suggests that the risk asso­ * * the AUC0–24 compared with 421C/C 1b/ 1b. ciated with SLCO1B1 polymorphisms is limited These functionally impaired alleles seem to to doses of simvastatin of 40–80 mg [58].

Executive summary Mechanism of action „„Pitavastatin is a synthetic HMG‑CoA reductase inhibitor with a novel cyclopropyl moiety. Pitavastatin binds avidly to and potently inhibits HMG‑CoA reductase, thereby reducing cholesterol levels. „„Pitavastatin’s ability to reduce triglyceride concentrations may arise from increased lipoprotein lipase production in adipocytes. „„Pitavastatin increases HDL‑C concentrations, probably by inhibiting HMG‑CoA reductase, suppressing Rho activity and protecting ApoA1 from catabolism. Pharmacokinetic properties „„Pitavastatin undergoes biliary excretion and enterohepatic circulation. „„CYP2C9 and CYP2C8 interact with pitavastatin, although resulting in negligible metabolism. The cyclopropyl group protects pitavastatin from metabolism by CYP3A4. „„OATP1B accounts for approximately 90% of hepatic clearance of pitavastatin. Clinical efficacy „„Pitavastatin was non-inferior to atorvastatin in reducing LDL‑C. Over three-quarters of those receiving pitavastatin 4 mg/day meet European Atherosclerosis Society (EAS) LDL‑C targets. „„Pitavastatin 4 mg/day is non-inferior to simvastatin 40 mg/day. Pitavastatin 2 mg/day reduced levels of LDL‑C, non‑HDL‑C and total cholesterol more than simvastatin 20 mg. More patients taking pitavastatin 2 mg/day achieved the EAS LDL‑C target than with simvastatin 20 mg. „„Open-label treatment with pitavastatin 4 mg daily for up to 52 weeks produced sustained target attainment and maintained the reduction in LDL‑C concentrations. HDL‑C levels rose continually. „„Pitavastatin and atorvastatin produce similar decreases in plaque volume and negative vessel remodeling. „„In the elderly, the decrease in LDL‑C levels was approximately 10% greater with pitavastatin than pravastatin. Pitavastatin improved several other lipid parameters compared with pravastatin: total cholesterol, ApoB, HDL‑C and triglycerides. Pitavastatin produced sustained benefits on HDL‑C, LDL‑C and target attainment over 60 weeks. „„The postmarketing LIVES study suggests that the benefits observed in clinical studies translate into naturalistic practice. „„Pitavastatin consistently produces clinically significant increases in HDL‑C levels. Other statins show inconsistent results on HDL‑C concentrations. Safety & tolerability „„Pitavastatin is well-tolerated. „„In post-marketing surveillance, increases in blood creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase, myalgia and g-glutamyltransferase were the most common adverse events. Drug interactions „„Although pitavastatin can interact with OATP1B1 inhibitors, the most marked interaction is with ciclosporin. „„Pitavastatin does not interact with agents that inhibit or induce CYP3A4, markedly reducing the risk of drug–drug and drug–diet interactions compared with some other statins. Dosage & administration „„The usual starting dose of pitavastatin is 1 mg once daily. The dose should be adjusted at intervals of at least 4 weeks according to LDL‑C levels, the goal of therapy and patient response. „„Most patients require pitavastatin 2 mg once daily. The maximum daily dose is 4 mg. „„No dose adjustment is required in the elderly or in patients with impaired renal function. However, clinicians should closely monitor patients with moderate or severe renal impairment. „„Patients with mild-to-moderate hepatic impairment can receive a maximum dose of 2 mg daily with close monitoring. However, the 4 mg dose is not recommended. „„Pitavastatin is contraindicated in patients with severe hepatic impairment, active liver disease or unexplained persistent elevations in serum transaminases that exceed three-times the upper limit of normal.

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Treatment goals may also evolve as evidence Financial & competing interests disclosure implicates a wider range of pathogenic lipids Kowa Research Europe Ltd funded the study and the and lipoproteins. Indeed, reductions in CHD p­reparation of this manuscript. Leiv Ose received risk are proportional to the absolute decline research grant funding from Merck, Pfizer, in LDL‑C. Therefore, some authors argue for Schering–Plough, Roche and Boehringer Ingelheim; and achieving ‘substantial absolute reductions’ in he is a consultant/advisor to Kowa; and has received LDL‑C rather than aiming at a particular target speakers bureau fees from AstraZeneca and Kowa. The [5]. Furthermore, the recognition that the factors author has no other relevant affiliations or financial associated with the non-LDL‑C residual risk involvement with any organization or entity with a are amenable to treatment argues for therapeu- financial interest in or financial conflict with the subject tic objectives that encompass a wider range of matter or m­aterials discussed in the m­anuscript apart factors. While the role of statins in CHD may from those disclosed. appear well established, there is much that clini- Mark Greener, a medical writer, assisted with the cians and researchers can still achieve to further drafting of this m­anuscript. However, the author is reduce the global burden imposed by CVD. responsible for the final document.

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