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Introduction: Currently, cardiovascular disease (CVD) drug discovery has focused primarily on addressing the inflammation and immunopathology aspects inherent to various CVD phenotypes such as cardiac fibrosis and coronary artery disease. However, recent findings suggest new biological pathways for cytoskeletal and extracellular matrix (ECM) regulation across diverse CVDs, such as the roles of matricellular proteins (e.g. tenascin-C) in regulating the cellular microenvironment. The success of anti-inflammatory drugs like colchicine, which targets microtubule polymerization, further suggests that the cardiac cytoskeleton and ECM provide prospective therapeutic opportunities., Areas Covered: Potential therapeutic targets include proteins such as gelsolin and calponin 2, which play pivotal roles in plaque development. This review focuses on the dynamic role that the cytoskeleton and ECM play in CVD pathophysiology, highlighting how novel target discovery in cytoskeletal and ECM-related genes may enable therapeutics development to alter the regulation of cellular architecture in plaque formation and rupture, cardiac contractility, and other molecular mechanisms., Expert Opinion: Further research into the cardiac cytoskeleton and its associated ECM proteins is an area ripe for novel target discovery. Furthermore, the structural connection between the cytoskeleton and the ECM provides an opportunity to evaluate both entities as sources of potential therapeutic targets for CVDs.

Background: Cardiovascular disease is an important driver of the increased mortality associated with chronic kidney disease (CKD). Higher left ventricular mass (LVM) predicts increased risk of adverse cardiovascular outcomes and total mortality, but previous reviews have shown no clear association between intervention-induced LVM change and all-cause or cardiovascular mortality in CKD., Methods: The primary objective of this meta-analysis was to investigate whether treatment-induced reductions in LVM over periods ≥12 months were associated with all-cause mortality in patients with CKD. Cardiovascular mortality was investigated as a secondary outcome. Measures of association in the form of relative risks (RRs) with associated variability and precision (95% confidence intervals [CIs]) were extracted directly from each study, when reported, or were calculated based on the published data, if possible, and pooled RR estimates were determined., Results: The meta-analysis included 42 trials with duration ≥12 months: 6 of erythropoietin stimulating agents treating to higher vs. lower hemoglobin targets, 10 of renin-angiotensin-aldosterone system inhibitors vs. placebo or another blood pressure lowering agent, 14 of modified hemodialysis regimens, and 12 of other types of interventions. All-cause mortality was reported in 121/2584 (4.86%) subjects in intervention groups and 168/2606 (6.45%) subjects in control groups. The pooled RR estimate of the 27 trials ≥12 months with ≥1 event in ≥1 group was 0.72 (95% CI 0.57 to 0.90, p = 0.005), with little heterogeneity across studies. Directionalities of the associations in intervention subgroups were the same. Sensitivity analyses of ≥6 months (34 trials), ≥9 months (29 trials), and >12 months (10 trials), and including studies with no events in either group, demonstrated similar risk reductions to the primary analysis. The point estimate for cardiovascular mortality was similar to all-cause mortality, but not statistically significant: RR 0.67, 95% CI 0.39 to 1.16., Conclusions: These results suggest that LVM regression may be a useful surrogate marker for benefits of interventions intended to reduce mortality risk in patients with CKD., (© 2022. The Author(s).)

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide that have been shown to have a strong association with dyslipidemia. Despite efficacious LDL-C lowering therapies, there is evidence of residual CVD risk prompting a need for a novel approach to mitigate CVD. This review aims to provide a comprehensive overview of recent and emerging therapies for various dyslipidemias., (Copyright © 2020. Published by Elsevier Inc.)

Dyslipidemia promotes atherosclerosis and causes cardiovascular diseases. Statins are potent lipid-lowering medications with a cardiovascular mortality benefit. They are generally safe and well tolerated but sometimes can be associated with side effects of variable severity. The most common side effect is statin-associated muscle symptoms. Uncommon side effects include new-onset diabetes mellitus and elevation in liver enzymes. These effects can lead to noncompliance and premature discontinuation of the medication. Hence, it is crucial to identify patients with true statin-associated side effects (SASE) to ensure optimal statin use. The appropriate evaluation of the patient before starting statins and proactive utilization of available diagnostic tests to rule out alternate etiologies mimicking adverse effects are essential for accurate diagnosis of SASE. In patients with true SASE, timely intervention with modified statin or non-statins is beneficial. Herein, we discuss key clinical trial data on statins and non-statins, and describe our center's approach toward patients with SASE.

Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk., Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk., Design, Setting, and Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa., Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins., Main Outcomes and Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization., Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%)., Conclusions and Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients., Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.

The treatment of lipid disorders begins with lifestyle therapy to improve nutrition, physical activity, weight, and other factors that affect lipids. Secondary causes of lipid disorders should be addressed, and pharmacologic therapy initiated based on a patient's risk for atherosclerotic cardiovascular disease (ASCVD). Patients at extreme ASCVD risk should be treated with high-intensity statin therapy to achieve a goal low-density lipoprotein cholesterol (LDL-C) of <55 mg/dL, and those at very high ASCVD risk should be treated to achieve LDL-C <70 mg/dL. Treatment for moderate and high ASCVD risk patients may begin with a moderate-intensity statin to achieve an LDL-C <100 mg/dL, while the LDL-C goal is <130 mg/dL for those at low risk. In all cases, treatment should be intensified, including the addition of other LDL-C-lowering agents (i.e., proprotein convertase subtilisin/kexin type 9 inhibitors, ezetimibe, colesevelam, or bempedoic acid) as needed to achieve treatment goals. When targeting triglyceride levels, the desirable goal is <150 mg/dL. Statin therapy should be combined with a fibrate, prescription-grade omega-3 fatty acid, and/or niacin to reduce triglycerides in all patients with triglycerides ≥500 mg/dL, and icosapent ethyl should be added to a statin in any patient with established ASCVD or diabetes with ≥2 ASCVD risk factors and triglycerides between 135 and 499 mg/dL to prevent ASCVD events. Management of additional risk factors such as elevated lipoprotein(a) and statin intolerance is also described., (© 2020 American Association of Clinical Endocrinologists. Published by Elsevier, Inc. All rights reserved.)

Background and Aims: Guidelines recommend high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). Subgroups with comorbidities that increase cardiovascular risk, such as diabetes mellitus (DM), chronic kidney disease (CKD) or polyvascular disease (PoVD), may derive greater absolute benefit from addition of non-statin therapies. We assessed the relationship between lower low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) risk reduction during alirocumab phase III ODYSSEY trials among these subgroups., Methods: Patient data were pooled from nine trials comparing alirocumab with control (placebo/ezetimibe), predominantly on background maximally tolerated statin. Patients with baseline ASCVD were stratified into subgroups with DM, CKD or PoVD, or without comorbidities, and between-group relative and absolute benefits were compared., Results: Among 3505 patients with ASCVD, 1573 had no comorbidities, 981 had DM, 660 had CKD and 943 had PoVD, with overlap between comorbidities; mean baseline LDL-C levels were 119 (ASCVD overall), 123, 117, 114 and 113 mg/dL, respectively. Overall, each 39 mg/dL lower on-study LDL-C was associated with a 25% lower MACE risk, hazard ratio 0.75 (95% confidence interval, 0.62-0.90, p = 0.0023), with a similar lower risk observed in each very high-risk subgroup (DM, CKD or PoVD; 30-35%) but not in the subgroup without these comorbidities (9%). Absolute benefits were greater for very high-risk subgroups; lowering LDL-C from 120 to 40 mg/dL would result in 2.76-4.35 fewer MACE/100 patient-years versus 0.3 for no comorbidities., Conclusions: Among patients with ASCVD and mean baseline LDL-C >100 mg/dL, patients with DM, CKD or PoVD appeared to derive greater absolute cardiovascular benefits from further LDL-C reduction than those without., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE., Methods: Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies., Results: Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were -25.6% vs. -2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebo-controlled trials, and -21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p=0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79-1.01; p=0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p-interaction vs. Lp(a) < 50 mg/dL: 0.0549)., Conclusions: In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The 2015 Dietary Guidelines for Americans recommend limiting the intake of saturated fatty acids (SFAs) to <10% of energy/d and replacing dietary SFAs with unsaturated fatty acids. A Presidential Advisory from the American Heart Association recently released its evaluation of the relation between dietary fats and cardiovascular disease (CVD), and also recommended a shift from SFAs to unsaturated fatty acids, especially polyunsaturated fatty acids (PUFAs), in conjunction with a healthy dietary pattern. However, the suggestion to increase the intake of PUFAs in general, and omega-6 (n-6) PUFAs in particular, continues to be controversial. This review was undertaken to provide an overview of the evidence and controversies regarding the effects of ω-6 PUFAs on cardiometabolic health, with emphasis on risks and risk factors for CVD (coronary heart disease and stroke) and type 2 diabetes mellitus (T2D). Results from observational studies show that higher intake of ω-6 PUFAs, when compared with SFAs or carbohydrate, is associated with lower risks for CVD events (10-30%), CVD and total mortality (10-40%), and T2D (20-50%). Findings from intervention studies on cardiometabolic risk factors suggest that ω-6 PUFAs reduce concentrations of LDL cholesterol and non-HDL cholesterol in a dose-dependent manner compared with dietary carbohydrate, and have a neutral effect on blood pressure. Despite the concern that ω-6 fatty acids increase inflammation, current evidence from studies in humans does not support this view. In conclusion, these findings support current recommendations to emphasize consumption of ω-6 PUFAs as a replacement of SFAs; additional randomized controlled trials with cardiometabolic disease outcomes will help to more clearly define the benefits and risks of this policy.

