Use Of Statins In Prevention Research Articles

A-216 Prevalence and status of Lipoprotein(a) in the Korean population visiting local clinics and hospitals

Abstract Background Lipoprotein a (Lp(a)) is a risk factor for cardiovascular disease (CVD) and has pro-atherogenic and pro-inflammatory effects. According to the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, a sub-analysis was published showing that the risk of residual CVD after sufficiently lowering low-density lipoprotein cholesterol can be explained by Lp(a) concentration. The purpose of this study is to determine the prevalence of elevated Lp(a) and to analyze the characteristics of Lp(a) results by age, gender, and region in the Korean population visiting local clinics and hospitals. Methods We retrospectively reviewed Lp(a) test results from the Korean population who visited 117 local clinics and hospitals nationwide between February 2023 and January 2024. Serum levels of Lp(a) were measured by immunoturbidimetric assay. Lp(a) was analyzed to three age groups (<20, 20-59, ≥60 years) according to Lp(a) values (<30 or ≥30 mg/dl). One hundred seventeen local clinics and hospitals across the country were reclassified into 7 regions. Results A total of 15,523 patients (7,702 males and 7,821 females), aged 12-104 years, were included. The median (interquartile range, IQR) age of the population was 59 (49-69) years; the median (IQR) Lp(a) concentration was 9.7 (4.2-21.6) mg/dl. The prevalence of elevated Lp(a) levels (≥30 mg/dl) in this study was 16.7% (13.9% for males, 19.5% for females, p <0.001). Prevalence of elevated Lp(a) levels by age groups were as follows: <20 (8.9%, 5/56), 20-59 (13.9%, 1,071/7,724), ≥60 years (19.6%, 1,516/7,743). The correlation coefficient r between Lp(a) and age was 0.139 (p <0.001). No significant relationship was found between Lp(a) and region. Among 15,523 patients, the number of patients with Lp (a) level ≥100 mg/dl was 174 (n=70 for males, n=104 for females, p=0.128), and median (IQR) Lp(a) concentration was 115.1 (106.8-131.6) mg/dl. Of them, four patients showed extremely high Lp(a) levels (>180 mg/dL). Conclusions The prevalence of elevated Lp(a) in our population visiting local clinics and hospitals nationwide was 14.4% and differed by gender and age group. For successful management and establishment of the policy of CVD, it is important to identify the prevalence of elevated Lp(a). Future study is needed including the clinical information to confirm the present findings.

One-Year Effects of High-Intensity Statin on Bioactive Lipids: Findings From the JUPITER Trial.

Statin effects extend beyond low-density lipoprotein cholesterol reduction, potentially modulating the metabolism of bioactive lipids (BALs), crucial for biological signaling and inflammation. These bioactive metabolites may serve as metabolic footprints, helping uncover underlying processes linked to pleiotropic effects of statins and yielding a better understanding of their cardioprotective properties. This study aimed to investigate the impact of high-intensity statin therapy versus placebo on plasma BALs in the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681), a randomized primary prevention trial involving individuals with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L. Using a nontargeted mass spectrometry approach, over 11 000 lipid features were assayed from baseline and 1-year plasma samples from cardiovascular disease noncases from 2 nonoverlapping nested substudies: JUPITERdiscovery (n=589) and JUPITERvalidation (n=409). The effect of randomized allocation of rosuvastatin 20 mg versus placebo on BALs was examined by fitting a linear regression with delta values (∆=year 1-baseline) adjusted for age and baseline levels of each feature. Significant associations in discovery were analyzed in the validation cohort. Multiple comparisons were adjusted using 2-stage overall false discovery rate. We identified 610 lipid features associated with statin randomization with significant replication (overall false discovery rate, <0.05), including 26 with annotations. Statin therapy significantly increased levels of 276 features, including BALs with anti-inflammatory activity and arterial vasodilation properties. Concurrently, 334 features were significantly lowered by statin therapy, including arachidonic acid and proinflammatory and proplatelet aggregation BALs. By contrast, statin therapy reduced an eicosapentaenoic acid-derived hydroxyeicosapentaenoic acid metabolite, which may be related to impaired glucose metabolism. Additionally, we observed sex-related differences in 6 lipid metabolites and 6 unknown features. Statin allocation was significantly associated with upregulation of BALs with anti-inflammatory, antiplatelet aggregation and antioxidant properties and downregulation of BALs with proinflammatory and proplatelet aggregation activity, supporting the pleiotropic effects of statins beyond low-density lipoprotein cholesterol reduction.

