pitavastatin and Hypertension

Hypertension and dyslipidemia are major risk factors for cardiovascular disease (CVD). In 2012, over 270 million patients (25.2%) in China were hypertensive and 40.4% was dyslipidemic. The majority of these patients rely on statins for the prevention of cardiovascular disease. However, certain types of statins (e.g., atorvastatin), compared to others (e.g., pitavastatin), may be associated with unfavorable effects on glucose metabolism. This leads to concerns when prescribing statins to patients who also have a predisposition to glucose metabolic disorders (i.e., prediabetes). Thus, this study aims to investigate the effect of pitavastatin, compared to atorvastatin, on glucose metabolism, as measured by hemoglobin A1c (HbA1c), in Chinese prediabetics with hypertension and dyslipidemias.. The China hemoglobin A1c Metabolism Protection Union Study (CAMPUS) is a multi-center, prospective, open-label, 12-month, two-arm parallel group, and non-inferiority randomized controlled trial (RCT). A total of 396 prediabetics with hypertension and dyslipidemias will be randomly assigned 1:1 to either pitavastatin 2 mg/day or atorvastatin 20 mg/day, and followed for 12 months (follow-up visits at 1, 3, 6, and 12 months) for HbA1c levels, as well as other measures of glucose metabolism, serum lipid levels, blood pressure control, measures of inflammation, vascular endothelial function, carotid atherosclerosis, and hypertension-related left ventricular hypertrophy. If the results of low-density lipoprotein cholesterol (LDL-C) levels in month 3 after treatment initiation do not meet individual target, drug dose for the participant would be doubled.. CAMPUS will be the first RCT to investigate the effect of pitavastatin, compared to atorvastatin, on glucose metabolism in Chinese prediabetics with hypertension and dyslipidemias. Further, this study might eventually provide information to design a clinical strategy, and facilitate the improvement of primary prevention in patients at risk for diabetes and CVD.. ClinicalTrials.gov number: NCT03532620. Registered 22 May 2018.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Atorvastatin; Biomarkers; Blood Glucose; Blood Pressure; China; Dyslipidemias; Equivalence Trials as Topic; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Male; Middle Aged; Multicenter Studies as Topic; Prediabetic State; Prospective Studies; Quinolines; Time Factors; Treatment Outcome; Young Adult

Evidence about the efficacy and safety of statin treatment in high-risk patients with hypercholesterolemia is available for some populations, but not for ethnic Chinese. To test the hypothesis that treatment with pitavastatin (2 mg/day) is not inferior to treatment with atorvastatin (10 mg/day) for reducing low-density lipoprotein cholesterol (LDL-C), a 12-week multicenter collaborative randomized parallel-group comparative study of high-risk ethnic Chinese patients with hypercholesterolemia was conducted in Taiwan. In addition, the effects on other lipid parameters, inflammatory markers, insulin-resistance-associated biomarkers and safety were evaluated.. Between July 2011 and April 2012, 251 patients were screened, 225 (mean age: 58.7 ± 8.6; women 38.2% [86/225]) were randomized and treated with pitavastatin (n = 112) or atorvastatin (n = 113) for 12 weeks. Baseline characteristics in both groups were similar, but after 12 weeks of treatment, LDL-C levels were significantly lower: pitavastatin group = -35.0 ± 14.1% and atorvastatin group = -38.4 ± 12.8% (both: p < 0.001). For the subgroup with diabetes mellitus (DM) (n = 125), LDL-C levels (-37.1 ± 12.9% vs. -38.0 ± 13.1%, p = 0.62) were similarly lowered after either pitavastatin (n = 63) or atorvastatin (n = 62) treatment. Triglycerides, non-high density lipoprotein cholesterol, and apoprotein B were similarly and significantly lower in both treatment groups. In non-lipid profiles, HOMA-IR and insulin levels were higher to a similar degree in both statin groups. Hemoglobin A1C was significantly (p = 0.001) higher in the atorvastatin group but not in the pitavastatin group. Both statins were well tolerated, and both groups had a similar low incidence of treatment-emergent adverse events.. Both pitavastatin (2 mg/day) and atorvastatin (10 mg/day) were well tolerated, lowered LDL-C, and improved the lipid profile to a comparable degree in high-risk Taiwanese patients with hypercholesterolemia.. ClinicalTrials.gov NCT01386853 http://clinicaltrials.gov/ct2/show/NCT01386853?term=NCT01386853&rank=1.

