Advances in Lipid Testing and Management in Patients with Diabetes Mellitus

ObjectiveTo review the pathophysiologic basis for the classic phenotype associated with diabetic dyslipidemia, discuss recent advances in lipid and lipoprotein testing for risk assessment and lipid therapy monitoring, and summarize a systematic approach to the clinical management of diabetic dyslipidemia.MethodsWe review the pertinent literature, including treatment guidelines and results of major clinical trials, and discuss the effectiveness of various pharmacologic interventions for management of lipid levels in patients with diabetes.ResultsThe incidence and prevalence of type 2 diabetes mellitus continue to escalate globally at alarming rates. Diabetes predisposes to multiple microvascular and macrovascular complications, including cardiovascular disease, the number 1 cause of mortality in the United States. The third report of the National Cholesterol Education Program Adult Treatment Panel in 2001 identified diabetes as a coronary heart disease (CHD) risk equivalent, in light of the evidence that CHD risk in persons with diabetes is similar to that of nondiabetic persons with established CHD. Diabetic dyslipidemia is characterized by a constellation of lipid derangements—hypertriglyceridemia, a low concentration of high-density lipoprotein cholesterol (HDL-C), and a high concentration of small, dense low-density lipoprotein (LDL) particles—that accelerate the progression of atherosclerotic disease and the development of atherothrombotic events.ConclusionStatin trials have demonstrated significant reductions in morbidity and mortality from cardiovascular diseases, including in patients with diabetes. Nevertheless, many patients who achieve their LDL cholesterol (LDL-C) goal still have residual CHD risk. Diabetic dyslipidemia contributes to this residual risk because of the increased concentration of atherogenic apolipoprotein B-containing lipoproteins that can persist despite normalized LDL-C levels and low HDL-C levels. Recent clinical trials emphasize the importance of intensive lipid lowering to achieve recommended goals for LDL-C, non-HDL-C, and apolipoprotein B. (Endocr Pract. 2009;15:641-652)     

Non-high-density lipoprotein cholesterol and cardiovascular disease

PURPOSE OF REVIEW: Non-HDL cholesterol was designated a secondary target of therapy in the recent Adult Treatment Panel III report. This paper reviews correlates of non-HDL cholesterol levels and summarizes the available data on non-HDL cholesterol as a predictor of cardiovascular events as well as data linking treatment-induced changes in non-HDL cholesterol to cardiovascular outcomes. RECENT FINDINGS: Non-HDL cholesterol levels in the population vary by age, sex, and race and are closely linked to measures of adiposity, especially visceral adiposity. Several reports in populations with and without cardiovascular disease have recently been published that document the prognostic utility of non-HDL cholesterol levels. Preliminary data are also available to suggest that pharmacologically induced changes in non-HDL cholesterol levels relate to prognosis. SUMMARY: Non-HDL cholesterol is a potent predictor of cardiovascular risk among a broad range of individuals with and without cardiovascular disease and is prognostic over a wide range of follow-up periods. The impact of pharmacologically induced changes in non-HDL cholesterol on cardiovascular outcomes is less clear and requires further study.     

Management strategies of dyslipidemia in the elderly: 2005

During the past 3 years, the treatment of dyslipidemia has evolved significantly. The impact of recent trial data on management strategies in older patients is especially important, because the elderly segment of the US population continues to grow. Several clinical trials have been completed since the publication of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines were published in 2001. Recent trial data strongly support the use of lipid-lowering therapy in the elderly population. Although therapeutic lifestyle changes remain highly important, supplementation with lipid-lowering therapy has been shown to reduce the risk of cardiovascular events in both primary and secondary prevention models. Compelling data noted from recent clinical trials have prompted the NCEP to publish an updated report that addresses the significant interim developments.     

