pitavastatin and Obesity

Although there have been several reports that statins cause insulin resistance that leads to the occurrence of type 2 diabetes in Caucasians, there has been no Japanese prospective studies investigating the effects of statins on the glucose metabolism system.. Our subjects were 86 Japanese patients with type 2 diabetes with hypercholesterolemia. Pitavastatin 2mg/day was administered for 12 months and the lipid-related values, glucose metabolism values, and the presence/absence of side effects were investigated.. None of these factors was found to differ between before and after administration of pitavastatin in overall analysis of all subjects. In subgroup analysis, fasting blood glucose showed a decrease in the BMI ≥ 25 group and there was a significant difference between the BMI<25 and BMI ≥2 5 groups (P-values: 0.021 and 0.0036). Although HbA1c showed an increase both in the group switched to pitavastatin and the BMI<25 group (P-values: 0.035 and 0.033) and HOMA-β showed a decrease in the BMI<25 group (P-values: 0.044), there were no significant differences in changes between each divided group and their counterparts.. In the Japanese obese group with BMI ≥ 25, pitavastatin elicited a significant decrease in fasting blood glucose. It is not clear whether or not this is due to improved insulin resistance as a direct effect of pitavastatin, but in contrast to findings in Caucasians pitavastatin does not worsen insulin resistance in Japanese patients with type 2 diabetes complicated by hypercholesterolemia.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Insulin Resistance; Lipids; Male; Middle Aged; Obesity; Prospective Studies; Quinolines; Treatment Outcome

Obesity is a well-established risk factor for the development and progression of coronary heart disease. Moreover, endothelial dysfunction is an early event in atherosclerosis and is known to be associated with postprandial hypertriglyceridemia. The purpose of this study was to determine whether a statin might have an effect on postprandial hypertriglyceridemia, and thereby on endothelial function in obese subjects. Twenty-four obese male subjects were recruited for this study. They were randomly assigned to receive pitavastatin (2 mg/day) or placebo for 2 weeks. The oral fat loading test using OFTT cream was performed pre- and post-treatment, in which the lipid profile and flow-mediated dilation (FMD) were assessed before and 4 h after an oral fat load. In the oral fat loading test conducted pretreatment, the oral fat load induced a marked increase of the serum triglyceride (TG) level and decrease in FMD in the pitavastatin and placebo group. In the test conducted post-treatment, the increase in postprandial TG was attenuated (+183 vs. +81 mg/dL, P < 0.001) and decrease in postprandial FMD was completely abolished (-1.1 vs. +0.1%, P < 0.01) by pitavastatin treatment. Moreover, there was a good correlation between the change in postprandial TG and the change in postprandial FMD after the 2 weeks of treatment (r = -0.737, P < 0.001). Pitavastatin might prevent endothelial dysfunction caused by postprandial hypertriglyceridemia within 2 weeks of therapy in obese subjects.

Topics: Adult; Aged; Biomarkers; Dietary Fats; Down-Regulation; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertriglyceridemia; Japan; Male; Middle Aged; Obesity; Postprandial Period; Quinolines; Regression Analysis; Time Factors; Treatment Outcome; Triglycerides; Ultrasonography; Vasodilation

The present study was undertaken to compare the efficacy of pitavastatin and colestimide in patients with diabetes mellitus complicated by hyperlipidemia and metabolic syndrome. 48 diabetic patients with metabolic syndrome were randomly assigned to a pitavastatin group or colestimide group. The clinical parameters, serum lipids, fasting (FPG) and postprandial plasma glucose(PPG), HOMA-IR, hemoglobin A1c(HbA1c), hs-CRP and urinary albumin were measured before/after 24-week administration. Treatment with pitavastatin reduced LDL-C and TG, while that with colestimide significantly reduced waist circumference, BMI, LDL-C, HbA1c, FPG, PPG, HOMA-R , hs-CRP and urinary albumin. Percent improvement in LDL-C was greater in the pitavastatin group than in the colestimide group. Colestimide appeared to be useful in the management of Japanese patients with diabetes mellitus complicated by metabolic syndrome, since it alleviates obesity and insulin resistance in addition to exhibiting lipid profile-improving effects, and can thus improve markers of atherosclerosis.

