Introduction. The objective of this study was to clarify how pitavastatin affects glucose and lipid metabolism, renal function, and oxidative stress. Methods. Ten Japanese men (average age of 33.9 years) were orally administered 2？mg of pitavastatin for 4 weeks. Postprandial glucose, lipoprotein metabolism, and oxidative stress markers were evaluated at 0 and 4 weeks of pitavastatin treatment (2？mg once daily) with a test meal consisting of total calories: 460？kcal, carbohydrates: 56.5？g (226？kcal), protein: 18？g (72？kcal), lipids: 18？g (162？kcal), and NaCl: 1.6？g. Metabolic parameters were measured at 0, 60, and 120 minutes after test meal ingestion. Results. After administration of pitavastatin, serum total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, arachidonic acid, insulin, and adjusted urinary excretion of uric acid decreased, whereas creatinine clearance ( ) and uric acid clearance ( ) increased. And postprandial versus fasting urine 8-hydroxydeoxyguanosine remained unchanged, while postprandial versus fasting isoprostane decreased after pitavastatin treatment. Next, we compared postprandial glucose and lipid metabolism after test meal ingestion before and after pitavastatin administration. Incremental areas under the curve significantly decreased for triglycerides ( ) and remnant-like particle cholesterol ( ), while those for apolipoprotein E (apoE), glucose, insulin, and high-sensitivity C-reactive protein remained unchanged. Conclusion. Pitavastatin improves postprandial oxidative stress along with hyperlipidemia. 1. Introduction It has been generally recognized that postprandial hyperglycemia and hyperlipidemia are highly related to the development of atherosclerosis [1–5]. Hyperglycemia is known to damage vascular endothelial cells, increase oxidative stress, promote the expression of adhesion molecules, and inhibit Nitric Oxide (NO) production . Remnant lipoprotein, an important component of postprandial hyperlipidemia, promotes foam cell formation of macrophages and proliferation of smooth muscle cells . A very recent study on a large number of subjects demonstrated that remnant cholesterol was a causal risk factor for ischemic heart disease . Lipid-lowering drugs, such as statins, fibrates, and ezetimibe are considered to be useful for the treatment of postprandial hyperlipidemia [9–15]. Pitavastatin, a member of the medication class of statins, has been available in the market in Japan since 2003. It has been well recognized that this statin is markedly effective in reducing low-density lipoprotein
Q. Qiao, S. Larsen, K. Borch-Johnsen et al., “Glucose tolerance and cardiovascular mortality. Comparison of fasting and 2-hour diagnostic criteria,” Archives of Internal Medicine, vol. 161, no. 3, pp. 397–405, 2001.
M. Tominaga, H. Eguchi, H. Manaka, K. Igarashi, T. Kato, and A. Sekikawa, “Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Funagata Diabetes Study,” Diabetes Care, vol. 22, no. 6, pp. 920–924, 1999.
T. B. Twickler, G. M. Dallinga-Thie, J. S. Cohn, and M. J. Chapman, “Elevated remnant-like particle cholesterol concentration: a characteristic feature of the atherogenic lipoprotein phenotype,” Circulation, vol. 109, no. 16, pp. 1918–1925, 2004.
A. Varbo, M. Benn, A. Tybjaerg-Hansen, A. B. Jorgensen, R. Frikke-Schmidt, and B. G. Nordestgaard, “Remnant cholesterol as a causal risk factor for ischemic heart disease,” Journal of the American College of Cardiology, vol. 61, pp. 427–436, 2013.
T. C. Ooi, M. Cousins, D. S. Ooi, K. Nakajima, and A. L. Edwards, “Effect of fibrates on postprandial remnant-like particles in patients with combined hyperlipidemia,” Atherosclerosis, vol. 172, no. 2, pp. 375–382, 2004.
E. J. Schaefer, J. R. McNamara, T. Tayler et al., “Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects,” The American Journal of Cardiology, vol. 93, no. 1, pp. 31–39, 2004.
J. G. Schneider, M. Von Eynatten, K. G. Parhofer et al., “Atorvastatin improves diabetic dyslipidemia and increases lipoprotein lipase activity in vivo,” Atherosclerosis, vol. 175, no. 2, pp. 325–331, 2004.
K. Schoonjans, J. Peinado-Onsurbe, J.-C. Fruchart, A. Tailleux, C. Fiévet, and J. Auwerx, “3-Hydroxy-3-methylglutaryl CoA reductase inhibitors reduce serum triglyceride levels through modulation of apolipoprotein C-III and lipoprotein lipase,” FEBS Letters, vol. 452, no. 3, pp. 160–164, 1999.
K. G. Parhofer, P. H. R. Barrett, and P. Schwandt, “Atorvastatin improves postprandial lipoprotein metabolism in normolipidemic subjects,” The Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 11, pp. 4224–4230, 2000.
K. G. Parhofer, E. Laubach, and P. H. R. Barrett, “Effect of atorvastatin on postprandial lipoprotein metabolism in hypertriglyceridemic patients,” Journal of Lipid Research, vol. 44, no. 6, pp. 1192–1198, 2003.
T. Hiro, T. Kimura, T. Morimoto 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),” Journal of the American College of Cardiology, vol. 54, no. 4, pp. 293–302, 2009.
M.-A. Kawashiri, A. Nohara, H. Tada et al., “Comparison of effects of pitavastatin and atorvastatin on plasma coenzyme Q10 in heterozygous familial hypercholesterolemia: results from a crossover study,” Clinical Pharmacology and Therapeutics, vol. 83, no. 5, pp. 731–739, 2008.
