The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials.

AIMS: The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. METHODS AND RESULTS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98). CONCLUSION: In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not.

Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.

BACKGROUND: Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented. OBJECTIVES: The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk. METHODS: This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. RESULTS: Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB. CONCLUSIONS: The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.

Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis.

BACKGROUND: It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. METHODS AND RESULTS: We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.81-0.86 per 1 standard deviation increment), as were apoA-I levels (HR, 0.79; 95% CI, 0.72-0.82). This association was also observed among patients achieving on-statin low-density lipoprotein cholesterol levels <50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR, 0.98; 95% CI, 0.94-1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR, 0.93; 95% CI, 0.90-0.97). CONCLUSIONS: Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low low-density lipoprotein cholesterol. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.

Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.

CONTEXT: The associations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB) levels with the risk of cardiovascular events among patients treated with statin therapy have not been reliably documented. OBJECTIVE: To evaluate the relative strength of the associations of LDL-C, non-HDL-C, and apoB with cardiovascular risk among patients treated with statin therapy. DESIGN: Meta-analysis of individual patient data from randomized controlled statin trials in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. DATA SOURCES: Relevant trials were identified by a literature search updated through December 31, 2011. Investigators were contacted and individual patient data were requested and obtained for 62,154 patients enrolled in 8 trials published between 1994 and 2008. DATA EXTRACTION: Hazard ratios (HRs) and corresponding 95% CIs for risk of major cardiovascular events adjusted for established risk factors by 1-SD increase in LDL-C, non-HDL-C, and apoB. RESULTS: Among 38,153 patients allocated to statin therapy, 158 fatal myocardial infarctions, 1678 nonfatal myocardial infarctions, 615 fatal events from other coronary artery disease, 2806 hospitalizations for unstable angina, and 1029 fatal or nonfatal strokes occurred during follow-up. The adjusted HRs for major cardiovascular events per 1-SD increase were 1.13 (95% CI, 1.10-1.17) for LDL-C, 1.16 (95% CI, 1.12-1.19) for non-HDL-C, and 1.14 (95% CI, 1.11-1.18) for apoB. These HRs were significantly higher for non-HDL-C than LDL-C (P = .002) and apoB (P = .02). There was no significant difference between apoB and LDL-C (P = .21). CONCLUSION: Among statin-treated patients, on-treatment levels of LDL-C, non-HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non-HDL-C than for LDL-C and apoB.

Altering the pathophysiology of atherosclerosis: the multidimensional role of statins.

The role of low-density lipoprotein cholesterol (LDL-C) in the pathogenesis of atherosclerosis is well recognized. Recent research has documented the importance of inflammation in atherosclerosis formation and disease progression. Lowering LDL-C with HMG-CoA reductase inhibitors ("statins") has been shown to decrease atheroma burden and reduce cardiovascular adverse events in patients with acute coronary syndromes as well as in asymptomatic patients with recognized risk factors. In addition, recent primary prevention studies have shown that aggressively lowering LDL-C with statins-even in people with so-called "normal" LDL-C and few cardiovascular risk factors-can substantially reduce the rate of myocardial infarction, stroke, and other cardiovascular outcomes. The impact of treatment is particularly notable in patients with elevated levels of C-reactive protein, a recognized marker of vascular inflammation.

Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.

BACKGROUND: Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes. METHODS: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I(2) statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis. FINDINGS: We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% CI 1.02-1.17), with little heterogeneity (I(2)=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150-852) patients with statins for 4 years resulted in one extra case of diabetes. INTERPRETATION: Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. FUNDING: None.

Overweight and obesity: the pathogenesis of cardiometabolic risk.

Obesity, particularly abdominal adiposity, is increasingly recognized as a cause of elevated cardiometabolic risk--the risk of developing type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). The predominate mechanisms appear to involve the promotion of insulin resistance, driven largely by excess free fatty acids secreted by an expanded adipose tissue mass, and the development of an inflammatory milieu due to increased secretion of inflammatory cytokines and adipokines from adipose tissue. Key proinflammatory cytokines secreted by adipocytes include tumor necrosis factor-alpha, interleukin-6, leptin, resistin, and plasminogen activator inhibitor-1. All have been variously associated with hyperinsulemia, hyperglycemia, insulin resistance, diabetes, and endothelial dysfunction, as well as plaque development, progression, and rupture. Adiponectin, another important adipocyte, has protective cardiometabolic actions; however, adiponectin levels decline with increasing obesity. Understanding the role of obesity in the pathogenesis of cardiometabolic risk is crucial for the development of treatment strategies that will provide maximum benefit for patients with, or at risk for, type 2 DM and CVD.