Topics: Adult; Aged; Albuminuria; Atherosclerosis; Biomarkers; C-Reactive Protein; Cholesterol, LDL; Diabetes Complications; Epichlorohydrin; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Hyperlipidemias; Hypolipidemic Agents; Imidazoles; Insulin Resistance; Japan; Male; Metabolic Syndrome; Middle Aged; Obesity; Quinolines; Resins, Synthetic; Triglycerides; Weight Loss

There has been a steady increase in the epidemiology of obesity over the last 30 years with developed countries leading the way. Oxidative stress was believed to be the principle contributor to the development of cardiovascular disorders that linked with obesity.. To evaluate the enhancement of antioxidant defense mechanism by Pitavastatin (PTV) and Rosuvastatin (RSV) on obesity-induced oxidative stress in Wistar rats.. Fifty Wistar albino rats were divided into five groups. High fat diet (HFD, 20 g/day/rat) pellets were given for 28 days to produce obesity-induced oxidative stress in Wistar rats. Oral administration of HFD along with PTV, RSV and Orlistat [(HFD for 28 days + from 8th day PTV (1 mg/kg), RSV (5 mg/kg) and Orlistat (10 mg/kg) to 28th day] were given respectively.. Both PTV and RSV produced significant (p < 0.01) reduction in serum apolipoprotein-B (Apo-B), total cholesterol (TC), triglycerides (TGs), cardiac-lipid peroxides (TBARS) levels and elevation in serum high density lipoprotein (HDL-C), cardiac antioxidant enzymes [glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catase (CAT)] levels.. Results were comparable with Orlistat, a standard antiobesity drug and present initial evidence that Pitavastatin and Rosuvastatin are useful for the treatment of obesity by enhancing the antioxidant defense mechanism. However, the effects of PTV were more prominent than RSV. The present findings of Pitavastatin and Rosuvastatin raise the possibility of a new application as an antiobesity therapeutic modality.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Antioxidants; Apolipoproteins B; Cholesterol, HDL; Disease Models, Animal; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lactones; Lipid Peroxides; Myocardium; Obesity; Orlistat; Oxidative Stress; Pyrimidines; Quinolines; Rats; Rats, Wistar; Rosuvastatin Calcium; Sulfonamides; Treatment Outcome; Triglycerides

Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-db/db (db/db) obese mice.. Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks.. At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of TNF-α and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition.. Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Apoptosis; bcl-Associated Death Protein; Cocarcinogenesis; Crosses, Genetic; Diethylnitrosamine; Drug Screening Assays, Antitumor; Dyslipidemias; Fatty Liver; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-6; Leptin; Lipids; Liver; Liver Diseases; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Organ Size; Precancerous Conditions; Proto-Oncogene Proteins c-bcl-2; Quinolines; Tumor Necrosis Factor-alpha

Obesity and related metabolic abnormalities are risk factors for colorectal cancer. A state of chronic inflammation and adipocytokine imbalance may play a role in colorectal carcinogenesis. Statins, which are commonly used for the treatment of hyperlipidemia, are known to possess anti-inflammatory effects. Statins also exert chemopreventive properties against various cancers. The present study examined the effects of pitavastatin, a recently developed lipophilic statin, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were administrated weekly subcutaneous injections of AOM (15 mg/kg body weight) for 4 weeks and then were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 8 weeks. Feeding with either dose of pitavastatin significantly reduced the number of colonic premalignant lesions, beta-catenin accumulated crypts, by inhibiting proliferation and the surrounding inflammation. Pitavastatin increased the serum levels of adiponectin while conversely decreasing the serum levels of total cholesterol, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-18, and leptin. Pitavastatin also caused a significant increase in the expression of phosphorylated form of the AMP-activated kinase (AMPK) protein on the colonic mucosa of AOM-treated mice. In addition, the expression levels of TNF-alpha, IL-6, IL-18, and COX-2 mRNAs on the colonic mucosa of AOM-treated mice were decreased by treatment with this agent. These findings suggest that pitavastatin attenuates chronic inflammation and improves the imbalance of adipocytokines, both of which are caused by the presence of excess adipose tissues, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model. Therefore, some types of statins, including pitavastatin, may be a useful chemoprevention modality for colon cancer in obese individuals.

Topics: Animals; Azoxymethane; Carcinogens; Cell Division; Colonic Neoplasms; Cytokines; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Precancerous Conditions; Quinolines

