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.     

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.     

Lipid management after acute coronary syndrome

PURPOSE OF REVIEW: Despite advances in medical therapy and percutaneous revascularization, patients with acute coronary syndrome face a high risk of early, recurrent cardiovascular events. Interventions targeting atherogenic lipoproteins may favorably modify this risk. RECENT FINDINGS: Two randomized clinical trials, MIRACL and PROVE-IT, demonstrated efficacy of early, intensive statin therapy after acute coronary syndrome. Recent observational and meta-analyses corroborate the findings of these trials. The benefit of intensive statin treatment appears to apply broadly to elderly as well as younger patients, and to patients with or without diabetes or metabolic syndrome. Randomized trials demonstrating the efficacy of early, intensive statin treatment after acute coronary syndrome employed fixed statin dosages, and there does not appear to be an initial or achieved LDL-cholesterol level below which benefit is absent. As such, broad application of intensive statin therapy after acute coronary syndrome may be preferable to titration of statin dose to achieve specific LDL goals. Low HDL-cholesterol predicts risk after acute coronary syndrome; therefore, pharmacologic interventions to raise HDL concentration or mimic its function may help reduce that risk. SUMMARY: Early, intensive statin therapy is safe and effective after acute coronary syndrome. Future research will determine whether drugs that raise or mimic HDL-cholesterol are effective adjuncts to statin therapy.     

The APOE locus and the pharmacogenetics of lipid response

Genetic variation at the APOE locus has been associated with plasma lipoprotein concentrations in the fasting (low-density, and high-density lipoproteins and triglycerides), and in the postprandial (triglyceride-rich lipoproteins) states. Resulting from these associations, the APOE locus has been found to be a significant genetic determinant of cardiovascular disease in the general population. Beyond the traditional association studies, APOE genetic variation has been shown to play a significant role, which explains some of the individual variations in therapies aimed at normalizing plasma lipid concentrations. Thus, the APOE E4 allele has been shown in some studies to be associated with increased response to dietary intervention. Conversely, APOE E2 carriers appear to be more responsive to statin therapy. The mechanisms behind these observations, however, have not been elucidated. Moreover, several other gene:environment and gene:therapy interactions have recently been demonstrated, thus further increasing the interest in this remarkable apolipoprotein.     

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.     

Statin therapy and angiogenesis

PURPOSE OF REVIEW: Clinical studies suggested that 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has an additional cardiovascular protective activity that may function independently of the ability of statins to lower serum cholesterol. This paper reviews the available data on these effects and discusses the potential intracellular mechanisms involved. RECENT FINDINGS: Experimental studies have clearly shown that statins protect against ischaemia-reperfusion injury of the heart, and exert pro-angiogenic effects by stimulating the growth of new blood vessels in ischaemic limbs of normocholesterolemic animals. The mechanisms underlying these serum lipid-independent statin effects are not completely understood, but there is increasing evidence that statins improve endothelial function through molecular mechanisms that mediate an increase in endothelium-derived nitric oxide. Recent research has revealed a link between statins and the serine/threonine protein kinase Akt that regulates multiple angiogenic processes in endothelial cells. In contrast to these data, it has also been reported that higher doses of statins can inhibit endothelial cell migration and angiogenesis. SUMMARY: Statins have biphasic potential either to promote or inhibit angiogenesis. Low statin doses induce a pro-angiogenic effect through Akt activation and increase nitric oxide production, whereas high statin doses may decrease protein prenylation and inhibit cell growth. Notwithstanding, the clinical relevance of these serum lipid-independent effects is not fully understood. Further studies on the actions of statins on endothelial cells may lead to the identification of new pharmacological targets for the control of angiogenesis.     