Statins and Venous Thromboembolic Disease - Where are we Now?

Classical risk factors for atherosclerosis also play a role in the pathogenesis of venous thromboembolism (VTE). Low-density lipoprotein cholesterol has prothrombotic and endothelium- deteriorating effects which are not limited to the arterial system. The association between hypercholesterolemia and VTE has been established, but the benefits of statins in the prevention of VTE assessed by observation studies seemed equivocal. The large, randomized trial Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) recorded the occurrence of VTE as a protocol-specified endpoint and reported a reduced incidence of VTE among subjects taking 20 mg of rosuvastatin daily vs placebo (hazard ratio 0.57; 95% confidence interval 0.37-0.86; p=0.007). Similar results were confirmed by meta-analyses of observation studies and randomized trials. Recently, a Mendelian randomization study that took the presence of gene variants coding for less efficient hydroxymethyl-glutaryl coenzyme A reductase activity as a proxy for statin treatment, confirmed a small, but significant negative association between the score of selected genetic polymorphisms and the incidence of VTE. However, since the protective effects of statins are limited, they should not be substituted for guideline-recommended VTE prophylaxis or anticoagulation treatment.

N-Glycosylation Profiles of Immunoglobulin G and Future Cardiovascular Events.

Posttranslational glycosylation of IgG can modulate its inflammatory capacity through structural variations. We examined the association of baseline IgG N-glycans and an IgG glycan score with incident cardiovascular disease (CVD). IgG N-glycans were measured in 2 nested CVD case-control studies: JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; NCT00239681; primary prevention; discovery; Npairs=162); and TNT trial (Treating to New Targets; NCT00327691; secondary prevention; validation; Npairs=397). Using conditional logistic regression, we investigated the association of future CVD with baseline IgG N-glycans and a glycan score adjusting for clinical risk factors (statin treatment, age, sex, race, lipids, hypertension, and smoking) in JUPITER. Significant associations were validated in TNT, using a similar model further adjusted for diabetes. Using least absolute shrinkage and selection operator regression, an IgG glycan score was derived in JUPITER as a linear combination of selected IgG N-glycans. Six IgG N-glycans were associated with CVD in both studies: an agalactosylated glycan (IgG-GP4) was positively associated, while 3 digalactosylated glycans (IgG glycan peaks 12, 13, 14) and 2 monosialylated glycans (IgG glycan peaks 18, 20) were negatively associated with CVD after multiple testing correction (overall false discovery rate <0.05). Four selected IgG N-glycans comprised the IgG glycan score, which was associated with CVD in JUPITER (adjusted hazard ratio per glycan score SD, 2.08 [95% CI, 1.52-2.84]) and validated in TNT (adjusted hazard ratio per SD, 1.20 [95% CI, 1.03-1.39]). The area under the curve changed from 0.693 for the model without the score to 0.728 with the score in JUPITER (PLRT=1.1×10-6) and from 0.635 to 0.637 in TNT (PLRT=0.017). An IgG N-glycan profile was associated with incident CVD in 2 populations (primary and secondary prevention), involving an agalactosylated glycan associated with increased risk of CVD, while several digalactosylated and sialylated IgG glycans associated with decreased risk. An IgG glycan score was positively associated with future CVD.

Statins Effects on Blood Clotting: A Review.

