Early effects on endothelial function of atorvastatin 40 mg twice daily and its withdrawal

Combined hyperlipidemia is associated with endothelial dysfunction. Atorvastatin has lipid-lowering and pleiotropic properties, including a protective effect on endothelial function. This study investigated the short- and medium-term effects of therapy with atorvastatin and of its discontinuation on lipid lowering and endothelial function. In 33 patients with combined hyperlipidemia who had been randomized and treated for 6 weeks with 40 mg of atorvastatin twice daily (n = 23) or placebo (n = 10), fasting lipid levels and flow-mediated dilation (FMD) of the brachial artery were measured at baseline, after 12 hours, 1 week, and 6 weeks during therapy, and 36 hours after discontinuation of therapy. Thereafter, all patients received 20 mg/day of atorvastatin for another 6 weeks. In the atorvastatin group, low-density lipoprotein cholesterol was decreased by 30% and 46% after 1 and 6 weeks, respectively (p <0.0001 for the 2 comparisons). In patients who already showed an impaired FMD at the beginning of the study (n = 15), atorvastatin caused a significant improvement in FMD, from 2.6% at baseline to 4.0% and 6.3% after 1 and 6 weeks, respectively (p <0.05 and <0.001). Thirty-six hours after withdrawal of atorvastatin, the FMD in this group decreased again to 2.8% (p <0.05), whereas low-density lipoprotein cholesterol level remained unchanged. The 6 patients with normal FMD at baseline showed no improvement in FMD during therapy or any decrease after withdrawal of the drug. In conclusion, only patients with endothelial dysfunction profit from high-dose atorvastatin treatment. When the treatment is abruptly discontinued, the effect on FMD disappears in 36 hours.     

Beyond lipids - the role of the endothelium in coronary artery disease

The beneficial effects of statin therapy in patients with coronary heart disease (CHD) outweigh those expected from simply lowering low-density lipoprotein (LDL) cholesterol, and occur too early in treatment to be due to this mechanism alone. Endothelial dysfunction is present in patients with atherosclerosis, even in the early stages before plaque formation, making it a useful marker for early cardiovascular disease. Statins reduce endothelial dysfunction, which improves myocardial perfusion and angina pectoris. In recent studies with statin therapy, the improvement in endothelial function has been attributed, in part, to an increased production of nitric oxide (NO), a key vasodilator, from the endothelium. These studies have shown that pravastatin and simvastatin improve endothelial function in the short term, with variable effects on vasodilation, which may be due to differences in their effects on NO production. Whether these differences between the statins may result in long-term differences in net clinical benefit has to be awaited.     

Comparisons of short- and intermediate-term effects of pitavastatin versus atorvastatin on lipid profiles, fibrinolytic parameter, and endothelial function

We compared short- and intermediate-term effects on lipid profiles, fibrinolytic parameter, and endothelial function between pitavastatin and atorvastatin. Short-term improvement of endothelial function was superior with pitavastatin compared to atorvastatin therapy. Pitavastatin could be a potentially better therapeutic choice for lipid-lowering and early alterations in endothelial function. Our study provides an important basis on which further trials involving larger numbers of patients may be studied prospectively.     

Atorvastatin but not L-arginine improves endothelial function in type I diabetes mellitus: a double-blind study

