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PubMed2001

Statins and blood pressure regulation.

Hypertension and high serum cholesterol levels are two of the most relevant risk factors for cardiovascular diseases. A combined increase in both risk factors has been reported in a significant proportion of patients with coronary artery disease. Statins are the most widely used drugs to treat hypercholesterolemia, and they interact with blood pressure control in different populations of hypertensive patients. A significant reduction in blood pressure associated with the use of statins has been described in patients with untreated hypertension and in patients treated with antihypertensive drugs, particularly angiotensin converting enzyme inhibitors and calcium channel blockers. The effect of statins on blood pressure control has also been reported in diabetic patients. The mechanisms responsible for the hypotensive effect seem to be largely independent of the effect of statins on lipid profile, and are probably related to their interaction with endothelial function or angiotensin II receptors. The capacity of statins to improve blood pressure control could be a useful consideration for an integrated approach to better prevention of cardiovascular diseases.

Blood Pressure↗
PubMed2004

Statins as potential therapeutic agents in multiple sclerosis.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) are oral cholesterol-lowering drugs. Statins are well tolerated and have an excellent safety record. These agents competitively inhibit HMG CoA reductase, which is the enzyme that catalyzes the conversion of HMG CoA to L-mevalonate. Although L-mevalonate is a key intermediate in cholesterol synthesis, several of its metabolites are involved in post-translational modification of specific proteins involved in cell proliferation and differentiation. Thus, independent of their cholesterol-reducing properties, statins have important pleiotropic biologic effects. Recent reports indicate that statins have anti-inflammatory and neuroprotective properties. Whether statins will be of clinical benefit for patients with multiple sclerosis and other neurodegenerative diseases of the central nervous system will only be known after they are evaluated in prospective randomized clinical trials.

Humans↗
PubMed1988

The disappearance of a cyclin-like protein and the appearance of statin is correlated with the onset of differentiation during myogenesis in vitro.

We have used monoclonal antibodies to statin (S-44) and a cyclin-like protein (S-132) to examine the distribution of these two antigens in proliferating and in nonproliferating populations of cells. We have found that this cyclin-like protein is present in proliferating fibroblasts, whereas statin is absent from these same cell populations; in contrast, in senescent populations of fibroblasts the cyclin-like antigen disappears and statin labeling of nuclei appears. During myogenesis in rat muscle cell cultures, S-132 labeling is present in proliferating myoblasts and disappears after cells fuse and differentiate as multinucleated myotubes. In contrast, statin is absent from proliferating myoblasts, but appears when these cells become postmitotic and begin to differentiate. Similar results were seen during chick myogenesis. We have also found similar results during serum-starvation-induced differentiation in neuroblastoma cells. These results indicate that the cyclin-like protein disappears and statin appears upon commitment to differentiation in vitro, and the presence or the absence of these proteins appears to provide cellular markers for the transition from the proliferative to the nonproliferative state during differentiation.

Animals↗
PubMed2004

Statins as the cornerstone of drug therapy for dyslipidemia: monotherapy and combination therapy options.

Low-density lipoprotein (LDL) cholesterol reduction with statin treatment remains the cornerstone of lipid-lowering therapy to reduce risk of coronary heart disease. Combination therapy with a statin poses advantages in certain settings and may allow use of lower doses of multiple drugs rather than maximum doses of a single drug. Bile-acid sequestrants or the cholesterol-absorption inhibitor ezetimibe can be added to a statin to achieve greater LDL cholesterol reductions. Niacin or fenofibrate can be added to a statin for treatment of mixed dyslipidemia. Differences in statin efficacy in reducing LDL cholesterol and meeting recommended LDL cholesterol targets as well as differences among these agents in beneficial effects on other lipid parameters can affect whether and how these agents are prescribed in monotherapy and combination therapy.

Alanine Transaminase↗
PubMed2004

Detection of increased temperature of the culprit lesion after recent myocardial infarction: the favorable effect of statins.