Fibrates, dyslipoproteinaemia and cardiovascular disease

Recent epidemiological data have reaffirmed that elevated plasma triglyceride and low HDL-cholesterol levels are important risk factors for atherosclerotic vascular disease. The rationale for the clinical use of fibric acid derivatives, which are designed to correct this metabolic nexus, is now on firmer ground. The mechanism of action of fibrates on lipoprotein metabolism has recently been elucidated at the molecular level and involves the activation of peroxisome proliferator-activated receptor-alpha 1 in the liver, with the net effect of improving the plasma transport rates of several lipoproteins. Other potential anti-atherothrombotic effects include the inhibition of coagulation and enhancement of fibrinolysis, as well as the inhibition of inflammatory mediators involved in atherogenesis. These consequences probably underpin the favourable effects of fibrates seen in recent angiographic and clinical trials. Two important clinical trials on the effect of gemfibrozil (Veterans Administration-HDL-Cholesterol Intervention Trial) and bezafibrate (Bezafibrate Infarction Prevention Study) have recently been completed in subjects with elevated triglyceride, low HDL and normal or near-normal LDL-cholesterol levels. The results testify to the efficacy of these agents in decreasing the incidence of cardiovascular events, particularly in patients with multiple risk factors and plasma triglyceride levels of over 2.2 mmol/l. The findings of these trials are compared with the statin-based Air Force/Texas Coronary Atherosclerosis Prevention Study, with a recommendation that future studies in appropriately selected patients should examine the synergistic effect of the fibrate/statin combination. The absolute risk reduction in the incidence of coronary events in the Veterans Administration-HDL-Cholesterol Intervention Trial compares favourably with the statin trials. The therapeutic aspects of the efficacy and safety of fibrates are reviewed. Besides primary mixed hyperlipidaemias, particular indications for the clinical use of fibrates include type 2 diabetes, the metabolic syndrome and renal insufficiency. The St Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention Study has suggested that fibrates may decrease the incidence of coronary events in type 2 diabetes, but this hypothesis will be more extensively tested in the Diabetes Atherosclerosis Intervention Study, Fenofibrate in Event Lowering in Diabetes Study and Lipids in Diabetes Study projects. Although significant new knowledge has accrued over the past few years concerning the fundamental and clinical aspects of fibrates, the success of these agents in clinical practice depends on the availability of methods for assessing cardiovascular risk as well as on treatment guidelines, which as presently designed and recommended may be inaccurate and suboptimal.     

Statin pharmacogenomics: what have we learned, and what remains unanswered?

PURPOSE OF REVIEW: Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary heart disease. Response to treatment varies considerably from person to person; however, inherited traits (genetic variability) may play a central role in this inter-individual variation. The purpose of this review is to summarize recent progress in the research for exploring genetic determinants of clinical efficacy and safety of statin therapy. RECENT FINDINGS: In addition to 41 previous studies of 19 genes, the results of 17 pharmacogenomic studies investigating the relationship between common genetic variants and response to statin therapy in terms of lipid responses, clinical outcomes, and adverse events have been reported since January 2004 - 15 candidate genes related to pharmacodynamics and three to pharmacokinetics of statins. These reported data suggest that genetic variations influencing intestinal cholesterol absorption, cholesterol production, and lipoprotein catabolism may all play a role in modulating responsiveness, as well as genes involved in drug metabolism of statins. They also suggest that combined analysis of multiple variants in several genes, all of which have possible functional relations, is more likely to give significant results, especially when being performed with a larger number of participants. SUMMARY: Pharmacogenomic studies of statin therapy will provide a better picture as to who is most likely and least likely to benefit from treatment, which results in more individualized management of coronary artery disease.     

Statin therapy in heart failure

PURPOSE OF REVIEW: The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors, or statins, have been shown to reduce cardiovascular morbidity and mortality among a wide spectrum of patients with established atherosclerotic vascular disease. Mounting experimental and clinical evidence also suggest a potential benefit as well as theoretical harm of statin therapy in patients with heart failure. RECENT FINDINGS: This article briefly summarizes the therapeutic properties of statins that may be of benefit to patients with heart failure and the theoretical adverse effects of cholesterol reduction in this group of patients. A number of nonrandomized clinical studies over the past several years have shown an association between statin use and reduced overall mortality. Several large-scale randomized studies designed to confirm these findings are currently under way. SUMMARY: Statin therapy appears to improve clinical outcomes in patients with both ischemic and nonischemic cardiomyopathy independently of their cholesterol-lowering properties. The theoretical adverse properties of statins in heart failure patients have not been substantiated in small to medium-sized clinical trials. Although the encouraging results of these preliminary studies suggest a role for statin therapy in heart failure, larger studies are needed to validate these findings. Several ongoing randomized trials are currently under way to evaluate the effect of statin therapy on cardiovascular outcomes in heart failure patients. The results of these studies, expected in the next several years, should provide scientific evidence for the role of statins in the treatment of failure.     