OBJECTIVES: We sought to determine the effects of oral L-arginine and the hexamethylglutaryl coenzyme A reductase inhibitor atorvastatin on endothelial function in young patients with type I diabetes mellitus (DM). BACKGROUND: Endothelial dysfunction, a key early event in atherosclerosis, occurs in young patients with type I DM, and its reversal may benefit the progression of vascular disease. Cholesterol reduction in L-arginine improve endothelial function in nondiabetic subjects, but their effect in patients with type I DM is unknown. METHODS: In a double-blind, 2x2 factorial study, we investigated the effect of L-arginine (7 g twice daily) and atorvastatin (40 mg/day) on conduit artery vascular function in 84 normocholesterolemic young adults (mean+/-SD: age 34 years [range 18 to 46], low density lipoprotein [LDL] cholesterol 2.96+/-0.89 mmol/liter) with type I DM. Brachial artery dilation to flow (flow-mediated dilation [FMD]) and to the direct smooth muscle dilator glyceryl trinitrate (GTN) were assessed noninvasively using high resolution ultrasound at baseline and after six weeks of treatment. RESULTS: Atorvastatin resulted in a 48+/-10% decrease in serum LDL cholesterol levels, whereas L-arginine levels increased by 247+/-141% after L-arginine therapy. By analysis of covariance, treatment with atorvastatin resulted in a significant increase in FMD (p = 0.018. L-Arginine therapy had no significant effect on endothelial function, and there was no significant change in dilation to GTN after either intervention. CONCLUSIONS: In young patients with type I DM, improvement in endothelial dysfunction can be demonstrated after just six weeks of treatment with atorvastatin. In contrast to studies of hypercholesterolemia, however, L-arginine had no benefit. Treatment with atorvastatin at an early stage may have an impact on the progression of atherosclerosis in these high risk patients.     

Effect of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia

This study was conducted to determine the efficacy of atorvastatin and niacin on lipoprotein subfractions in patients with atherogenic dyslipidemia. This was a multicenter, randomized, open-label, parallel-design study of patients with total cholesterol >200 mg/dl, triglycerides between 200 and 800 mg/dl, and apolipoprotein B >110 mg/dl. Patients were randomly assigned to atorvastatin 10 mg or immediate release niacin 3,000 mg daily for 12 weeks following a low-fat diet stabilization period. Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy. Atorvastatin and niacin both significantly reduced the concentrations of very low-density lipoprotein (VLDL) particles (-31% and -29%, respectively) and small low-density lipoprotein (LDL) particles (-44% and -35%, respectively). Niacin increased the concentration of large LDL (+75%). Atrovastatin reduced the number of LDL particles more than niacin (31% vs 14%). In patients with atherogenic dyslipidemia, both drugs had important effects on lipoprotein subfractions, which contributed to a reduction in coronary heart disease risk. The drugs equally reduced VLDL subclass levels. Niacin shifted the LDL subclass distribution toward the larger particles, more effectively converted patients from LDL phenotype B to phenotype A, and increased levels of the larger and perhaps more cardioprotective high-density lipoprotein particles. In contrast, atorvastatin preferentially lowered the concentration of small LDL particles without increasing levels of large LDL, and more effectively, reduced LDL particle numbers. Atorvastatin had a preferred LDL effect, whereas niacin had a preferred high-density lipoprotein effect.     

Short-term effect of atorvastatin on ischaemic threshold in hypercholesterolaemic patients with stable ischaemic heart disease

OBJECTIVE: Hypercholesterolaemia is associated with a loss of endothelium-dependent vasodilation, which may facilitate the occurrence of myocardial ischaemia in patients with coronary artery disease (CAD). The improvement of endothelial dilator function after 4 to 6 weeks of oral lipid-lowering therapy has been documented. Whether this early restoration of endothelial function by statins translates into anti-ischaemic effects is unknown. This study was designed to determine the effect of 4 weeks' treatment with 80 mg atorvastatin daily on exercise-induced ischaemia in patients with stable ischaemic heart disease (IHD) receiving standard anti-anginal drug therapy. METHODS AND RESULTS: A total of 41 patients with documented CAD, exercise-induced ischaemia and LDL-cholesterol > 130 mg/dl underwent exercise ECG, angina score and lipid level assessment at baseline, after 4 weeks of placebo treatment, and after 4 weeks of therapy with atorvastatin 80 mg. Primary endpoint was the change in time to 1 mm ST-segment depression (= ischaemic threshold) between placebo and treatment period. Atorvastatin treatment resulted in a 55% reduction of low-density lipoprotein (LDL) cholesterol (from mean of 162 (SD 32) to 72 (20) mg/dl). For a comparable rate-pressure product, the average time to 1 mm ST-segment depression was 295 (112) s at baseline, 314 (149) s after placebo and 301 (131) s after atorvastatin, indicating that the ischaemic threshold was not significantly modulated after 4 weeks of atorvastatin treatment. There was also no significant change in global angina score or in time to maximal ST-segment depression. CONCLUSIONS: High-dose atorvastatin treatment for 4 weeks drastically reduced LDL-cholesterol. However, the present study did not demonstrate a significant effect on the ischaemic threshold in patients with stable IHD already under treatment with anti-ischaemic agents.     