Treating dyslipidemia in the elderly

PURPOSE OF REVIEW: The treatment of dyslipidemia has been dynamic over the past several years. Of special importance is the impact of recent clinical trial data on management strategies of dyslipidemia in the elderly. People 65 years and older are living longer and are the fastest growing subset of the US population, necessitating more attention to chronic disease conditions that manifest in this age group. This review addresses guidelines of lipid management, discusses data that support their use, and examines the benefits of lipid-lowering therapy in the elderly with attention to the chronic conditions that are common in this population. RECENT FINDINGS: Clinical trials completed since the publication of the 2001 National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines support the use of lipid-lowering therapy in the elderly population. Lipid-lowering therapy has not only proven to be generally safe in the elderly, but has also proven effective in helping manage the chronic disease conditions that are common in this age group. SUMMARY: The elderly segment of our population continues to grow. Along with this growth in population is a growth in incidence of cardiovascular disease, the metabolic syndrome, chronic kidney disease, cerebrovascular disease, and diabetes mellitus. There is no known panacea for managing these chronic disease conditions; however, lipid-lowering therapy has been shown to prevent or delay the progression of these diseases and the mortality and morbidity that accompanies them.     

The role of high-density lipoprotein cholesterol in the prevention and possible treatment of cardiovascular diseases

Despite significant progress in the management of atherosclerosis and its resultant complications, cardiovascular disease remains the principal cause of death in the world. The National Cholesterol Education Project Adult Treatment Panel III (NCEP ATP III) recognizes low levels of high-density lipoprotein cholesterol (HDL) as a risk factor for coronary heart disease (CHD) and high levels of HDL as a risk-reducing factor; however, the elevation of HDL as a specific therapeutic target for the prevention and treatment of CHD has yet to be accepted on the same level as low-density lipoprotein (LDL)-reducing therapies. Current HDL elevators including nicotinic acid, fibric acid derivatives, peroxisome proliferator activated receptor (PPAR) agonists and statins also affect other lipid constituents which make interpretation of the clinical trials of these drugs difficult in teasing out the independent effect of HDL elevation. Ample laboratory investigation suggests that HDL elevation would reduce atherosclerotic burden through multiple independent mechanisms. In this review, we explore HDL biology, its potential mechanisms in the treatment of atherosclerotic disease, and promising new drugs with HDL-raising activity.     

Aggressive lipid management for cardiovascular prevention: evidence from clinical trials

Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases the risk of coronary heart disease (CHD). Moreover, large-scale intervention trials demonstrate that treatment with HMG-CoA reductase inhibitors (statins), the most effective drug class for lowering LDL-C, significantly reduces the risk of CHD events. Unfortunately, only a moderate percentage of hypercholesterolemic patients are achieving LDL-C targets specified by the National Cholesterol Education Program (NCEP), in part because clinicians are not effectively titrating medications as needed to achieve LDL-C goals. Recent evidence suggests that more aggressive LDL-C lowering may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. Furthermore, recent studies suggest that statins have cardioprotective effects in many high-risk individuals, including those with baseline LDL-C <100 mg/dl. High-density lipoprotein cholesterol (HDL-C) was recognized by the NCEP-Adult Treatment Panel II (ATP II) as a negative risk factor for CHD. The NCEP-ATP III guidelines have also reaffirmed the importance of HDL-C by increasing the low HDL-C designation from <35 to <40 mg/dl as a major risk factor for CHD. Similarly, triglyceride control will play a larger role in dyslipidemia management. As more clinicians effectively treat adverse lipid and lipoprotein cardiovascular risk factors, patients will likely benefit from reductions in cardiovascular events.     

