(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Insulin-Resistance

Among hypertensive patients, cardiovascular disease morbidity is common, even in those who are adequately treated. New pharmacological strategies to mitigate the burden of arterial hypertension are needed. This 12-month, randomized, double-blind placebo-controlled study investigated the effect of statin (fluvastatin) treatment on ambulatory blood pressure (ABP), exercise blood pressure (EBP), myocardial structure, endothelial function and insulin resistance in 50 hypertensive patients. At baseline, the groups were comparable in terms of demographic characteristics, ABP, EBP, endothelial function and homeostasis model assessment of insulin resistance (HOMA-IR). At the end of the study, there was no difference between groups in terms of resting systolic blood pressure. However, maximum systolic EBP was lower in the treatment group than in the placebo group (175 ± 18 vs 192 ± 23 mm Hg, P<0.05), as was left ventricular mass index (LVMI; 82 ± 15 vs 100 ± 23, P<0.05), and HOMA-IR index was lower after fluvastatin treatment (2.77 ± 1.46 vs 3.33 ± 1.73, P<0.05). Changes in lipid profile were not correlated with blood pressure, endothelial function, LVMI or HOMA-IR data. In hypertensive patients, fluvastatin can improve maximum systolic EBP, myocardial remodelling and insulin resistance, independently of lipid profile variations and endothelial function.

Topics: Adult; Blood Pressure; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Indoles; Insulin Resistance; Male; Middle Aged; Myocardium

Statins have multiple actions, independent of their classical effects on lipoproteins. The data about the effects of statins on insulin resistance is controversial. This study was designed to search the statin effects on nondiabetic dyslipidemic patients. Thirty-five (17 male, 18 female) consecutive dyslipidemic patients 54.25 +/- 8.81 yr were enrolled in the study. After a standard follow-up period of lifestyle modification, the patients were given fluvastatin 40 mg/d for 8 wk. Serum analyses were done both before and after treatment. Insulin resistance was assessed by homeostasis assessment model (HOMA). Fasting plasma triglyceride, total and LDL cholesterol, fasting insulin, and HOMA index were significantly reduced and HDL cholesterol was improved after fluvastatin treatment. HOMA-IR was not correlated with triglycerides, LDL, HDL, or total cholesterol levels. The same situation was present for both fasting plasma insulin and fasting plasma glucose levels. Also age was not associated with HOMA-IR and fasting plasma insulin levels. As a conclusion, the present study indicates that fluvastatin treatment improves insulin resistance in dyslipidemic patients who do not have diabetes or impaired fasting glucose. Also, the effect of fluvastatin on insulin resistance is not associated with the lowering of triglycerides. The latter finding indicates that the effect of statins on insulin sensitivity may not be related with the lowering of triglycerides in dyslipidemic patients.

Topics: Anticholesteremic Agents; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hyperlipidemias; Indoles; Insulin; Insulin Resistance; Male; Middle Aged; Treatment Outcome; Triglycerides

Statins reduce lipid levels and are widely prescribed. Statins have been associated with an increased incidence of type 2 diabetes, but the mechanisms are unclear. Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3)/caspase-1 inflammasome, promotes insulin resistance, a precursor of type 2 diabetes. We showed that four different statins increased interleukin-1β (IL-1β) secretion from macrophages, which is characteristic of NLRP3 inflammasome activation. This effect was dose dependent, absent in NLRP3(-/-) mice, and prevented by caspase-1 inhibition or the diabetes drug glyburide. Long-term fluvastatin treatment of obese mice impaired insulin-stimulated glucose uptake in adipose tissue. Fluvastatin-induced activation of the NLRP3/caspase-1 pathway was required for the development of insulin resistance in adipose tissue explants, an effect also prevented by glyburide. Fluvastatin impaired insulin signaling in lipopolysaccharide-primed 3T3-L1 adipocytes, an effect associated with increased caspase-1 activity, but not IL-1β secretion. Our results define an NLRP3/caspase-1-mediated mechanism of statin-induced insulin resistance in adipose tissue and adipocytes, which may be a contributing factor to statin-induced development of type 2 diabetes. These results warrant scrutiny of insulin sensitivity during statin use and suggest that combination therapies with glyburide, or other inhibitors of the NLRP3 inflammasome, may be effective in preventing the adverse effects of statins.

Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Carrier Proteins; Caspase 1; Fatty Acids, Monounsaturated; Fluvastatin; Glyburide; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammasomes; Insulin Resistance; Interleukin-1beta; Macrophages; Male; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity

Inflammation plays an important role in the pathogenesis of metabolic syndrome (MS). We investigated the effect of fluvastatin treatment on inflammatory markers in patients with MS.. The study included 47 patients (36 females; 11 males; mean age 55+/-8 years) with MS. The diagnosis of MS was based on the presence of at least three criteria of the NCEP ATP III guidelines. All the patients received 80 mg fluvastatin treatment for six weeks. Laboratory parameters were measured before and after treatment, and flow cytometric analysis of peripheral blood leukocytes was performed. The results were compared with those of 47 age- and sex-matched healthy controls (33 females, 14 males; mean age 52+/-8 years).. Fluvastatin treatment resulted in significant decreases in levels of total cholesterol, LDL cholesterol, triglyceride (p<0.005), and C-reactive protein (p<0.05). Thirty-three patients (70.2%) had insulin resistance, which remained unchanged following treatment. Flow cytometric analysis after treatment showed significant decreases in total lymphocytes, and in surface antigens of CD16+56 and CD8+(CD28+) on leukocytes, CD11c on granulocytes, and a significant increase in the CD4/CD8 ratio (p<0.05). Compared to the control group, the mean baseline values of fluorescence density (FD) of CD14, CD11b, CD11c, and CD63 on monocytes, and CD11b and CD11c on granulocytes were significantly higher in patients with MS (p<0.05). Following fluvastatin treatment, there were significant decreases in the mean FD of CD3 on lymphocytes, and of CD11b and CD11c on both monocytes and granulocytes (p<0.05); of these, all FD values were similar to those in the control group (p>0.05).. Our data demonstrate that inflammation may have a significant role in the pathogenesis of MS and that this effect can be controlled with statin treatment.

Topics: Antigens, CD; Biomarkers; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Fatty Acids, Monounsaturated; Female; Flow Cytometry; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Inflammation; Insulin Resistance; Lymphocyte Count; Male; Metabolic Syndrome; Middle Aged; Triglycerides

Feeding rats with a high-fructose diet induced insulin resistance, leading to hypertension or metabolic disorders. Although hypertension is known to accelerate osteoporosis, it is not obvious whether insulin resistance would accelerate osteoporosis. In this study, we evaluated whether osteoporosis might accelerate in fructose-fed rats (FFR), and examined the effect of fluvastatin through a blockade of the mevalonate pathway and an antioxidant action. Stimulation of recombinant receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) expressed by osteoblasts/ stromal cells and macrophage-colony stimulating factor (M-CSF) significantly increased TRAP-positive multinuclear osteoclasts and pit formation, accompanied by an increase in reactive oxygen species as assessed by dichlorodihydrofluorescein (DCF) staining. Interestingly, it was completely abolished by treatment with fluvastatin, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), but not pravastatin. These actions of fluvastatin were partially abolished by co-treatment with geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP). In the estrogen-deficient model by ovariectomy, FFR exhibited a decrease in bone mineral density, activation of osteoclasts, and an increase in urinary deoxypyridinoline. Importantly, the treatment of fluvastatin, but not pravastatin, attenuated FFR-induced osteoporosis. The present study demonstrates that fructose fed to rats induced insulin resistance and accelerated osteoporosis, while fluvastatin, but not pravastatin, significantly attenuated osteoclast differentiation and activation through a blockade of the classical mevalonate pathway and an antioxidant action, leading to prevention of osteoporosis.

Topics: Animals; Animals, Newborn; Antioxidants; Cell Differentiation; Cells, Cultured; Diet; Down-Regulation; Drug Evaluation, Preclinical; Fatty Acids, Monounsaturated; Female; Fluvastatin; Fructose; Indoles; Insulin Resistance; Mevalonic Acid; Osteoclasts; Osteoporosis; Rabbits; Rats; Rats, Wistar; Signal Transduction

Currently available data and clinical observations which suggest that there is a pathogenetic relationship between hypertension, diabetes mellitus, and atherosclerosis have provided a concept of the X syndrome, by which hypertensive patients, mainly males, have impaired insulin tolerance along with hyperinsulinemia and concurrent atherogenic disorders of lipid metabolism. The paper discussed the specific pathogenetic mechanisms, clinical manifestations, and prospects for drug correction of the metabolic syndrome. The treatment of arterial hypertension with the calcium antagonist Lomir has indicated there are no negative changes as a control of non-insulin-dependent diabetes mellitus in the presence of effective correction of arterial hypertension and atherogenic dyslipidemias. With the monotherapy of essential hypertension concurrent with hypercholesterolemia with the alpha 1-adrenoblocker Doxazosin, in addition to the agent's high antihypertensive effects, the authors noted its favourable action on lipid spectral parameters and platelet functional activity. There is abundant evidence for the use of specific hypolipidemic agents in patients with essential hypertensive refractory to current antihypertensive drugs. The data obtained with the use of Lescol (fluvastatin) in patients with hypertensive disease and hypercholesterolemia suggest that by substantially reducing the levels of total cholesterol, triglycerides, low density lipoprotein cholesterol and its transport protein apo B does not deteriorate the quality of correction of arterial hypertension in this group of patients.

Topics: Anticholesteremic Agents; Arteriosclerosis; Diabetes Mellitus; Diabetes Mellitus, Type 2; Doxazosin; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertension; Indoles; Insulin Resistance; Isradipine; Lipid Metabolism; Male; Middle Aged; Syndrome