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PubMed2006

Combination therapy with statins and omega-3 fatty acids.

Combined dyslipidemia is the concurrent presence of multiple abnormalities in various lipid subfractions, including elevated concentrations of low-density lipoprotein (LDL) cholesterol and triglycerides (TGs), as well as decreased concentrations of high-density lipoprotein (HDL) cholesterol. The Adult Treatment Panel III (ATP III) guidelines of the US National Cholesterol Education Program (NCEP) lowered the cut points for classification of TG levels, established non-HDL cholesterol levels as a secondary target of therapy in patients with TGs of >or=2.26 mmol/L (200 mg/dL), and defined the metabolic syndrome as a secondary target of therapy. Although 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are first-line therapy for most patients with elevated LDL cholesterol, statin monotherapy may not be sufficient to achieve recommended non-HDL cholesterol goals, and statins have only modest effects on reducing TG levels. Similarly, patients whose TG levels remain elevated despite treatment with a TG-lowering agent may require the addition of a statin to provide further TG reduction. In addition, statin therapy may be needed to offset the secondary increase in levels of LDL cholesterol that frequently results from treatment with a TG-lowering agent in patients with marked hypertriglyceridemia. In a number of small studies, the combination of statins and omega-3 fatty acids has been consistently shown to be an effective, safe, and well-tolerated treatment for combined dyslipidemia. Patients with recent myocardial infarction may also benefit from this combination. When considering risks and benefits of adding a second agent to statins for treatment of combined dyslipidemia, omega-3 fatty acids provide additional lipid improvements without requiring additional laboratory tests and do not increase risk for adverse muscle or liver effects.

Anti-Inflammatory Agents↗
PubMed2006

Evaluation of the National Cholesterol Education Program Adult Treatment Panel III algorithm for selecting candidates for statin therapy: insights from the A to Z trial.

The National Cholesterol Education Program Adult Treatment Panel III recommends an algorithm to integrate iterative risk-stratification information with low-density lipoprotein (LDL) cholesterol levels to identify candidates for statin therapy. We used the Aggrastat to Zocor (A to Z) trial, in which all patients presented with an acute coronary syndrome (ACS) event in the absence of previous statin therapy, to evaluate the performance of this algorithm. Of 1,750 patients with ACS included in this analysis, 1,126 (64%) had an indication for statin therapy before enrollment and 624 (36%) did not have a statin indication before enrollment. We estimate that initiating statin therapy at moderate dosages (decreasing LDL by 1 mmol/L) according to the National Cholesterol Education Program Adult Treatment Panel III guidelines would have prevented approximately 15% of the ACS events leading to enrollment in the A to Z trial, whereas more intensive statin therapy (decreasing LDL by 1.5 mmol/L) would have prevented >21% of events. Aspirin use before enrollment was reported in only 38% of subjects with a statin indication. In conclusion, these observations represent missed opportunities for primary and secondary prevention and highlight the need for assessment of patient risk and better adherence to existing prevention guidelines.

Aged↗
PubMed2004

Current overview of statin-induced myopathy.

Statins are an efficacious and well-tolerated class of lipid-altering agents that have been shown to reduce the risk of initial and recurrent cardiovascular events. However, cerivastatin was withdrawn from the world market because of its potential for severe myotoxic effects. Since the benefits of statin treatment outweigh the small risk of adverse events, statins remain the first-line therapy for lipid lowering and preventing atherosclerotic cardiovascular diseases. The risk of myopathy may be minimized with the appropriate choice of agent and by identifying patients at risk of myotoxic effects. Elderly or female patients, or those with concomitant medications or impaired metabolic processes, may be at increased risk and should be monitored closely. The risk of myopathy may also be inferred from the pharmacologic and pharmacokinetic properties of the statin used. Since myotoxic events are more frequent at higher doses, statins that are effective in reducing cholesterol levels and helping patients to reach target levels at start doses may be useful. The lipophilicity of a statin and its potential for drug-drug interactions may also help to determine the likelihood of muscular effects. Drug-drug interactions may be avoided by selecting a statin that does not share the same metabolic pathway.