Statins are powerful lipid-lowering drugs that inhibit cholesterol biosynthesis via downregulation of hydroxymethylglutaryl coenzyme-A reductase, which are largely used in patients with or at risk of cardiovascular disease. Available data on thromboembolic disease include primary and secondary prevention as well as bleeding and mortality rates in statin users during anticoagulation for VTE. Experimental studies indicate that statins alter blood clotting at various levels. Statins produce anticoagulant effects via downregulation of tissue factor expression and enhanced endothelial thrombomodulin expression resulting in reduced thrombin generation. Statins impair fibrinogen cleavage and reduce thrombin generation. A reduction of factor V and factor XIII activation has been observed in patients treated with statins. It is postulated that the mechanisms involved are downregulation of factor V and activated factor V, modulation of the protein C pathway and alteration of the tissue factor pathway inhibitor. Clinical and experimental studies have shown that statins exert antiplatelet effects through early and delayed inhibition of platelet activation, adhesion and aggregation. It has been postulated that statin-induced anticoagulant effects can explain, at least partially, a reduction in primary and secondary VTE and death. Evidence supporting the use of statins for prevention of arterial thrombosis-related cardiovascular events is robust, but their role in VTE remains to be further elucidated. In this review, we present biological evidence and experimental data supporting the ability of statins to directly interfere with the clotting system.

Disparities in Guideline-Recommended Statin Use for Prevention of Atherosclerotic Cardiovascular Disease by Race, Ethnicity, and Gender : A Nationally Representative Cross-Sectional Analysis of Adults in the United States.

Although statins are a class I recommendation for prevention of atherosclerotic cardiovascular disease and its complications, their use is suboptimal. Differential underuse may mediate disparities in cardiovascular health for systematically marginalized persons. To estimate disparities in statin use by race-ethnicity-gender and to determine whether these potential disparities are explained by medical appropriateness of therapy and structural factors. Cross-sectional analysis. National Health and Nutrition Examination Survey from 2015 to 2020. Persons eligible for statin therapy based on 2013 and 2018 American College of Cardiology/American Heart Association blood cholesterol guidelines. The independent variable was race-ethnicity-gender. The outcome of interest was use of a statin. Using the Institute of Medicine framework for examining unequal treatment, we calculated adjusted prevalence ratios (aPRs) to estimate disparities in statin use adjusted for age, disease severity, access to health care, and socioeconomic status relative to non-Hispanic White men. For primary prevention, we identified a lower prevalence of statin use that was not explained by measurable differences in disease severity or structural factors among non-Hispanic Black men (aPR, 0.73 [95% CI, 0.59 to 0.88]) and non-Mexican Hispanic women (aPR, 0.74 [CI, 0.53 to 0.95]). For secondary prevention, we identified a lower prevalence of statin use that was not explained by measurable differences in disease severity or structural factors for non-Hispanic Black men (aPR, 0.81 [CI, 0.64 to 0.97]), other/multiracial men (aPR, 0.58 [CI, 0.20 to 0.97]), Mexican American women (aPR, 0.36 [CI, 0.10 to 0.61]), non-Mexican Hispanic women (aPR, 0.57 [CI, 0.33 to 0.82), non-Hispanic White women (aPR, 0.69 [CI, 0.56 to 0.83]), and non-Hispanic Black women (aPR, 0.75 [CI, 0.57 to 0.92]). Cross-sectional data; lack of geographic, language, or statin-dose data. Statin use disparities for several race-ethnicity-gender groups are not explained by measurable differences in medical appropriateness of therapy, access to health care, and socioeconomic status. These residual disparities may be partially mediated by unobserved processes that contribute to health inequity, including bias, stereotyping, and mistrust. National Institutes of Health.

IDF21-0540 HbA1c as a marker of HDL cholesterol in Indian subjects with type 2 diabetes