The future direction of cholesterol-lowering therapy

PURPOSE OF REVIEW: Observational studies suggest a continuous positive relationship between vascular risk and cholesterol without any lower threshold level. We review recent and future clinical trials addressing the question of optimal treatment goals for cholesterol reduction and how these relate to present guidelines. With increasing focus on greater cholesterol reduction, new approaches to lipid-lowering therapy are being developed; we discuss some of these agents including the new statin, rosuvastatin and novel cholesterol transport inhibitors such as ezetimibe. RECENT FINDINGS: The Heart Protection Study demonstrated that LDL cholesterol reduction to levels as low as 1.7 mmol/l was associated with significant clinical benefit in a wide range of high-risk individuals, irrespective of baseline cholesterol levels, with no apparent threshold level for LDL cholesterol with respect to cardiovascular risk. The Heart Protection Study also demonstrated that the benefits of LDL cholesterol reduction extend into peripheral vascular disease and cerebrovascular disease prevention and suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL cholesterol targets of 2.6 mmol/l, may result in undertreatment of a large number of patients. Various large end-point trials, including Treating to New Targets and Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine will attempt to further address the issue of optimal LDL cholesterol reduction. New therapies are being developed to meet the challenge of more intensive cholesterol lowering. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL cholesterol of 40-69% over its dose range of 5-80 mg. Ezetimibe is a selective cholesterol absorption inhibitor, with a site of action at the intestinal epithelium. Optimum reductions in LDL cholesterol of up to 25 and 60% reduction in chylomicron cholesterol content are seen with a 10-mg dose. SUMMARY: Evidence is accumulating supporting the safety and benefits of aggressive cholesterol reduction, with no apparent threshold for LDL cholesterol. New therapies will aid in achieving lower cholesterol levels and the use of combination therapies targeting different aspects of cholesterol metabolism may produce additional benefits. Outcome studies are awaited to further address these issues.     

Connections between obesity and dyslipidaemia.

The importance of the obesity-lipid connection has suffered from the traditional reductionism view of science. Excess body weight has rarely been deemed an independent risk factor for coronary heart disease, directing physicians to target therapies towards the risk factors that excess body weight modifies (e.g. raising HDL, lowering blood pressure) instead of targeting the cause. The efforts of Adult Treatment Panel III to define and identify the metabolic syndrome as a secondary target may spur practitioners to revisit the need for weight management in patients with lipid disorders.     

Cost-Effectiveness of Coronary Artery Calcium Testing for Coronary Heart and Cardiovascular Disease Risk Prediction to Guide Statin Allocation: The Multi-Ethnic Study of Atherosclerosis (MESA)

Background

The Multi-Ethnic Study of Atherosclerosis (MESA) showed that the addition of coronary artery calcium (CAC) to traditional risk factors improves risk classification, particularly in intermediate risk asymptomatic patients with LDL cholesterol levels <160 mg/dL. However, the cost-effectiveness of incorporating CAC into treatment decision rules has yet to be clearly delineated.

Objective

To model the cost-effectiveness of CAC for cardiovascular risk stratification in asymptomatic, intermediate risk patients not taking a statin. Treatment based on CAC was compared to (1) treatment of all intermediate-risk patients, and (2) treatment on the basis of United States guidelines.

Methods

We developed a Markov model of first coronary heart disease (CHD) and cardiovascular disease (CVD) events. We modeled statin treatment in intermediate risk patients with CAC≥1 and CAC≥100, with different intensities of statins based on the CAC score. We compared these CAC-based treatment strategies to a “treat all” strategy and to treatment according to the Adult Treatment Panel III (ATP III) guidelines. Clinical and economic outcomes were modeled over both five- and ten-year time horizons. Outcomes consisted of CHD and CVD events and Quality-Adjusted Life Years (QALYs). Sensitivity analyses considered the effect of higher event rates, different CAC and statin costs, indirect costs, and re-scanning patients with incidentalomas.

Results

We project that it is both cost-saving and more effective to scan intermediate-risk patients for CAC and to treat those with CAC≥1, compared to treatment based on established risk-assessment guidelines. Treating patients with CAC≥100 is also preferred to existing guidelines when we account for statin side effects and the disutility of statin use.

Conclusion

Compared to the alternatives we assessed, CAC testing is both effective and cost saving as a risk-stratification tool, particularly if there are adverse effects of long-term statin use. CAC may enable providers to better tailor preventive therapy to patients'' risks of CVD.     

Strategies for Primary Prevention of Coronary Heart Disease Based on Risk Stratification by the ACC/AHA Lipid Guidelines,ATP III Guidelines,Coronary Calcium Scoring,and C-Reactive Protein,and a Global Treat-All Strategy: A Comparative--Effectiveness Modeling Study

Background

Several approaches have been proposed for risk-stratification and primary prevention of coronary heart disease (CHD), but their comparative and cost-effectiveness is unknown.