Anticholesteremic Agents↗
PubMed2005

Evaluation of cases of severe statin-related transaminitis within a large health maintenance organization.

PURPOSE: To describe the rate, potential causes, symptoms, time to onset, and time to resolution of severe transaminitis associated with increased 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitor ("statin") usage in a large group model health maintenance organization. SUBJECTS AND METHODS: Health plan members 18 years of age and older, not receiving chemotherapy, who had received at least 1 statin prescription between January 1, 1997, and December 31, 2001 were eligible. All eligible patients with an alanine aminotransferase greater than 10 times the upper limit of normal at any time during the study period were identified using computerized laboratory records. Medical records were subsequently reviewed in order to determine whether the elevation was attributable to statin therapy. RESULTS: Alanine aminotransferase had never been measured in 2334 of 25334 (9%) of eligible patients. In the remaining 23000 patients, 62 (0.3%) were identified with an alanine aminotransferase greater than 10 times the upper limit of normal during the 5-year study period. Of these, 17 (0.1% of 23000 patients) had severe transaminitis deemed directly attributable to statin use. All except 4 of these 17 cases were associated with drug interactions. In 16 cases, transaminitis resolved upon statin discontinuation. CONCLUSIONS: In the observed study sample, statin-related severe transaminitis occurred infrequently. These findings support less frequent liver enzyme monitoring for most patients on statins. Continued monitoring remains warranted for patients on concomitant medications or those with comorbid conditions.

Adult↗
PubMed2005

Statin therapy in the treatment of Alzheimer disease: what is the rationale?

Alzheimer disease (AD) is a chronic neurodegenerative disorder that is manifested by cognitive decline, neuropsychiatric symptoms, and diffuse structural abnormalities in the brain. Its prevalence is predicted to rise 4-fold in the next 50 years. AD is characterized pathologically by deposition of extracellular beta-amyloid and accumulation of neurofibrillary tangles. Neuronal death and specific neurotransmitter deficits also are part of the pathologic picture. Strategies to delay symptom progression have focused on addressing the neurotransmitter deficits. Strategies to delay the onset or biologic progression of AD largely have targeted the plaques formed by the deposition of beta-amyloid. AD and cardiovascular disease share common risk factors, notably hypercholesterolemia, and occur together more often than expected by chance. Therapy with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is the first-line treatment option for hypercholesterolemia, and observational studies have suggested that the risk of AD is reduced in patients who receive statin therapy in midlife. This reduction in risk of AD observed with statin therapy may be due to statins reducing beta-amyloid formation and deposition or to their known anti-inflammatory effects. Two randomized double-blind statin trials in patients with AD to assess the potential for statins to slow disease progression are currently under way. If successful, statin AD primary prevention trials may be developed.

Alzheimer Disease↗
PubMed2006

Clinical perspectives of statin-induced rhabdomyolysis.

Fear of muscle toxicity remains a major reason that patients with hyperlipidemia are undertreated. Recent evaluations of statin-induced rhabdomyolysis offer new insights on the clinical management of both muscle symptoms and hyperlipidemia after rhabdomyolysis. The incidence of statin-induced rhabdomyolysis is higher in practice than in controlled trials in which high-risk subjects are excluded. Accepted risks include age; renal, hepatic, and thyroid dysfunction; and hypertriglyceridemia. New findings suggest that exercise, Asian race, and perioperative status also may increase the risk of statin muscle toxicity. The proposed causes and the relationship of drug levels to statin rhabdomyolysis are briefly reviewed along with the problems with the pharmacokinetic theory. Data suggesting that patients with certain metabolic abnormalities are predisposed to statin rhabdomyolysis are presented. The evaluation and treatment of patients' muscle symptoms and hyperlipidemia after statin rhabdomyolysis are presented. Patients whose symptoms are related to other disorders need to be identified. Lipid management of those whose symptoms are statin-related is reviewed including treatment suggestions.

Asian People↗
PubMed2005

Statins prevent NF-kappaB transactivation independently of the IKK-pathway in human endothelial cells.