Effects of increasing high-density lipoprotein cholesterol and decreasing low-density lipoprotein cholesterol on the incidence of first acute coronary events (from the Air Force/Texas Coronary Atherosclerosis Prevention Study).

Reducing low-density lipoprotein (LDL) cholesterol with statins reduces cardiovascular risk, but the associations between increases in high-density lipoprotein (HDL) cholesterol and cardiovascular risk at different LDL levels have been less well characterized. To evaluate the associations between the 1-year changes in HDL cholesterol and LDL cholesterol with lovastatin and subsequent acute major coronary events (AMCEs), we studied 2,928 patients in the lovastatin arm who were followed for 5.2 years in a post-hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). The percentage of HDL cholesterol increase and apolipoproteins at year 1 and the incidence of AMCEs thereafter were assessed stratified by the LDL cholesterol levels. With lovastatin, LDL cholesterol was reduced by 25% on average to 115 mg/dl at year 1, and HDL cholesterol increased 6.0%. Patients with both an increase in HDL cholesterol of > or =7.5% and LDL cholesterol of <115 mg/dl at year 1 had the lowest event rate (3.53/1,000 person-years; p = 0.028). Similar results were found for an increase in HDL cholesterol of > or =7.5% and a decrease in LDL cholesterol of >25%, as well as for apolipoproteins A-I and B. The 1-year percent increase in HDL cholesterol appeared to be associated with a reduction in AMCEs in subsequent follow-up (p = 0.07 with the percentage of HDL cholesterol increase analyzed continuously). Patients with an HDL cholesterol increase of > or =7.5% had an AMCE rate of 5.18 compared with 7.66/1,000 person-years in patients with a lower HDL cholesterol increase (p = 0.08). In conclusion, lovastatin therapy was associated with a greater risk reduction of AMCEs when LDL cholesterol was substantially reduced and the HDL cholesterol increased by > or =7.5%.

Clinical practice characteristics of osteopathic and allopathic primary care physicians at academic health centers: results from the National Ambulatory Medical Care Survey.

PURPOSE: To explore characteristics of patient visits to osteopathic physicians (DOs) and allopathic physicians (MDs) in the provision of ambulatory primary care services at academic health centers (AHCs) relative to non-AHC sites. METHOD: Physicians report patient visits to the National Ambulatory Medical Care Survey (NAMCS). The authors used NAMCS data (2002-2006) to statistically estimate, characterize, and compare patient visits of four physician provider type- and AHC site-specific subgroups: DOs and MDs at non-AHC sites, and DOs and MDs at AHC sites. RESULTS: The 134,369 patient visits reported in the NAMCS database represented 4.57 billion physician office visits after the authors applied patient weights. These visits included 2.03 billion primary care patient visits (205.1 million DO visits and 1.77 billion MD visits at non-AHC sites; 5.8 million DO visits and 52.3 million MD visits at AHC sites). Practicing at an AHC site appeared to change the dynamic of the patient visit to an osteopathic physician. Most notably, these changes involved patient demographics (sex), patient visit context (practice metropolitan statistical area status, patient symptom chronicity, and injury as reason for the visit), and medical management (diagnostic testing, frequency and intensity of ordering drugs, and use of osteopathic manipulative treatment). CONCLUSIONS: Evidence suggests that osteopathic physicians in community, non-AHC settings offer a more distinctive osteopathic approach to primary care than osteopathic physicians at AHC sites, which both indicates a need for further research to explain this phenomenon and has potentially important implications for osteopathic medical education.

Research funding at colleges of osteopathic medicine: 15 years of growth.

CONTEXT: Colleges of osteopathic medicine (COMs) trying to stimulate research and develop research infrastructures must overcome the challenge of obtaining adequate funding to support growing research interests. The authors examine changes in research funding at COMs during the past 15 years. OBJECTIVES: To track 1999-2004 data on COM research funding, COM faculty size, educational backgrounds of principal investigators receiving funding, and funding institutions. To compare these data with published results from 1989 to 1999. METHODS: Data on number of grants, funding amounts by extramural source, percent of total dollars by extramural source, percent of total dollars by COM, and total amount of extramural funding were obtained from the American Association of Colleges of Osteopathic Medicine databases. Data on the Osteopathic Research Center (ORC) were obtained from the ORC's databases. RESULTS: Research, both in terms of number of grants and funding amounts within the osteopathic medical profession, increased substantially from 1999 to 2004. The largest single source of funding remained the National Institutes of Health. The number of COMs whose research funding exceeded $1 million annually more than doubled, increasing from 5 in 1999 to 12 in 2004. The osteopathic medical profession's decision to direct research dollars into a national research center devoted to research specific to osteopathic manipulative medicine resulted in an almost eightfold return on initial investment in 4 years. CONCLUSIONS: The amount of research productivity at a COM may be aligned with the size of the COM's full-time faculty, suggesting that once "critical mass" for teaching, service, and administration are achieved, a productive research program can be realized. Expanding the evidence base for those aspects of medicine unique to the osteopathic medical profession is dependent on the future growth of research.