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.     

Lipidomic analysis of variation in response to simvastatin in the Cholesterol and Pharmacogenetics Study

Statins are commonly used for reducing cardiovascular disease risk but therapeutic benefit and reductions in levels of low-density lipoprotein cholesterol (LDL-C) vary among individuals. Other effects, including reductions in C-reactive protein (CRP), also contribute to treatment response. Metabolomics provides powerful tools to map pathways implicated in variation in response to statin treatment. This could lead to mechanistic hypotheses that provide insight into the underlying basis for individual variation in drug response. Using a targeted lipidomics platform, we defined lipid changes in blood samples from the upper and lower tails of the LDL-C response distribution in the Cholesterol and Pharmacogenetics study. Metabolic changes in responders are more comprehensive than those seen in non-responders. Baseline cholesterol ester and phospholipid metabolites correlated with LDL-C response to treatment. CRP response to therapy correlated with baseline plasmalogens, lipids involved in inflammation. There was no overlap of lipids whose changes correlated with LDL-C or CRP responses to simvastatin suggesting that distinct metabolic pathways govern statin effects on these two biomarkers. Metabolic signatures could provide insights about variability in response and mechanisms of action of statins.     

Enteric microbiome metabolites correlate with response to simvastatin treatment

Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy.     

The effect of genetic variation on the lipid response to dietary change: recent findings

PURPOSE OF REVIEW: Dyslipidaemia is an important risk factor for cardiovascular disease, and can be modified by diet. However, the lipid response to dietary change may be influenced by genetic variation. This review examines recent research (published since August 2003) on the effect of genetic variation on the lipid response to dietary change. RECENT FINDINGS: In 10 reports describing intervention studies and seven reports describing observational studies, the lipid response to diet was modified by polymorphisms within the genes for apoE, apoB, apoCIII, lipoprotein lipase, hepatic lipase, endothelial lipase, the liver fatty acid-binding protein, the beta3-adrenergic receptor, adipsin and the peroxisome proliferator-activated receptor gamma. The studies varied widely in terms of the number and type of study participants, the composition and duration of the dietary interventions, the nutrients studied and dietary assessment methods used in the observational studies, and the polymorphisms analysed--some of which had not been studied before with regard to the lipid response to diet. SUMMARY: The lipid response to dietary change is highly complex. Future studies will have to be large in order to assess the effects of multiple polymorphisms, and will have to control for many factors other than diet. At present, it is premature to recommend the use of genotyping in the design of therapeutic diets. However, such studies may be useful in identifying the mechanisms by which dietary components influence lipid levels.     

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.     

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.     

Serum C‐reactive protein in the prediction of cardiovascular diseases: Overview of the latest clinical studies and public health practice

Cardiovascular disease is the most common cause of morbidity and mortality globally. Epidemiological studies using high‐sensitivity assays for serum C‐reactive protein have shown a consistent association between cardiovascular disease risk and serum C‐reactive protein concentrations. C‐reactive protein is a biomarker for inflammation, and has been established in clinical practice as an independent risk factor for cardiovascular disease events. There is evidence that serum C‐reactive protein is an excellent biomarker of cardiovascular disease and is also an independent and strong predictor of adverse cardiovascular events. Further characterization of the impact and influence of lifestyle exposures and genetic variation on the C‐reactive protein response to cardiovascular disease events may have implications for the therapeutic approaches to reduce cardiovascular disease events. This review summarizes the studies that have examined the association between serum C‐reactive protein and the risk of cardiovascular disease. We also discuss the impact of independent factors and C‐reactive protein genetic polymorphisms on baseline plasma C‐reactive protein levels.     