Topics: Aged; Anticholesteremic Agents; Atorvastatin; Cholesterol; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertension; Lipoproteins; Male; Middle Aged; Pyrroles; Quinolines; Risk Factors; Treatment Outcome; Triglycerides

Lipid-lowering therapy with a statin not only powerfully lowers cholesterol but also exerts anti-inflammatory effects by decreasing serum C-reactive protein (CRP). Since an angiotensin II, type-1 receptor antagonist (ARB) also decreases CRP levels, the add-on effect of statins on CRP may be worth exploring. We determined the effect of pitavastatin on serum levels of highly sensitive CRP (hs-CRP) in 30 patients with hypercholesterolemia undergoing treatment with anti-hypertensive medication including ARBs. Pitavastatin, 2 mg daily, was given. The control group consisted of hypertensive patients without hyperlipidemia. The low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and hs-CRP were measured at baseline, 1, 3, 6, and 12 months after treatment. For the atherosclerotic index, LDL-C/HDL-C ratios at 12 months were calculated. The LDL-C level was markedly reduced at 1 month and thereafter. The baseline level of hs-CRP in the hyperlipidemia group was significantly higher than that in the control group (1.647 ± 0.210 mg/L vs. 0.666 ± 0.097 mg/L p < 0.0001). After 3 months, the percentage of reduction of hs-CRP was significantly higher than that in the control group. The absolute values of hs-CRP were significantly decreased to a level similar to the control group, and the hs-CRP in both groups was remained at the same level for 12 months. Although the LDL-C/HDL-C ratios of the pitavastatin group was significantly reduced from 3.3 to 1.8, those of the control group were not changed. In conclusion, pitavastatin was found to have powerful anti-inflammatory, add-on effects over the similar effects of ARB as assessed by hs-CRP.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; C-Reactive Protein; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertension; Male; Middle Aged; Quinolines; Treatment Outcome

Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats.. Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated.. After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone.. Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.

Topics: Animals; Aorta, Thoracic; Benzoxazoles; Blood Pressure; Butyrates; Cholesterol; Cholesterol, HDL; Cholesterol, VLDL; Chylomicrons; Diet, High-Fat; Drug Therapy, Combination; Endothelium; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypolipidemic Agents; Insulin Resistance; Lipoproteins, HDL; PPAR alpha; Quinolines; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Triglycerides; Vasodilation

Topics: Atorvastatin; China; Dyslipidemias; Glucose; Glycated Hemoglobin; Humans; Hypertension; Prediabetic State; Quinolines

Topics: Atorvastatin; Cardiovascular Diseases; China; Dyslipidemias; Glucose; Glycated Hemoglobin; Humans; Hypertension; Prediabetic State; Quinolines; Risk Factors

Clinical trials show potent renoprotective effects of pitavastatin (PTV), although the precise mechanism for these renoprotective effects is not fully clarified. The aim of this study was to examine the antihypertensive and renoprotective effects of PTV, focusing on the nitric oxide (NO) system.. Male, 6-week-old, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were randomized to receive vehicle or PTV (2 mg/kg bodyweight) for 8 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks. After 8 weeks, plasma biochemical parameters and renal histology were examined. NO synthase isoform (neuronal, nNOS; inducible, iNOS; and endothelial, eNOS) expression and eNOS phosphorylation were examined by western blotting.. PTV attenuated hypertension and albuminuria development in SHR. PTV decreased glomerular desmin expression and medullary interstitial fibrosis in SHR. PTV tended to increase plasma NO in both strains but significantly increased urinary NO excretion only in WKY. PTV significantly increased nNOS and eNOS expression, enhanced eNOS phosphorylation at serine1177, and inhibited eNOS phosphorylation at threonine495 in the kidney of both strains.. PTV treatment led to increased renal NOS expression and upregulated eNOS activity in both SHR and WKY. The antihypertensive and renoprotective effects of PTV may be related to upregulation of the NO system.