Purpose of the Review: To summarize advances in genomic medicine and anticipated future directions to improve cardiovascular risk reduction., Recent Findings: Mendelian randomization and genome-wide association studies have given significant insights into the role of genetics in dyslipidemia and cardiovascular disease (CVD), with over 160 gene loci found to be associated with coronary artery disease to date. This has enabled the creation of genetic risk scores that have demonstrated improved risk prediction when added to clinical markers of CVD risk. Incorporation of genomic data into clinical patient care is on the horizon. Genomic medicine is expected to offer improved risk assessment, determination of targeted treatment strategies, and improved detection of lipid disorders causal to CVD development.

It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels., (© 2018 Wiley Periodicals, Inc.)

Background In statin trials, men and women derived similar relative risk reductions in cardiovascular events per 39 mg/ dL low-density lipoprotein cholesterol ( LDL -C) reduction. We explored whether lower LDL -C levels and greater LDL -C percentage reductions than those achieved with statins are associated with reduced major adverse cardiovascular event ( MACE ) rates in women as well as men. Methods and Results Data pooled from 10 phase 3 ODYSSEY randomized trials (n=4983) comparing alirocumab with control (placebo/ezetimibe) were assessed for association between 39 mg/dL lower on-treatment LDL -C and percentage LDL -C change from baseline, and MACE risk by sex, using multivariable Cox regression. Mean baseline LDL -C was 135 mg/dL (women) and 121 mg/dL (men). Average on-treatment LDL -C levels with alirocumab, ezetimibe, and placebo were 71, 114, and 134 mg/dL, respectively, in women (n=1882) and 52, 93, and 122 mg/dL, respectively, in men (n=3090). Overall, 36.5% and 58.7% of women and men, respectively, achieved on-treatment LDL -C <50 mg/dL. Each 39 mg/dL lower LDL -C was associated with a 33% and 22% lower risk of MACE in women ( P=0.0209) and men ( P=0.0307), respectively, with no significant between-sex difference ( P for heterogeneity=0.4597). Results were similar when analyzed per 50% LDL -C reduction, 24% ( P=0.1094) and 29% ( P=0.0125) lower MACE risk in women and men, respectively ( P for heterogeneity=0.7499). Alirocumab was generally well tolerated in both sexes. Conclusions The present analysis reinforces the notion that both sexes derive a similar cardiovascular benefit from LDL -C lowering. Although women had slightly higher on-treatment LDL -C than men, both sexes showed a similar lower MACE risk with lower LDL -C.

Omega-3 fatty acids have shown modest benefit in certain subgroups at higher cardiovascular risk. Ongoing trials are investigating cardiovascular event rate reduction with newer, more efficacious formulations with a focus on these higher risk patients. This article focuses on the previously demonstrated benefits of omega-3 fatty acid therapies, currently available formulations, and their current and future role in reducing cardiovascular risk., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: A continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls (placebo/ezetimibe), mainly as add-on therapy to maximally tolerated statin., Methods: Data were pooled from 10 double-blind trials (6699 patient-years of follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 taking alirocumab, 1174 taking placebo, 618 taking ezetimibe). In a post hoc analysis, the relationship between average on-treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) in multivariable analyses., Results: Overall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7%-52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event, 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63-0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57-0.89 per additional 50% reduction from baseline; P=0.003). Strengths of association materially similar to those described for LDL-C were observed with achieved non-high-density lipoprotein cholesterol and apolipoprotein B100 levels or percentage reductions., Conclusions: In a post hoc analysis from 10 ODYSSEY trials, greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, and NCT01709513., (© 2016 The Authors.)

