Pleiotropic effects of pitavastatin

Abstract

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are established first line treatments for hypercholesterolaemia. In addition to the direct effects of statins in reducing concentrations of atherogenic low density lipoprotein cholesterol (LDL-C), several studies have indicated that the beneficial effects of statins may be due to some of their cholesterol-independent, multiple (pleiotropic) effects which may differ between different members of the class. Pitavastatin is a novel synthetic lipophilic statin that has a number of pharmacodynamic and pharmacokinetic properties distinct from those of other statins, which may underlie its potential pleiotropic benefits in reducing cardiovascular risk factors. This review examines the principal pleiotropic effects of pitavastatin on endothelial function, vascular inflammation, oxidative stress and thrombosis. The article is based on a systematic literature search carried out in December 2010, together with more recent relevant publications where appropriate. The available data from clinical trials and in vitro and animal studies suggest that pitavastatin is not only effective in reducing LDL-C and triglycerides, but also has a range of other effects. These include increasing high density lipoprotein cholesterol, decreasing markers of platelet activation, improving cardiac, renal and endothelial function, and reducing endothelial stress, lipoprotein oxidation and, ultimately, improving the signs and symptoms of atherosclerosis. It is concluded that the diverse pleiotropic actions of pitavastatin may contribute to reducing cardiovascular morbidity and mortality beyond that achieved through LDL-C reduction.

Figure 1

Molecular structures of (A) HMG-CoA and (B) hydrophilic and (C) lipophilic currently available statins. Adapted from Shitara et al. [126]

Figure 2

Isoprene synthesis, separate from cholesterol synthesis, modulates cellular function by activating GTPases and G-proteins, such as Ras, Rac1 and RhoA, via addition of an isoprene chain (farnesol or geranylgeraniol). Statin-induced decreases in HMG-CoA reductase activity reduce downstream protein prenylation and have the potential to improve vascular function through multiple pathways. GTP, guanosine triphosphate; PAI-1, plasminogen activator inhibitor-1; Ras, rat sarcoma subfamily; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homologue gene family, A

Figure 3

Effects of pitavastatin on forearm blood flow during reactive hyperaemia in patients with coronary artery disease and controls after 6 months' treatment. Blood flow was measured using strain-gauge plethysmography directly before and 2 h after, patients consumed a modified standard test meal (Japan Diabetes Society) after an overnight fast. *P < 0.05 vs. baseline preprandial data, †P < 0.05 vs. baseline postprandial data. Reproduced with permission from Arao et al. [48]. CAD, coronary artery disease. Before meal (□); After meal ()

Figure 4

Increase in endothelial-dependent vasodilation following 1 month of treatment with 2 mg pitavastatin daily in chronic smokers. Endothelial function was assessed noninvasively, using high-resolution ultrasound, by measuring endothelium-dependent and -independent dilation of the brachial artery by reactive hyperaemia and glycerol trinitrate, respectively. *P < 0.05 vs. patients not treated with pitavastatin. Reproduced with permission from Yoshida et al. [49]. FMD, endothelium-dependent flow-mediated dilatation; GTD, endotheliumindependent glycerol trinitrate-induced vasodilatation. Controls (□); Pitavastatin ()

Figure 5

Treatment with pitavastatin (2 mg day⁻¹) for 4 weeks increased serum urocortin concentrations, measured using an enzyme-linked immunosorbent assay, in 15 healthy male volunteers. *P < 0.01 vs. before pitavastatin treatment. Reproduced with permission from Honjo et al. [68]

Figure 6

Changes in (A) urinary 8-hydroxy-2′-deoxyguanosine (a marker of oxidative stress), (B) malondialdehyde-LDL (a form of oxidized LDL) and (C) cardio-ankle vascular index in 45 patients with type 2 diabetes mellitus treated with pitavastatin 2 mg day⁻¹ for 12 months (mean ± SD). Urinary 8-hydroxy-2′-deoxyguanosine and malondialdehyde-LDL were measured using enzyme-linked immunosorbent assays. The results for the former were adjusted for serum creatinine concentrations. The cardio-ankle vascular index reflects the stiffness of the aorta and femoral and tibial arteries, independent of blood pressure, and was measured using blood pressure cuffs attached to the biceps and ankles with patients in a supine position. *P < 0.05; **P < 0.01 vs. before treatment, paired t-test. Adapted from Miyashita et al. [74]. 8-OHdG, 8-hydroxy-2′-deoxyguanosine; CAVI, cardio-ankle vascular index; MDA-LDL, malondialdehyde-low-density lipoprotein

Figure 7

Changes in carotid arterial stiffness in 30 patients with hypercholesterolaemia randomized to receive either pitavastatin (1–2 mg day⁻¹, n = 15) or diet and exercise therapy for 12 months. Carotid ultrasonography was used to reveal end-systolic and end-diastolic diameters of the common carotid artery, Ds and Dd, respectively, and arterial stiffness, β, was calculated using the formula ln(SBP/DBP)/[(Ds – Dd)/Dd], where SBP and DBP are the systolic and diastolic blood pressures, respectively. *P < 0.05 vs. no statin group after treatment. Data from Mizuguchi et al. [102]. Baseline (□); 12 months ()

Figure 8

Improvements in markers of (A and B) renal function, (C) serum cholesterol and (D) oxidative stress in patients with chronic kidney disease and dyslipidaemia after treatment with 2 mg pitavastatin daily alone, or in combination with 10 mg ezetimibe, for 6 months. 8-hydroxy-2′-deoxyguanosine and L-fatty acid binding protein were measured enzymatically using enzyme-linked immunosorbent assays, proteinuria was measured using a pyrogallol red method and LDL-C concentrations were calculated using Friedewald's formula. *P < 0.001 vs. before pitavastatin treatment, †P < 0.001 vs. before pitavastatin + ezetimibe treatment, ‡P < 0.05 vs. after pitavastatin treatment alone. Data from Nakamura et al. [112]. Before (□); After (). 8-OHdG,8-hydroxy-2′-deoxyguanosine; LDL-C, low density lipoprotein cholesterol; L-FABP, L-fatty acid binding protein

Figure 9

Stabilization of carotid plaques, measured as the change in integrated backscatter (IBS) on carotid ultrasound, following treatment with pitavastatin 4 mg day⁻¹ for 1 month in patients with acute coronary syndromes (mean ± SD). *P < 0.05 vs. baseline within treatment group; †P < 0.05 vs. placebo at 1 month. Data from Nakamura et al. [114]. Baseline (□); 1 month ()

Figure 10

Lack of correlation between stabilization of coronary plaques (expressed as reduction in yellow plaque content) and change in LDL-C in patients with coronary artery disease treated with pitavastatin 2 mg day⁻¹ for 52 weeks. Intravascular ultrasound and coronary angiography were used to grade yellow atherosclerotic plaques and to assess their regression during treatment. Reproduced with permission from Kodama et al. [116]. LDL-C, low density lipoprotein cholesterol