Topics: Albuminuria; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Hypertension; Kidney; Male; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Phosphorylation; Quinolines; Rats, Inbred SHR; Rats, Inbred WKY; Up-Regulation

Intensive as compared to mild statin therapy has been proven to be superior in improving cardiovascular outcome, whereas the effects of intensive statin therapy on inflammation and lipoprotein biomarkers are not well defined.. This study assigned essential hypertensive patients with dyslipidemia to 6 months administration of mild (1 mg/day, n = 34) or intensive pitavastatin therapy (4 mg/day, n = 29), and various lipid and inflammation biomarkers were measured at baseline, and 3 and 6 months after the start of treatment.. Both pitavastatin doses were well tolerated, and there were no serious treatment-related adverse events. After 6 months, significant improvements in total cholesterol, triglycerides, low-density lipoprotein (LDL-) cholesterol, LDL/high-density lipoprotein cholesterol (LDL/HDL), apolipoproteins B, C-II, and E, apolipoprotein-B/apolipoprotein-A-I (Apo B/Apo A-I), and malondialdehyde (MDA-) LDL were observed in both groups. Compared with the mild pitavastatin group, the intensive pitavastatin therapy showed significantly greater decreases in C reactive protein (F = 3.76, p<0.05), total cholesterol (F = 10.65), LDL-cholesterol (F = 23.37), LDL/HDL (F = 12.34), apolipoproteins B (F = 19.07) and E (F = 6.49), Apo B/Apo A-I (F = 13.26), and MDA-LDL (F = 5.76) (p<0.01, respectively).. Intensive pitavastatin therapy may have a more favorable effect not only in decreasing LDL-cholesterol but also in pleiotropic benefits in terms of improvement of apolipoproteins, inflammation, or oxidation.

Topics: Aged; Aged, 80 and over; Biomarkers; Dose-Response Relationship, Drug; Drug Administration Schedule; Dyslipidemias; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Inflammation; Lipid Metabolism; Male; Middle Aged; Quinolines; Retrospective Studies; Treatment Outcome

The aim of this prospective study was to determine whether statin therapy (pitavastatin) has a beneficial effect on the prevention of new-onset atrial fibrillation (AF) in elderly patients with hypertension (HTN) and to evaluate the relationships among statin treatment, the development of AF, and left atrial (LA) and ventricular (LV) structure and function.. We enrolled eligible elderly patients (≥65 years old) with HTN and LV hypertrophy until the number of patients reached 110 in both groups. The 110 patients with HTN who needed statin therapy (HTN with statin group) were started on pitavastatin (1-2 mg/day), and both groups continued with appropriate medication for HTN. LV and LA structure and function were examined by conventional and speckle-tracking echocardiography at baseline and after 1 year. LA volume and function in the HTN with statin group improved more than in the HTN without statin group. There was a significant difference in survival free of new-onset AF in the patients with and without statin therapy during the 2-year follow-up (hazard ratio: 0.32, P=0.027).. Pitavastatin had a beneficial effect on LV diastolic function and LA structure and function in elderly patients with HTN. Pitavastatin treatment may be associated with a lower incidence of new-onset AF.