The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management placed greater emphasis on statin therapy given the well-established benefits in primary and secondary prevention of cardiovascular disease. Residual risk may remain after statin initiation, in part because of triglyceride-rich lipoprotein cholesterol. Several large trials have failed to show benefit with non-statin cholesterol-lowering medications in the reduction of cardiovascular events. Yet, subgroup analyses showed a benefit in those with hypertriglyceridemia and lower high-density lipoprotein cholesterol level, a high-risk pattern of dyslipidemia. This review discusses the benefits of omega-3 carboxylic acids, a recently approved formulation of omega-3 fatty acid with enhanced bioavailability, in the treatment of dyslipidemia both as monotherapy and combination therapy with a statin., Competing Interests: Michael H Davidson was the Chief Medical Officer of Omthera until June of 2015. Omthera Pharmaceuticals clinically developed omega-3 carboxylic acid for FDA approval and was acquired by Astra Zeneca in July, 2013. The authors report no other conflicts of interest in this work.

Background: Cardiovascular outcomes trials of fibrates, niacin, or omega-3 fatty acids alone, or added to a statin, have not consistently demonstrated reduced risk, but larger, statistically significant clinical benefits have been reported in subgroups with elevated triglycerides (TG) and/or elevated TG plus low high-density lipoprotein cholesterol (HDL-C)., Objective: To perform a meta-analysis of the effects of therapies targeting TG and TG-rich lipoprotein cholesterol on cardiovascular disease event risk in subjects with elevated TG or elevated TG paired with low HDL-C., Methods: Publications were identified using PubMed, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform, and Internet Stroke Center. Random-effects meta-analysis models were used to generate summary relative risk estimates and 95% confidence intervals. Heterogeneity was assessed by χ(2) and I(2) statistics, and the impact of each trial was assessed in one study-removed sensitivity analyses., Results: Six trials of fibrates, 2 of niacin, 1 of fibrate + niacin, and 1 of omega-3 eicosapentaenoic acid ethyl esters were identified. For the prespecified primary cardiovascular disease or coronary heart disease end point used in each trial, the summary relative risk estimate (95% confidence interval) for subjects with elevated TG was 0.82 (0.73-0.91), p-heterogeneity = 0.13, I(2) = 36.2, and for subjects with elevated TG and low-HDL-C, it was 0.71 (0.63-0.81), p-heterogeneity = 0.52, I(2) = 0.0. There was no evidence of publication bias, and the results remained statistically significant when each individual trial was removed., Conclusion: Drugs that substantially, but not exclusively, lower TG and TG-rich lipoprotein cholesterol may have cardiovascular benefits in individuals with elevated TG, particularly if accompanied by low HDL-C., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

The inverse relationship between high-density lipoprotein cholesterol (HDL-C) concentrations and coronary heart disease risk is well established. As a result, in recent years there have been significant resources focused on identifying therapies that raise HDL-C and ultimately reduce cardiovascular events. Unfortunately, a number of trials aimed at increasing HDL-C have failed to show improved outcomes, and hence, have cast doubt on the importance of HDL-C as a therapeutic target. HDL-C, however, is only one measure of HDL. HDL levels can also been estimated by quantifying apolipoprotein A-I (apoA-I) levels using enzyme immunoassay or by measuring HDL particle number (HDL-P) using nuclear magnetic resonance spectroscopy (NMR) or ion mobility. While these surrogate measures are correlated, they are not comparable. Lipoprotein-altering therapies have been shown to have different effects on HDL-C, apoA-I and HDL-P and several studies have demonstrated that HDL-P is a stronger predictor of coronary heart disease risk than HDL-C and/or apoA-I. This paper will review available evidence supporting the use of HDL-P as the biomarker of choice to assess the contribution of HDL to cardiovascular risk and as the primary goal of HDL-raising therapies.

Triglycerides represent 1 component of a heterogeneous pool of triglyceride-rich lipoproteins (TGRLs). The reliance on triglycerides or TGRLs as cardiovascular disease (CVD) risk biomarkers prompted investigations into therapies that lower plasma triglycerides as a means to reduce CVD events. Genetic studies identified TGRL components and pathways involved in their synthesis and metabolism. We advocate that only a subset of genetic mechanisms regulating TGRLs contribute to the risk of CVD events. This "omic" approach recently resulted in new targets for reducing CVD events., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardiovascular (CV) disease remains the major cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). The pathogenesis of CV disease in T2DM is complex and multifactorial, and includes abnormalities in endothelial cells, vascular smooth muscle cells, myocardium, platelets, and the coagulation cascade. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of agents that act by potentiating the action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. This review summarizes CV disease pathophysiology in T2DM and the potential effect of DPP-4 inhibitors on CV risk in patients with T2DM. Preclinical and small observational studies and post hoc analyses of clinical trial data suggest that DPP-4 inhibitors may have beneficial CV effects. Some effects of DPP-4 inhibitors are GLP-1 dependent, whereas others may be due to GLP-1-independent actions of DPP-4 inhibitors. Analyses of major adverse CV events occurring during clinical development of DPP-4 inhibitors found no increased risk of CV events or mortality and even a potential reduction in CV events. Two large CV outcome trials have been completed and report that saxagliptin and alogliptin did not increase or decrease adverse CV outcomes in patients with T2DM and CV disease or at high risk for adverse CV events. More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure, and there was a similar numerically increased risk of hospitalization for heart failure with alogliptin; however, the risk was not significantly greater compared with placebo. Dipeptidyl peptidase-4 inhibitors may affect some of the pathologic processes involved in the increased CV risk inherent in T2DM.

