Benoit J. Arsenault

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.

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.

Predictors of New-Onset Diabetes in Patients Treated With Atorvastatin Results From 3 Large Randomized Clinical Trials

OBJECTIVES We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin. BACKGROUND Statin therapy might modestly increase the risk of new-onset T2DM. METHODS We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM. RESULTS In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69). CONCLUSIONS High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.

Beyond low-density lipoprotein cholesterol: respective contributions of non-high-density lipoprotein cholesterol levels, triglycerides, and the total cholesterol/high-density lipoprotein cholesterol ratio to coronary heart disease risk in apparently healthy men and women.

OBJECTIVES This study was designed to test the hypothesis that at any low-density lipoprotein cholesterol (LDL-C) level, other lipid parameters such as non-high-density lipoprotein cholesterol (HDL-C) levels, triglyceride (TG) levels, and the total cholesterol (TC)/HDL-C are still associated with an increased coronary heart disease (CHD) risk. BACKGROUND Although LDL-C is considered to be the primary target of lipid-lowering therapy, other parameters of the lipoprotein-lipid profile may more closely associated with CHD risk. METHODS In the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk prospective population study, 21,448 participants without diabetes or CHD between age 45 and 79 years were followed for 11.0 years. A total of 2,086 participants developed CHD during follow-up. RESULTS Among individuals with low LDL-C levels (<100 mg/dl), after adjustment for age, sex, smoking, systolic blood pressure, waist circumference, physical activity, and hormone replacement therapy (in women), those with non-HDL-C >130 mg/dl had a hazard ratio (HR) for future CHD of 1.84 (95% confidence interval [CI]: 1.12 to 3.04) when compared with those with non-HDL-C levels <130 mg/dl. In a similar model, individuals with TG levels >150 mg/dl had an HR of 1.63 (95% CI: 1.02 to 2.59) when compared with those with TG levels <150 mg/dl, and individuals with a TC/HDL-C ratio >5 had an HR of 2.19 (95% CI: 1.22 to 3.93) when compared with those with a TC/HDL-C ratio <5. CONCLUSIONS In this prospective study, independently of their plasma LDL-C levels, participants with high non-HDL-C levels, high TG levels, or with an elevated TC/HDL-C ratio were at increased CHD risk. CHD risk assessment algorithms as well as lipid targets of lipid-lowering trials may also need to consider other easily available parameters such as non-HDL-C.

Clinical ResearchLipid-Lowering and DiabetesPredictors of New-Onset Diabetes in Patients Treated With Atorvastatin: Results From 3 Large Randomized Clinical Trials

OBJECTIVES We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin. BACKGROUND Statin therapy might modestly increase the risk of new-onset T2DM. METHODS We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM. RESULTS In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69). CONCLUSIONS High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.

