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

Patients with type 2 diabetes are at increased cardiovascular risk. The aim was to explore whether the impaired arterial wall characteristics typical of these patients could be improved by the unique beneficial effects of a very low-dose combination of fluvastatin and valsartan (low-flu/val).. Forty middle-aged males (50.4±6.1years) with type 2 diabetes were recruited to a double-blind, randomized study. Patients (N=20) received low-flu/val (10/20mg) or placebo (N=20) over 30days in addition to their regular therapy. Brachial artery flow mediated dilation (FMD), common carotid artery pulse wave velocity (PWV) and β-stiffness were assessed before and after treatment, and 3 and 6months after treatment discontinuation. The treatment was then repeated.. Arterial wall characteristics significantly improved. After 30days of intervention, FMD increased from 2.4±0.3 to 4.2±0.3 (p<0.001), PWV decreased from 6.4±0.1 to 5.8±0.2 (p<0.001) and β stiffness decreased from 7.8±0.4 to 6.7±0.4 (p<0.001). Lipids and arterial pressure did not change. After treatment discontinuation, the beneficial effects decreased over the following months. The repetition of treatment completely regained the initial benefits. No changes were observed in the placebo group.. Low-flu/val added on-top of optimal therapy substantially improves arterial wall characteristics in patients with type 2 diabetes.

Topics: Angiotensin II Type 1 Receptor Blockers; Arteries; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Endothelium, Vascular; Fatty Acids, Monounsaturated; Fluvastatin; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Pulse Wave Analysis; Ultrasonography; Valsartan; Vascular Stiffness; Vasodilation

To study the mechanisms of vascular dysfunction in diabetes mellitus, we examined the responses of the aorta to adrenomedullin (AM) and ANG II in obese Zucker (OZ), lean Zucker (LZ), and OZ rats administered fluvastatin (OZ + Flu). AM-induced endothelium-dependent vasorelaxation was impaired in OZ rats compared with LZ rats, and fluvastatin restored AM-induced, endothelium-dependent vasorelaxation (%Deltatension at 10(-7) mol/l AM; LZ, -85.1 +/- 3.1%; OZ, -50.7 +/- 2.5%; OZ + Flu, -75.6 +/- 2.7%). Expression of endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in response to AM (10(-7) mol/l) were also diminished in OZ rats. Fluvastatin restored the eNOS expression and Akt phosphorylation [eNOS expression (relative intensity): LZ, 2.3 +/- 0.4; OZ, 1.0 +/- 0.2; OZ + Flu, 1.8 +/- 0.3; Akt phosphorylation (relative intensity): LZ, 2.3 +/- 0.2; OZ, 1.0 +/- 0.3; OZ + Flu, 1.9 +/- 0.2]. ANG II-induced vasoconstriction was enhanced in the aortic rings of OZ rats compared with LZ rats, and this enhanced vasoconstriction was partially normalized by fluvastatin and was abolished when the aorta of OZ rats was preincubated with the Rho kinase inhibitor Y-27632. GTPgammaS-induced contraction of permeabilized aortic smooth muscle cells, which is an indicator of the Rho-dependent Ca(2+) sensitization of contraction, was enhanced in OZ rats compared with LZ rats, and this enhanced contraction was suppressed in OZ + Flu rats. These results suggested that endothelium-dependent vasorelaxation was impaired, Ca(2+) sensitization of contraction was augmented in blood vessels of OZ rats and that fluvastatin restored vascular function by activating the Akt-dependent pathway and inhibiting the Rho-dependent pathway.

Topics: Adrenomedullin; Angiotensin II; Animals; Aorta; Calcium; Diabetic Angiopathies; Endothelium, Vascular; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Obesity; Peptides; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; rho GTP-Binding Proteins; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

To assess the cost and cost effectiveness of hydroxymethylglutaryl (HMG)-CoA reductase inhibitor (statin) therapy for the primary prevention of major coronary events in the U.S. population with diabetes and LDL cholesterol levels > or =100 mg/dl, especially in the population with LDL cholesterol levels 100-129 mg/dl.. Analyses were performed using population estimates from National Health and Nutrition Examination Survey (NHANES)-III, cost estimates from a health system perspective, statin LDL-lowering effectiveness from pivotal clinical trials, and treatment effectiveness from the diabetic subgroup analysis of the Heart Protection Study.. -There are approximately 8.2 million Americans with diabetes, LDL cholesterol levels > or =100 mg/dl, and no clinical evidence of cardiovascular disease. Each year, statin therapy could prevent approximately 71,000 major coronary events in this population. In the subgroup with LDL cholesterol levels 100-129 mg/dl, the annual cost of statin treatment ranges from 600 to 1,000 US dollars per subject. In the population with LDL cholesterol levels > or =130 mg/dl, the annual cost ranges from 700 to 2,100 US dollars. Annual incremental cost per subject, defined as the cost of statin treatment plus the cost of major coronary events with statin treatment minus the cost of major coronary events without statin treatment, ranges from 480 to 950 US dollars in the subgroup with LDL cholesterol levels 100-129 mg/dl and from 590 to 1,920 US dollars in the population with LDL cholesterol levels > or =130 mg/dl.. Statin therapy for the primary prevention of major coronary events in subjects with type 2 diabetes and LDL cholesterol levels 100-129 mg/dl is affordable and cost effective relative to statin therapy in subjects with higher LDL cholesterol levels.

Topics: Atorvastatin; Cholesterol, LDL; Coronary Disease; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lovastatin; Pravastatin; Pyrroles; Randomized Controlled Trials as Topic; Reproducibility of Results; Sensitivity and Specificity; Simvastatin; United States

To investigate the direct anti-atherosclerotic properties of statins.. Using in vitro and ex vivo models, the effect of different statins on key events involved in atherogenesis has been investigated. We studied the ability of statins to modulate modified LDL-induced cholesterol esterification, metalloproteinase secretion by macrophages, and arterial myocyte migration and proliferation. The mechanisms underlying the inhibitory effect of statins have also been explored. Finally, the antiproliferative effect of sera from statin-treated patients has been confirmed in a cell culture system.. Fluvastatin, simvastatin, lovastatin, atorvastatin, and cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cell (SMC) migration and proliferation. Moreover, statins are able to reduce cholesterol accumulation in macrophages in vitro by blocking cholesterol esterification and endocytosis of modified lipoproteins and matrix-degrading enzyme secretion. This in vitro inhibition was completely prevented by mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites (probably through prenylated protein[s]) in regulating these cellular events. The inhibitory effect of statins on SMC proliferation has been shown in different models of proliferating cells, such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits, independently of their ability to reduce plasma cholesterol. Finally, ex vivo studies showed that sera from fluvastatin-treated patients interfere with SMC proliferation.. These results suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors exert a direct anti-atherosclerotic effect in the arterial wall, beyond their effects on plasma lipids that could translate into a more significant prevention of cardiovascular disease. These findings provide a basis for the beneficial effect of statins in clinical trials also involving diabetic patients--a population with a higher absolute risk of recurrent cardiovascular events.

Topics: Animals; Arteriosclerosis; Atorvastatin; Cell Division; Cell Movement; Cells, Cultured; Cholesterol; Cholesterol Esters; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Endocytosis; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipoproteins; Lovastatin; Macrophages; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Muscle, Smooth; Pyridines; Pyrroles; Simvastatin