Comparison of the efficacy and safety of rosuvastatin 10 mg and atorvastatin 20 mg in high-risk patients with hypercholesterolemia--Prospective study to evaluate the Use of Low doses of the Statins Atorvastatin and Rosuvastatin (PULSAR).

BACKGROUND: Many patients at high risk of cardiovascular disease do not achieve recommended low-density lipoprotein cholesterol (LDL-C) goals. This study compared the efficacy and safety of low doses of rosuvastatin (10 mg) and atorvastatin (20 mg) in high-risk patients with hypercholesterolemia. METHODS: A total of 996 patients with hypercholesterolemia (LDL-C > or = 3.4 and < 5.7 mmol/L [130 and 220 mg/dL]) and coronary heart disease (CHD), atherosclerosis, or a CHD-risk equivalent were randomized to once-daily rosuvastatin 10 mg or atorvastatin 20 mg. The primary endpoint was the percentage change from baseline in LDL-C levels at 6 weeks. Secondary endpoints included LDL-C goal achievement (National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] goal < 100 mg/dL; 2003 European goal < 2.5 mmol/L for patients with atherosclerotic disease, type 2 diabetes, or at high risk of cardiovascular events, as assessed by a Systematic COronary Risk Evaluation (SCORE) risk > or = 5% or 3.0 mmol/L for all other patients), changes in other lipids and lipoproteins, cost-effectiveness, and safety. RESULTS: Rosuvastatin 10 mg reduced LDL-C levels significantly more than atorvastatin 20 mg at week 6 (44.6% vs. 42.7%, p < 0.05). Significantly more patients achieved NCEP ATP III and 2003 European LDL-C goals with rosuvastatin 10 mg compared with atorvastatin 20 mg (68.8% vs. 62.5%, p < 0.05; 68.0% vs. 63.3%, p < 0.05, respectively). High-density lipoprotein cholesterol was increased significantly with rosuvastatin 10 mg versus atorvastatin 20 mg (6.4% vs. 3.1%, p < 0.001). Lipid ratios and levels of apolipoprotein A-I also improved more with rosuvastatin 10 mg than with atorvastatin 20 mg. The use of rosuvastatin 10 mg was also cost-effective compared with atorvastatin 20 mg in both a US and a UK setting. Both treatments were well tolerated, with a similar incidence of adverse events (rosuvastatin 10 mg, 27.5%; atorvastatin 20 mg, 26.1%). No cases of rhabdomyolysis, liver, or renal insufficiency were recorded. CONCLUSION: In high-risk patients with hypercholesterolemia, rosuvastatin 10 mg was more efficacious than atorvastatin 20 mg at reducing LDL-C, enabling LDL-C goal achievement and improving other lipid parameters. Both treatments were well tolerated.

Hemodynamic effects of osteopathic manipulative treatment immediately after coronary artery bypass graft surgery.

CONTEXT: Coronary artery bypass graft (CABG) surgery is a common procedure for patients with coronary artery disease. The physiologic effects of postoperative osteopathic manipulative treatment (OMT) following CABG have not been documented previously. OBJECTIVE: To determine the effects of OMT on cardiac hemodynamics post-CABG surgery. DESIGN: Pilot prospective clinical study (N=29). SETTING AND PATIENTS: Treatment subjects (n=10) undergoing CABG surgery were recruited for postoperative OMT. The primary assessment compared, pre-OMT versus post-OMT, measurements of thoracic impedance, mixed venous oxygen saturation (SvO2), and cardiac index. Records of control subjects (n=19) who underwent CABG surgery--but who did not receive OMT--were assessed for SvO2 and cardiac index at 1 hour and 2 hours postsurgery. INTERVENTION: Immediately following CABG surgery (< or = 2 h), OMT was provided to subjects to alleviate anatomic dysfunction of the rib cage caused by median sternotomy and to improve respiratory function. This adjunctive treatment occurred while subjects were completely anesthetized. RESULTS: A post-OMT increase in thoracic impedance (P < or = .02) in OMT subjects demonstrated that central blood volume was reduced after OMT, suggesting an improved peripheral circulation. Mixed venous oxygen saturation also increased (P < or = .005) after OMT. These increases were accompanied by an improvement in cardiac index (P < or = .01). Comparisons of postoperative measurements in OMT subjects versus those in control subjects revealed statistically significant differences for SvO2 (P < or = .005) and cardiac index (P < or = .02) between the two groups. CONCLUSION: The observed changes in cardiac function and perfusion indicated that OMT had a beneficial effect on the recovery of patients after CABG surgery. The authors conclude that OMT has immediate, beneficial hemodynamic effects after CABG surgery when administered while the patient is sedated and pharmacologically paralyzed.