Topics: Age Factors; Aged; Aged, 80 and over; Atrial Fibrillation; Atrial Function, Left; Chi-Square Distribution; Disease-Free Survival; Dyslipidemias; Electrocardiography; Female; Follow-Up Studies; Heart Atria; Heart Ventricles; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypertrophy, Left Ventricular; Japan; Kaplan-Meier Estimate; Male; Multivariate Analysis; Proportional Hazards Models; Prospective Studies; Quinolines; Stroke Volume; Time Factors; Treatment Outcome; Ultrasonography; Ventricular Dysfunction, Left; Ventricular Function, Left

Vascular endothelial dysfunction has been demonstrated in obesity, but the molecular basis for this link has not been clarified. We examined the role of free fatty acids (FFA) on vascular reactivity in the obese fa/fa Zucker diabetic fatty (ZDF) rat. Addition of acetylcholine produced a dose-dependent relaxation in aortic rings of ZDF and lean +/+ rats, but the ED(50) value was higher in ZDF (-6.80 +/- 0.05 vs. -7.11 +/- 0.05 log(10) mol/liter, P = 0.033). A 2-wk treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pitavastatin (3 mg/kg/d) or a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (5 mmol/liter in drinking water), improved the response in ZDF (ED(50), -7.16 +/- 0.03 and -7.14 +/- 0.05 log(10) mol/liter, P = 0.008 and P = 0.015 vs. vehicle, respectively). Vasodilator response to sodium nitroprusside was identical between ZDF and +/+ rats. Vascular reactive oxygen species (ROS) levels and NADPH oxidase activity in aorta were increased in ZDF rats but were decreased by pitavastatin. In in vitro cell culture, intracellular ROS signal and NADPH oxidase subunit mRNA were increased by palmitate, but this palmitate-induced ROS production was inhibited by NADPH oxidase inhibitor or pitavastatin. In conclusion, FFA-induced NADPH oxidase subunit overexpression and ROS production could be involved in the endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatin or NADPH oxidase inhibitors.

Topics: Acetophenones; Animals; Cells, Cultured; Diabetes Mellitus, Type 2; Dyslipidemias; Endothelium, Vascular; Enzyme Inhibitors; Fatty Acids, Nonesterified; Humans; Hypertension; Intra-Abdominal Fat; Male; NADPH Oxidases; Nitric Oxide Synthase Type III; Obesity; Oxidative Stress; Quinolines; Rats; Rats, Zucker; Reactive Oxygen Species; Umbilical Veins; Vasoconstriction

Statin therapy may be associated with lower mortality in patients with heart failure, but the underlying mechanism of such an association is unknown. We have evaluated the effects of pitavastatin on cardiac function and survival in a rat model of hypertensive heart failure and investigated the molecular mechanism of the observed effects. Dahl salt-sensitive rats fed with high-salt diet from 7 weeks of age developed compensatory left ventricular hypertrophy at 12 weeks and heart failure at 19 weeks. Dahl salt-sensitive rats were treated with either vehicle or pitavastatin (0.3 mg/kg per day) from 7 or 12 weeks. Both early-onset and late-onset pitavastatin treatment reduced left ventricular fibrosis, improved cardiac function, and increased the survival rate apparent at 19 weeks. The increases in the expression levels of hypertrophic, profibrotic, and metalloproteinase genes as well as in gelatinase activities in the heart induced by the high-salt diet were suppressed by pitavastatin treatment. Furthermore, the level of cardiac endothelin-1 was increased in association with the development of heart failure in a manner sensitive to treatment with pitavastatin. Both early and late pitavastatin treatment thus improved cardiac function and survival, with modulation of extracellular matrix remodeling and endothelin-1 signaling possibly contributing to these beneficial effects.

