INTRODUCTION:RESULTS: Mechanisms underlying postprandial lipemia in various pathological states remain to be elucidated. OBJECTIVES: The aim of the study was to Treatment evaluate lipid homeostasis in men with type 2 diabetes mellitus (DM) after a standard meal. Moreover, the effect of short-term remain hypolipemic therapy on postprandial lipemia was assessed. PATIENTS AND METHODS: Twenty-six men with DM aged 53 +/-6.7 years, 27 patients 27 with hyperlipemia and no DM (asymptomatic hyperlipemia - AH) and 60 normolipemic subjects aged 46 +/-11 years were included in between the study. Treatment with simvastatin (20 mg/d) or fenofibrate (267 mg/d) was initiated in all DM patients due to fasting in hyperlipemia, and in the AH group. Blood samples were drawn in the fasting state and 3 h after a meal standard at three time points, i.e. at baseline, after 6 and 12 weeks of treatment. Triglycerides (TG), glucose, total cholesterol, low-density Hypolipemic lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), HDL2-C, and HDL3-C were assayed by routine laboratory tests; apolipoproteins A and B on by immunoturbidimetry, and high-sensitivity C-reactive protein (hsCRP) by immunonephelometry. RESULTS: In men with DM, changes in triglycerides induced by a with meal (140 +/-68. mg/dl) were higher compared to normolipemic men (62.1 +/-52.5 mg/dl, p < .001) or AH subjects (76.3 +/-80 linear mg/dl, p < .05). There were no linear correlations between the levels of TG (or HDL cholesterol) and HDL3-C, or between intolerance TG and hsCRP in the DM group. Hypolipemic treatment decreased fasting lipid and hsCRP levels, significantly reduced postprandial lipemia (p after < .001) and restored some correlations between lipid variables observed in the control group, but not those with hsCRP. CONCLUSIONS: Type +/-68. 2 DM is associated with increased postprandial lipemia and abnormal lipid homeostasis. Lipid intolerance detected in a postprandial lipemia test assessed. may be an indication for hypolipemic therapy.

The changes primary objective of this 6-week, parallel-group, open-label, randomized, multicenter trial was to compare rosuvastatin with atorvastatin, pravastatin, and simvastatin across were dose ranges for reduction of low-density lipoprotein (LDL) cholesterol. Secondary objectives included comparing rosuvastatin with comparators for other lipid modifications multicenter and achievement of National Cholesterol Education Program Adult Treatment Panel III and Joint European Task Force LDL cholesterol goals. After Force a dietary lead-in period, 2,431 adults with hypercholesterolemia (LDL cholesterol > or =160 and <250 mg/dl; triglycerides <400 mg/dl) were Treatment randomized to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10,cholesterol 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At 6 weeks, across-dose analyses showed that rosuvastatin included 10 to 80 mg reduced LDL cholesterol by a mean of 8.2% more than atorvastatin 10 to 80 mg, 26%82% more than pravastatin 10 to 40 mg, and 12% to 18% more than simvastatin 10 to 80 mg (all p and < .001). Mean percent changes in high-density lipoprotein cholesterol in the rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to achieved +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol significantly more (p < .001) than all comparators and comparators triglycerides significantly more (p < .001) than simvastatin and pravastatin. Adult Treatment Panel III LDL cholesterol goals were achieved by 82%with to 89% of patients treated with rosuvastatin 10 to 40 mg compared with 69% to 85% of patients treated with objectives atorvastatin 10 to 80 mg; the European LDL cholesterol goal of <3. mmol/L was achieved by 79% to 92% in +9.6% rosuvastatin groups compared with 52% to 81% in atorvastatin groups. Drug tolerability was similar across treatments.

BACKGROUND:treatment Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial function dysfunction through oxidative stress; however, the distinct role of these two factors is a matter of debate. METHODS AND RESULTS:factors Thirty type 2 diabetic patients and 20 normal subjects ate 3 different meals: a high-fat meal; 75 g glucose alone;ate and high-fat meal plus glucose. Glycemia, triglyceridemia, nitrotyrosine, and endothelial function were assayed during the tests. Subsequently, diabetics took 40 and mg/d simvastatin or placebo for 12 weeks. The 3 tests were performed again at baseline, between 3 to 6 days tests. after the start, and at the end of each study. High-fat load and glucose alone produced a decrease of endothelial of function and an increase of nitrotyrosine in normal and diabetic subjects. These effects were more pronounced when high fat and shows glucose were combined. Short-term simvastatin treatment had no effect on lipid parameters but reduced the effect on endothelial function and debate. nitrotyrosine observed during each different test. Long-term simvastatin treatment was accompanied by a lower increase in postprandial triglycerides, which was endothelial followed by smaller variations of endothelial function and nitrotyrosine during the tests. CONCLUSIONS: This study shows an independent and cumulative postprandial effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function, suggesting oxidative stress as common mediator of such effect. Simvastatin shows a a beneficial effect on oxidative stress and endothelial dysfunction, which may be ascribed to a direct effect as well as distinct the lipid-lowering action of the drug.