Prevention of cardiovascular complications in obese patients frequently includes statin administration for coexisting dyslipidemia. Herein, we investigated the impacts of pitavastatin at clinically relevant doses on adipose dysfunction and insulin resistance.. We treated 3T3-L1 preadipocytes with 10-100 ng/ml pitavastatin from initiation of differentiation (Day 0) to Day 8 (differentiation/maturation phase) or from Day 8 to Day 16 (post-maturation phase). Subsequently, we administered pitavastatin (6.2mg/day/kg) to 7-week-old female KKAy mice for 6 weeks; untreated KKAy mice served as obese controls.. Pitavastatin impaired neither lipogenesis nor adiponectin expression during the differentiation/maturation phase. During the post-maturation phase, pitavastatin prevented excessive triglyceride accumulation, which was associated with attenuated glucose transporter-4 expression, and dose-dependently upregulated hormone-sensitive lipase expression. Decrements in the adiponectin/plasminogen activator-1 ratio were also dose-dependently inhibited. In KKAy mice, Coulter counter analyses revealed that pitavastatin treatment significantly decreased (by 16.8%) the frequency of hypertrophic adipocytes (>150 microm in diameter) in parametrial adipose pads, of which total weight remained unaltered. Correspondingly, plasma adiponectin was significantly higher in pitavastatin-treated KKAy mice than in the untreated KKAy mice (12.5+/-3.8 microg/ml vs. 8.3+/-1.5 microg/ml, p<0.05). Moreover, the area under the time-glucose curve after intraperitoneal insulin was decreased by 16% in pitavastatin-treated KKAy mice (p<0.05 vs. untreated controls).. Pitavastatin did not impair differentiation/maturation of preadipocytes and prevented their deterioration with hypertrophy after maturation at clinical concentrations in vitro. These effects likely contributed to improved insulin sensitivity, in an obese model, via prevention of adipocyte hypertrophy and adipocytokine dysregulation.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiponectin; Animals; Blood Glucose; Cell Size; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Dyslipidemias; Female; Glucose Transporter Type 4; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophy; Insulin; Insulin Resistance; Lipogenesis; Lipoprotein Lipase; Mice; Obesity; Plasminogen Activator Inhibitor 1; Quinolines; Time Factors; Triglycerides

Macrophage-mediated chronic inflammation of adipose tissue is causally linked to insulin resistance in obesity. The beneficial effects of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors (statins) on glucose metabolism have been suggested, but the effects of these agents on adipose tissue inflammation are unclear. The aim of the present study is to define the effects of statins on adipose tissue inflammation and macrophages.. Pravastatin or pitavastatin treatment of obese mice attenuated an increase in mRNA expressions of proinflammatory genes, including MCP1 and IL6, in adipose tissue. The supernatant of TLR4-stimulated RAW264 macrophages strongly induced the expression of these genes in 3T3-L1 adipocytes, which was inhibited by pretreatment of macrophages with either statin. Statins inhibited TLR4-mediated activation of interferon (IFN) regulatory factor (IRF)3 by either lipopolysaccharide (LPS) or palmitic acid, resulting in suppression of IFN-beta expression, but not that of NF-kappaB or JNK. Moreover, statins strongly downregulated TLR3-mediated gene expressions by poly(I:C), but not TLR2-stimulation by zymosan A. Neutralization of IFN-beta attenuated proinflammatory activities of the macrophage supernatant.. Statins partially attenuated the development of adipose tissue inflammation in obese mice, which might be associated with an inhibitory effect of statins on TLR4-triggered expression of IFN-beta via MyD88-independent signaling pathway in macrophages.

Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interferon Regulatory Factor-3; Interferon-beta; Interleukin-6; Macrophages; Male; Mice; Mice, Obese; Myeloid Differentiation Factor 88; Obesity; Pravastatin; Quinolines; Signal Transduction; Toll-Like Receptor 4

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

3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) may benefit the vasculopathy of insulin resistance independent of its lipid-lowering effects. Because imbalance of nitric oxide (NO) and superoxide anion (O(2)(-)) formation may lead to vascular dysfunction, we investigated the effect of statin on vasomotion of insulin-resistant state to clarify the mechanism by which statin ameliorates the impaired function. In the isolated aorta, contraction induced by angiotensin II was more potent in Zucker fatty rats (ZF) compared with that in Zucker lean rats. Both angiotensin II type 1 receptor expression and O(2)(-) production were upregulated in ZF. In addition, deficiency of tetrahydrobiopterin (BH4) contributes to the endothelial dysfunction in ZF. Oral administration of pitavastatin for 8 weeks normalized angiotensin II-induced vasoconstriction and endothelial function in ZF. Pitavastatin treatment of ZF increased vascular BH4 content, which was associated with twofold increase in endothelial NO synthase (eNOS) activity as well as a 60% reduction in endothelial O(2)(-) production. The treatment also markedly downregulated protein expression of angiotensin II type 1 receptor and gp91phox, whereas expression of guanosine triphosphate cyclohydrolase I was upregulated. Pitavastatin restores vascular dysfunction by inhibiting NAD(P)H oxidase activity and uncoupled eNOS-dependent O(2)(-) production.

Topics: Angiotensin II; Animals; Aorta; Blotting, Western; Endothelium, Vascular; Enzyme Inhibitors; Gene Expression Regulation; GTP Cyclohydrolase; Insulin Resistance; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type III; Obesity; Quinolines; Rats; Rats, Zucker; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; Superoxides