Evaluating cardiovascular pathophysiology and anatomy in atherosclerosis

The process of atherosclerosis begins with endothelial dysfunction from impaired bioavailability of NO and progresses through multiple stages of plaque development. Impaired endothelial function decreases NO and increases oxidized macromolecules such as low-density lipoprotein cholesterol. Oxidized low-density lipoprotein cholesterol accumulates in subendothelial space, forming plaques that may eventually compromise the lumen. Acute coronary events result from plaque rupture and consequent thrombus formation and abrupt occlusion of the vessel lumen. New diagnostic methods such as flow-mediated dilation of the brachial artery can detect endothelial dysfunction, and intravascular ultrasound can detect early plaque formation in the arterial wall. These techniques may provide a means to identify patients at risk for adverse cardiovascular outcomes, thereby enabling physicians to potentially prevent adverse events by early initiation of lipid-lowering therapy.     

Comparison of effectiveness of atorvastatin 10 mg versus 80 mg in reducing major cardiovascular events and repeat revascularization in patients with previous percutaneous coronary intervention (post hoc analysis of the Treating to New Targets [TNT] Study)

The Treating to New Targets (TNT) study demonstrated that intensive atorvastatin therapy to achieve low-density lipoprotein cholesterol concentrations well below recommended target levels provides an incremental clinical benefit in patients with stable coronary artery disease. This post hoc analysis of the TNT study was conducted to investigate whether this benefit extends to patients with previous percutaneous coronary intervention (PCI). A total of 10,001 patients with clinically evident coronary artery disease, including 5,407 patients with previous PCI, were randomized to atorvastatin 10 or 80 mg/day and followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event. Revascularization, a component of a secondary end point, was also examined. In patients with previous PCI, mean low-density lipoprotein cholesterol levels at study end were 79.5 mg/dl in the 80-mg arm and 100.8 mg/dl in the 10-mg arm. First major cardiovascular events occurred in 230 patients (8.6%) receiving high-dose atorvastatin and 289 patients (10.6%) receiving low-dose atorvastatin (hazard ratio 0.79, 95% confidence interval 0.67 to 0.94, p = 0.008). Repeat revascularization during follow-up (PCI or coronary artery bypass grafting) was performed in 466 patients (17.3%) in the 80-mg arm and 624 patients (22.9%) in the 10-mg arm (hazard ratio 0.73, 95% confidence interval 0.65 to 0.82, p <0.0001). In conclusion, intensive lipid lowering to a mean low-density lipoprotein cholesterol level of 79.5 mg/dl (2.1 mmol/L) with atorvastatin 80 mg/day in patients with previous PCI reduces major cardiovascular events by 21% and repeat revascularizations by 27% compared with a less intensive lipid-lowering regimen.     

Short-term effects of low-dose atorvastatin on inflammatory status and lipid profiles in perimenopausal hypercholesterolemic, hypertriglyceridemic women

The short-term and small-dose pleiotropic effects of atorvastatin and influence on sex steroid production were investigated in 35 premenopausal and 71 postmenopausal hypercholesterolemic, hypertriglyceridemic women, as well as the temporal differences in these pleiotropic effects. Atorvastatin (10 mg daily) was given for 6 months and fasting lipid concentrations, high sensitive CRP, and coagulo-fibrinolytic parameters were measured at baseline and after 3 and 6 months of therapy. Atorvastatin reduced the low-density lipoprotein cholesterol, remnant-like particle lipoprotein cholesterol, and malondialdehyde-modified low-density lipoprotein cholesterol after 3 and 6 months in both pre- and postmenopausal women. Atorvastatin decreased significantly high-sensitivity C-reactive protein concentration (-47.6% and -58.0%, P<0.01) and tissue plasminogen activator/plasminogen activator inhibitor-1 ratio (-31.8% and -40.0%, P<0.001) after 6 months in pre- and postmenopausal women. There was no correlation between the pleiotropic effects and the improvement in the lipid profile. Furthermore, atorvastatin has no influence on sex steroid production in both pre- and postmenopausal period. The results indicate some short-term pleiotropic effects of small-dose atorvastatin therapy without influence of endocrinological status, which may be important with respect to the early benefits of statin therapy in the perimenopausal hyperlipidemic women.     