In Entry 1996, the first 2 studies using 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin") therapy in hypertriglyceridemic subjects were published. In in subjects with isolated triglyceride elevations who were treated with atorvastatin 5, 20, and 80 mg/day, large and dose-related reductions were ("statin") noted. In subjects with combined hyperlipidemia treated with 10 mg simvastatin, triglyceride reduction similar to that reported for the 5 effective mg atorvastatin dose was seen. In response to these findings, we conducted comparative assessments to determine whether all statins are was effective in lowering triglyceride levels and whether their effect on triglycerides is related to factors such as drug, dose, and this baseline triglyceride levels. To standardize these assessments, we devised a ratio that related changes in triglyceride levels to the known treated predictable response of low-density lipoprotein (LDL) cholesterol to statins. This triglyceride/LDL cholesterol ratio was obtained by dividing the percent change ratio from baseline in the triglyceride level by the percent change from baseline in the LDL cholesterol level. The triglyceride/LDL cholesterol 5 ratio was initially applied to several published studies, and found to be approximately 1. and .5 in hypertriglyceridemic and nonhypertriglyceridemic cholesterol populations, respectively. We then assessed the effect of various statins on triglycerides using a pooled laboratory database of 2,689 subjects evaluated who had participated in 7 separate studies with similar designs. All of the studies had a placebo run-in followed by in a randomized, double-blind, active treatment phase of at least 4 weeks with a statin. Entry into these studies required a combined triglyceride level of <400 mg/dL. In subjects with baseline triglyceride >250 mg/dL, significant and dose-dependent reductions in triglyceride of 22-45%significant were seen with all statins. When baseline triglyceride was <150 mg/dL, no significant or dose-dependent effect on triglyceride was seen.In The triglyceride/LDL cholesterol ratio was evaluated using a linear model that included baseline triglyceride level, drug, and dose. Only the In baseline triglyceride level was significantly (p < .001) related to this ratio. Moreover, the triglyceride/LDL cholesterol ratio was fairly constant across changes all statins and doses for patients with baseline triglyceride levels of <150 mg/dL, 150-250 mg/dL, and >250 mg/dL, at . +/- .3,statins. .5+/- .2, and 1.2+/- .3, respectively. We conclude that all statins are effective in decreasing triglyceride levels, but only in hypertriglyceridemic patients.to Due to the relatively constant triglyceride/LDL cholesterol ratio, our analysis indicates that the more effective the statin is in decreasing triglyceride LDL cholesterol, the more effective it will also be in decreasing triglyceride levels in patients with hypertriglyceridemia.

BACKGROUND:ANOVA). Lipoproteins affect endothelium-dependent vasomotor responsiveness. Because lipoprotein effects of estrogen and cholesterol-lowering therapies differ, we studied the vascular responses to cholesterol these therapies in hypercholesterolemic postmenopausal women. METHODS AND RESULTS: We randomly assigned 28 women to conjugated equine estrogen (CE) .625 lipoprotein mg, simvastatin 10 mg, and their combination daily for 6 weeks. Compared with respective baseline values, simvastatin alone and combined their with CE reduced LDL cholesterol to a greater extent than CE alone (both P< .05). CE alone and combined with simvastatin and raised HDL cholesterol and lowered lipoprotein(a) to a greater extent than simvastatin alone (all P< .05). Flow-mediated dilation of the brachial differing artery (by ultrasonography) improved (all P< .001 versus baseline values) on CE (4. +/-2.6% to 10.2+/-3.9%), simvastatin (4.3+/-2.4% to 10. +/-3.9%), and CE women. combined with simvastatin (4.6+/-2. % to 9.8+/-2.6%), but similarly among therapies (P= .507 by ANOVA). None of the therapies improved the dilator lipoprotein response to nitroglycerin (all P>/= .184). Only therapies including CE lowered levels of plasminogen activator inhibitor type 1 and the cell women adhesion molecule E-selectin (all P< . 05 versus simvastatin). CONCLUSIONS: Although estrogen and statin therapies have differing effects on lipoprotein levels,properties specific improvement in endothelium-dependent vasodilator responsiveness is similar. However, only therapies including estrogen improved markers of fibrinolysis and vascular inflammation.molecule Thus, estrogen therapy appears to have unique properties that may benefit the vasculature of hypercholesterolemic postmenopausal women, even if they hypercholesterolemic are already on cholesterol-lowering therapy.