Methods

We constructed a state-transition microsimulation model to compare multiple approaches to the primary prevention of CHD in a simulated cohort of men aged 45–75 and women 55–75. Risk-stratification strategies included the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of blood cholesterol, the Adult Treatment Panel (ATP) III guidelines, and approaches based on coronary artery calcium (CAC) scoring and C-reactive protein (CRP). Additionally we assessed a treat-all strategy in which all individuals were prescribed either moderate-dose or high-dose statins and all males received low-dose aspirin. Outcome measures included CHD events, costs, medication-related side effects, radiation-attributable cancers, and quality-adjusted-life-years (QALYs) over a 30-year timeframe.

Results

Treat-all with high-dose statins dominated all other strategies for both men and women, gaining 15.7 million QALYs, preventing 7.3 million myocardial infarctions, and saving over $238 billion, compared to the status quo, far outweighing its associated adverse events including bleeding, hepatitis, myopathy, and new-onset diabetes. ACC/AHA guidelines were more cost-effective than ATP III guidelines for both men and women despite placing 8.7 million more people on statins. For women at low CHD risk, treat-all with high-dose statins was more likely to cause a statin-related adverse event than to prevent a CHD event.

Conclusions

Despite leading to a greater proportion of the population placed on statin therapy, the ACC/AHA guidelines are more cost-effective than ATP III. Even so, at generic prices, treating all men and women with statins and all men with low-dose aspirin appears to be more cost-effective than all risk-stratification approaches for the primary prevention of CHD. Especially for low-CHD risk women, decisions on the appropriate primary prevention strategy should be based on shared decision making between patients and healthcare providers.     

Hypertriglyceridemia and low HDL: therapeutic considerations

The recently revised guidelines for cholesterol management in Europe and the USA have focused attention on triglycerides and HDL cholesterol as risk factors for coronary heart disease. In the present review, I shall discuss therapeutic considerations in the treatment of patients with hypertriglyceridemia or low HDL cholesterol in the context of these new recommendations. I shall also consider recent studies in which the effect of triglyceride-lowering drugs on the concentrations and metabolism of lipoproteins in patients with dyslipidemia are evaluated.     

Colesevelam Hydrochloride-Ezetimibe Combination Lipid-Lowering Therapy in Patients with Diabetes or Metabolic Syndrome and a History of Statin Intolerance

ObjectiveTo determine the effectiveness and safety of colesevelam hydrochloride (HCl) and ezetimibe combination therapy in statin-intolerant patients with dyslipidemia and diabetes mellitus (DM) or metabolic syndrome (MS).MethodsWe identified potential study subjects through a computerized text search of patient electronic medical records using the terms colesevelam, WelChol, ezetimibe, and Zetia. Medical records were subsequently reviewed to identify all patients with DM or MS. Baseline total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triglyceride levels immediately before the initiation of therapy with colesevelam HCl (1.875 g twice a day) or ezetimibe (10 mg daily) were compared with those after a minimum of 3 months of single drug therapy and after a minimum of 3 months of combination therapy. Drug safety was evaluated by review of transaminase levels and reports of side effects or drug discontinuation.ResultsThe computerized search initially identified 91 electronic medical records; 16 patients fulfilled all study criteria. Baseline patient demographics included a mean age of 62.5 (± 11.8) years and a mean body mass index of 31.4 (± 5.2) kg/m²; 50% of patients were female, 75% had type 2 DM, and 25% had MS. In comparison with baseline, colesevelam HCl-ezetimibe combination therapy was associated with significant reductions in mean levels of total cholesterol (27.5%), LDL-C (42.2%), and non-HDL-C (37.1%). In addition, 50% of patients achieved the National Cholesterol Education Program Adult Treatment Panel III LDL-C target of less than 100 mg/dL. Therapy was well tolerated, with no significant changes in mean transaminase levels, no reports of myalgia, and no discontinuation of therapy.ConclusionColesevelam HCl-ezetimibe combination therapy was associated with improved TC, LDL-C, and non-HDL-C lipid profiles and was well tolerated. Such therapy may be a reasonable consideration for statin-intolerant patients with DM or MS who have elevated cholesterol levels. (Endocr Pract. 2007;13:11-16)     