C-reactive protein: a new risk assessment tool for cardiovascular disease.

Recent research has focused on the use of high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, in the detection of patients at increased risk for cardiovascular disease. Several prospective studies have demonstrated that hs-CRP is an independent predictor of future risk for cardiovascular events among healthy individuals, as well as among patients with acute coronary syndromes. In addition, because half of all cardiovascular events occur in persons with low to average levels of low-density lipoprotein cholesterol, hs-CRP may aid in identifying patients at high risk for a first cardiovascular event who might otherwise be missed by lipid screening alone. Thus, hs-CRP is a potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. The Centers for Disease Control and Prevention and the American Heart Association have therefore proposed joint guidelines for the use of hs-CRP in determining cardiovascular disease risk. The author reviews numerous studies examining the prognostic value of hs-CRP and outlines ongoing efforts to assess the effect of statin therapy in healthy individuals with low levels of low-density lipoprotein cholesterol and high levels of hs-CRP.

Weight of the evidence in statin clinical trials: comparing the results.

This review of lipid-lowering trials looks at both the primary and secondary prevention of coronary heart disease. It also introduces evidence pointing toward the emerging importance of nonlipid risk factors in the pathogenesis of atherosclerosis. This review is designed to enhance the primary care physician's working knowledge of the evidence supporting the importance of LDL-C reduction and the central role of statin therapy in the reduction of the risk of coronary heart disease, as well as provide a greater understanding of emerging risk factors.

The national cholesterol education program adult treatment panel ill guidelines.

Coronary heart disease (CHD) remains the leading cause of death in the United States with more than 40% of all deaths each year directly attributed to the disease. Current evidence suggests that early identification and aggressive modification of risk factors offer the most promising approach to reducing the burden of CHD. Dyslipidemia has been identified as the primary risk factor leading to the development of CHD. It is estimated that nearly 65 million Americans require some form of lipid-modification therapy. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) set of guidelines released in May 2001 provides physicians with evidence-based recommendations on the classification, diagnosis, and treatment of lipid disorders. New features of the guidelines include a scoring system for calculating CHD risk, as well as the identification of CHD risk equivalents, lower treatment target goals, and an emphasis on conditions conferring a higher risk for CHD, such as the metabolic syndrome. The ATP III emphasis on risk assessment substantially increases the number of patients considered at risk for CHD and will expand the number eligible for lifestyle and drug interventions. This article highlights the new recommendations and reviews the impact of ATP III on osteopathic physicians.

Underidentification and undertreatment of dyslipidemia.

Despite increased attention placed on the identification and treatment of dyslipidemia, this condition remains undiagnosed and untreated in a significant number of patients. The recently released National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) set of cholesterol management guidelines increases to more than 65 million the number of Americans eligible for lipid-modifying therapy. Recent data, however, suggest that even with the availability of multiple regimens with proven efficacy, as many as 50% of all patients do not have their cholesterol assessed and less than 45% receive lipid-modifying therapy. In addition, less than 25% of patients are treated to their NCEP target low-density lipoprotein cholesterol (LDL-C) level. Persistence with therapy is another challenge, as more than 70% of patients fail to maintain their therapy beyond 12 months. If a realistic attempt is to be made to reduce the risk of coronary heart disease (CHD) among Americans, diagnosis of dyslipidemia and treatment to therapeutic targets must be improved. This artide discusses the underdiagnosis and undertreatment of lipid disorders and reviews the role of osteopathic physicians in strategies achieving ATP III LDL-C goals.

A novel therapeutic approach to dyslipidemia.