The aim of this analysis was to evaluate changes in cardiovascular risk factors in obese patients with dyslipidemia and/or hypertension receiving phentermine (PHEN) and topiramate extended-release (TPM ER). In the 56-week, randomized, double-blind, placebo-controlled, multicenter CONQUER trial, PHEN/TPM ER demonstrated significant weight loss compared with placebo in overweight or obese participants with ≥2 weight-related co-morbidities. Participants with body mass indexes of 27 to 45 kg/m(2) were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg, or PHEN 15 mg/TPM ER 92 mg; participants also received lifestyle modification counseling. Primary end points were percentage weight loss and the proportion of participants achieving ≥5% weight loss. Additional end points were changes in lipid variables in the dyslipidemia population and blood pressure in the hypertensive population, stratified by treatment and magnitude of weight loss. PHEN/TPM ER produced significantly greater dose-related mean percentage weight loss compared with placebo in the subgroups of participants with dyslipidemia and those with hypertension. Regardless of treatment group assignment, participants with dyslipidemia who lost ≥5% of their baseline weight experienced significantly greater reductions in triglycerides (-14.5% to -39.8%), and in non-high-density lipoprotein cholesterol (-9.4% to -14.8%) than those losing <5% of their weight (p <0.05). Similarly, participants with hypertension at baseline showed reduced systolic blood pressure by -7.5 to -11.8 mm Hg (p <0.001 vs those with <5% weight loss). In conclusion, the dose-related weight loss induced by PHEN/TPM ER treatment was accompanied by significant improvements in cardiovascular disease risk factors in participants who had dyslipidemia or hypertension at baseline, suggesting that facilitating weight loss by augmenting lifestyle changes with pharmacotherapies may decrease the risk for cardiovascular disease in obese and overweight patients with co-morbidities., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder, associated with elevated levels of low-density lipoprotein-cholesterol (LDL-C), which can lead to premature cardiovascular disease. Early diagnosis of FH is important to prevent morbidity and mortality. Familial hypercholesterolaemia is usually diagnosed using clinical characteristics, such as family history, and cholesterol levels; however, genetic testing may provide a definite diagnosis of FH by detecting a pathological mutation. Current guidelines highlight the importance of reducing LDL-C levels in patients with FH. Statins are the current standard treatment for the majority of these patients, and have been shown to be effective in reducing the incidence of cardiovascular heart disease in patients with FH. Nevertheless, many FH patients do not achieve their target LDL-C levels; as such, new treatment options are required to decrease LDL-C levels beyond those currently achieved. There are currently several new classes of pharmacotherapy under investigation to control LDL-C levels. These include agents which modify LDL-C production, such as inhibitors of apolipoprotein B, or those which affect LDL-C catabolism, such as inhibition of pro-protein convertase subtilisin/kexin 9, a protein which is responsible for the degradation of the LDL receptor. Therapies which raise high-density lipoprotein cholesterol are also being evaluated. In this article, we consider the diagnosis of FH and the goals of therapy and review the current and potential future treatment options for patients with FH.

In patients with diabetes mellitus (DM), a cardiovascular event is of critical concern because of the impact on long-term survival. Cardiovascular disease (CVD) is the leading cause of death for patients with DM, which makes the modification of risk factors in the patient with DM and CVD a primary focus of the preventive cardiologist. Management of this patient population should include pharmacologic interventions, such as antidyslipidemics (mainly statins) and oral anti-DM (or insulin) agents, as well as diet control, physical exercise, and smoking cessation. It is hoped that focus on the ABCs of treatment--hemoglobin A(1c), blood pressure, and cholesterol-lipid profile--along with ongoing and future studies on the effects of these interventions will help to reduce the significant morbidity and mortality from microvascular and macrovascular complications in these high-risk patients with DM., (Copyright © 2012 Elsevier Inc. All rights reserved.)

