Are statins anti-inflammatory?

Large scale clinical trials demonstrate significant reductions in cardiovascular event rates with statin therapy. The observed benefit of statin therapy, however, may be larger in these trials than that expected on the basis of lipid lowering alone. Emerging evidence from both clinical trials and basic science studies suggest that statins have anti-inflammatory properties, which may additionally lead to clinical efficacy. Measurement of markers of inflammation such as high sensitivity C-reactive protein in addition to lipid parameters may help identify those patients who will benefit most from statin therapy.     

Statins – Do we really know all mechanisms of action of this group of drugs?

The role of statins in the treatment and prevention of cardiovascular diseases, such as coronary artery disease, acute coronary syndromes, diabetes or stroke is well established. However, there are still many questions regarding the role of statins in patients with heart failure (HF)/cardiomyopathy (CM), hypertension, atrial fibrillation (AF) and chronic kidney disease (CKD). As for patients with HF/CM inhibition of inflammation, reducing endothelial dysfunction might comprise part of the underlying mechanisms leading to the improvement of left ventricular function and exercise tolerance in these groups of patients. Therefore the candidates for statin therapy with HF/CM should be in New York Heart Association class II or III and should have normal or increased levels of lipids. We should avoid reducing lipids levels in these patients. At present, it is also difficult to unequivocally assess the impact of statins on blood pressure (BP). However, according to most available studies, the impact of statins on the decrease in BP is slight, but significant, especially among patients with hypertension. Moreover statins significantly reduce cardiovascular events in patients with hypertension. Although the results of trials concerning the use of statins in CKD patients are conflicting, it is suggested that the benefits of statin use outweigh the drawbacks in patients with early-stage CKD, when the benefits can be effectively predicted. However, available large randomized clinical trials suggest a lack of efficacy in patients on renal replacement therapy. We also needs further data on the role of statins on AF, however the existing studies suggest beneficial impact of statins in these patients.     

Early initiation of statin therapy after a coronary event

PURPOSE OF REVIEW: Despite improvements in the early management of acute coronary syndromes, the risk of major cardiovascular complications remains high. Lipid-modifying treatment with statins has the potential to further improve outcomes through improved endothelial function, antithrombotic and antiinflammatory actions. Statins are of proven benefit in patients with stable coronary heart disease. There has been speculation on potential mechanisms of benefit but, until recently, little data on the efficacy and safety of statins in the acute setting. Recent observational studies and randomized trials have addressed some of the questions regarding early initiation of statins in acute coronary syndromes. RECENT FINDINGS: Recent observational and randomized trials have shown that early commencement of statins in acute coronary syndromes is safe as early as 6 hours after the event and is likely to improve longer-term compliance. The current data are not sufficient to draw conclusions about the efficacy of statins early in the course of acute coronary syndromes. SUMMARY: Current management for acute coronary syndromes should include the commencement of statin therapy during initial hospital admission. This recommendation is based on safety and compliance data. More randomized trial evidence is required to determine whether early initiation will produce better outcomes than later initiation after an acute coronary event.     

Cardiovascular disease with diabetes or the metabolic syndrome: should statins or fibrates be first line lipid therapy?