Debate: "How low should LDL cholesterol be lowered?" Viewpoint: "It doesn't need to be very low"

The importance of low-density lipoprotein (LDL) control in the management of patients at high risk of cardiovascular events is unquestionable. The major statin trials have shown that the benefits of LDL lowering extend throughout the range of risk and the range of serum cholesterol, and have indicated that the protective effects of the intervention are mostly related to the baseline risk. Statin therapy is, for this reason, currently seen as an anti-atherogenic approach for the majority of high risk individuals and possibly all coronary heart disease patients. This debate is not about the value of statin therapy or the importance of LDL reduction, but about the goals to be set once we decide that LDL cholesterol must be reduced. With the National Cholesterol Education Program (NCEP) guidelines representing a solid middle ground, the two viewpoints in this debate try to argue, on one hand, that the LDL goals should be substantially lower than our current standards or, on the other, that a specific on-treatment LDL value may not be the most important goal to pursue. We defend the latter position by presenting the case that the most effective LDL intervention in high risk patients is to achieve a reduction of at least 30%. This strategy complies with the NCEP guidelines, as most of the high risk patients treated with an average dose of an average statin would experience a 30-40% LDL reduction that would put on-treatment LDL levels safely below goal. Our position differs from both the guidelines and the proponents of more aggressive LDL goals in the management of the two extremes of the cholesterol distribution, where our lack of interest in a predefined on-treatment LDL concentration would make us more aggressive than guidelines on low baseline LDL patients and less aggressive than guidelines on high baseline LDL patients.     

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 Profile and Management of Patients With Hypertension and Chronic Ischemic Heart Disease According to BMI

Obesity is associated with numerous risk factors and comorbidities such as hypertension, metabolic syndrome, type 2 diabetes, and cardiovascular diseases. However, numerous studies have reported an obesity paradox; the overweight and obese patients with established cardiovascular disease have better prognosis than those with a BMI <25 kg/m². This study was designed to assess potential differences in the clinical profile and management of hypertensive outpatients with chronic ischemic heart disease in obese and lean patients that could explain these two apparently contradictory points. Overweight and obesity were defined as a BMI 25–29.9 kg/m² and ≥30 kg/m², respectively. Cardiovascular risk factors goals were considered according to European Society of Hypertension‐European Society of Cardiology 2003, National Cholesterol Education Program Adult Treatment Panel III and American Diabetes Association 2005 guidelines. A sample of 2,024 patients (66.8 ± 10.1 years; 31.7% women) was included. Of these, 0.1% had a BMI <20 kg/m²; 17.1% BMI 20–24.9 kg/m²; 53.7% BMI 25–29.9 kg/m²; 23.7% BMI 30–34.9 kg/m²; 4.3% BMI 35–39.9 kg/m²; and 1.1% BMI ≥40 kg/m². The subgroup of patients with BMI ≥30 kg/m² had a higher proportion of women, diastolic dysfunction, diabetes, dyslipidemia, left ventricular hypertrophy, and heart failure. There was an inverse relationship between risk factors control rates and BMI (all comparisons BMI 20–24.9 kg/m² vs. 25–29.9 kg/m² vs. ≥30 kg/m²): blood pressure (BP) control (51.7% vs. 42.4% vs. 29.2%, P < 0.001); low‐density lipoprotein cholesterol (LDL‐C) control (35.2% vs. 30.5% vs. 27.9%, P = 0.03) and diabetes control (38.6% vs. 27.6% vs. 22.2%, P = 0.023). In conclusion, in patients with hypertension and chronic ischemic heart disease, as BMI increases, the clinical profile worsens as well as risk factors control rates.     