With the increasing use of drug therapy and lifestyle modification for primary and secondary prevention of cardiovascular disease, there remain questions on how to quantify residual risk, particular in patients with diabetes mellitus or obesity. Clinicians have turned to other screening modalities to identify individuals who would benefit from even more intensive therapy or to identify those with difficult-to-assess risk factors. Once a patient has been identified for aggressive risk factor modification, lipid biomarkers such as Apo B, LDL-P, and Lp (a) can potentially have clinical utility, and inflammatory markers such as hs-CRP may be useful for evaluating residual risk.

The National Cholesterol Education Program Adult Treatment Panel guidelines have established low-density lipoprotein cholesterol (LDL-C) treatment goals, and secondary non-high-density lipoprotein (HDL)-C treatment goals for persons with hypertriglyceridemia. The use of lipid-lowering therapies, particularly statins, to achieve these goals has reduced cardiovascular disease (CVD) morbidity and mortality; however, significant residual risk for events remains. This, combined with the rising prevalence of obesity, which has shifted the risk profile of the population toward patients in whom LDL-C is less predictive of CVD events (metabolic syndrome, low HDL-C, elevated triglycerides), has increased interest in the clinical use of inflammatory and lipid biomarker assessments. Furthermore, the cost effectiveness of pharmacological intervention for both the initiation of therapy and the intensification of therapy has been enhanced by the availability of a variety of generic statins. This report describes the consensus view of an expert panel convened by the National Lipid Association to evaluate the use of selected biomarkers [C-reactive protein, lipoprotein-associated phospholipase A(2), apolipoprotein B, LDL particle concentration, lipoprotein(a), and LDL and HDL subfractions] to improve risk assessment, or to adjust therapy. These panel recommendations are intended to provide practical advice to clinicians who wrestle with the challenges of identifying the patients who are most likely to benefit from therapy, or intensification of therapy, to provide the optimum protection from CV risk., (Copyright © 2011 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Prospective studies of coronary heart disease patients with disorders of insulin resistance, metabolic syndrome (MetSyn) and type 2 diabetes (T2DM), have shown that these patients usually display high levels of low-density lipoprotein particles (LDL-P) and low levels of high-density lipoprotein particles (HDL-P). In multiple prospective studies, high levels of LDL-P are more predictive of CHD risk than low-density lipoprotein cholesterol (LDL-C). The conventional goal of lipid lowering treatment is to lower LDL-C levels; however LDL-C is unrelated to the severity of insulin resistance. Among high cardiometabolic risk patients with LDL-C <100 mg/dL, about two-thirds of patients have a high LDL-P (>1000 nmol/L) despite this "optimal" level of LDL-C. For high cardiometabolic risk patients, LDL-P should be considered a primary goal of therapy due to its stronger association with cardiovascular risk. Further, we propose that certain lipid-altering therapies may be particularly useful in reducing cardiovascular events in statin-treated patients, not simply due to their improvement in LDL-C goal attainment, but due to their effects on lowering the number of low-density lipoprotein particles (LDL-P)., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The high-density lipoproteins (HDLs) are complex, polymolecular assemblies produced by the jejunum, liver, in serum, and on the surface of macrophages. HDL cholesterol (HDL-C) levels are an independent predictor of risk for cardiovascular events in both men and women. High serum levels of this lipoprotein are associated with reduced risk for atherosclerosis and its clinical sequelae, such as myocardial infarction, ischemic stroke, and death. The molecular basis for the apparent vasculoprotection afforded by elevated HDL-C is widely attributed to the ability of HDL particles to drive reverse cholesterol transport. The proteosome (protein cargo) of HDL also appears to endow this lipoprotein with a capacity to reduce oxidized lipids, promote endothelial cell nitric oxide production, reduce adhesion molecule expression, inhibit platelet activation, stimulate endothelial proliferation and inhibit apoptosis, and reduce inflammatory mediator expression, among other functions. Recent investigation suggests that among patients with coronary artery disease, HDL can also be dysfunctional, yielding a pro-inflammatory and pro-oxidative phenotype. Numerous drugs are currently in development in an effort to devise the means by which to optimally increase serum levels of functional, antiatherogenic HDL species. These drugs exploit a diverse range of mechanisms with potential for beneficially impacting the development and progression of atherosclerotic disease., (Copyright © 2010 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