PURPOSE OF REVIEW: Subgroups with diabetes or with features of the metabolic syndrome have been increasingly highlighted in large clinical endpoint trials with lipid therapy. This review will focus on the results of trials with statins or fibrates and examine the strength of the evidence for major cardiovascular event reduction with each kind of therapy in these high-risk subgroups that typically have low-to-moderate levels of LDL cholesterol. RECENT FINDINGS: Of six statin trials in populations with moderately increased LDL cholesterol only one, the Heart Protection Study, has shown that statin therapy will significantly reduce the major coronary heart disease events of non-fatal myocardial infarction or coronary heart disease death in diabetes. None of these trials has shown that statins have a particular predilection for reducing cardiovascular events in individuals with higher levels of body weight or other features of the metabolic syndrome. There are far fewer trial data with fibrates than with statins. However, the Veterans Affairs High Density Lipoprotein Intervention Trial has shown that a fibrate can significantly reduce major cardiovascular events, most particularly coronary heart disease death, in those with diabetes as well as those without diabetes who have insulin resistance. Indeed, all fibrate trials show that this therapy appears to selectively benefit the individual with obesity and features of the metabolic syndrome. SUMMARY: Based principally on evidence from the Veterans Affairs High Density Lipoprotein Intervention Trial and the cumulative experience with statins, trial data would thus far suggest that the patient with a modest increase in LDL cholesterol who has diabetes or features of the metabolic syndrome might be likely to achieve more substantial cardiovascular benefit from fibrate than from statin therapy.     

The safety and efficacy of achieving very low LDL-cholesterol concentrations with high dose statin therapy

PURPOSE OF REVIEW: The benefits of lipid lowering with statins are established in patients with or at risk for coronary artery disease. Recent trials with high doses of potent statins have examined treating to very low levels of LDL-cholesterol. Concerns have been raised about the safety of this strategy. This review examines the safety and efficacy of treating to very low LDL-cholesterol. RECENT FINDINGS: Four clinical trials, Treating to New Targets (TNT) and Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) in stable coronary artery disease and Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 following acute coronary syndromes, have examined intensive statin therapy compared to moderate statin therapy. These trials and a meta-analysis demonstrated that intensive statin therapy reduces cardiovascular events. Subsequent analyses from these trials suggest that very low levels of LDL-cholesterol can be achieved safely and may improve clinical outcomes. A note of caution regarding hemorrhagic events following stroke with intensive statin therapy was raised by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial despite impressive reductions in cardiovascular events. SUMMARY: A growing body of evidence suggests progressive benefit for lowering LDL-cholesterol aggressively with intensive statin therapy in coronary artery disease. Future trials will be needed to define whether there is a level of LDL-cholesterol beyond which further benefit is not seen or safety concerns emerge.     

Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses

PURPOSE OF REVIEW: To summarize the evidence from recent clinical trials and metaanalyses on the efficacy of statin therapy to reduce death, myocardial infarction and stroke, and to review the effects of statins in patients with low LDL cholesterol, diabetes, end-stage renal disease, and acute coronary syndrome. RECENT FINDINGS: In large metaanalyses of randomized controlled trials relative risk reductions from statins compared with placebo for patients with manifest or with risk factors for coronary artery disease were 13% for overall mortality, 26% for fatal and nonfatal myocardial infarction, and 18% for fatal and nonfatal stroke. Evidence from large trials suggests that patients with type II diabetes compared with patients without diabetes have similar risk reductions from statins for cardiovascular events, but this benefit is not seen in patients with diabetes and end-stage renal disease. In patients with acute coronary syndrome, early treatment with high-dose atorvastatin reduces cardiovascular morbidity after the first 4 months following the event, but the impact on mortality endpoints remains less clear. Results from recent trials in patients with stable coronary artery disease or type II diabetes suggest that statins provide benefit at considerable low LDL cholesterol levels. Therefore, target values for LDL cholesterol of less than 1.8 mmol/l (<70 mg/dl) should be considered for all patients with coronary artery disease or equivalent coronary risk. SUMMARY: For patients at high risk of coronary artery disease there is growing evidence for the concept of 'the lower, the better' regarding LDL cholesterol levels. Ongoing trials are further investigating the safety of lower target values in patients at various risk of coronary artery disease.     