Cost effectiveness of rosuvastatin in treating patients to low-density lipoprotein cholesterol goals compared with atorvastatin, pravastatin, and simvastatin (a US Analysis of the STELLAR Trial)

Statin therapy decreases low-density lipoprotein cholesterol levels and the risk of coronary heart disease but has a considerable short-term effect on health care budgets. The cost effectiveness of rosuvastatin (Crestor) has been compared with those of atorvastatin, pravastatin, and simvastatin in lowering low-density lipoprotein cholesterol levels and achieving National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. The analysis was conducted from the perspective of health care payers in the United States. Clinical data were obtained from the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial. Drug costs were based on wholesale acquisition costs. Cost effectiveness was assessed with the net monetary benefit approach and a 1-year time horizon. Rosuvastatin at 10 mg, the recommended starting dose, was the most cost-effective statin over a large range of "willingness-to-pay" values for a unit of clinical effect (i.e., a 1% decrease in low-density lipoprotein cholesterol or a patient achieving the goal).     

The benefit of aggressive lipid lowering

The beneficial effects of lipid-lowering therapy for the primary and secondary prevention of coronary heart disease (CHD) have been conclusively demonstrated in large-scale clinical trials. Does more aggressive lipid lowering provide even greater clinical benefit? The post coronary artery bypass graft (post-CABG) study was the first angiographic trial to show that aggressive lipid-lowering therapy was more effective at reducing disease progression than conventional approaches to cholesterol management. Recently, the results of the atorvastatin versus revascularization treatments (AVERT) trial have also shown significant benefit on clinical events with aggressive lipid lowering. A total of 341 patients with stable CHD were randomly assigned to receive medical therapy with atorvastatin 80 mg/day plus conventional treatment or angioplasty followed by usual care. Atorvastatin therapy resulted in a 46% reduction in the mean low-density lipoprotein cholesterol level compared with an 18% decrease for patients in the angioplasty/usual care group. Patients treated with atorvastatin had fewer ischemic events compared with those who had angioplasty (13 vs. 21%, P = 0.048) and a significantly greater time to first ischemic event (P = 0.027). AVERT is the first clinical study demonstrating that patients with stable CHD achieve significant cardiovascular benefit by aggressively lowering cholesterol levels with atorvastatin. It would therefore appear that an aggressive approach to lipid-lowering therapy is beneficial in patients with existing CHD.     

The effect of high dose atorvastatin therapy on lipids and lipoprotein subfractions in overweight patients with type 2 diabetes

Few data are available on the effects of high dose statin therapy on lipoprotein subfractions in type 2 diabetes. In a double blind randomised placebo-controlled trial we have studied the effects of 80 mg atorvastatin over 8 weeks on LDL, VLDL and HDL subfractions in 40 overweight type 2 diabetes patients. VLDL and LDL subfractions were prepared by density gradient ultracentrifugation. Triglycerides, cholesterol, total protein and phospholipids were measured and mass of subfractions calculated. HDL subfractions were prepared by precipitation. Atorvastatin 80 mg produced significant falls in LDL subfractions (LDL(1) 66.2 mg/dl:36.6 mg/dl, LDL(2) 118:56.6 mg/dl, LDL(3) 36.9:19.9 mg/dl all P < 0.01 relative to placebo) and VLDL subfractions (VLDL(1) 55:22.1 mg/dl, VLDL(2) 40.1:19.1 mg/dl, VLDL(3) 52.6:30 mg/dl all P < 0.01 relative to placebo). There was no change in the proportion of LDL present as LDL(3). There was a reduction in the proportion of VLDL as VLDL(1) and a reciprocal increase in the proportion as VLDL(3). Changes in VLDL subfractions were associated with changes in lipid composition, particularly a reduction in cholesterol ester and a reduction in the cholesterol ester/triglyceride ratio. Effects on HDL subfractions were largely neutral. High dose atorvastatin produces favourable effects on lipoprotein subfractions in type 2 diabetes which may enhance antiatherogenic potential.     