It is well established that low high-density lipoprotein (HDL) cholesterol is a risk factor for coronary artery disease (CAD). Growing evidence from epidemiologic as well as intervention studies have identified that a low level of HDL cholesterol contributes to cardiovascular disease risk. In addition, a number of clinical trials have substantiated that an inverse association between HDL cholesterol concentrations and cardiovascular risk exists. Decreasing low-density lipoprotein cholesterol levels with statins has a major impact on cardiovascular risk reduction, and statin therapy plays a significant role in the management of CAD. However, low levels of HDL cholesterol remain as a cardiovascular risk factor despite statin therapy. This article presents an overview of statin clinical trials and discusses implications for the clinical management of patients with low HDL cholesterol levels and increased cardiovascular risk.

Apolipoprotein (apo) B may be a more sensitive measure of atherogenicity than low-density lipoprotein cholesterol (LDL-C) and a better index for assessing cardiovascular risk. The refined risk assessment provided by apo B may be important in patients at high cardiometabolic risk such as those with diabetes mellitus or metabolic syndrome, as these conditions are often associated with normal LDL-C values but increased numbers of small, dense low-density lipoprotein (LDL) particles (indicating increased levels of apo B). Although apo B is not currently a treatment target in the United States cholesterol-lowering guidelines, a consensus conference endorsed by the American Diabetes Association and the American College of Cardiology recently recommended that apo B be added as a therapeutic target in patients at high cardiometabolic risk and in patients with clinical cardiovascular disease or diabetes. Suggested target goals are < 90 for high risk and < 80 mg/dL for highest risk patients. Current clinical data indicate that intensive statin therapy can lower apo B to meet this aggressive goal. While the proatherogenic/antiatherogenic ratio of apo B/apo A-I is a better risk discriminator than the single proatherogenic measurement (apo B), clinical trial data are lacking regarding the impact of increasing apo A-I and high-density lipoprotein on outcomes., (Copyright 2009 Wiley Periodicals, Inc.)

Purpose of Review: To summarize the available data regarding the benefits of combination therapy with statins and ezetimibe in patients with cardiovascular disease., Recent Findings: Extensive evidence, mostly in statin outcome trials, has shown that the magnitude of cardiovascular benefit is directly proportional to the degree of LDL cholesterol (LDL-C) reduction. As such, aggressive target goals for LDL-C levels have been established by guideline committees. Although statins are considered first-line agents in lipid therapy, LDL-C targets are difficult to achieve with statin therapy alone. Ezetimibe, a cholesterol absorption inhibitor, has been shown to be well tolerated and effective in lowering LDL-C. Adding ezetimibe to ongoing statin therapy leads to a substantial additional reduction in LDL-C, facilitating the achievement of target goals., Summary: The combination of ezetimibe, a cholesterol absorption inhibitor, and statins has been shown to be well tolerated and effective in lowering LDL-C and high-sensitivity C-reactive protein to target goals. Whether this greater LDL-C reduction translates into reduced cardiovascular events is the subject of ongoing clinical trials. Until such data is available, ezetimibe seems to be a reasonable choice for a second-line, lipid-lowering agent in patients on a potent statin who are not at their LDL-C goal.

Identification of the widely accepted cardiovascular risk factors of age, sex, hypertension, hyperlipidemia, smoking, obesity, diabetes, and physical inactivity from the Framingham Heart Study have led to dramatic reductions in cardiovascular morbidity and mortality. The Framingham estimation of coronary heart disease remains the mainstay of clinical risk assessment. However, novel risk predictors present opportunities to identify more patients at risk and to more accurately define that risk. Such predictors include lipoprotein analysis, measurement of lipoprotein-associated phospholipase A(2) and C-reactive protein, and assessment of hyperglycemia, liver function, and central obesity. Vascular imaging can also provide useful risk information. Using Framingham as a basis, several international groups have developed risks-coring systems that more closely reflect their individual populations and the clinical practicalities of their countries. When used accordingly, the newer risk predictors build upon the Framingham framework to allow physicians and their patients to effectively minimize, or even avoid, the burden of cardiovascular disease.

High-sensitivity assays that accurately measure levels of the inflammatory biomarker C-reactive protein have been proposed for use in assessments of risk for cardiovascular disease (CVD). A growing body of evidence supports recommendations for these tests in selected asymptomatic individuals deemed to be at intermediate risk of CVD according to traditional risk-factor assessments and who do not already warrant chronic treatment with aspirin and statin therapy. Data suggests that these high-sensitivity assays should be used in combination with measurements of LDL-cholesterol levels to assist risk stratification of selected patients for prevention of CVD.