High-Density Lipoprotein Particle Size and Concentration and Coronary Risk

Context High-density lipoprotein (HDL) particles are heterogeneous in size and composition. Contribution This nested casecontrol study found that both HDL size and HDL particle concentration were associated with risk for coronary artery disease (CAD). High-density lipoprotein size was strongly associated with risk factors characteristic of the metabolic syndrome, such as triglyceride and apolipoprotein B levels. Adjustment for those factors explained the association between HDL size and CAD risk, but not the association between HDL particle concentration and CAD risk. Implication High-density lipoprotein size and HDL particle concentration are differentially associated with cardiovascular risk factors and CAD risk. The association between HDL size and CAD risk may be explained by metabolic parameters. The Editors The strong inverse relationship between high-density lipoprotein (HDL) (see Glossary) cholesterol levels and risk for coronary artery disease (CAD) is well established (1). However, at any given level of HDL cholesterol (see Glossary), HDL particle concentration (see Glossary) and HDL size (see Glossary) distribution may differ substantially between individuals. The atheroprotective role of HDL cholesterol is believed to be mediated mainly by its role in reverse cholesterol transport, the biological pathway that facilitates removal of cholesterol from macrophages in the arterial wall back to the liver (2). Substantial evidence suggests that HDL particles are heterogeneous in their efficacy to facilitate adenosine triphosphatebinding cassette A1 (see Glossary)mediated cholesterol efflux from macrophages and scavenger receptor class B1 (see Glossary)mediated hepatic uptake of cholesterol from HDL particles. In particular, this heterogeneity has been associated with HDL particle size (35). Accumulating evidence suggests that, in addition to their role in reverse cholesterol transport, HDL particles have anticoagulant, antioxidative, and anti-inflammatory properties that contribute to the antiatherogenic capacity of HDL cholesterol. In fact, HDL particles were recently shown to carry a wide array of proteins that mediate these properties (6). The binding affinity of these proteins to the surface of HDL particles may depend on their size (7, 8). Under certain conditions, HDL particles may lose their antiatherogenic capacity and become dysfunctional (9, 10). As a consequence, various HDL subpopulations may differ substantially in their capacity to play an atheroprotective role. Despite this functional heterogeneity, HDL has thus far been regarded as a single entity in epidemiologic studies, and the amount of cholesterol transported by HDL particles is traditionally being used for this purpose. However, we have recently shown that higher HDL cholesterol levels may not necessarily be associated with lower cardiovascular risk (11), and the HDL cholesterol levelincreasing drug torcetrapib has been shown to have detrimental effects (12). These findings emphasize that a broader perspective on HDL metabolism is warranted. We hypothesized that HDL particle concentration and HDL size distribution are differentially associated with cardiovascular risk factors and with cardiovascular risk. We tested these hypotheses in a casecontrol study nested in the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk cohort. Methods We performed a nested casecontrol study among participants of the EPIC-Norfolk study, a prospective population-based study of 25663 men and women age 45 to 79 years living in Norfolk, United Kingdom, who completed a baseline questionnaire survey and attended a clinic visit (Figure). Participants were recruited from agesex registers of general practices in Norfolk as part of the 10-country collaborative EPIC study, which was designed to investigate dietary and other determinants of cancer. Additional data were obtained in EPIC-Norfolk to enable the assessment of determinants of other diseases. Figure. Study flow diagram. ApoAI = apolipoprotein A-I; ApoB = apolipoprotein B; CRP = C-reactive protein; EPIC = European Prospective Investigation into Cancer and Nutrition; HDL = high-density lipoprotein; LDL = low-density lipoprotein; NMR = nuclear magnetic resonance. *Individual case patients and control participants may have several missing variables. The design and methods of the study have been described in detail (13). Eligible participants were recruited by mail. At the baseline survey between 1993 and 1997, participants completed a detailed health and lifestyle questionnaire. Nonfasting blood samples were obtained by venipuncture into plain and citrate bottles. Blood samples were processed for assay at the Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom, or were stored at 80C. All individuals have been monitored for death certification at the United Kingdom Office of National Statistics, with vital status ascertained for the entire cohort. In addition, hospitalized participants were identified by their unique National Health Service number and data linkage with the East Norfolk Health Authority database, which identifies all hospital contacts throughout England and Wales for Norfolk residents. Coronary artery disease was defined as codes 410 to 414 according to the International Classification of Diseases, Ninth Revision. Participants were identified as having CAD during follow-up if they had had a hospital admission or had died with CAD as the underlying cause. Previous validation studies in our cohort indicate high specificity of such case ascertainment (14). We report results with follow-up to November 2003, an average of about 6 years. The study was approved by the Norwich District Health Authority Ethics Committee, and all participants gave signed, informed consent. Participants We have previously described other analyses within this prospective, nested casecontrol study (14, 15). We excluded all individuals who reported a history of heart attack or stroke or use of lipid-lowering drugs at the baseline clinic visit. Case patients were individuals who developed fatal or nonfatal CAD during follow-up until November 2003. Control participants were study participants who remained free of cardiovascular disease during follow-up. We matched 2 control participants to each case patient by age (within 5 years), sex, and time of enrollment (within 3 months). We performed the current analysis on all participants who had a complete data set available for baseline characteristics, apolipoproteins A-I and B, gradient gel electrophoresis (GGE)measured HDL size, and lipoprotein nuclear magnetic resonance (NMR) spectroscopy. We selected 1138 persons who were apparently healthy at baseline but did develop CAD during follow-up. For every case patient, we aimed to select 2 control participants who were healthy at baseline and remained free of cardiovascular disease during follow-up. From the original data set of 1138 case patients and 2237 control participants, 270 case patients and 430 control participants were excluded because at least 1 value was missing for any of the parameters mentioned. We excluded 46 case patients because they had no matching control participants and 406 control participants because they had no matching case patients. The analyses are therefore based on a data set of 822 case patients and 1401 control participants (243 case patients were matched with 1 control participant each, and 579 case patients were matched with 2 control participants each). Measurements We obtained data on smoking and alcohol consumption by health questionnaires at the baseline clinic visit. We obtained information on physical activity with a physical activity questionnaire (13). In the original cohort, we classified smoking into current cigarette smokers, former smokers, and those who never smoked. In the present study, we recorded smoking as yes or no. We divided physical activity into 4 categories: inactive, moderately inactive, moderately active, and active. We defined use of large amounts of alcohol as more than 21 units of alcohol per week. Diabetes mellitus and use of hormone replacement therapy was self-reported. We asked participants about medical history with the question, Has a doctor ever told you that you have any of the following?, followed by a number of choices, including diabetes. We recorded blood pressure by taking 2 measurements of diastolic and systolic blood pressure by using the Accutorr sphygmomanometer (Datascope, Huntingdon, United Kingdom) after 3 minutes of resting. We measured serum levels of total cholesterol, HDL cholesterol, and triglycerides on fresh samples with the RA 1000 (Bayer Diagnostics, Basingstoke, United Kingdom). We calculated low-density lipoprotein (LDL) cholesterol levels with the Friedewald formula to closely approach current clinical procedures. We measured plasma concentrations of C-reactive protein with a sandwich-type enzyme-linked immunosorbent assay as previously described (16). We measured serum levels of apolipoprotein A-I and apolipoprotein B by using rate immunonephelometry (Behring Nephelometer BNII, Dade Behring, Marburg, Germany) with calibration traceable to the International Federation of Clinical Chemistry primary standards (17). We measured serum concentration of myeloperoxidase (see Glossary) by using a commercially available enzyme-linked immunosorbent assay (CardioMPO Test, Prognostix, Cleveland, Ohio) (15). We measured paraoxonase 1 (see Glossary) activity as previously described (18). We measured HDL size by 4% to 30% nondenaturing polyacrylamide GGE as previously described (19). We measured lipoprotein subclass particle concentrations and average size of particles by proton NMR spectroscopy (LipoScience, Raleigh, North Carolina) as previously described (20). In brief, we obtained particle concentrations of lipoprotein subclasses of different size directly from the measured amplitudes of t