BACKGROUND: Increased thermal heterogeneity has been demonstrated in atherosclerotic plaques, with the higher temperature recorded in acute myocardial infarction (MI). Dietary or treatment interventions reduce heat production. The purpose of the present study was to investigate whether increased plaque temperature is maintained for a prolonged period after MI and the role of statin administration. METHODS: We enrolled 55 patients, 29 with recent MI and 26 with chronic stable angina (CSA). Total cholesterol, C-reactive protein (CRP), interleukin-6 (IL-6) and soluble adhesion molecules were measured in the study population. All patients underwent coronary plaque temperature measurements. Temperature difference (DeltaT) was designated as the temperature of the culprit atherosclerotic plaque minus the temperature of the proximal healthy vessel wall. RESULTS: Under treatment with statins were 19 patients with recent MI and 14 with CSA. In patients with recent MI DeltaT was 0.19 +/- 0.18 degrees C, while in patients with CSA was 0.10 +/- 0.08 degrees C (P = .03). Patients treated with statins had lower DeltaT compared to untreated patients (0.10 +/- 0.11 versus 0.20 +/- 0.18 degrees C, P = .01). Treated patients with recent MI had similar DeltaT compared to CSA patients treated with statins (0.13 +/- 0.13 versus 0.07 +/- .06 degrees C, P = .14), while untreated patients with recent MI had substantially increased DeltaT compared to untreated patients with CSA (0.28 +/- 0.22 versus 0.14 +/- 0.10 degrees C, P = .04). DeltaT was positively correlated with CRP (R = 0.50, P < .01), IL-6 (R = 0.58, P < .01), and intercellular adhesion molecule-1 (R = 0.40, P = .03) levels. CONCLUSION: Increased plaque temperature is observed for an extended period after myocardial infarction, indicating that the inflammatory process is sustained after plaque rupture. Statins have a beneficial effect after MI on plaque temperature.

Aged↗
PubMed2005

Association between lipid testing and statin therapy in acute myocardial infarction patients.

BACKGROUND: Clinical guidelines recommend lipid testing in all hospitalized acute myocardial infarction (AMI) patients. Inhospital lipid testing has also been proposed as a quality indicator for AMI care, but little is known about its use or importance. We sought to examine rates of inhospital lipid testing and its association with statin therapy at hospital discharge. METHODS: We performed an analysis using medical chart abstraction data that included demographic and comprehensive clinical information for patients hospitalized in Ontario, Canada, with an AMI from 1999 to 2001. RESULTS: Among 11,468 patients, inhospital lipid testing was performed in 6,019 (52.5%) patients and in 4,169 (36.4%) patients within 24 hours of admission. Patients who had lipid testing were significantly more likely to be discharged on statin therapy compared with patients not tested (41.4% vs 23.0%, P < .001). In addition, inhospital lipid testing was strongly associated (odds ratio 3.61, 95% CI 3.15-4.14) with statin therapy prescription at hospital discharge after adjusting for other clinical, physician, and hospital factors. CONCLUSIONS: Despite endorsements from practice guidelines, less than half of all admitted AMI patients received lipid testing within 24 hours of hospital admission. Because inhospital lipid testing was strongly associated with the initiation of statin therapy at discharge, many opportunities to initiate statin therapy were lost. Efforts to increase the use of lipid testing in hospitalized AMI patients may translate into higher rates of lipid-lowering therapy and improved patient outcomes.

Aged↗
PubMed2006

Racial differences in reaching target low-density lipoprotein goal among individuals treated with prescription statin therapy.

BACKGROUND: Studies indicate that, overall, African Americans are less likely to achieve control of hyperlipidemia compared with whites. No population-based studies have examined the effect of race on achieving target low-density lipoprotein (LDL) goals among treated individuals. METHODS: Using computerized encounter and laboratory result data, we identified all African American and white patients in a Midwestern health system filling a statin prescription from January 1, 1997, through June 30, 2001 (index prescription), with no prescriptions filled 1 year before index prescription. We followed LDL results for 1 year after index prescription. RESULTS: A total of 16052 new statin users (32.5% African American) were identified. Mean baseline LDL was higher for African Americans (170.2 +/- 36.6) than for whites (161.8 +/- 37.2) (P < .001). Whites were more adherent to therapy, with 48.6% of white patients exposed to statins >80% of follow-up time (31.2% of African Americans) (P < .001). By the end of follow-up, 49.5% of African Americans and 71.1% of whites reached LDL goal. A proportional hazards model adjusting for age, sex, median household income, physician specialty, clinic site, baseline LDL, starting dose, and target LDL indicated that African Americans were less likely to reach goal compared with whites (hazard ratio 0.64, 95% CI 0.61-0.68). Results persisted after controlling for racial differences in statin adherence and LDL testing (hazard ratio 0.60, 95% CI 0.57-0.63). CONCLUSIONS: African American patients initiating statin therapy are less likely to achieve LDL goal, even after controlling for adherence differences and other factors, suggesting that African Americans may require different pharmacologic management.

Black or African American↗
PubMed2004

The National Lipid Association surveys of consumers, physicians, and pharmacists regarding an over-the-counter statin in the United States: is this a good idea?

Surveys commissioned by the National Lipid Association (NLA) were conducted to determine the current attitudes and perceptions of physicians, consumers, and pharmacists regarding the impact of an over-the-counter (OTC) statin. Individuals from preexisting independent databases were randomly invited to participate in the online surveys that were open from January 26 to 30, 2004 for physicians and consumers and from March 1 to 12, 2004 for pharmacists. The results of these surveys indicate that consumers and pharmacists are more positive regarding the idea of an OTC statin, whereas physicians are more guarded. Concerns of both physicians and pharmacists included the discontinuation by patients of their prescription cholesterol-lowering therapy without consulting their physician, safety issues such as potential drug interactions and side effects, and patient ability to self-manage OTC statins. Consumers interested in purchasing an OTC statin reported that they would consult their physician before doing so, and pharmacists were interested in supporting consumers who use OTC statins. Although such support would require further training and time, pharmacists believed that they could facilitate consumer self-care programs and follow-up with physicians.

Anticholesteremic Agents↗
PubMed2004

Is there value in liver function test and creatine phosphokinase monitoring with statin use?

Statins have transformed the care of patients with vascular disease. Patients in almost every category that has been studied have benefited substantially. On the other hand, although the incidence of side effects is remarkably low, statins, like any other therapy, are not entirely free of serious risks. From the outset, based on the mechanism of action of statins, hepatotoxicity has been a concern. Moreover, although the mechanisms remain obscure, significant skeletal muscle injury, which can lead to renal failure and death, unquestionably does occur. To mitigate these risks, screening and monitoring programs for hepatic and skeletal muscle injury were put in place when statins were introduced into clinical practice. This article reviews the benefits and the costs of these efforts. Although the benefits have not been shown, the costs are real and substantial. These include the harm caused by inappropriate withdrawal of therapy, which has been shown to be life-saving, as well as the considerable financial expenditure. The conclusion that follows, based on the evidence in hand, is that although these programs were appropriate at the time statins were introduced, they are not appropriate now.

Anticholesteremic Agents↗
PubMed2005

Relation of C-reactive protein and one-year survival after acute myocardial infarction with versus without statin therapy.

We evaluated the interaction between inflammation and survival benefit from statin therapy in patients who had acute myocardial infarction. Although 1-year mortality did not differ between patients who used statin therapy and those who did not, among patients who had C-reactive protein (CRP) concentrations in the lower 2 tertiles (<2.9 mg/L), 1-year mortality was higher in patients who used statin therapy than in those who did not within the highest CRP-defined tertile (> or =2.9 mg/L). Statin therapy significantly decreased the hazard ratio for 1-year mortality in patients who had high CRP levels to approximately the hazard present for patients who had low CRP levels and did not receive statin therapy.

C-Reactive Protein↗
PubMed2005

Early time to benefit with intensive statin treatment: could it be the pleiotropic effects?

Acute coronary syndrome (ACS) is associated with a number of abnormalities in inflammation, endothelial function, and coagulation, all of which appear to be modulated by statins. We examined the time to benefit of different statin regimens in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial and other ACS trials that compared statin therapies in patients with ACS. In PROVE IT-TIMI 22, apparent clinical benefit was observed as early as 30 days, with significant reduction in all-cause mortality, myocardial infarction, unstable angina requiring rehospitalization, revascularization performed 30 days postrandomization, or stroke observed as early as 4 months. In PROVE IT-TIMI 22, atorvastatin 80 mg lowered both low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP) at 30 days and 4 months to a greater extent than pravastatin 40 mg. Those who achieved the lowest LDL and the lowest CRP levels at 30 days after ACS had the lowest risk of acute cardiac events. The very early benefits of statin therapy appeared to be correlated with CRP reductions, which may relate to the intensity of the pleiotropic effects of statins.

Atorvastatin↗
PubMed2005

Pharmacogenomics of statin responsiveness.

Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary artery disease. However, the benefit of treatment varies between patients. Genetic variation can contribute to interindividual variations in clinical efficacy of drug therapy, and significant progress has been made in identifying common genetic polymorphisms that influence responsiveness to statin therapy. To date, >30 candidate genes related to pharmacokinetics and pharmacodynamics of statins have been investigated as potential determinants of drug responsiveness in terms of low-density lipoprotein cholesterol lowering. Genetic variation at gene loci that affect intestinal cholesterol absorption include apolipoprotein (apo) E; adenosine triphosphate-binding cassette transporter G5 and G8; cholesterol production, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase; and lipoprotein catabolism, such as apoB and the low-density lipoprotein receptor, all may play a role in modulating responsivesness as well genes involved in metabolism of statins such as cytochrome P450. However, there is considerable variation in results reported, and the data suggest that combined analysis of multiple genetic variants in several genes, all of which have possible functional significance, is more likely to give significant results than single gene studies in small sample populations. In the future, pharmacogenomic studies with a greater number of participants (>2,000 participants) should provide a better picture as to who is most likely and who is least likely to benefit from statin therapy.

Cholesterol, LDL↗
PubMed2005

Mortality and size of abdominal aortic aneurysm at long-term follow-up of patients not treated surgically and treated with and without statins.

Of 130 patients with abdominal aortic aneurysms (AAAs) not treated surgically, 75 (58%) were treated with statins. The sizes of the AAAs were 4.6 +/- 0.6 cm at baseline and 4.5 +/- 0.6 cm at 23-month follow-up in patients treated with statins (p = NS) and 4.5 +/- 0.6 cm at baseline and 5.3 +/- 0.6 cm at 24-month follow-up in patients not treated with statins (p < 0.001). Four of 75 patients (5%) treated with statins died at 45-month follow-up, and 9 of 55 patients (16%) not treated with statins died at 44-month follow-up (p < 0.05).

Aged↗
PubMed2006

Statins, cardiovascular disease, and drug safety.

Available for almost 2 decades, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have emerged at the forefront of preventive drugs for cardiovascular disease because of a substantial clinical trial database demonstrating that statins reduce the risk for coronary artery disease morbidity and death across a broad range of at-risk patient cohorts. Although generally well tolerated, statins may be associated with infrequent adverse events that warrant serious and frank discussion, including myopathy and rhabdomyolysis. In 2005, the National Lipid Association (NLA), a multidisciplinary, nonprofit association of healthcare providers and researchers in the lipid field, convened a Safety Task Force to undertake an intensive, fair-minded evaluation of available data on the effects of statins on muscle, liver, kidneys, and the brain. In the end, physicians and patients must weigh the potential clinical benefits of statin treatment against the potential risks when deciding whether to initiate treatment.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Regulation of connexin expression after balloon injury: possible mechanisms for antiproliferative effect of statins.

Statins, the 3-hydroxy-3-methylglutaryl-cooenzyme A (HMG-CoA) reductase inhibitors, have been shown to inhibit the migration of macrophages and smooth muscle cell proliferation leading to an antiproliferative effect. Although this beneficial effect of statins has been suggested to be independent of lipid lowering properties, the possible mechanisms responsible for this action is largely unknown. Gap junctions, which serve as channels for direct intercellular exchange of ions, secondary messengers, and small signaling molecules, play an important role in tissue homeostasis and regulation of growth, differentiation, and development. This study was designed to test the hypothesis that expression of the component proteins of gap junctions, connexins 40 and 43 (Cx40 and Cx43), is upregulated in arteries subjected to balloon injury and that this upregulation can be suppressed by statin therapy. Male New Zealand white rabbits were subjected to injury in which an angioplasty catheter was introduced into the right iliac artery from the femoral artery under fluoroscopic guidance. Five groups of rabbits (n = 6 to 7) were treated for 2 weeks with one of the following: balloon injury (BL); BL+lovastatin (BL+L, 10 mg/kg/day); BL+fluvastatin (BL+F, 10 mg/kg/day); sham operation (Sham); and control (Con). Immunohistochemistry studies showed that Cx40 and Cx43 were expressed in normal smooth muscle cells (SMC) throughout the media. Reverse transcription-polymerase chain reaction and Western blot analysis showed that Cx40 and Cx43 mRNA and protein expression was elevated after injury (P < .001 for both proteins and both assays), and these elevations were suppressed by lovastatin and fluvastatin to a similar degree (P < .05 for both drugs and both assays). Immunostaining of Cx40 and Cx43 was consistently enhanced in the neointimal area after injury and lovastatin and fluvastatin reduced staining of these proteins in the lessened neointimal layer. Transmission electron microscopy revealed that there were abundant gap junctions between neointimal SMC as well as fewer and smaller gap junctions after statin treatment. Therefore, balloon injury causes upregulation of Cx40 and Cx43 in neointimal SMC. Lovastatin and fluvastatin suppress upregulated Cx40 and Cx43 expression and reduce neointimal proliferation, suggesting that Cx40 and Cx43 may play a role in statin-induced antiproliferative effect.