Statins have been linked to a wide range of vascular benefits, many of them are likely to be due to attenuation of chronic vascular inflammation. Nuclear factor kappaB (NF-kappaB) is one of the key regulators of transcription of a variety of genes involved in immune and inflammatory responses. Therefore, we investigated the effect of statins on TNF-alpha-induced NF-kappaB signaling in human endothelial cells (EC). ECs were pre-incubated for 16 h with cerivastatin (10(-9) to 10(-7) M) or vehicle in the presence or absence of mevalonate, followed by stimulation with 20 ng/ml TNF-alpha. Statin-treatment prevented TNF-alpha-induced NF-kappaB binding activity, nuclear translocation of the NF-kappaB p65 subunit, as well as NF-kappaB controlled tissue factor (TF) gene transcription in cultured EC. IkappaBalpha phosphorylation and IkappaBalpha degradation, however, still occurred in statin-treated cells. TNF-alpha also activated phosphatidylinositol (PI)3-kinase, as reflected by phosphorylation of Akt. Statin treatment of cells abrogated TNF-alpha-induced Akt phosphorylation and p65 nuclear translocation. As observed with statins, inhibition of PI3-kinase activity by Ly294002 also blocked TNF-alpha-induced p65 translocation, but did not prevent IkappaBalpha phosphorylation nor IkappaBalpha degradation. These studies demonstrate that TNF-alpha-induced NF-kappaB activation is abrogated by statin treatment in HUVEC independently of the classical IKK-pathway but via inhibition of PI3-kinase/Akt signaling.

Cells, Cultured↗
PubMed2006

Effects of statin treatment and withdrawal on angiotensin II-induced phosphorylation of p38 MAPK and ERK1/2 in cultured vascular smooth muscle cells.

Abrupt discontinuation of 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors (statins) is associated with increased cardiovascular risk. To investigate the molecular mechanisms determining the increased cardiovascular risk after statin withdrawal, we studied the effects of statin treatment and withdrawal on angiotensin II (AII) actions in rat aortic vascular smooth muscle cells (VSMC) in culture. In VSMC, AII stimulated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), and of p38 mitogen-activated protein kinase (p38 MAPK), with an EC50% of 0.86 and 3 nM, respectively. Maximal stimulation was observed after 5-10 min of exposure to AII. Pretreatment with 1-3 microM simvastatin for 24h inhibited AII-mediated stimulation of ERK1/2 and p38 MAPK phosphorylation; without affecting the levels on non-phosphorylated MAPK. Washout of simvastatin produced a rebound increase above control levels of AII-mediated phosphorylation of ERK1/2 and p38 MAPK. As previously reported for other agonists, the rebound increase of AII effects was observed from 1 to 3h after statin withdrawal, and was lost at later times. The basal levels of phosphorylation and the amount of non-phosphorylated kinases were unaffected by statin withdrawal. Similar effects were observed with lovastatin. Our results suggest that statins modulate AII effects in VSMC, and that transient increases in AII effects mediated via the MAPK pathway may play a role in the vascular dysfunction associated with statin withdrawal.

Angiotensin II↗
PubMed2006

On the association between statin and fracture: a Bayesian consideration.

BACKGROUND: The association between statin use and fracture risk is controversial, due to conflicting findings from previous studies. This study utilized the Bayesian approach to combine existing evidence and update the association with consideration of potential bias. METHODS: Data on the association between statin use and fracture incidence from 11 observational studies and 4 RCTs were synthesized by both empirical Bayesian analysis and fully Bayesian random-effects meta-analysis models. RESULTS: Empirical Bayesian analysis showed that statin use was associated with a reduction in hip fracture risk (OR=0.57, 95% credible interval (CrI): 0.46-0.71) and for non-vertebral (OR=0.69, 95% CrI, 0.63-0.74). These results were comparable with results from the fully Bayesian random-effects meta-analysis only for hip fracture (OR 0.56, 95% CrI, 0.42-0.73), but not for non-vertebral fracture (OR 0.77, 95% CrI, 0.58-1.03). The probability that statin use reduces fracture risk by at least 20% was 0.995 for hip fracture and 0.61 for non-vertebral fracture. Under the assumption that bias over-estimates the true OR by 20%, there is still a probability of 0.97 that statin use reduces hip fracture risk by at least 20%; however, the effect on non-vertebral fracture was much less robust with a probability of 0.27. CONCLUSIONS: Results of this Bayesian consideration are highly consistent with the hypothesis that statin use reduces hip fracture, but the association between statin use and non-vertebral fracture remains uncertain. The Bayesian approach presented here has the ability to help updating existing evidence as new data becomes available.