The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications

The depletion of the essential nutrient CoQ10 by the increasingly popular cholesterol lowering drugs, HMG CoA reductase inhibitors (statins), has grown from a level of concern to one of alarm. With ever higher statin potencies and dosages, and with a steadily shrinking target LDL cholesterol, the prevalence and severity of CoQ10 deficiency is increasing noticeably. An estimated 36 million Americans are now candidates for statin drug therapy. Statin-induced CoQ10 depletion is well documented in animal and human studies with detrimental cardiac consequences in both animal models and human trials. This drug-induced nutrient deficiency is dose related and more notable in settings of pre-existing CoQ10 deficiency such as in the elderly and in heart failure. Statin-induced CoQ10 deficiency is completely preventable with supplemental CoQ10 with no adverse impact on the cholesterol lowering or anti-inflammatory properties of the statin drugs. We are currently in the midst of a congestive heart failure epidemic in the United States, the cause or causes of which are unclear. As physicians, it is our duty to be absolutely certain that we are not inadvertently doing harm to our patients by creating a wide-spread deficiency of a nutrient critically important for normal heart function.     

Protecting the heart: a practical review of the statin studies

The aim of this review of the landmark HMG-CoA reductase inhibitors (statins) studies is to enable the clinician to draw practical lessons from these trials. The Scandinavian Simvastatin Survival Study (4S) established the importance of treating the hypercholesterolemic patient with established cardiovascular heart disease. The West of Scotland Coronary Prevention Study (WOSCOPS) showed the benefit of treating healthy hypercholesterolemic men who were nevertheless at high risk of developing cardiovascular heart disease in the future. The Cholesterol and Recurrent Events (CARE) study, a secondary prevention trial, proved the benefit of treating patients with myocardial ischemia and cholesterol levels within normal limits. This conclusion was confirmed by the Long-term Intervention With Pravastatin in Ischemic Disease (LIPID) study, another secondary prevention study that enrolled patients with a wide range of cholesterol levels (4-7 mmol/dL), into which the large majority of patients would belong. The importance of treating patients with established ischemic heart disease (IHD), and those at high risk of developing cardiovascular heart disease, regardless of cholesterol level, was being realized. The Air Force/Texas Coronary Artery Prevention Study (AFCAPS/TexCAPS) then showed that treatment can reduce adverse cardiovascular events even in the primary prevention of patients with normal cholesterol levels. The Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) trial showed that hypocholesterolemic therapy is useful in the setting of an acute coronary syndrome, while the Atorvastatin Versus Revascularisation Treatment (AVERT) study showed that aggressive statin therapy is as good as angioplasty in reducing ischemic cardiac events in patients with stable angina pectoris. Finally, the Heart Protection Study (HPS) randomized more than 20,000 patients, and the value of statins in reducing adverse cardiovascular events in the high-risk patient, including the elderly, women, and even in those with low cholesterol levels, is beyond doubt. The emphasis is now on the risk level for developing cardiovascular events, and treatment should target the high-risk group and not be dependent on the actual cholesterol level of the patient. It is interesting to compare the large amount of data on the value and safety of the statins with the much more limited and less convincing data on antioxidant vitamins.     

Statins: are any questions unanswered?

PURPOSE OF REVIEW: To summarize recent and ongoing randomized trials of statin therapy for the prevention of major vascular events. RECENT FINDINGS: Four large-scale randomized trials have compared high-dose vs. standard doses of statin therapy among patients with coronary heart disease, and their results suggest that higher doses are more effective for preventing major vascular events, albeit with evidence of increased toxicity. There is now clear evidence that statin therapy is effective among most patients with type 2 diabetes, although uncertainty remains about the benefits in those with advanced nephropathy. Ongoing trials will assess whether statin therapy is beneficial among patients with noncoronary vascular disease (such as congestive heart failure, cerebrovascular disease, or aortic stenosis), and among people with comorbid conditions or risk factors that increase the risk of vascular disease (including chronic kidney disease and raised C-reactive protein with below average low-density lipoprotein cholesterol). SUMMARY: Statin therapy safely reduces the risk of vascular events in a wide range of patients. Uncertainties persist about the effects of higher statin doses and the role of statins among patients with specific conditions or risk factors.     