Animals↗
PubMed2004

Effects of statins on stroke prevention in patients with and without coronary heart disease: a meta-analysis of randomized controlled trials.

PURPOSE: To assess if lipid-lowering interventions (statins, fibrates, resins, n-3 fatty acids, diet) prevent nonfatal and fatal strokes in patients with and without coronary heart disease. METHODS: We systematically searched the literature up to August 2002 to retrieve all randomized controlled trials of lipid-lowering interventions that reported nonfatal and fatal stroke and mortality data. The search yielded 65 trials with 200,607 patients for a meta-analysis to determine whether treatment effects differed between types of lipid-lowering interventions and between patient samples with and without coronary heart disease. RESULTS: The risk ratio for nonfatal and fatal stroke for statins as compared with control interventions was 0.82 (95% confidence interval [CI]: 0.76 to 0.90). The corresponding risk ratios for statins as compared with control were 0.75 (95% CI: 0.65 to 0.87) for patients with coronary heart disease and 0.77 (95% CI: 0.62 to 0.95) for those without coronary heart disease. The confidence intervals of risk ratios for nonfatal and fatal stroke associated with fibrates, resins, n-3 fatty acids, and diet all included 1, as did the confidence intervals for these interventions in patients with and without coronary heart disease. Weighted meta-regression analysis suggested a stronger association of stroke reduction with statin treatment than with the extent of cholesterol reduction. CONCLUSION: This meta-analysis suggests that statins reduce the incidence of stroke in patients with and without coronary heart disease.

Aged↗
PubMed2005

Potential vascular benefits of statins.

Atherosclerosis is associated with a number of functional abnormalities that affect endothelium-dependent vasomotor function, inflammation, and thrombosis. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have effects on many of these functions, likely explaining their benefit in reducing the incidence of clinical events in patients at high risk of cardiovascular disease. Statins may improve this vascular biology by lowering levels of low-density lipoprotein (LDL) or potentially by a number of non-LDL-related mechanisms. Cell culture and some animal studies have demonstrated LDL-independent effects of statins. The non-LDL mechanisms include effects on isoprenoid production and function, interactions between caveolin and nitric oxide synthase, and direct immunomodulatory effects. Although these mechanisms are clearly demonstrated in the experimental setting, their relevance to the clinical use of statins is unknown. From a purely pragmatic viewpoint, the debate of lipid versus nonlipid effects of statins matters little to clinical practice. Their proven effect on vascular biology and risk reduction justifies their important therapeutic role.

Atherosclerosis↗
PubMed2004

A persistent increase in C-reactive protein is a risk factor for restenosis in patients with stable angina who are not receiving statins.

Inflammation has been postulated to be a major contributor to restenosis after angioplasty. We examined the correlation between inflammatory and coagulatory reactions and the occurrence of restenosis, and how treatment with statins influences this correlation. A total of 243 patients with stable angina who were scheduled for a percutaneous coronary intervention (PCI) and follow-up coronary angiography were enrolled in the study. Eighty-one of these patients were treated with statins for at least 1 month before their PCI and throughout the study period. Blood was withdrawn on the day of the PCI and on the day of the follow-up catheterization. Patients with the highest hs-CRP at the time of the initial PCI maintained elevated hs-CRP levels over time and showed significantly higher rates of restenosis or TLR after 6 +/- 1 months than subjects with low initial hs-CRP. Statin treatment abolished this difference. Fibrinogen levels were also increased in subjects with high initial hs-CRP, both at the time of the initial PCI and at follow-up. In an univariate analysis, both initial and follow-up levels of hs-CRP and fibrinogen correlated with restenosis. However, both the initial and follow-up levels of hs-CRP only were independent predictors of increased restenosis in a multivariate analysis, except in the statin-treated subgroup. In conclusions, the persistent increase in CRP is a risk factor for restenosis in patients with stable angina who have not been treated with statins.

Aged↗