Bayes Theorem↗
PubMed2005

Statin therapy is associated with improved cardiovascular outcomes and levels of inflammatory markers in patients with heart failure.

BACKGROUND: We wished to determine whether the addition of statins affect cardiovascular events and markers of inflammation in patients with heart failure. METHODS AND RESULTS: A total of 446 patients with heart failure and ejection fraction < or =35% were followed in a prospective, nonrandomized fashion and were classified according to treatment with a statin. We determined all-cause mortality, cardiovascular morbidity, and serum markers of inflammation over a 24-month period. Statin therapy in patients with heart failure was associated with decreased all-cause mortality at 2 years compared with those not on statin therapy (15% versus 33%, P < .005) as well as hospitalizations for heart failure (22% versus 38%, P = .001) and nonfatal myocardial infarction (11% versus 15%, P < .001). In addition, statin therapy was associated with a decrease in serum levels of C-reactive protein (1.12 +/- 0.13 versus 1.47 +/- 0.11 mg/dL, P = .001), interleukin-6 (13.3 +/- 0.8 versus 17.3 +/- 1.4 ng/dL, P = .001), and tumor necrosis factor-alpha receptor II (24.3 +/- 1.0 versus 34.5 +/- 3.0 ng/dL, P = .001). CONCLUSION: The use of statin therapy in this nonrandomized trial was associated with a significant reduction in all-cause mortality and cardiac morbidity. In addition, the improvement in levels of several serum inflammatory markers with statin therapy suggests in part possible mechanisms by which these agents may exert their benefits.

Adult↗
PubMed2006

Effects of statin therapy on the development and progression of heart failure: mechanisms and clinical trials.

BACKGROUND: Statin therapy has been shown to effectively lower low-density lipoprotein cholesterol levels and reduce cardiovascular events. Statins also appear to exert other favorable effects, including anti-inflammatory actions and improvement in endothelial function. Statin therapy may therefore yield important clinical benefits in patients with heart failure-a physiologic state characterized by systemic inflammation and endothelial dysfunction. METHODS AND RESULTS: This review summarizes basic and clinical investigations regarding the role of statin therapy in heart failure, focusing on potential mechanisms and preliminary clinical data. There is now extensive evidence suggesting that statins improve endothelial function, inhibit neurohormonal activation, restore autonomic balance, reduce inflammation, and prevent ventricular remodeling. Retrospective and small-scale prospective studies suggest that statins prevent the development of heart failure and reduce mortality in patients with established HF. CONCLUSION: Preliminary evidence supports a role for statins in improving surrogate markers and clinical outcomes in ischemic and nonischemic heart failure. Large-scale randomized clinical trials are needed to definitively address this important topic.

Animals↗
PubMed2005

The potential of statins as part of anti-cancer treatment.

Statins are known to reduce mortality related to cardiovascular diseases. In recent years, evidence has accumulated that statins also exert anti-tumour activity for which numerous potential underlying mechanisms of action have been suggested. Accordingly, several case-control studies showed a reduction in cancer incidence in patients treated with statins. Furthermore, statins interact synergistically with several anti-tumour treatments in preclinical studies. Until now, only a few clinical studies are available that explore the optimal dose, feasibility, and efficacy of statins applied as single agents to control the growth of existing tumours. Studies investigating statins as part of a multi-drug regimen are completely lacking. Nevertheless, the interesting pre-clinical anti-tumour activity of statins combined with a favourable toxicity profile warrant their further development as anti-tumour agents, in particular as part of multi-drug regimens.

Antineoplastic Agents↗
PubMed2006

The rationale for using HMG-CoA reductase inhibitors ('statins') in peripheral arterial disease.