Comparison of efficacy and safety of rosuvastatin versus atorvastatin in African-American patients in a six-week trial

The lipid-modifying effects of statin therapy in hypercholesterolemic African-Americans have not been well characterized. This study compared the efficacy and safety of rosuvastatin and atorvastatin treatment for 6 weeks in hypercholesterolemic African-American adults. In the African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial (4522US/0002), 774 adult African-Americans with low-density lipoprotein cholesterol > or = 160 and < or = 300 mg/dl and triglycerides < 400 mg/dl were randomized to receive open-label rosuvastatin 10 or 20 mg or atorvastatin 10 or 20 mg for 6 weeks. At week 6, significantly greater reductions in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B concentrations, as well as lipoprotein and apolipoprotein ratios, were seen with rosuvastatin versus milligram-equivalent atorvastatin doses (analysis of variance with Bonferroni-adjusted critical p < 0.017 for all comparisons). Rosuvastatin 10 mg also increased high-density lipoprotein cholesterol significantly more than atorvastatin 20 mg (p < 0.017). Although statistical comparisons were not performed, larger proportions of rosuvastatin-treated patients than atorvastatin-treated patients achieved National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. The median high-sensitivity C-reactive protein levels were significantly reduced statistically from baseline with rosuvastatin 20 mg and atorvastatin 20 mg among all patients and with rosuvastatin 10 and 20 mg and atorvastatin 20 mg in those patients with a baseline C-reactive protein level > 2.0 mg/L. The 2 study medications were well tolerated during the 6-week study period. In conclusion, rosuvastatin 10 and 20 mg improved the overall lipid profile of hypercholesterolemic African-Americans better than did milligram-equivalent doses of atorvastatin.     

Modulation of angiogenic processes in cultured endothelial cells by low density lipoproteins subfractions from patients with familial hypercholesterolemia

OBJECTIVE: Electronegative low density lipoprotein (LDL) subfractions are cytotoxic to endothelial cells. To continue our study of homozygotic familial hypercholesterolemic (FH)-LDL, we report the effects of FH-LDL subfractions (FH-L1 to FH-L5) on the angiogenic processes in cultured endothelial cells. METHODS AND RESULTS: Subconfluent bovine aortic endothelial cells (BAEC) were treated with LDL subfractions (20 microg/ml), and the effects on angiogenic functions, including cell proliferation, migration, apoptosis, tube formation, secretion of matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF) were determined. The electronegative FH-L4 and FH-L5 inhibited cell proliferation while the other FH-LDL subfractions and LDL from normocholesterolemic subjects (N-LDL) had negligible effects. Like Cu2+ ox-LDL, FH-L5 strongly inhibited endothelial cell viability and FH-L4 had a milder effects. Similarly, FH-L4 and FH-L5 but not the other subfractions retarded cell migration, induced cell apoptosis, and perturbed tube formation by BAEC in matrigel. FH-L5 inhibited secretion of MMP-2 and MMP-9 by BAEC without affecting their endogenous levels. In contrast, FH-L5 increased the VEGF expression in endothelial cells. CONCLUSIONS: Our results show for the first time that FH-L5, a circulating LDL subfraction from hypercholesterolemic patients, modulates various angiogenic processes, thereby dysregulating endothelial function in a way that may be atherogenic.     

