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Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial.

ABSTRACT: Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo.In 11?186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility-measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88-1.21). In contrast, associations with CVD events were observed for baseline non-high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01-1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11-1.48), and ion mobility-measured non-HDL particles (HR, 1.19; 95% CI, 1.05-1.35) and LDL particles (HR, 1.21; 95% CI, 1.07-1.37). Association with CVD events was also observed for several LDL and very-low-density lipoprotein subfractions but not for ion mobility-measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-C, non-HDL cholesterol, and apolipoprotein B; these were also associated with CVD/all-cause death, as were several LDL and very-low-density lipoprotein subfractions, albeit with a pattern of association that differed from the baseline risk.In JUPITER, baseline LDL-C was not associated with CVD events, in contrast with significant associations for non-HDL cholesterol and atherogenic particles: apolipoprotein B and ion mobility-measured non-HDL particles, LDL particles, and select subfractions of very-low-density lipoprotein particles and LDL particles. During high-intensity statin therapy, on-treatment levels of LDL-C and atherogenic particles were associated with residual risk of CVD/all-cause death.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

SUBMITTER: Mora S

PROVIDER: S-EPMC4674425 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial.

Mora Samia S Caulfield Michael P MP Wohlgemuth Jay J Chen Zhihong Z Superko H Robert HR Rowland Charles M CM Glynn Robert J RJ Ridker Paul M PM Krauss Ronald M RM

Circulation 20150925 23

<h4>Background</h4>Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo.<h4>Methods and results</h4>In 11 186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvast ...[more]

PMID: 26408274

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Project description:Lipoprotein(a) [Lp(a)] is a low-density lipoprotein-like particle largely independent of known risk factors and predictive of cardiovascular disease. Statins may offset the risk associated with elevated Lp(a), but it is unknown whether Lp(a) is a determinant of residual risk in the setting of low low-density lipoprotein cholesterol after potent statin therapy.Baseline and on-treatment Lp(a) concentrations were assessed in 9612 multiethnic participants in the JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) before and after random allocation to rosuvastatin 20 mg/d or placebo, with outcomes reported for whites (n=7746). Lp(a) concentrations (median [25th-75th percentile], in nmol/L) were highest in blacks (60 [34-100]), then Asians (38 [18-60]), Hispanics (24 [11-46]), and whites (23 [10-50]; P<0.001). Although the median change in Lp(a) with rosuvastatin and placebo was zero, rosuvastatin nonetheless resulted in a small but statistically significant positive shift in the overall Lp(a) distribution (P<0.0001). Baseline Lp(a) concentrations were associated with incident cardiovascular disease (adjusted hazard ratio per 1-SD increment in Ln[Lp(a)], 1.18; 95% confidence interval, 1.03-1.34; P=0.02). Similarly, on-statin Lp(a) concentrations were associated with residual risk of cardiovascular disease (adjusted hazard ratio, 1.27; 95% confidence interval, 1.01-1.59; P=0.04), which was independent of low-density lipoprotein cholesterol and other factors. Rosuvastatin significantly reduced incident cardiovascular disease among participants with baseline Lp(a) greater than or equal to the median (hazard ratio, 0.62; 95% confidence interval, 0.43-0.90) and Lp(a) less than the median (hazard ratio, 0.46; 95% confidence interval, 0.30-0.72), with no evidence of interaction. Similar results were obtained when analyses included nonwhites.Among white JUPITER participants treated with potent statin therapy, Lp(a) was a significant determinant of residual risk. The magnitude of relative risk reduction with rosuvastatin was similar among participants with high or low Lp(a).http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Project description:BackgroundRecent failures of drugs that raised high-density lipoprotein (HDL) cholesterol levels to reduce cardiovascular events in clinical trials have led to increased interest in alternative indices of HDL quality, such as cholesterol efflux capacity, and HDL quantity, such as HDL particle number. However, no studies have directly compared these metrics in a contemporary population that includes potent statin therapy and low low-density lipoprotein cholesterol.MethodsHDL cholesterol levels, apolipoprotein A-I, cholesterol efflux capacity, and HDL particle number were assessed at baseline and 12 months in a nested case-control study of the JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), a randomized primary prevention trial that compared rosuvastatin treatment to placebo in individuals with normal low-density lipoprotein cholesterol but increased C-reactive protein levels. In total, 314 cases of incident cardiovascular disease (CVD) (myocardial infarction, unstable angina, arterial revascularization, stroke, or cardiovascular death) were compared to age- and gender-matched controls. Conditional logistic regression models adjusting for risk factors evaluated associations between HDL-related biomarkers and incident CVD.ResultsCholesterol efflux capacity was moderately correlated with HDL cholesterol, apolipoprotein A-I, and HDL particle number (Spearman r= 0.39, 0.48, and 0.39 respectively; P<0.001). Baseline HDL particle number was inversely associated with incident CVD (adjusted odds ratio per SD increment [OR/SD], 0.69; 95% confidence interval [CI], 0.56-0.86; P<0.001), whereas no significant association was found for baseline cholesterol efflux capacity (OR/SD, 0.89; 95% CI, 0.72-1.10; P=0.28), HDL cholesterol (OR/SD, 0.82; 95% CI, 0.66-1.02; P=0.08), or apolipoprotein A-I (OR/SD, 0.83; 95% CI, 0.67-1.03; P=0.08). Twelve months of rosuvastatin (20 mg/day) did not change cholesterol efflux capacity (average percentage change -1.5%, 95% CI, -13.3 to +10.2; P=0.80), but increased HDL cholesterol (+7.7%), apolipoprotein A-I (+4.3%), and HDL particle number (+5.2%). On-statin cholesterol efflux capacity was inversely associated with incident CVD (OR/SD, 0.62; 95% CI, 0.42-0.92; P=0.02), although HDL particle number again emerged as the strongest predictor (OR/SD, 0.51; 95% CI, 0.33-0.77; P<0.001).ConclusionsIn JUPITER, cholesterol efflux capacity was associated with incident CVD in individuals on potent statin therapy but not at baseline. For both baseline and on-statin analyses, HDL particle number was the strongest of 4 HDL-related biomarkers as an inverse predictor of incident events and biomarker of residual risk.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Project description:The goal of this study was to determine whether residual risk after high-dose statin therapy for primary prevention individuals with reduced levels of low-density lipoprotein cholesterol (LDL-C) is related to on-treatment apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), trigylcerides, or lipid ratios, and how they compare with on-treatment LDL-C.Guidelines focus on LDL-C as the primary target of therapy, yet residual risk for cardiovascular disease (CVD) among statin-treated individuals remains high and not fully explained.Participants in the randomized placebo-controlled JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial were adults without diabetes or CVD, with baseline LDL-C levels <130 mg/dl, high-sensitivity C-reactive protein levels ?2 mg/l, and triglyceride concentrations <500 mg/dl. Individuals allocated to receive rosuvastatin 20 mg daily with baseline and on-treatment lipids and lipoproteins were examined in relation to the primary endpoint of incident CVD (nonfatal myocardial infarction or stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death).Using separate multivariate Cox models, statistically significant associations of a similar magnitude with residual risk of CVD were found for on-treatment LDL-C, non-HDL-C, apolipoprotein B, total cholesterol/HDL-C, LDL-C/HDL-C, and apolipoprotein B/A-I. The respective adjusted standardized hazard ratios (95% confidence intervals) for each of these measures were 1.31 (1.09 to 1.56), 1.25 (1.04 to 1.50), 1.27 (1.06 to 1.53), 1.22 (1.03 to 1.44), 1.29 (1.09 to 1.52), and 1.27 (1.09 to 1.49). The overall residual risk and the risk associated with these measures decreased among participants achieving on-treatment LDL-C ?70 mg/dl, on-treatment non-HDL-C ?100 mg/dl, or on-treatment apolipoprotein B ?80 mg/dl. In contrast, on-treatment triglycerides showed no association with CVD.In this primary prevention trial of nondiabetic individuals with low LDL-C and elevated high-sensitivity C-reactive protein, on-treatment LDL-C was as valuable as non-HDL-C, apolipoprotein B, or ratios in predicting residual risk. (JUPITER-Crestor 20mg Versus Placebo in Prevention of Cardiovascular [CV] Events; NCT00239681).