UNLABELLED: Atherosclerosis is a systemic process, and the leading cause of morbidity and mortality in the developed world. HMG-CoA reductase inhibitors ('statins') are potent lipid lowering drugs, which have been shown to reduce morbidity and mortality in patients with coronary atherosclerosis. OBJECTIVE: To present the up-to-date data concerning statin use in the prevention and treatment of extra-coronary atherosclerosis. METHODS: Clinical trials with statins in patients with extra-coronary atherosclerosis were searched for via PUBMED. FINDINGS AND CONCLUSIONS: The different forms of peripheral arterial disease (e.g. cerberovascular disease, lower extremity peripheral arterial disease) are associated with significant cardiovascular morbidity and mortality, and hence constitute a coronary artery disease equivalent in terms of published practice guidelines. There is some evidence from small randomized controlled trials that statin therapy decreases cardiovascular morbidity and mortality in patients with peripheral arterial disease. The mechanism of action of statins may derive from their lipid lowering properties, or from other, pleiotropic effects. Further, larger randomized controlled studies with statins are needed to evaluate the efficacy of statin therapy in patients with stable peripheral arterial disease and in those undergoing vascular or endovascular surgery.

Humans↗
PubMed2004

The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells.

Cholesterol-independent, pleiotropic actions of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert anti-inflammatory and antioxidant action by as yet unidentified mechanisms. This study explores the role of heme oxygenase 1 (HO-1) as a target and mediator of statins. In cultured endothelial cells derived from human umbilical vein, simvastatin and lovastatin increased HO-1 mRNA levels in a concentration- and time-dependent fashion. HO-1 induction by statins remained unaffected by mevalonate and N-nitro-l-arginine methyl ester, precluding the involvement of isoprenoid- and NO-dependent pathways. HO-1 mRNA induction was abrogated in the presence of actinomycin D and cycloheximide. In cells transfected with a reporter gene construct containing the proximal 4 kB of the HO-1 gene promoter 5'-flanking region, significant upregulation of promoter activity was detected, indicating that regulatory elements binding to this region were involved in transcriptional HO-1 induction by statins. Increased transcriptional expression of HO-1 was associated with elevated HO-1 protein levels and reduction of free radical formation. Our results show that the antioxidant defense protein HO-1 is a target site of statins in endothelial cells. Statins lead to HO-1 promoter activation, transcript and protein accumulation. This novel pathway may contribute to and explain the pleiotropic antioxidant, anti-inflammatory, and antiatherogenic actions of statins.

Antioxidants↗
PubMed2005

Effects of statins beyond lipid lowering: potential for clinical benefits.

BACKGROUND: The role of statin drugs in the reduction of serum lipids has been well documented. More recently, evidence suggesting that statins may positively impact many organ systems and disease states independent of lipid reduction has emerged. The term "pleiotropic effects" has been used to refer to these properties. We reviewed the evidence exploring such potential effects. METHODS: A search of the MEDLINE database was conducted for articles published between 1985 to 2005 on the pleiotropic and the lipid-lowering independent effects of statin drugs. The search terms "statin", "HMG-CoA reductase inhibitor", "pleiotropic effects", and "inflammation" were used. English language articles were selected for inclusion along with selected cross-references. RESULTS: Numerous animal and clinical studies support the presence of a spectrum of beneficial effects for statins that are independent of their lipid-lowering properties. These effects are mediated by a variety of mechanisms and they suggest that the therapeutic role of statins may expand. CONCLUSION: Statins have shown great promise beyond their lipid-lowering effects. Ongoing and future studies will help to further clarify the potential clinical impact of these "pleiotropic effects".

Animals↗
PubMed2006

Statins in heart failure. Beyond the lipid lowering effect.