N. Poolsup, N. Suksomboon, K. Wongyaowarat, B. Rungkanchananon, P. Niyomrat, and S. Kongsuwan, “Meta-analysis of the comparative efficacy and safety of pitavastatin and atorvastatin in patients with dyslipidaemia,” Journal of Clinical Pharmacy and Therapeutics, vol. 37, no. 2, pp. 166–172, 2012.
A. L. Catapano, “Statin-induced myotoxicity: pharmacokinetic differences among statins and the risk of rhabdomyolysis, with particular Reference to pitavastatin,” Current Vascular Pharmacology, vol. 10, no. 2, pp. 257–267, 2012.
H. Nagashima and M. Endo, “Pitavastatin prevents postprandial endothelial dysfunction via reduction of the serum triglyceride level in obese male subjects,” Heart and Vessels, vol. 26, no. 4, pp. 428–434, 2011.
K. Arao, T. Yasu, T. Umemoto et al., “Effects of pitavastatin on fasting and postprandial endothelial function and blood rheology in patients with stable coronary artery disease,” Circulation Journal, vol. 73, no. 8, pp. 1523–1530, 2009.
A. M. Nuernberg, P. D. Boyce, J. M. Cavallari, S. C. Fang, E. A. Eisen, and D. C. Christiani, “Urinary 8-isoprostane and 8-OHdG concentrations in boilermakers with welding exposure,” Journal of Occupational and Environmental Medicine, vol. 50, no. 2, pp. 182–189, 2008.
A. A. Commodore, J. J. Zhang, Y. Chang, et al., “Concentrations of urinary 8-hydroxy-2'-deoxyguanosine and 8-isoprostane in women exposed to woodsmoke in a cookstove intervention study in San Marcos, Peru.,” Environment International, vol. 60, pp. 112–122, 2013.
J. D. Morrow, K. E. Hill, R. F. Burk, T. M. Nammour, K. F. Badr, and L. J. Roberts II, “A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 23, pp. 9383–9387, 1990.
E. Nagai, T. Katsuno, J.-I. Miyagawa et al., “Effects of miglitol in combination with intensive insulin therapy on blood glucose control with special reference to incretin responses in type 1 diabetes mellitus,” Endocrine Journal, vol. 58, no. 10, pp. 869–877, 2011.
J. R. McNamara, P. K. Shah, K. Nakajima et al., “Remnant-like particle (RLP) cholesterol is an independent cardiovascular disease risk factor in women: results from the Framingham Heart Study,” Atherosclerosis, vol. 154, no. 1, pp. 229–236, 2001.
F. Karpe, S. Boquist, R. Tang, G. M. Bond, U. De Faire, and A. Hamsten, “Remnant lipoproteins are related to intima-media thickness of the carotid artery independently of LDL cholesterol and plasma triglycerides,” Journal of Lipid Research, vol. 42, no. 1, pp. 17–21, 2001.
M. Guerin, P. Egger, W. L. Goff, C. Soudant, R. Dupuis, and M. John Chapman, “Atorvastatin reduces postprandial accumulation and cholesteryl ester transfer protein-mediated remodeling of triglyceride-rich lipoprotein subspecies in type IIB hyperlipidemia,” The Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 11, pp. 4991–5000, 2002.
A. Saiki, T. Murano, F. Watanabe, T. Oyama, Y. Miyashita, and K. Shirai, “Pitavastatin enhanced lipoprotein lipase expression in 3T3-L1 preadipocytes,” Journal of Atherosclerosis and Thrombosis, vol. 12, no. 3, pp. 163–168, 2005.
S. Morikawa, M. Umetani, S. Nakagawa et al., “Relative induction of mRNA for HMG CoA reductase and LDL receptor by five different HMG-CoA reductase inhibitors in cultured human cells,” Journal of Atherosclerosis and Thrombosis, vol. 7, no. 3, pp. 138–144, 2000.
S. Lally, C. Y. Tan, D. Owens, and G. H. Tomkin, “Messenger RNA levels of genes involved in dysregulation of postprandial lipoproteins in type 2 diabetes: the role of Niemann-Pick C1-like 1, ATP-binding cassette, transporters G5 and G8, and of microsomal triglyceride transfer protein,” Diabetologia, vol. 49, no. 5, pp. 1008–1016, 2006.
R. Carnevale, P. Pignatelli, S. Di Santo et al., “Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients,” Atherosclerosis, vol. 213, no. 1, pp. 225–234, 2010.
S. Nomura, N. Inami, A. Shouzu et al., “The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients,” Platelets, vol. 20, no. 1, pp. 16–22, 2009.
H. Kakuda, K. Kanasaki, D. Koya, and N. Takekoshi, “The administration of pitavastatin augments creatinine clearance associated with reduction in oxidative stress parameters: acute and early effects,” Clinical and Experimental Nephrology, vol. 17, pp. 240–247, 2013.
B. Sadowitz, K. G. Maier, and V. Gahtan, “Basic science review: statin therapy-part I: the pleiotropic effects of statins in cardiovascular disease,” Vascular and Endovascular Surgery, vol. 44, no. 4, pp. 241–251, 2010.
J. N. Bech, C. B. Nielsen, and E. B. Pedersen, “Effects of systemic NO synthesis inhibition on RPF, GFR, UNa, and vasoactive hormones in healthy humans,” American Journal of Physiology, vol. 270, no. 5, pp. F845–F851, 1996.