Project description:ImportanceOsteoporosis and cardiovascular disease may share common biological pathways, with inflammation playing a role in the development of both. Although observational studies have suggested that statin use is associated with a lower risk of fractures, randomized trial data addressing this issue are scant.ObjectiveTo determine whether statin therapy reduces the risk of fracture and, in a secondary analysis, whether baseline levels of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) are associated with the risk of fracture.Design, setting, and participantsThe JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial was an international, randomized, double-blind, placebo-controlled study enrolling 17,802 men older than 50 years and women older than 60 years with hs-CRP level of at least 2 mg/L. Participants were screened from 2003 to 2006 and observed prospectively for up to 5 years (median follow-up, 1.9 years).InterventionRosuvastatin calcium, 20 mg daily, or placebo.Main outcomes and measuresIncident fracture was a prespecified secondary end point of JUPITER. Fractures were confirmed by radiographs, computed tomography, bone scan, or other methods. Cox proportional hazards models were used to calculate hazard ratios (HRs) and associated 95% confidence intervals for the risk of fracture according to randomized treatment assignment, as well as increasing tertiles of hs-CRP, controlling for potential confounders.ResultsDuring the study, 431 incident fractures were reported and confirmed. Among participants allocated to rosuvastatin, 221 fractures were confirmed, compared with 210 among those allocated to placebo, such that the incidence of fracture in the rosuvastatin and placebo groups was 1.20 and 1.14 per 100 person-years, respectively (adjusted HR, 1.06 [95% CI, 0.88-1.28]; P = .53). Overall, increasing baseline hs-CRP level was not associated with an increased risk of fractures (adjusted HR for each unit increase in hs-CRP tertile, 1.06 [95% CI, 0.94-1.20]; P for trend, .34).Conclusions and relevanceAmong men and women with elevated hs-CRP level enrolled in a large trial of rosuvastatin therapy for cardiovascular disease, statin therapy did not reduce the risk of fracture. Higher baseline hs-CRP level was not associated with an increased risk of incident fracture.Trial registrationclinicaltrials.gov Identifier: NCT00239681.