Lipid parameters for measuring risk of cardiovascular disease

Besides measuring blood pressure and glucose levels, assessing the lipid spectrum is the method most commonly used to identify individuals at high risk of cardiovascular disease (CVD), as well as those who are likely to benefit most from lipid-lowering therapy. Although lowering LDL-cholesterol levels is the primary target of therapy in most clinical guidelines, accumulating evidence indicates that other lipoprotein–lipid measurements could provide a predictive value over and above that of LDL-cholesterol levels. For example, individuals treated with statins who achieve low LDL-cholesterol levels, but have high concentrations of either non-HDL cholesterol or apolipoprotein (apo) B, remain at increased cardiovascular risk. Similarly, individuals with low levels of either HDL cholesterol or apo A-I are also likely to experience cardiovascular events, despite having normal LDL-cholesterol levels. The residual cardiovascular risk, beyond that characterized by LDL-cholesterol levels alone, is exacerbated by physical inactivity and abdominal obesity, which are both increasingly prevalent risk factors for CVD. In this Review, we discuss the measurement of various lipoprotein–lipid parameters for the prediction of CVD risk, and their importance in identifying those patients who are likely to benefit from lipid-lowering therapy. The impact of recent studies on clinical guidelines is also considered.

The hypertriglyceridemic-waist phenotype and the risk of coronary artery disease: results from the EPIC-Norfolk Prospective Population Study

Background: Screening for increased waist circumference and hypertriglyceridemia (the hypertriglyceridemic-waist phenotype) has been proposed as an inexpensive approach to identify patients with excess intra-abdominal adiposity and associated metabolic abnormalities. We examined the relationship between the hypertriglyceridemic-waist phenotype to the risk of coronary artery disease in apparently healthy individuals. Methods: A total of 21 787 participants aged 45–79 years were followed for a mean of 9.8 (standard deviation 1.7) years. Coronary artery disease developed in 2109 of them during follow-up. The hypertriglyceridemic-waist phenotype was defined as a waist circumference of 90 cm or more and a triglyceride level of 2.0 mmol/L or more in men, and a waist circumference of 85 cm or more and a triglyceride level of 1.5 mmol/L or more in women. Results: Compared with participants who had a waist circumference and triglyceride level below the threshold, those with the hypertriglyceridemic-waist phenotype had higher blood pressure indices, higher levels of apolipoprotein B and C-reactive protein, lower levels of high-density lipoprotein cholesterol and apolipoprotein A-I, and smaller low-density lipoprotein particles. Among men, those with the hypertriglyceridemic-waist phenotype had an unadjusted hazard ratio for future coronary artery disease of 2.40 (95% confidence interval [CI] 2.02–2.87) compared with men who did not have the phenotype. Women with the phenotype had an unadjusted hazard ratio of 3.84 (95% CI 3.20–4.62) compared with women who did not have the phenotype. Interpretation: Among participants from a European cohort representative of a contemporary Western population, the hypertriglyceridemic-waist phenotype was associated with a deteriorated cardiometabolic risk profile and an increased risk for coronary artery disease.

Association Between Plasma LDL Particle Size, Valvular Accumulation of Oxidized LDL, and Inflammation in Patients With Aortic Stenosis

Objective—In patients with severe aortic stenosis (AS), we examine the association between: (1) the content of oxidized LDL (oxLDL) in the aortic valve and the degree of inflammation and remodeling; (2) The proportion of small dense LDL particles in the plasma and the presence of oxLDL in the valve along with hemodynamic progression of valve stenosis. Methods and Results—We have examined 102 explanted AS valves. Tissue remodeling, inflammation, and accumulation of oxLDL were determined. A complete plasma lipid profile including the measurement of the relative proportion of small low-density lipoprotein (%LDL<255Å) was obtained. Valves with higher oxLDL content had a significantly higher density of inflammatory cells, expression of tumor necrosis factor (TNF)-&agr;, and increased tissue remodeling score. The %LDL<255Å was significantly associated with oxLDL score within the aortic valve. In a subset of 59 patients in whom stenosis progression was measured, the %LDL<255Å correlated with the annualized peak gradient (r=0.29; P=0.04). Conclusion—Increased proportion of circulating small dense LDL particles is associated with faster progression rate of stenosis and greater accumulation of oxLDL in the aortic valve. These findings suggest that therapeutic interventions aimed at lowering the production of small dense LDL particles in patients with AS might represent a potentially interesting therapeutic avenue.

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.