A randomized study comparing the effects of a low-carbohydrate diet and a conventional diet on lipoprotein subfractions and C-reactive protein levels in patients with severe obesity

PURPOSE: To compare the effects of a low-carbohydrate diet and a conventional (fat- and calorie-restricted) diet on lipoprotein subfractions and inflammation in severely obese subjects. METHODS: We compared changes in lipoprotein subfractions and C-reactive protein levels in 78 severely obese subjects, including 86% with either diabetes or metabolic syndrome, who were randomly assigned to either a low-carbohydrate or conventional diet for 6 months. RESULTS: Subjects on a low-carbohydrate diet experienced a greater decrease in large very low-density lipoprotein (VLDL) levels (difference = -0.26 mg/dL, P = 0.03) but more frequently developed detectable chylomicrons (44% vs. 22%, P = 0.04). Both diet groups experienced similar decreases in the number of low-density lipoprotein (LDL) particles (difference = -30 nmol/L, P = 0.74) and increases in large high-density lipoprotein (HDL) concentrations (difference = 0.70 mg/dL, P = 0.63). Overall, C-reactive protein levels decreased modestly in both diet groups. However, patients with a high-risk baseline level (>3 mg/dL, n = 48) experienced a greater decrease in C-reactive protein levels on a low-carbohydrate diet (adjusted difference = -2.0 mg/dL, P = 0.005), independent of weight loss. CONCLUSION: In this 6-month study involving severely obese subjects, we found an overall favorable effect of a low-carbohydrate diet on lipoprotein subfractions, and on inflammation in high-risk subjects. Both diets had similar effects on LDL and HDL subfractions.     

普罗布考联合阿托伐他汀和阿司匹林治疗颈动脉粥样硬化的疗效

目的观察普罗布考、阿托伐他汀、阿司匹林联合应用（PAS疗法）对颈动脉粥样硬化症的疗效。方法入选73例经B超证实有颈动脉粥样硬化斑块的患者,随机分为PAS组和AS组,随访6个月。其中PAS组37例,给予普罗布考0．375g×2次／d、阿托伐他汀10mg／d、阿司匹林100mg／d;AS组36例,给予阿托伐他汀10mg／d、阿司匹林100mg／d。观察治疗前后患者的血脂水平、血清氧化型低密度脂蛋白（OX-LDL）及血清C反应蛋白（CRP）水平,超声检测治疗前后颈动脉内-中膜厚度（IMT）及斑块厚度。结果治疗前PAS组及AS组血脂、OX-LDLCRP、IMT及斑块厚度基线水平差异无统计学意义（P〉O．05）。治疗后PAS组及AS组以上指标均降低,差异有统计学意义（P〈0．05）;除TG和HDL-C外,PAS组较AS组降低更明显,差异有统计学意义（P〈0．05）。结论普罗布考联合阿托伐他汀和阿司匹林治疗在降低血脂的同时,可降低患者的ox-LDL及CRP水平,疗效较单纯阿托伐他汀和阿司匹林治疗明显,同时也可改善患者的IMT及斑块总积分;稳定颈动脉粥样硬化斑块需长期干预治疗及随访观察。     

Gender differences in short-term effects of atorvastatin on lipid profile, fibrinolytic parameters, and endothelial function

Background and aimLittle is known about the impact of gender on short-term effects of atorvastatin. We investigated the gender differences in the short-term lipid-lowering and pleiotropic effects of atorvastatin therapy.Methods and resultsSeventy-two consecutive patients including 48 women with primary hypercholesterolemia, were assigned prospectively to treatment with atorvastatin (10 mg/day) for 3 months. We measured fasting lipid concentrations, thiobarbituric acid reactive substances (TBARS) as marker of lipid peroxide, fibrinolytic parameters, and endothelial function by flow-mediated vasodilation of the brachial artery (FMD), at baseline and after 3 months of therapy. We assessed the impact of gender on temporal differences in these parameters.In men, atorvastatin decreased total, low-density lipoprotein (LDL), and small, dense LDL-cholesterol concentrations, and increased FMD after 3 months. In women, atorvastatin decreased TBARS, triglyceride, and total, LDL, small, dense LDL, and remnant-like lipoprotein particle-cholesterol concentrations, and increased FMD after 3 months. Fibrinolytic parameters did not change significantly in either men or women. With respect to the percent change in those parameters after 3 months, TBARS (−17.6 ± 12.4 vs. −0.4 ± 18.8%, p < 0.01) and small, dense LDL-cholesterol (−96.7 ± 8.3 vs. −68.6 ± 29.7%, p < 0.01) decreased to a greater degree in women, although the relative changes in other parameters were similar between men and women.ConclusionsWe found gender differences in some of the lipid altering changes, including TBARS and small, dense LDL-cholesterol concentrations, after short-term atorvastatin therapy, which were greater in women. However, short-term atorvastatin therapy may be beneficial in improving endothelial function equally in both men and women.     