Background: HbA1c is the gold standard means of accessing long term glycemia and for diagnosing diabetes. Cardiovascular disease (CVD) is the leading cause of death in type 2 diabetes (T2DM). HDL‐c has been considered as a surrogate marker of CVD. Aim: In this study we aimed to find the relationship between HbA1c and HDL‐c in Odia subjects with T2DM. Method: T2DM adults, who visited Diabetic OPD were requested to participate. Subjects with type 1 diabetes, secondary diabetes, GDM, nourishing mothers, pregnant women, as well as individuals who were on lipid lowering medicines, thyroid hormone therapy, steroids, immunosupressants were excluded. Comprehensive medical and drug history were recorded. After consent, participants underwent overnight fasting for estimation of HbA1c and lipid panel measurement. Results: Mean age and duration of diabetes for the sample (n = 1352, M/F = 832/520) were 51.8 ± 10.5 and 9.8 ± 6.0 years respectively. Mean HbA1c and HDL‐c values were 8.7 ± 2.4% and 40.6 ± 8.7mg/dl in order. The prevalence of low HDL (n = 697, 51.6%) and hypertriglyceridemia (n = 689, 51.0%) were almost similar. Uncontrolled HbA1c (≥7%) was documented in two third (66.7%) of persons with low HDL. While HDL was seen to be inversely related to HbA1c values, triglyceride level was found to be proportionate to HbA1c. Discussion: The study shows that elevated HbA1c is associated with low HDL and high triglyceride levels in Odia T2DM subjects and warrants the use of statins for prevention of cardiovascular events in this resource restricted community.

Cardiovascular Disease in Patients With Systemic Lupus Erythematosus: Potential for Improved Primary Prevention With Statins.

Cardiovascular disease (CVD) is a significant cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). This is especially true in SLE patients with traditional CVD risk factors (eg, hypertension, hyperlipidemia, obesity) and disease-related risk factors (eg, increased SLE disease activity, elevated C-reactive protein levels, and antiphospholipid antibodies). The only guidelines in the primary prevention of CVD in SLE patients involve reducing traditional risk factors, but there are additional therapies that may be beneficial, including statin use. Current data on statin use for prevention of CVD in SLE patients are limited, but there have been some promising results. Statin use has been shown to be especially important in SLE patients for decreasing low-density lipoprotein levels and preventing CVD in hyperlipidemic patients. In addition, there is evidence suggesting that it may be beneficial to use statins in SLE patients with chronically elevated high-sensitivity C-reactive protein levels and antiphospholipid antibodies. It is important to continue to investigate the impact of statins on CVD in SLE patients, as they could significantly improve outcomes in patients with this disease.

Statins for the Prevention of Post-Stroke Seizure and Epilepsy Development: A Systematic Review and Meta-Analysis

ObjectivesCerebrovascular disease is the leading cause of seizures and incident epilepsy of known etiology in older adults. Statins have increasingly garnered attention as a potential preventive strategy due to their pleiotropic effects beyond lipid-lowering, which may include neuroprotective and anti-epileptogenic properties. We aim to assess the evidence on statin use for prevention of post-stroke early-onset seizures and post-stroke epilepsy. Materials and methodsWe conducted a systematic review and meta-analysis in accordance with PRISMA guidelines, which was prospectively registered with PROSPERO (CRD42019144916). PubMed and Embase were searched from database inception to 05/2020 for English-language, full-text studies examining the association between statin use in adults and development of early-onset seizures (≤7 days post-stroke) or post-stroke epilepsy. Pooled analyses were based on random-effects models using the inverse-variance method. ResultsOf 182 citations identified, 175 were excluded due to duplication or ineligibility. The 7 eligible publications were all cohort studies from East Asia or South America, with a total of 53,579 patients. Pre-stroke statin use was not associated with post-stroke epilepsy (3 studies pooled: OR 1.14, CI 0.91-1.42). However, post-stroke statin use was associated with lower risk of both early-onset seizures (3 studies pooled: OR 0.36, CI 0.25-0.53), and post-stroke epilepsy (6 studies pooled: OR 0.64, CI 0.46-0.88). ConclusionsReview of 7 cohort studies suggested post-stroke, but not pre-stroke, statin use may be associated with reduced risk of early-onset seizures and post-stroke epilepsy. Further research is warranted to validate these findings in broader populations and better parse the temporal components of the associations.

Anti-Inflammatory HDL Function, Incident Cardiovascular Events, and Mortality: A Secondary Analysis of the JUPITER Randomized Clinical Trial.