Topics: Animals; Blood Pressure; Cardiac Output, Low; Disease Models, Animal; Endothelin-1; Extracellular Matrix; Gene Expression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypertrophy, Left Ventricular; Lipids; Male; Matrix Metalloproteinases; Protein Prenylation; Quinolines; Rats; Rats, Inbred Dahl; Receptors, Endothelin; Renin-Angiotensin System; Survival Rate; Tissue Inhibitor of Metalloproteinases; Ventricular Remodeling

1. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) manifest pleiotropic effects that may contribute to their therapeutic efficacy. However, the mechanism of the beneficial action of statins on cardiac hypertrophy and fibrosis remains unclear. We have now investigated this action of pitavastatin in Dahl salt-sensitive (DS) rats. 2. The DS rats progressively develop marked hypertension when fed a diet containing 8% NaCl from 7 weeks of age. These animals exhibited pronounced cardiac hypertrophy and fibrosis, as well as upregulation of fetal-type cardiac gene expression at 12 weeks of age, compared with DS rats fed a diet containing 0.3% NaCl. The abundance of mRNAs for collagen types I and III, angiotensin-converting enzyme, transforming growth factor-beta1 and connective tissue growth factor was also increased in the heart of rats on the high-salt diet. 3. Treatment of rats on the high-salt diet with a non-antihypertensive dose of pitavastatin (0.3 or 1 mg/kg per day) from 7 to 12 weeks of age attenuated the development of cardiac hypertrophy and fibrosis, as well as inhibiting the upregulation of cardiac gene expression. Pitavastatin also blocked the translocation of RhoA to the membrane fraction of the left ventricle and RhoA activation, as well as the phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)-1 and ERK-2 and an increase in the DNA binding activity of serum response factor (SRF) in the heart induced by the high-salt diet. 4. These findings suggest that the effects of pitavastatin on load-induced cardiac hypertrophy and fibrosis are independent of its cholesterol-lowering action and may be mediated, at least in part, through inhibition of RhoA-ERK-SRF signalling.

Topics: Aging; Animals; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Electrophoretic Mobility Shift Assay; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Gene Expression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Hypertrophy, Left Ventricular; Immunoblotting; Lipids; Male; Myocardium; Quinolines; Rats; Rats, Inbred Dahl; rhoA GTP-Binding Protein; Signal Transduction; Sodium Chloride

Since the rat is an atherosclerosis-resistant species, the study of atherosclerosis using rats is limited. The present study was undertaken to develop an atherosclerotic model in rats, to investigate the effect of nitric oxide (NO) inactivation and hyperlipidemia, and to evaluate the effect of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor, on NO inactivation and on hyperlipidemia-induced changes in the cardiovascular system. Four-month-old male spontaneously hypertensive hyperlipidemic rats (SHHR) and Sprague-Dawley (SD) rats were used to study 1) the effect of the period of treatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 mg/L) on high fat diet (HFD)-treated SHHR and SD rats, and 2) the effect of pitavastatin (Pit, 0.3 mg/kg/day) on the changes in the aorta of L-NAME- and HFD-treated SHHR and SD rats. L-NAME administration for 1 month then HFD feeding for 2 months markedly increased the deposition of lipids and the thickness of the endothelium in SHHR. Continuous L-NAME treatment with HFD produced severe injury and stripped of endothelium in both strains. The plasma total cholesterol of L-NAME + HFD-treated and L-NAME + HFD + Pit-treated SHHR was significantly higher than that of control SHHR. Lipid deposition, however, was comparatively less in the aorta of L-NAME + HFD + Pit-treated SHHR. The concentration of cholesterol in the aorta of control SHHR was significantly lower than that in the aorta of L-NAME + HFD-treated SHHR, whereas that of L-NAME + HFD + Pit-treated SHHR was the same as that in control SHHR. These data indicated that Pit blocked lipid deposition in the aorta of L-NAME + HFD treated SHHR without changing plasma lipid profiles. In conclusion, NO inactivation and HFD induce lipid deposition in the endothelium, and the HMG-CoA reductase inhibitor blocks the deposition in SHHR.

Topics: Animals; Aorta; Arteriosclerosis; Cholesterol; Dietary Fats; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Enzyme Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Quinolines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley