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

ABSTRACT: 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.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.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.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.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.

SUBMITTER: Boekholdt SM

PROVIDER: S-EPMC4443441 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Boekholdt S Matthijs SM Hovingh G Kees GK Mora Samia S Arsenault Benoit J BJ Amarenco Pierre P Pedersen Terje R TR LaRosa John C JC Waters David D DD DeMicco David A DA Simes R John RJ Keech Antony C AC Colquhoun David D Hitman Graham A GA Betteridge D John DJ Clearfield Michael B MB Downs John R JR Colhoun Helen M HM Gotto Antonio M AM Ridker Paul M PM Grundy Scott M SM Kastelein John J P JJ

Journal of the American College of Cardiology 20140801 5

<h4>Background</h4>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.<h4>Objectives</h4>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 ...[more]

PMID: 25082583

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Project description:Randomized controlled trials (RCTs) show that decreases in low-density lipoprotein cholesterol (LDL-C) by the use of statins cause a significant reduction in the development of cardiovascular disease (CVD). However, one of our previous studies showed that, among eight RCTs that investigated the effect of statins vs. a placebo on CVD development, 56-79% of patients had residual CVD risk after the trials. In three RCTs that investigated the effect of a high dose vs. a usual dose of statins on CVD development, 78-87% of patients in the high-dose statin arms still had residual CVD risk. The risk of CVD development remains even when statins are used to strongly reduce LDL-C, and this type of risk is now regarded as statin residual CVD risk. Our study shows that elevated triglyceride (TG) levels, reduced high-density lipoprotein cholesterol (HDL-C), and the existence of obesity/insulin resistance and diabetes may be important metabolic factors that determine statin residual CVD risk. Here, we discuss atherogenic lipoproteins that were not investigated in such RCTs, such as lipoprotein (a) (Lp(a)), remnant lipoproteins, malondialdehyde-modified LDL (MDA-LDL), and small-dense LDL (Sd-LDL). Lp(a) is under strong genetic control by apolipoprotein (a), which is an LPA gene locus. Variations in the LPA gene account for 91% of the variability in the plasma concentration of Lp(a). A meta-analysis showed that genetic variations at the LPA locus are associated with CVD events during statin therapy, independent of the extent of LDL lowering, providing support for exploring strategies targeting circulating concentrations of Lp(a) to reduce CVD events in patients receiving statins. Remnant lipoproteins and small-dense LDL are highly associated with high TG levels, low HDL-C, and obesity/insulin resistance. MDA-LDL is a representative form of oxidized LDL and plays important roles in the formation and development of the primary lesions of atherosclerosis. MDA-LDL levels were higher in CVD patients and diabetic patients than in the control subjects. Furthermore, we demonstrated the atherogenic properties of such lipoproteins and their association with CVD as well as therapeutic approaches.

Project description:It is uncertain whether pharmacological reductions in very-low-density lipoproteins (VLDLs), and their component triglyceride and cholesterol could reduce residual risk of atherosclerotic cardiovascular disease (ASCVD) events among individuals in whom low-density lipoprotein cholesterol (LDL-C) has been adequately lowered. We examined whether individuals with greater on-statin reductions in VLDL-related measures-beyond reductions in LDL-C-were at further reduced risk of ASCVD. In 9423 participants in the JUPITER (Justification for the Use of Statins in Prevention) trial (NCT00239681), at baseline and on statin we measured standard lipids, 400-MHz proton nuclear magnetic resonance spectroscopy-measured VLDL particle subclasses (small, medium, and large VLDL lipoprotein particle concentration), and total VLDL cholesterol mass. Compared with individuals allocated to placebo, we examined risk of incident ASCVD (N=211) among statin-allocated participants who achieved minimal (<median) or greater (≥median) marker reductions using adjusted Cox models. On-statin changes in VLDL-related markers were only modestly correlated (Spearman r≤0.29) with change in LDL-C. On-statin median LDL-C was 54 mg/dL and triglyceride was 101 mg/dL. Dose-response reductions in ASCVD risk were observed for greater reductions in LDL-C, VLDL cholesterol mass, and small VLDL lipoprotein particle concentration; the latter 2 remained significant after incremental adjustment for change in LDL-C (P≤0.006). Conversely, there was no further risk reduction with greater reductions in triglycerides or large/medium VLDL lipoprotein particle concentration. Pharmacological reduction in small, cholesterol-enriched, triglyceride-depleted VLDL was associated with reduction in ASCVD risk. Chemically measured triglycerides may not sufficiently capture risk related to VLDL pathways. These findings also support broader profiling of lipid and lipoprotein changes in response to statins as prognostic markers of individual benefit, supporting more precision-medicine, individualized approaches to cardiovascular risk reduction. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Project description:ObjectivesThis study sought to determine whether coronary artery calcium (CAC) could be used to optimize statin allocation among individuals for whom trial-based evidence supports efficacy of statin therapy.BackgroundRecently, allocation of statins was proposed for primary prevention of atherosclerotic cardiovascular disease (ASCVD) based on proven efficacy from randomized controlled trials (RCTs) of statin therapy, a so-called trial-based approach.MethodsThe study used data from MESA (Multi-Ethnic Study of Atherosclerosis) with 5,600 men and women, 45 to 84 years of age, and free of clinical ASCVD, lipid-lowering therapy, or missing information for risk factors at baseline examination.ResultsDuring 10 years' follow-up, 354 ASCVD and 219 hard coronary heart disease (CHD) events occurred. Based on enrollment criteria for 7 RCTs of statin therapy in primary prevention, 73% of MESA participants (91% of those >55 years of age) were eligible for statin therapy according to a trial-based approach. Among those individuals, CAC = 0 was common (44%) and was associated with low rates of ASCVD and CHD (3.9 and 1.7, respectively, per 1,000 person-years). There was a graded increase in event rates with increasing CAC score, and in individuals with CAC >100 (27% of participants) the rates of ASCVD and CHD were 18.9 and 12.7, respectively. Consequently, the estimated number needed to treat (NNT) in 10 years to prevent 1 event varied greatly according to CAC score. For ASCVD events, the NNT was 87 for CAC = 0 and 19 for CAC >100. For CHD events, the NNT was 197 for CAC = 0 and 28 for CAC >100.ConclusionsMost MESA participants qualified for trial-based primary prevention with statins. Among the individuals for whom trial-based evidence supports efficacy of statin therapy, CAC = 0 and CAC >100 were common and associated with low and high cardiovascular risks, respectively. This information may guide shared decision making aimed at targeting evidence-based statins to those who are likely to benefit the most.

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

Publications

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

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