BackgroundHigh‐density lipoprotein (HDL) cholesterol has inverse association with cardiovascular disease. HDL possesses anti‐inflammatory properties in vitro, but it is unknown whether this may be protective in individuals with inflammation.Methods and ResultsThe functional capacity of HDL to inhibit oxidation of oxidized low‐density lipoprotein (ie, the HDL inflammatory index; HII) was measured at baseline and 12 months after random allocation to rosuvastatin or placebo in a nested case‐control study of the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Evaluating Rosuvastatin) trial. There were 517 incident cases of cardiovascular disease and all‐cause mortality compared to 517 age‐ and sex‐matched controls. Multivariable conditional logistic regression was used to examine associations of HII with events. Median baseline HII was 0.54 (interquartile range, 0.50–0.59). Twelve months of rosuvastatin decreased HII by a mean of 5.3% (95% CI, −8.9% to −1.7%; P=0.005) versus 1.3% (95% CI, −6.5% to 4.0%; P=0.63) with placebo (P=0.22 for between‐group difference). HII had a nonlinear relationship with incident events. Compared with the reference group (HII 0.5–1.0) with the lowest event rates, participants with baseline HII ≤0.5 had significantly increased risk of cardiovascular disease/mortality (adjusted hazard ratio, 1.53; 95% CI, 1.06–2.21; P=0.02). Furthermore, there was significant (P=0.002) interaction for HDL particle number with HII, such that having more HDL particles was associated with decreased risk only when HDL was anti‐inflammatory.ConclusionsIn JUPITER participants recruited on the basis of chronic inflammation, HII was associated with incident cardiovascular disease/mortality, with an optimal anti‐inflammatory HII range between 0.5 and 1.0. This nonlinear relationship of anti‐inflammatory HDL function with risk may account in part for the HDL paradox.RegistrationURL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00239681.

Abstract P280: Revisiting CVD Risk Prediction Using Machine Learning Approaches: A Case Study

Introduction: Applications of machine learning (ML) methods have been demonstrated by the recent FDA approval of new ML-based biomedical image processing methods. In this study, we examine applications of ML, specifically artificial neural networks (ANN), for predicting risk of cardiovascular (CV) events. Hypothesis: We hypothesized that using the same CV risk factors, ML-based CV prediction models can improve the performance of current predictive models. Methods: Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER; NCT00239681) is a multi-ethnic trial that randomized non-diabetic participants with LDL-C&lt;130 mg/dL and hsCRP≥2 mg/L to rosuvastatin versus placebo. We restricted the analysis to white and black participants allocated to the placebo arm, and estimated the race- and sex-specific Pooled Cohorts Equations (PCE) 5-year risk score using race, sex, age, HDL-C, total cholesterol, systolic BP, antihypertensive medications, and smoking. A total of 218 incident CV cases occurred (maximum follow-up 5 years). For every participant in the case group, we randomly selected 4 controls from the placebo arm after stratifying for the baseline risk factors (Table 1). The risk factors from a total of n=1,090 participants were used to train and test the ANN model. We used 80% of the participants (n=872) for designing the network and left out 20% of the data (n=218) for testing the predictive model. We used the TensorFlow software to design, train, and evaluate the ANN model. Results: We compared the performances of the ANN and the PCE score on the 218 test subjects (Figure 1). The high AUC of the neural network (0.85; 95% CI 0.78-0.91) on this dataset suggests advantages of machine learning methods compared to the current methods. Conclusions: This result demonstrates the potential of machine learning methods for enhancing and improving the current techniques used in cardiovascular risk prediction and should be evaluated in other cohorts.