Efficacy of Standard and Intensive Statin Treatment for the Secondary Prevention of Cardiovascular and Cerebrovascular Events in Diabetes Patients: A Meta-Analysis

Aims

To estimate the efficacy of standard and intensive statin treatment in the secondary prevention of major cardiovascular and cerebrovascular events in diabetes patients.

Methods

A systematic search was conducted in Medline over the years 1990 to September 2013. Randomized, double-blind, clinical trials comparing a standard-dose statin with placebo or a standard-dose statin with an intensive-dose statin for the secondary prevention of cardiovascular and cerebrovascular events in diabetes patients were selected. Trial and patient characteristics were extracted independently by two researchers. The combined effect on the composite primary endpoint was measured with a fixed-effect model. Potential publication bias was examined with a funnel plot.

Results

Five trials were included in the analysis comparing standard-dose statins with placebo with a total of 4 351 participants. Four trials were included for comparing standard-dose with intensive-dose statins, including 4 805 participants. Compared with placebo, standard-dose statin treatment resulted in a significant relative risk (RR) reduction of 15% in the occurrence of any major cardiovascular or cerebrovascular event (RR 0.85, 95% CI 0.79–0.91). Compared with standard-dose statin treatment, intensive-dose statin treatment resulted in an additional 9% relative risk reduction (RR 0.91, 95% CI 0.84–0.98).

Conclusion

Treatment with standard-dose statins to prevent cardiovascular or cerebrovascular events in diabetes patients with manifest cardiovascular disease results in an estimated 15% relative risk reduction and intensive-dose statin treatment adds 9%. If proven cost-effective, more intensive statin treatment should be recommended for diabetes patients at high cardiovascular risk.     

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.     

Carotid intimal-media thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase inhibitors

BACKGROUND: Surrogate measures for cardiovascular disease events have the potential to increase greatly the efficiency of clinical trials. A leading candidate for such a surrogate is the progression of intima-media thickness (IMT) of the carotid artery; much experience has been gained with this endpoint in trials of HMG-CoA reductase inhibitors (statins). METHODS AND RESULTS: We examine two separate systems of criteria that have been proposed to define surrogate endpoints, based on clinical and statistical arguments. We use published results and a formal meta-analysis to evaluate whether progression of carotid IMT meets these criteria for HMG-CoA reductase inhibitors (statins).IMT meets clinical-based criteria to serve as a surrogate endpoint for cardiovascular events in statin trials, based on relative efficiency, linkage to endpoints, and congruency of effects. Results from a meta-analysis and post-trial follow-up from a single published study suggest that IMT meets established statistical criteria by accounting for intervention effects in regression models. CONCLUSION: Carotid IMT progression meets accepted definitions of a surrogate for cardiovascular disease endpoints in statin trials. This does not, however, establish that it may serve universally as a surrogate marker in trials of other agents.     

Atherosclerosis imaging as a benchmark in the development of novel cardiovasular drugs

PURPOSE OF REVIEW: Imaging of the arterial wall yields validated surrogate markers that can provide an early indication with regards to efficacy of novel cardiovascular drugs. This paper attempts to address the use of atherosclerosis imaging as a benchmarking tool for a well informed decision whether to proceed to large morbidity and mortality studies in the assessment of a novel therapeutic strategy. RECENT FINDINGS: Imaging of the artery wall can be used to evaluate individual cardiovascular risk and has additive value over conventional risk scores as it directly addresses the disease process. In controlled clinical trials, vascular imaging has shown that the efficacy of lipid-modifying pharmacotherapy can be evaluated in both high and low-risk populations and that the findings parallel outcomes of clinical studies with similar interventions. SUMMARY: Arterial imaging may provide the first glimpse of the efficacy or failure of a novel strategy to combat atherosclerosis. These findings suggest that vascular imaging could be employed to probe whether or not a large morbidity and mortality endpoint study should be the next step in a clinical development program.