The evolving role of statins in the management of atherosclerosis

Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.     

Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia

Diabetic dyslipoproteinemia characterized by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and often elevated low-density lipoprotein (LDL) cholesterol with predominance of small, dense LDL is a strong risk factor for atherosclerosis. It is unclear whether fibrate or statin therapy is more effective in these patients. We compared atorvastatin (10 mg/day) with fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men and 8 women; mean age 60.0+/-6.8 years; body mass index 30.0+/-3.0 kg/m2) with type 2 diabetes mellitus (hemoglobin A1c 7.3+/-1.1%) and mixed hyperlipoproteinemia (LDL cholesterol 164.0+/-37.8 mg/dl, triglycerides 259.7+/-107 mg/dl, HDL cholesterol 48.7+/-11.0 mg/dl) using a randomized, crossover design. Lipid profiles, LDL subfraction distribution, fasting plasma viscosity, red cell aggregation, and fibrinogen concentrations were determined before and after each drug. Atorvastatin decreased all LDL subfractions (LDL cholesterol, -29%; p <0.01) including small, dense LDL. Fenofibrate predominantly decreased triglyceride concentrations (triglycerides, -39%; p <0.005) and induced a shift in LDL subtype distribution from small, dense LDL (-31%) to intermediate-dense LDL (+36%). The concentration of small, dense LDL was comparable during therapy to both drugs (atorvastatin 62.8+/-19.5 mg/dl, fenofibrate 63.0+/-18.1 mg/dl). Both drugs induced an increase in HDL cholesterol (atorvastatin +10%, p <0.05; fenofibrate +11%, p = 0.06). In addition, fenofibrate decreased fibrinogen concentration (-15%, p <0.01) associated with a decrease in plasma viscosity by 3% (p <0.01) and improved red cell aggregation by 15% (p <0.05), whereas atorvastatin did not affect any hemorheologic parameter. We conclude that atorvastatin and fenofibrate can improve lipoprotein metabolism in type 2 diabetes. However, the medications affect different aspects of lipoprotein metabolism.     

The next step in cardiovascular protection

While aggressive interventional therapy and anti-thrombotic therapy have revolutionized the management of acute coronary syndromes (ACS), defined as acute myocardial infarction (MI) or unstable angina (UA), long-term event rates remain high. Elevated lipids, inflammation and infection have each been implicated as additional mechanisms contributing to instability of vulnerable plaques. The new frontier in ACS management has focussed on treatment of these components of vascular disease. Preliminary trials have shown that early treatment with statins after ACS reduces coronary events but additional studies are needed to confirm this benefit. Furthermore, it is not clear what degree of low-density lipoprotein cholesterol (LDL-C) lowering is needed to stabilize the ACS patient. Chlamydia pneumoniae has been implicated in the development of coronary heart disease (CHD) but the results of preliminary trials investigating anti-chlamydial antibiotics have been inconsistent. Therefore, the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT TIMI 22) trial has been designed specifically to determine whether standard LDL-C reduction (with pravastatin 40 mg) provides a similar clinical benefit to more aggressive LDL-C reduction (with atorvastatin 80 mg). In 4162 ACS patients over a 2-year period, this trial will also evaluate the long-term effect of the quinolone antibiotic, gatifloxacin, in reducing cardiovascular events.