Abstract P260: Determinants of Statin Response: A Secondary Analysis of the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)

Introduction: Wide variability in LDLC change is observed with statins, yet determinants of statin response are uncertain. Hypotheses: Some markers of inflammation are associated with decreased statin response. Components of metabolic syndrome and older age are associated with better response. Methods: JUPITER (NCT00239681) randomized participants with LDLC&lt;130 mg/dL and hs-CRP≥2 mg/L to rosuvastatin 20 mg/d or placebo. Baseline and 1-year levels of LDLC and a panel of 20 other biomarkers were measured. We defined optimal statin response as ≥50% LDLC reduction; suboptimal response as &lt;50% reduction; and non-response as no change or increase in LDLC. χ 2 , t-tests and ANOVA were used to compare variables across optimal (N=3,801), suboptimal (N=3,235) and non-responders (N=868). Multinomial regression models evaluated associations of determinants of statin response after adjusting for risk factors including compliance. Backward selection identified variables that associated with response. t-distributed Stochastic Neighbor Embedding (t-SNE) suggested predictor clusters for statin response. Results: Compliance was the strongest determinant of statin response (Table). On multivariable analyses, blacks and Hispanics were at higher risk for suboptimal/non-response compared with whites as were greater alcohol use and HbA1c. Higher baseline levels of lipids [lipoprotein(a), apolipoprotein (apo) AI and B], inflammatory biomarkers, and lower branched-chain amino acids associated with decreased statin response (Table). By contrast, determinants of better response included older age, female sex, and higher waist circumference and baseline levels of LDLC, triglycerides, and blood pressure. We observed systematic patterns in t-SNE clustering for statin response by LDLC, LDL particle number, and apo B. Conclusions: This study identified determinants for high-intensity statin response and suggests other pathways of CVD risk beyond those addressed by statin treatment that require further investigation.

Abstract TP164: Statins for the Prevention of Post-Stroke Seizure and Epilepsy Development: A Systematic Review and Meta-Analysis

Introduction: Cerebrovascular disease is the leading cause of seizures and incident epilepsy of known etiology in older adults. As prophylactic use of antiepileptic drugs remains controversial, statins have garnered attention as an alternate preventive strategy due to pleiotropic effects, beyond lipid-lowering, which may include neuroprotective and anti-epileptogenic properties. Our objective was to assess the current evidence on statin use for prevention of post-stroke seizure and post-stroke epilepsy (PSE). Methods: We conducted a systematic review following PRISMA guidelines. Pubmed and Embase were searched from database inception to May 2019 for English-language, full-text experimental, observational analytic, or systematic reviews/meta-analytic studies examining the association between statin use in adults and development of early-onset seizures (ES; seizures ≤7 days after stroke) or PSE. Pooled analyses were based on random-effects models using the inverse-variance method. Results: Of 157 citations, 154 were excluded due to duplication or ineligibility, yielding 3 cohort studies from East Asia. Two studies reported on outcomes of ischemic stroke and 1 on hemorrhagic stroke. Only 1 study reported on ES, finding a significantly reduced risk following post-stroke statin use (OR 0.35, CI 0.20-0.60). Two studies reported on pre-stroke statin use, with findings demonstrating a lack of association with PSE (pooled OR 1.17, CI 0.93-1.48; Figure 1.1). However, post-stroke statin use was associated with less PSE (pooled OR 0.61, CI 0.50-0.74), without evidence of heterogeneity (Figure 1.2). Conclusions: Systematic review and meta-analysis of 3 high-quality cohort studies suggests post-stroke, but not pre-stroke, statin use may be associated with reduced risk of PSE. Further research is warranted to verify if these findings are replicable in other populations, as well as to explore the influence of timing and duration of statin use on outcomes.

Group IIA Secretory Phospholipase A2, Vascular Inflammation, and Incident Cardiovascular Disease.