Statin use in the secondary prevention of coronary heart disease in primary care: cohort study and comparison of inclusion and outcome with patients in randomised trials

Objective To compare the social and demographic profiles of patients who receive statin treatment after myocardial infarction and patients included in randomised trials. To estimate the effect of statin use in community based patients on subsequent all cause mortality and cardiovascular recurrence, contrasting effects with trial patients.Design Observational cohort study using a record linkage database.Setting Tayside, Scotland (population size and characteristics: about 400 000, mixed urban and rural).Subjects 4892 patients were discharged from hospital after their first myocardial infarction between January 1993 and December 2001. 2463 (50.3%) were taking statins during an average follow-up of 3.7 years (3.1% in 1993 and 62.9% in 2001).Main outcome measures All cause mortality and recurrence of cardiovascular events.Results 319 deaths occurred in the statin treated group (age adjusted rate 4.1 per 100 person years, 95% confidence interval 3.2 to 4.9), and 1200 in the statin untreated group (12.7 per 100 person years, 11.1 to 14.3). More older people and women were represented in the population of patients treated with statins than among those recruited into clinical trials (mean age 67.8 v 59.8; women 39.6% v 16.9%, respectively). The effects of statins in routine clinical practice were consistent with, and similar to, those reported in clinical trials (adjusted hazard ratio for all cause mortality 0.69, 95% confidence interval 0.59 to 0.80; adjusted hazard ratio for cardiovascular recurrence 0.82, 0.71 to 0.95).Conclusions The community effectiveness of statins in those groups that were not well represented in clinical trials was similar to the efficacy of statins in these trials.     

Pleiotropic effects of statins: do they matter?

Treatment with the 3-hydroxy-3-methylglutaryl coenyzme A reductase inhibitors (or statins) reduces the risk for cardiovascular events across a broad spectrum of patient profiles, as evidenced by both primary prevention and secondary prevention trials. Improved survival by way of reduced deaths from coronary heart disease was also reported with these agents, which are primarily indicated for substantial reduction in LDL-cholesterol levels. However, the statins are extremely complex drugs and exhibit a wide variety of vascular effects that may or may not be dependent on their lipid-modifying properties. These so-called pleiotropic effects include alterations of endothelial function, inflammation, coagulation, and plaque stability. The relative contribution of the nonlipid effects of statin therapy to the well-documented clinical benefits is currently under intense investigation.     

Which is the best lipid-modifying strategy in metabolic syndrome and diabetes: fibrates, statins or both?

Although less clinical intervention studies have been performed with fibrates than with statins, there are evidences indicating that fibrates may reduce risk of cardiovascular events. The potential clinical benefit of the fenofibrate will be specified by the ongoing Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which rationale, methods and aims have been just published. Controlled clinical trials show similar or even greater cardiovascular benefits from statins-based therapy in patient subgroups with diabetes compared with overall study populations. Therefore, statins are the drug of first choice for aggressive lipid lowering actions and reducing risk of coronary artery disease in these patients. However, current therapeutic use of statins as monotherapy is still leaving many patients with mixed atherogenic dyslipidemia at high risk for coronary events. A combination statin/fibrate therapy may be often necessary to control all lipid abnormalities in patients with metabolic syndrome and diabetes adequately, since fibrates provide additional important benefits, particularly on triglyceride and HDL-cholesterol levels. Thus, this combined therapy concentrates on all the components of the mixed dyslipidemia that often occurs in persons with diabetes or metabolic syndrome, and may be expected to reduce cardiovascular morbidity and mortality. Safety concerns about some fibrates such as gemfibrozil may lead to exaggerate precautions regarding fibrate administration and therefore diminish the use of the seagents. However, other fibrates, such as bezafibrate and fenofibrate appear to be safer and better tolerated. We believe that a proper co-administration of statins and fibrates, selected on basis of their safety, could be more effective in achieving a comprehensive lipid control as compared with monotherapy.     