BACKGROUND:heart Low-density lipoprotein cholesterol (LDL-C) is the primary therapeutic target in the National Cholesterol Education Program Adult Treatment Panel III (ATP 40, III) guidelines. This study tested the hypothesis that ezetimibe/simvastatin, a lipid-lowering agent that inhibits both intestinal cholesterol absorption and cholesterol therapeutic synthesis, provides greater LDL-C reductions than atorvastatin across dose ranges. METHODS: This multicenter, double-blind, 6-week parallel-group study randomized 1902 patients ranges. with LDL-C above ATP III goal to atorvastatin (10, 20, 40, or 80 mg) or to ezetimibe/simvastatin (10/10, 10/20, 10/40,significantly or 10/80 mg). Patients were stratified by prerandomization LDL-C level. RESULTS: At each milligram-equivalent statin dose comparison, and averaged across patients doses, ezetimibe/simvastatin provided greater LDL-C reductions (47%-59%) than atorvastatin (36%-53%). Ezetimibe/simvastatin 10/40 and 10/80 mg also provided significantly greater high-density ezetimibe/simvastatin, lipoprotein cholesterol (HDL-C) increases than atorvastatin 40 and 80 mg. Triglyceride reductions were similar for all comparisons. More ezetimibe/simvastatin than No atorvastatin patients with coronary heart disease (CHD) or CHD risk equivalents attained the ATP III LDL-C goal of <100 mg/dL cholesterol and the optional LDL-C target of <70 mg/dL. C-reactive protein reductions were similar between treatment groups. Consecutive elevations in alanine HDL-C aminotransferase and/or aspartate aminotransferase occurred in significantly more atorvastatin patients than ezetimibe/simvastatin patients. No myopathy or liver-related adverse events led groups. to study discontinuation with either drug. CONCLUSIONS: Ezetimibe/simvastatin was more effective than atorvastatin in lowering LDL-C at each dose comparison dose. and provided greater increases in HDL-C at the 40- and 80-mg statin dose. Ezetimibe/simvastatin is a highly efficacious, well-tolerated treatment hypothesis option for hypercholesterolemic patients.

AIMS:All The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and five pharmacokinetic interaction between ezetimibe .25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between placebo/positive-controlled, ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin METHODS: was a secondary objective. METHODS: Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C)>or=130 mg dl-1 received study drug once 20 daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg statistically alone, or with ezetimibe .25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects a received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids (mean in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only. RESULTS: In both (Study studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of additive pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P< .01) decreases in LDL-C concentration vs placebo from (HDL-C) baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with studies no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg 1), or 20 mg caused a statistically (P< .01) greater percentage reduction (mean -17%, 95% CI -27.7,-6.2, and -18%,-28.4,-7.4,baseline respectively) in LDL-C than simvastatin alone. CONCLUSIONS: The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 the or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional the clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.

3-Hydroxy-3-methylglutaryl was coenzyme A (HMG-CoA) reductase inhibitors are effective agents in lowering cholesterol and triglycerides and are being used by human immunodeficiency two virus-positive patients to treat the lipid elevation that may be associated with antiretroviral therapy. Many HMG-CoA reductase inhibitors and protease effective inhibitors are metabolized by the same cytochrome P450 enzyme 3A4 (CYP3A4). In addition, many protease inhibitors are potent inhibitors of same CYP3A4. Therefore, coadministration of these two classes of drugs may cause significant drug interactions. This open-label, multiple-dose study was performed 74% to determine the interactions between nelfinavir, a protease inhibitor, and two HMG-CoA reductase inhibitors, atorvastatin and simvastatin, in healthy volunteers.maximum Thirty-two healthy subjects received either atorvastatin calcium (10 mg once a day) or simvastatin (20 mg once a day) for lipid the first 14 days of the study. Nelfinavir (1,250 mg twice a day) was added on days 15 to 28.atorvastatin Pharmacokinetic assessment was performed on days 14 and 28. The study drugs were well tolerated. Nelfinavir increased the steady-state area therapy. under the plasma concentration-time curve during one dosing period (AUC(tau)) of atorvastatin 74% and the maximum concentration (C(max)) of atorvastatin that 122% and increased the AUC(tau) of simvastatin 505% and the C(max) of simvastatin 517%. Neither atorvastatin nor simvastatin appeared to plasma alter the pharmacokinetics of nelfinavir. It is recommended that coadministration of simvastatin with nelfinavir should be avoided, whereas atorvastatin should be be used with nelfinavir with caution.