Objective- Inflammation is a causal risk factor for cardiovascular disease (CVD). sPLA2-IIA (group IIA secretory phospholipase A2) plays an integral role in regulating vascular inflammation. Although studies investigated sPLA2-IIA in secondary prevention, we prospectively evaluated sPLA2-IIA mass and genetic variants with CVD events in a primary prevention population with chronic inflammation. Approach and Results- The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) randomized participants with LDL (low-density lipoprotein) <130 mg/dL and hsCRP (high-sensitivity C-reactive protein) ≥2 mg/L to high-intensity rosuvastatin versus placebo. Baseline and 1-year plasma sPLA2-IIA mass was measured (N=11 269 baseline; N=9620 1 year). We also identified genetic variants influencing sPLA2-IIA using genome-wide association and examined them with CVD. Three hundred thirteen incident CVD events occurred during follow-up. Baseline sPLA2-IIA mass (median, 25th-75th percentile: 3.81, 2.49-6.03 ng/mL) was associated with increased risk of CVD: risk factor-adjusted hazard ratio (95% CI; P) per SD increment: 1.22 (1.08-1.38; P=0.002). This remained significant (1.18; 1.04-1.35; P=0.01) after incrementally adjusting for hsCRP. Similar estimates were observed in rosuvastatin and placebo groups ( P treatment interaction>0.05). The rs11573156C variant in PLA2G2A (encoding sPLA2-IIA) had the strongest effect on sPLA2-II: median (25th-75th percentile, ng/mL) for CC and GG genotypes: 2.79 (1.97-4.01) and 7.38 (5.38-10.19), respectively; and had nonsignificant trend for higher CVD risk (hazard ratio, 1.11; 95% CI, 0.89-1.38; P=0.34). Conclusions- In the JUPITER population recruited on chronic inflammation, sPLA2-IIA mass was associated with CVD risk relating to vascular inflammation not fully reflected by hsCRP. Additional studies, including larger functional genetic and clinical studies, are needed to determine whether sPLA2-IIA may be a potential pharmacological target for primary prevention of CVD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.

Comparison of Methods to Generalize Randomized Clinical Trial Results Without Individual-Level Data for the Target Population.

Our study explored the application of methods to generalize randomized controlled trial results to a target population without individual-level data. We compared 4 methods using aggregate data for the target population to generalize results from the international trial, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), to a target population of trial-eligible patients in the UK Clinical Practice Research Datalink (CPRD). The gold-standard method used individual data from both the trial and CPRD to predict probabilities of being sampled in the trial and to reweight trial participants to reflect CPRD patient characteristics. Methods 1 and 2 used weighting methods based on simulated individual data or the method of moments, respectively. Method 3 weighted the trial's subgroup-specific treatment effects to match the distribution of an effect modifier in CPRD. Method 4 calculated the expected absolute benefits in CPRD assuming homogeneous relative treatment effect. Methods based on aggregate data for the target population generally yielded results between the trial and gold-standard estimates. Methods 1 and 2 yielded estimates closest to the gold-standard estimates when continuous effect modifiers were represented as categorical variables. Although individual data or data on joint distributions remains the best approach to generalize trial results, these methods using aggregate data might be useful tools for timely assessment of randomized trial generalizability.

Lipoprotein(a) and Cardiovascular Risk Prediction Among Women

BackgroundAlthough lipoprotein(a) [Lp(a)] is associated with incident cardiovascular disease (CVD), its contribution to prediction remains controversial. ObjectivesThis study examined the association and clinical utility of Lp(a) with incident CVD in women. MethodsA turbidimetric assay assessed Lp(a) in 3 cohorts of women (the WHS [Women’s Health Study] [N = 24,558], a case-cohort sample from the WHI [Women’s Health Initiative] Observational Study [n = 1,815 cases, subcohort n = 1,989], and the JUPITER [Justification for Use of Statins in Prevention] trial [n = 2,569]) and in men from JUPITER (n = 5,161). A WHS derivation sample (n = 16,400) determined the form of association with incident CVD. This was tested in WHS validation data (n = 8,158) and the other study samples. Models including traditional CV risk factors but with and without Lp(a) were compared using risk reclassification. ResultsIn the WHS, there was a curvilinear association, with increased CVD risk among those with Lp(a) >50 mg/dl, but only among women with total cholesterol (TC) >220 mg/dl. In the WHS test sample, there was a small but significant change in the C-statistic (0.790 to 0.797; p = 0.035) but no improvement in measures of reclassification. This pattern was replicated among women in the WHI and JUPITER trial. In contrast, there was a strong association of Lp(a) with CVD among men with low TC levels in JUPITER. ConclusionsIn 3 cohorts of women, Lp(a) was associated with CVD only among those with high TC, and improvement in prediction was minimal. These data have implications for Lp(a) in clinical practice among women and for trials of Lp(a)-lowering agents.