Update for primary healthcare providers: recent statin trials and revised National Cholesterol Education Program III guidelines

Statins produce large, clinically important beneficial effects on total low-density lipoprotein (LDL) cholesterol and triglycerides while raising high-density lipoprotein (HDL) cholesterol--each of which increases the risks for cardiovascular disease (CVD). In randomized trials of secondary and primary prevention, and their meta-analyses, statins confer statistically significant, clinically important reductions in myocardial infarction, stroke, and CVD death. In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III included LDL as the primary target, recommending optional goals of < 100 mg/dL for high-risk patients, < 130 mg/dL for moderate-risk patients, and < 160 mg/dL for low-risk patients. We conducted a search of randomized trials of statins whose results were published since May 15, 2001. We extracted overall trial results and data on adverse events, when available. We reviewed 7 published trials of statins, some of which contributed to the recent addendum to the NCEP ATP III guidelines that recommend reducing LDL goals to < 70 for very high-risk and < 100 for moderately high-risk patients via statins. Data from these trials demonstrate that greater LDL reductions produce larger CVD benefits in various categories of high- and moderate-risk patients, including a large number of primary prevention patients with metabolic syndrome who should be treated as aggressively as patients who have survived a myocardial infarction or stroke. Together, these recent statin trials and the NCEP ATP III revised guidelines, if implemented by primary healthcare providers, would result in many more patients receiving statins of proven benefit and reassuring adverse event profile.     

Clinical implications for statin pleiotropy

PURPOSE OF REVIEW: Atherosclerosis is a multi-factorial condition involving dyslipidemia that can result in cardiovascular disease. Statins are potent inhibitors of cholesterol biosynthesis, and in clinical trials, statins have been shown to be beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to occur much earlier and to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. SUMMARY OF FINDINGS: Recent studies indicate that some of the cholesterol-independent or 'pleiotropic' effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent upon isoprenylation, may play an important role in mediating the pleiotropic effects of statins. SUMMARY: The potential clinical implications of statin pleiotropy suggests that perhaps other biomarkers, in addition to lipid levels, should be used to gauge the full efficacy of statin therapy in patients with cardiovascular risks or that statin therapy may be effective in disease states, such as inflammatory conditions, ischemic stroke or cancer, where elevated cholesterol levels have not been shown to be a strong epidemiological risk for these diseases.     

Cardiovascular outcomes among participants with diabetes in the recent large statin trials

PURPOSE OF REVIEW: Despite their increased cardiovascular risk and its continuous relationship with cholesterol, until recently only diabetic patients with marked dyslipidaemia were routinely offered lipid-lowering therapy. The secondary prevention statin trials led to more widespread cholesterol lowering in patients with coronary disease and diabetes. Here we review the results of recent randomized trials, which included substantial numbers of patients with diabetes and no vascular disease. RECENT FINDINGS: The MRC/BHF Heart Protection Study included 5963 participants with diabetes, of whom 2912 had no history of vascular disease at baseline. Patients were randomized to 40 mg simvastatin daily or matching placebo for 5 years, which, on average, reduced LDL by 1.0 mmol/l compared with placebo. Highly significant reductions of about one-quarter in major vascular events were seen both overall and in different types of patient with diabetes, including those with average and below average lipid levels. Recent data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and the Anglo-Scandinavian Cardiac Outcomes Trial support these findings and are consistent with these effects. SUMMARY: Good quality, randomized trials including substantial numbers of patients with diabetes show that such patients obtain the same proportional benefit as other groups studied. Given their increased cardiovascular risk, these findings argue for a simple strategy of considering routine statin therapy for patients with type 2 diabetes and adult patients with type 1 diabetes, irrespective of lipid levels. As generic statins become available this could have a greater impact on the burden of cardiovascular disease in diabetes than restricted and targeted therapy.     

Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis

Background:

Statins were initially used to improve cardiovascular outcomes in people with established coronary artery disease, but recently their use has become more common in people at low cardiovascular risk. We did a systematic review of randomized trials to assess the efficacy and harms of statins in these individuals.

Methods:

We searched MEDLINE and EMBASE (to Jan. 28, 2011), registries of health technology assessments and clinical trials, and reference lists of relevant reviews. We included trials that randomly assigned participants at low cardiovascular risk to receive a statin versus a placebo or no statin. We defined low risk as an observed 10-year risk of less than 20% for cardiovascular-related death or nonfatal myocardial infarction, but we explored other definitions in sensitivity analyses.

Results:

We identified 29 eligible trials involving a total of 80 711 participants. All-cause mortality was significantly lower among patients receiving a statin than among controls (relative risk [RR] 0.90, 95% confidence interval [CI] 0.84–0.97) for trials with a 10-year risk of cardiovascular disease < 20% [primary analysis] and 0.83, 95% CI 0.73–0.94, for trials with 10-year risk < 10% [sensitivity analysis]). Patients in the statin group were also significantly less likely than controls to have nonfatal myocardial infarction (RR 0.64, 95% CI 0.49–0.84) and nonfatal stroke (RR 0.81, 95% CI 0.68–0.96). Neither metaregression nor stratified analyses suggested statistically significant differences in efficacy between high-and low-potency statins, or larger reductions in cholesterol.

Interpretation:

Statins were found to be efficacious in preventing death and cardiovascular morbidity in people at low cardiovascular risk. Reductions in relative risk were similar to those seen in patients with a history of coronary artery disease.Although statins are known to improve survival and relevant clinical outcomes in high-risk populations,¹ evidence of their clinical benefit in lower risk populations is more equivocal. Initially, low-risk populations were defined by the absence of known coronary artery disease (and their treatment was termed “primary prevention”). However, it was subsequently recognized that these populations included both patients at very high risk of coronary artery disease (e.g., those with severe peripheral vascular disease) and those at very low risk (e.g., those aged < 40 years who have no diabetes or hypertension and have low-density lipoprotein cholesterol level of less than 1.8 mmol/L). Accordingly, current guidelines for the use of statins are based on the projected risk of an atherosclerotic event rather than solely on the presence or absence of known coronary artery disease.^2,3Results of the recent JUPITER study (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)⁴ have renewed enthusiasm for the use of statins in people without a history of coronary artery disease and have generated further controversy as to whether high-potency statins such as rosuvastatin and atorvastatin lead to better clinical outcomes than low-potency statins such as pravastatin, simvastatin, fluvastatin and lovastatin. We did a systematic review of randomized trials to assess the efficacy and harms of statins in people at low cardiovascular risk, including indirect comparisons of high-potency and low-potency statins.     

Statin-induced myositis: a commonly encountered or rare side effect?

PURPOSE OF REVIEW: Statins are well established as first-line agents for cholesterol lowering in cardiovascular disease, with accumulating evidence supporting their initiation and guidelines recommending treatment to lower LDL levels. Although generally well tolerated with few side effects, including headaches and gastrointestinal symptoms, concerns are raised regarding myopathy, which may lead to fatal rhabdomyolysis. This review examines current evidence on statin interactions, mechanism of injury and toxicity. RECENT FINDINGS: Significant myopathy is rare with an incidence of less than 0.5% of patients. Statin side effects may be dose-related, associated with other drug interactions that interfere with statin metabolic pathways through cytochrome p450 pathways or glucuronidation, or related to co-morbidities. Several theories have suggested that statin myotoxicity may be due to intracellular cholesterol depletion, or interference with oxidative phosphorylation pathways. Exact mechanisms are yet to be fully defined. Individuals with mixed dyslipidaemia may require combination therapy to achieve target lipid levels. No large-scale randomized trials have yet reported on the safety of combination therapy, although more recent studies may shed some light when they report. CONCLUSION: As most individuals on statins are 'high-risk' patients, they tend to be on multiple agents for cardiovascular disease which may interact with their statin. Progression of myalgia or myositis to rhabdomyolysis is rare (one in 30-100,000 patient-years of exposure), but if progressive muscle symptoms are ignored then fatalities can occur. When prescribing statins, physicians should be alert to potential risks and educate patients to report any potentially significant symptoms.     