BACKGROUND:to Statin therapy reduces adverse outcomes, with a minimal decrease in vessel stenosis. Magnetic resonance imaging (MRI) noninvasively detects atherosclerotic plaque to (AP) reduction. We hypothesized that statin-induced AP regression can be monitored by MRI and detected earlier than previously reported and minimal is significantly associated with its lipid-lowering effect. METHODS AND RESULTS: APs in thoracic aorta were measured by combined surface/transesophageal MRI METHODS in 27 patients (treated with simvastatin 20 to 80 mg daily) before and after 6 months of therapy. AP volume related and luminal dimensions were measured from 6 cross sections used to construct a 2.4-cm 3D volume of the aorta that reduction included plaque and lumen. Method reproducibility was studied in 10 patients imaged twice, 1 week apart. AP volume was reduced AP from 3.3+/- .1.4 to 2.9+/-1.4 cm3 at 6 months (P< .02), whereas luminal volume increase was less accentuated (from 12. +/-3.9 to 12.2+/-3.7 volume cm3, P< .06). LDL cholesterol decreased by 23%(from 125+/-32 to 97+/-27 mg/dL, P< .05) in 6 months. AP regression (plaque volume/area detected reduction) was significantly related to LDL cholesterol reduction (P< .02 and P< .005, respectively), and luminal volume increase was inversely related to detected LDL cholesterol reduction (P< .04). Plaque volume measurement was highly reproducible (intraclass correlation R= .98 and variability=4.8%). Intraobserver ( .91) and interobserver ( .81)(P< .02 concordances were documented for plaque volume assessment. CONCLUSIONS: AP regression and reverse remodeling can be detected accurately by MRI 6 therapy months after statin therapy initiation, and it is strongly associated with LDL cholesterol reduction.

OBJECTIVES:in The aim of this study was to determine whether the combination of lipid-lowering therapy and vitamin E supplementation improves peripheral ultrasound endothelial function and whether it is more effective than lipid-lowering therapy alone. BACKGROUND: Endothelium-dependent vasodilation is impaired in coronary and of peripheral arteries of patients with hypercholesterolemia. Coronary endothelial function has been shown to improve under lipid-lowering and antioxidant therapy, but unknown. the effect of additive vitamin E supplementation in the brachial artery is unknown. METHODS: Seven patients with hypercholesterolemia (mean+/-SD; age p 51+/-10 yr) were studied. Endothelium-dependent, flow-mediated dilation (FMD) and endothelium-independent nitroglycerin-induced dilation (NMD) were assessed in the brachial artery using (17.9+/-4.3 high resolution ultrasound 1) at baseline (BL I), 2) after 8 weeks of simvastatin (20 mg) and vitamin E (300 arteries IU) therapy (Comb I), 3) after withdrawal of vitamin E for 4 weeks (Statin), 4) after therapy as in #2 .05) for 4 weeks (Comb II) and 5) after withdrawal of both drugs for 4 weeks (BL II). RESULTS: Combined simvastatin to and vitamin E therapy reduced total cholesterol (Comb I vs. BL I: 276+/-22 vs. 190+/-14 mg/dl, p < .0001) and artery low-density lipoprotein (LDL)-C (197+/-22 vs. 106+/-22 mg/dl, p < .00001), augmented alpha tocopherol levels normalized to LDL (12.2+/-4.1 vs. 4.9+/- .9 of microg alpha-T/100 mg% LDL-C, p < .01) and resulted in significant improvements in FMD (16.4+/-4.7 vs. 4.9+/-2.5%, p < .001)pronounced as well as NMD (17.9+/-4.3 vs. 11.2+/-2.8%, p < .01). The ratio of FMD to NMD ( .92+/- .17 vs. .46+/- .24%, p and < .05) also increased under combination therapy, indicating a greater improvement of FMD than that of NMD. After withdrawal of vs. vitamin E, both FMD (Comb I vs. Statin: 16.4+/-4.7 vs. 7.9+/-4.7%, p < .01) and NMD (17.9+/-4.3 vs. 10.9+/-4.5%, p therapy, < .05) decreased significantly such that simvastatin alone only tended to improve FMD and did not change NMD. Results under therapy, combination therapy (Comb II vs. BL II) were reproducible. CONCLUSIONS: Combined vitamin E and simvastatin therapy leads to an improvement resolution of FMD and NMD in the brachial artery of patients with hypercholesterolemia. The improvement of FMD is more pronounced after ( .92+/- .17 combination therapy than after lipid-lowering therapy alone, similar to previous findings in the coronary circulation.