A Deeper Dive Into the CANTOS “Responders” Substudy

Inflammation plays a key role in atherogenesis.1 High-sensitivity C-reactive protein (hsCRP) and other inflammatory biomarkers can predict atherosclerotic cardiovascular disease (ASCVD) events independently of traditional risk factors.2 The efficacy of statins in mitigating cardiovascular risk may in part be due to their anti-inflammatory properties.3 The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin confirmed the benefit of statins for ASCVD risk-lowering among individuals with elevated hsCRP levels (≥2 mg/L), but with low-density lipoprotein cholesterol (LDL-C) levels of less than 130 mg/dL.

Reduction of Vascular Inflammation, LDL-C, or Both for the Protection from Cardiovascular Events?

Background:Low density lipoprotein cholesterol (LDL-C) and low grade arterial inflammation are key pathogenic factors for atherosclerosis and its manifestation, cardiovascular disease (CVD).Objective:In this narrative review we assessed if decreasing LDL-C levels or inflammation or both is more effective in reducing CVD events.Results:In the Scandinavian Simvastatin Survival Study (4S), all statin trials of the 90s’ and the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) the benefit came from the LDL-C reduction. In the GREak and Atorvastatin Coronary heart disease Evaluation (GREACE), the Treating to New Targets (TNT), and the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trials both mechanisms in combination produced significant benefits. In the Atorvastatin for Reduction of MYocardial Damage during Angioplasty (ARMYDA) trials and the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) with a human antibody targeting IL-1β with no lipid lowering effect, the reduction in arterial inflammation played the only beneficial role because there was no change in lipids levels.Conclusion:Both LDL-C and inflammation reduction are beneficial to the reduction of CVD risk. However, canakinumab is a very expensive drug that only induced a 15% reduction in CVD events, thus drastically reducing the possibility for it to be used in clinical practice. Besides, canakinumab is associated with increased infections, some fatal. A potent statin with anti-inflammatory effects is probably the best choice for the majority of those needing hypolipidaemic drug therapy.

High-Density Lipoprotein Function in Cardiovascular Disease and Diabetes Mellitus.

Cardiovascular disease (CVD) is the most common cause of death worldwide.1 Major CVD risk factors are hypertension, smoking, physical inactivity, abnormal glucose levels/diabetes mellitus, and dyslipidemia. Among these, dyslipidemia characterized by a low level of HDL-C (high-density lipoprotein cholesterol) is strongly and inversely correlated with CVD risk,2–4 and low HDL-C levels is part of the atherogenic dyslipidemia complex associated with diabetes mellitus.5 These observations triggered intense interest in increasing HDL-C levels for therapeutic intervention of CVD.6,7 However, several recent lines of evidence now suggest that the association between HDL-C levels and CVD status may be indirect or more complicated than previously recognized.7 Thus, human genetic studies demonstrate that genetically altered HDL-C levels do not necessarily translate to an altered risk of CVD.8–12 Phase III clinical trials of drugs that elevate HDL-C, such as niacin and CETP (cholesteryl ester transfer protein) inhibitors, also have largely failed to reduce CVD events in statin-treated subjects with established CVD.13–15 For several CETP inhibitors, improvement in CVD prevention was unsuccessful because of off-target effects (torcetrapib) or lack of efficacy (dalcetrapib and evacetrapib).14,16–18 The exception is the recent REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification), which included more subjects and was performed for longer than previous CETP inhibitor trials. The REVEAL demonstrated that the CETP inhibitor anacetrapib exhibited beneficial effects on cardiovascular outcomes on top of those of statin therapy, although the risk reduction was moderate19,20 and might have been due, at least in part, to a reduction in non-HDL-C rather than elevated HDL-C.21 Considering these cumulative observations, it remains uncertain whether increased HDL-C directly impacts atherosclerosis and the …

Residual Risk of Atherosclerotic Cardiovascular Events in Relation to Reductions in Very-Low-Density Lipoproteins.

BackgroundIt 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.Methods and ResultsIn 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.ConclusionsPharmacological 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.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.