The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines call for more aggressive lowering of low-density lipoprotein cholesterol (LDL-C) and will substantially increase the number of patients eligible for lipid-lowering therapy. Statins, the current treatment standard, have proven to be highly efficacious in lowering LDL-C and reducing coronary heart disease (CHD) risk. Because some patients are unable to tolerate 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) or they are not candidates for statin therapy, however, other cholesterol-lowering modes of therapy are needed. Currently available nonstatin drugs often do not reliably reduce LDL-C to a desired extent or are limited in their safety and tolerability. Ezetimibe, a novel lipid-lowering agent until recently in phase III development, is the first in a new class of selective cholesterol absorption inhibitors and offers a promising new approach to the treatment of dyslipidemia. This article reviews the cholesterol metabolic pathways and the mechanism of action of the currently available lipid-modifying agents and introduces ezetimibe, the first selective cholesterol absorption inhibitor.

Lability of serum low-density lipoprotein cholesterol levels during screening in subgroup of Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) cohort.

In the enrollment phase of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a number of heart disease-free potential subjects did not qualify to participate in the study because their low-density lipoprotein cholesterol (LDL-C) levels fluctuated. This report looks at the incidence of lability of LDL-C levels and premature coronary heart disease (CHD) in the nuclear family based on data collected on a group excluded primarily based on lipid levels during the enrollment phase at the TexCAPS site. Lipid inclusion criteria were total cholesterol (TC), 180 mg/dL to 264 mg/dL; low-density lipoprotein cholesterol (LDL-C), 130 mg/dL to 190 mg/dL; high-density lipoprotein cholesterol (HDL-C), less than or equal to 45 mg/dL for men and less than or equal to 47 mg/dL for women; and triglyceride (TG) concentrations, less than or equal to 400 mg/dL. After participants had been on the American Heart Association (AHA) step 1 diet for 8 to 10 weeks, lipid parameters were again tested in a total of 4257 individuals. Both lipid screening measurements at 8 and 10 weeks were required to be within 15% of each other for inclusion in subsequent study. A total of 2868 individuals met the study criteria and were randomly assigned to groups; 1389 failed to qualify for a variety of reasons. Of these, 1070 (25.1% of those who initially qualified based on lipid levels) were excluded because of unacceptable lipid levels on the evaluations repeated at 8 and 10 weeks. This excluded subpopulation (n = 1070) was stratified into three groups based on changes of LDL-C between 8 and 10 weeks on the AHA step 1 diet. One group had a less than 15% fluctuation in LDL-C (LN group, n = 637, 15.0% of cohort, n = 4257). Of those with LDL-C variability, 177 had a greater than 15% increase in LDL-C (LI group, n = 177, 4.2% of cohort); and 256 had a greater than 15% decrease in LDL-C (LD, n = 256, 6.0% of cohort). At week 8, TC and LDL-C levels were lower and the HDL-C level was higher in the LN group compared with both groups having labile lipid levels (LI and LD groups). Changes by gender showed similar trends; however, HDL-C was 5 mg/dL lower at 8 weeks in both groups of women with labile LDL-C levels (groups LI and LD) when compared with the women in the LN group (P < .01). The frequency of TG concentrations greater than 150 mg/dL was greater in men having labile LDL-C level when compared with the control group. The trend was similar for women. In assessing the incidence of CHD in the nuclear family, parents of probands with labile LDL-C levels (LI and LD groups) had a higher frequency (P = .0044) of premature CHD than parents of probands with stable LDL-C (LN). The following conclusions can be drawn: (1) within the general population, there is a substantial number (10%, 433 of 4257) of individuals with labile LDL-C levels; (2) labile LDL-C levels in the probands were found to be associated with an increased familial frequency of premature CHD in their parents. Definition of the molecular basis for this lability of LDL-C could reveal new opportunities to regulate plasma cholesterol levels and thus have an impact on CHD-associated morbidity and mortality in a substantial portion of the general population.

Adult Treatment Panel III: do we really need another set of cholesterol guidelines?

Reducing high levels of plasma low-density lipoprotein cholesterol (LDL-C) is still the primary focus of the Adult Treatment Panel III (ATP III) guidelines developed by the National Cholesterol Education Program. The LDL-C goal of less than 100 mg/dL for those with coronary heart disease (CHD) is now extended to patients with diabetes and those with a Framingham risk score of greater than 20% in 10 years, both of which are now considered "CHD risk equivalents." Consequently, many more people will be considered candidates for aggressive lipid-lowering therapy under the new ATP III guidelines. Other prominent features in the new guidelines include determining an individual's absolute risk category by using a nine-step process, instituting therapeutic lifestyle changes to reduce LDL-C levels, and strategies for treating patients with other forms of dyslipidemia such as metabolic syndrome.