Fibric acid derivatives in cardiovascular disease prevention: results from the large clinical trials

PURPOSE OF REVIEW: Results from five large placebo-controlled trials with second-generation fibrates have shown varying success in reducing cardiovascular events. This review focuses on a number of extended analyses from these trials that may relate to the success or failure of fibrate therapy and indicate who might likely benefit from this therapy. RECENT FINDINGS: Results have been far from uniform and several trials have been adversely impacted by high off-trial statin use. Collective evidence suggests, however, that fibrates have optimum cardiovascular benefit in diabetes or other manifestations of insulin resistance. Much of this evidence comes from posttrial analysis in subgroups with more sharply defined clinical characteristics than in the overall trial population. Analyses also suggest that different fibrates have a different range of favorable clinical properties, that the cardiovascular benefit of fibrates may not be readily measured or mostly predicted by changes in traditional lipid measurements, and that other nonlipid properties of fibrates as peroxisome proliferator-activated receptor agents might explain some of the benefit of these drugs. SUMMARY: Results of major clinical endpoint trials with fibrates, although not uniformly positive, provide substantial evidence for a selective therapeutic role of these drugs in cardiovascular event reduction in diabetes or insulin resistance.     

Statin use in acute coronary syndromes: cellular mechanisms and clinical evidence

PURPOSE OF REVIEW: Review the cellular mechanisms and clinical evidence for the use of statins in patients with unstable coronary syndromes. RECENT FINDINGS: Clinical trials of statin therapy in acute coronary syndromes demonstrate a rapid improvement in endothelial function, improved perfusion to ischemic myocardium, and an early reduction in cardiovascular events. The early benefit of statin therapy is related to a combination of molecular mechanisms that involve the oxidized LDL receptor (LOX-1), endothelial localized nitric oxide synthase, inflammatory cytokines, interstitial collagenases, and tissue factor expression. In human atheroma, 3 months' use of statin (pravastatin) therapy reduced the content of oxidized LDL, inflammatory cells (macrophage, T cells) infiltrates, and improved plaque stability by increasing the collagen content of the fibrous cap. SUMMARY: The antiatherothrombotic effects of statin therapy appear to have important clinical relevance to patients with impaired myocardial perfusion and acute coronary syndrome.     

The Effect of Statins on Mortality in Septic Patients: A Meta-Analysis of Randomized Controlled Trials

Objective

Statins are among the most prescribed drugs worldwide and their recently discovered anti-inflammatory effect seems to have an important role in inhibiting proinflammatory cytokine production, chemokines expression and counteracting the harmful effects of sepsis on the coagulation system. We decided to perform a meta-analysis of all randomized controlled trials ever published on statin therapy in septic patients to evaluate their effect on survival and length of hospital stay.

Data sources and study selection

Articles were assessed by four trained investigators, with divergences resolved by consensus. BioMedCentral, PubMed, Embase and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocation to treatment and comparison of statins versus any comparator in septic patients.

Data extraction and synthesis

Data from 650 patients in 5 randomized controlled studies were analyzed. No difference in mortality between patients receiving statins versus control (44/322 [14%] in the statins group vs 50/328 [15%] in the control arm, RR = 0.90 [95% CI 0.65 to 1.26], p = 0.6) was observed. No differences in hospital stay (p = 0.7) were found.

Conclusions

Published data show that statin therapy has no effect on mortality in the overall population of adult septic patients. Scientific evidence on statins role in septic patients is still limited and larger randomized trials should be performed on this topic.