Statins, the most widely prescribed medications in patients with hyperlipidemia and coronary heart disease, have a number of pleiotropic actions beyond cholesterol lowering. They improve endothelial function, they have antioxidant and anti-inflammatory effects, they regulate neovascularization and have immunomodulatory activities. Experimental evidence suggests that statins may be beneficial in heart failure as they can inhibit myocardial hypertrophy, reduce cardiomyocyte loss by apoptosis, reduce oxidative stress and restore neurohormonal imbalance. Furthermore small randomised clinical trials showed that short term statin administration may improve key pathophysiological aspects of this syndrome. Finally retrospective analyses of large statin trials imply a long term profit on clinical outcome in this group of patients. These results however need to be reviewed with caution as certain studies have demonstrated that low serum cholesterol is associated with worse prognosis in HF and that ubiquinone levels, a micronutrient with antioxidant actions, reduces significantly following statin administration. Large prospective randomised controlled trials are needed to confirm the beneficial effect of statins on cardiovascular outcome in HF patients and further elucidate the contributing mechanisms. Finally the statin dose and the interaction with co-administered drugs need to be studied.

Endothelium, Vascular↗
PubMed2006

Statin use and functional decline in patients with and without peripheral arterial disease.

OBJECTIVES: We determined whether statin use (vs. non-use) is associated with less annual decline in lower-extremity functioning in patients with and without lower-extremity peripheral arterial disease (PAD) over three-year follow-up. BACKGROUND: It is unclear whether statin use is associated with less functional decline in patients with PAD. METHODS: Participants included 332 men and women with an ankle brachial index (ABI) <0.90 and 212 with ABI 0.90 to 1.50. Functional outcomes included 6-min walk distance and usual and rapid-pace 4-m walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for five repeated chair rises into an ordinal score ranging from 0 to 12 (12 = best). RESULTS: Adjusting for age, race, gender, comorbidities, education, health insurance, total cholesterol/high-density lipoprotein level, body mass index, pack-years of smoking, leg symptoms, immediately previous year functioning, statin use/non-use, ABI, and change in ABI, the PAD participants using statins had less annual decline in usual-pace walking velocity (0.002 vs. -0.024 m/s/year, p = 0.013), rapid-pace walking velocity (-0.006 vs. -0.042 m/s/year, p = 0.006), 6-min walk performance (-34.5 vs. -57.9 feet/year, p = 0.088), and the summary performance score (-0.152 vs. -0.376, p = 0.067) compared with non-users. These associations were attenuated slightly by additional adjustment for high-sensitivity C-reactive protein levels. Among non-PAD participants, there were no significant associations between statin use and functional decline. CONCLUSIONS: The PAD patients on statins have less annual decline in lower-extremity performance than PAD patients who are not taking statins.

Aged↗
PubMed2004

A study of statin use in the prevention of cognitive impairment of vascular origin in the UK.

INTRODUCTION: There is increasing evidence suggesting that control of hypertension and antiplatelet therapy may prevent or reduce progression of vascular-related cognitive impairment (VCI), though a similar role of statins in this group of patients has yet to be established. METHODS: We conducted a postal survey of a group of 296 medical practitioners (comprising of physicians and psychiatrists specialising in the elderly, and general practitioners) inquiring into their management of (a) patients at high risk of developing VCI and (b) patients with established VCI. RESULTS: The overall response rate was 60% (177/296), with the highest response rate from psychiatrists. (a) For patients at high risk of developing VCI: 47% of clinicians believed that statins had an important role in preventing subsequent dementia: 4% would commence statins at a total cholesterol (TC) of 4-5 mmol/L; 38% with a TC of 5.1-6.5 mmol/L; and 32% with a TC of 6.6-8 mmol/L. Cardiovascular risk profile, age, cost and gender were other factors considered as important factors influencing statin prescription. (b) In those patients with established VCI: 32% of clinicians felt that statins had an important role in arresting progression, usually in people with a mild degree of cognitive impairment: 4% would commence statins at a TC of 4-5 mmol/L; 25% with a TC of 5.1-6.5 mmol/L; and 22% with a TC of 6.6-8 mmol/L. There were no major differences between clinicians in their prescribing habits. CONCLUSIONS: A substantial proportion of clinicians favour the use of statins in primary and secondary prevention of cognitive impairment of vascular origin, despite a lack of definite evidence to support their use at the present time.

Aged↗