Continuously improving the practice of cardiology

Guidelines for the management of patients with cardiovascular disease are designed to assist cardiologists and other physicians in their practice. Surveys are conducted to assess whether guidelines are followed in practice. The results of surveys on acute coronary syndromes, coronary revascularisation, secondary prevention, valvular heart disease and heart failure are presented. Comparing surveys conducted between 1995 and 2002, a gradual improvement in use of secondary preventive therapy is observed. Nevertheless, important deviations from established guidelines are noted, with a significant variation among different hospitals in the Netherlands and in other European countries. Measures for further improvement of clinical practice include more rapid treatment of patients with evolving myocardial infarction, more frequent use of clopidogrel and glycoprotein IIb/IIIa receptor blockers in patients with acute coronary syndromes, more frequent use of β-blockers in patients with heart failure and more intense measures to encourage patients to stop smoking. Targets for the proportion of patients who might receive specific therapies are presented.     

Recent discoveries in inclusive food-based approaches and dietary patterns for reduction in risk for cardiovascular disease

PURPOSE OF REVIEW: To discuss new evidence-based dietary recommendations founded on an inclusive food strategy and to address the challenges that are posed by integrating a growing list of heart healthy foods into the diet without increasing energy intake beyond that required to achieve a healthy body weight. RECENT FINDINGS: New food-based dietary recommendations issued by the American Heart Association with the objective of reducing risk for cardiovascular disease (CVD) promote an inclusionary approach. The American Heart Association recommends a variety of foods to target four major goals: achieve a healthy overall diet, achieve a healthy weight, promote desirable lipid levels, and promote desirable blood pressure. Specific foods recommended include fruits and vegetables, grain products (including whole grains), fish, lean meat and poultry, fat-free or low-fat dairy products, and legumes. In addition, the new National Cholesterol Education Program Adult Treatment Panel III recommends reductions in saturated fat and cholesterol and therapeutic dietary options for enhancing LDL-cholesterol lowering, with inclusion of plant stanols/sterols (2 g/day) and increased viscous (soluble) fiber (10-25 g/day). In parallel with the evolution of new dietary recommendations is the expanding list of specific foods that have cardioprotective effects. Additional foods on this list are nuts, soy, legumes, alcohol, tea, and garlic. SUMMARY: It will be challenging to include all foods that reduce CVD risk in the diet and still maintain energy control. Strategies are needed that facilitate developing heart healthy dietary patterns that maximally reduce CVD risk.     

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.     

Cholesterol lowering and mortality: the importance of considering initial level of risk.

OBJECTIVE--To investigate the level of risk of death from coronary heart disease above which cholesterol lowering treatment produces net benefits. DESIGN--Meta-analysis of results of randomised controlled trials of cholesterol lowering treatments. METHODS--Published and unpublished data from all identified randomised controlled trials of cholesterol lowering treatments with six months or more follow up and with at least one death were included in the meta-analysis. The analyses were stratified by the rate of death from coronary heart disease in the control arms of the trials. MAIN OUTCOME MEASURES--Death from all causes, from coronary heart disease, and from causes other than coronary heart disease. RESULTS--In the pooled analysis, net benefit in terms of total mortality from cholesterol lowering was seen only for trials including patients at very high initial risk of coronary heart disease (odds ratio 0.74; 95% confidence interval 0.60 to 0.92). In a medium risk group no net effect was seen, and in the low risk group there were adverse treatment effects (1.22; 1.06 to 1.42). In a weighted regression analysis a significant (p < 0.001) trend of increasing benefit with increasing initial risk of coronary heart disease was shown. Raised mortality from causes other than coronary heart disease was seen in trials of drug treatment (1.21; 1.05 to 1.39) but not in the trials of non-drug treatments (1.02; 0.88 to 1.19). Cumulative meta-analysis showed that these results seem to have been stable as new trials appeared. CONCLUSION--Currently evaluated cholesterol lowering drugs seem to produce mortality benefits in only a small proportion of patients at very high risk of death from coronary heart disease. Population cholesterol screening could waste resources and even result in net harm in substantial groups of patients. Overall risk of coronary heart disease should be the main focus of clinical guidelines, and a cautious approach to the use of cholesterol lowering drugs should be advocated. Future trials should aim to clarify the level of risk above which treatment is of net benefit.