Project description:We aimed to comprehensively evaluate lipoprotein profile including lipid particle size following a lifestyle intervention in metabolic syndrome (MetS) volunteers and to assess the associations between lipoprotein subfractions and carotid-intima-media-thickness (CIMT) - a surrogate indicator of atherogenesis.100 participants (50-70 years) from the RESOLVE trial, underwent a one-year follow-up beginning with a three-week residential program combining high exercise volume (15-20 h/week), restrictive diet (-500 kcal/day), and education. For baseline references, 40 aged-matched healthy controls were recruited. Independent associations between subfractions of lipoproteins and CIMT were evaluated using a generalized estimating equations model accounting for variation in correlations between repeated measures. The lipoprotein subfractions profile was assessed using Lipoprint® electrophoresis allowing to separate: the very low-density lipoprotein (VLDL) fraction, then the intermediate-density lipoprotein (IDL) C, B and A, the low-density lipoprotein (LDL) with subfractions 1 and 2 as large LDL and subfractions 3 to 7 as small dense LDL (sdLDL), and the high density lipoprotein (HDL) subfractions categorized into large, intermediate, and small HDL. Apolipoproteins A1 and B were also measured.78 participants completed the program. At baseline, apolipoproteins B/A1, VLDL, sdLDL and small HDL were higher in MetS than in healthy controls; IDL, LDL size, large and intermediate HDL were lower. Despite time-related regains during the follow-up, lipoprotein subfractions traditionally involved in cardiovascular risk, such as sdLDL, improved immediately after the residential program with values closest to those of healthy controls. CIMT improved throughout the lifestyle intervention. Using a generalized estimating equations model, none of the subfractions of lipoproteins nor apolipoproteins were linked to CIMT.Lipoprotein subfractions traditionally involved in CVR, decreased after the 3-week residential program. During a 12 month follow-up, the time-related regains remained closer to the values of healthy controls than they were at baseline. CIMT improved throughout the lifestyle intervention. However, we failed to demonstrate a link between some lipoprotein subfractions and the atherogenicity directly measured from the wall thickness of arteries (CIMT). Further investigations are required to explore the atherogenicity of lipoprotein subfractions.NCT00917917.

Project description:BackgroundIn view of evidence that statin therapy increases risk of diabetes, the balance of benefit and risk of these drugs in primary prevention has become controversial. We undertook an analysis of participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazard of statin use.MethodsIn the randomised, double-blind JUPITER trial, 17,603 men and women without previous cardiovascular disease or diabetes were randomly assigned to rosuvastatin 20 mg or placebo and followed up for up to 5 years for the primary endpoint (myocardial infarction, stroke, admission to hospital for unstable angina, arterial revascularisation, or cardiovascular death) and the protocol-prespecified secondary endpoints of venous thromboembolism, all-cause mortality, and incident physician-reported diabetes. In this analysis, participants were stratified on the basis of having none or at least one of four major risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body-mass index 30 kg/m(2) or higher, or glycated haemoglobin A(1c) greater than 6%. The trial is registered at ClinicalTrials.gov, NCT00239681.FindingsTrial participants with one or more major diabetes risk factor (n=11,508) were at higher risk of developing diabetes than were those without a major risk factor (n=6095). In individuals with one or more risk factors, statin allocation was associated with a 39% reduction in the primary endpoint (hazard ratio [HR] 0·61, 95% CI 0·47-0·79, p=0·0001), a 36% reduction in venous thromboembolism (0·64, 0·39-1·06, p=0·08), a 17% reduction in total mortality (0·83, 0·64-1·07, p=0·15), and a 28% increase in diabetes (1·28, 1·07-1·54, p=0·01). Thus, for those with diabetes risk factors, a total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. For trial participants with no major diabetes risk factors, statin allocation was associated with a 52% reduction in the primary endpoint (HR 0·48, 95% CI 0·33-0·68, p=0·0001), a 53% reduction in venous thromboembolism (0·47, 0·21-1·03, p=0·05), a 22% reduction in total mortality (0·78, 0·59-1·03, p=0·08), and no increase in diabetes (0·99, 0·45-2·21, p=0·99). For such individuals, a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed. In analysis limited to the 486 participants who developed diabetes during follow-up (270 on rosuvastatin vs 216 on placebo; HR 1·25, 95% CI 1·05-1·49, p=0·01), the point estimate of cardiovascular risk reduction associated with statin therapy (HR 0·63, 95% CI 0·25-1·60) was consistent with that for the trial as a whole (0·56, 0·46-0·69). By comparison with placebo, statins accelerated the average time to diagnosis of diabetes by 5·4 weeks (84·3 [SD 47·8] weeks on rosuvastatin vs 89·7 [50·4] weeks on placebo).InterpretationIn the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including in participants at high risk of developing diabetes.FundingAstraZeneca.

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.

Dataset Information

Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial.

Publications

Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial.

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