A substantial body of peer-reviewed studies has been published validating the role of inflammation in atherogenesis and supporting lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) as a cardiovascular risk marker independent of and additive to traditional risk factors. As with elevated high-sensitivity C-reactive protein, an elevated Lp-PLA(2) level approximately doubles the risk for primary and secondary cardiovascular events. Interestingly, when both inflammatory markers are increased together, they provide an even greater predictive capability to help identify very-high-risk individuals who would benefit most from aggressive lipid-lowering therapy. High levels of Lp-PLA(2) are present in inflamed, rupture-prone plaques, and it appears that Lp-PLA(2) is released from these plaques into the circulation. Over 25 prospective epidemiologic studies have demonstrated the association of elevated Lp-PLA(2) levels with future coronary events and stroke-11 of 12 prospective studies have shown a statistically significant association between elevated Lp-PLA(2) and primary coronary or cardiovascular events, 12 of 13 have shown a statistically significant association with recurrent coronary or cardiovascular events, and 6 studies have shown a positive association with stroke. Lp-PLA(2) should be viewed today as an important cardiovascular risk marker whose utility is as an adjunct to the major risk factors to adjust absolute risk status and thereby modify low-density lipoprotein cholesterol goals. The low biologic fluctuation and high vascular specificity of Lp-PLA(2) makes it possible to use a single measurement in clinical decision making, and it also permits clinicians to follow the Lp-PLA(2) marker serially. Ultimately, Lp-PLA(2) may also be classified as a risk factor, but this should not detract from its utility today as a risk marker.

A consensus panel was formed to review the rapidly emerging literature on the vascular-specific inflammatory marker lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and to update recommendations for the appropriate use of this novel biomarker in clinical practice. The recommendations of the panel build on guidelines of the Adult Treatment Panel III (ATP III) and the American Heart Association/Centers for Disease Control (AHA/CDC) for cardiovascular risk assessment. Consistent with the ATP III guideline recommendations for the use of inflammatory markers, Lp-PLA(2) is recommended as an adjunct to traditional risk assessment in patients at moderate and high 10-year risk. A simplified framework for traditional Framingham risk factor assessment is proposed. As a highly specific biomarker for vascular inflammation, elevated Lp-PLA(2) levels should prompt consideration of increasing the cardiovascular risk category from moderate to high or high to very high risk, respectively. Because intensification of lifestyle changes and low-density lipoprotein (LDL) cholesterol lowering is beneficial in high-risk patients, regardless of baseline LDL cholesterol levels, consideration should be given to lowering the LDL cholesterol target by 30 mg/dL (1 mg/dL = 0.02586 mmol/L) in patients with high levels of Lp-PLA(2). Lp-PLA(2) is recommended as a diagnostic test for vascular inflammation to better identify patients at high or very high risk who will benefit from intensification of lipid-modifying therapies. However, at this time Lp-PLA(2) cannot be recommended as a target of therapy.

In patients with symptomatic coronary heart disease, skin cholesterol (SC) content is associated with the presence and extent of coronary artery disease; however, its relation to subclinical arterial disease in asymptomatic patients is unknown. The purpose of this study was to determine the relations between SC and carotid intima-media thickness (CIMT) in asymptomatic subjects across a wide range of cardiovascular risk. SC was measured using a noninvasive assay. CIMT and carotid plaque presence were determined by high-resolution B-mode ultrasound. Associations among SC, CIMT, carotid plaque presence, and cardiovascular risk factors were evaluated by multivariable logistic regression analyses. SC and CIMT were measured in 565 asymptomatic subjects (57 +/- 10 years of age, 38% women) from 6 sites in North America. The mean Framingham 10-year cardiovascular risk was 8.4 +/- 7.2%. A 10-U increase in SC was associated with a 12% increase in the odds of having increased CIMT (p = 0.006) and a 15% increase in carotid plaque presence (p = 0.002). Odds ratios (95% confidence intervals) associated with SC >110 U were 2.19 (1.25 to 3.85, p = 0.006) for increased CIMT and 2.89 (1.61 to 5.19, p <0.001) for carotid plaque presence. In conclusion, SC identified the presence of advanced subclinical atherosclerosis. The relations among increasing SC, increasing CIMT, and carotid plaque presence were consistent across all levels of cardiovascular risk and were independent of cardiovascular risk factors. SC may be a useful test for cardiovascular risk prediction.

Cardiovascular (CV) disease is the leading cause of mortality and one of the leading causes of disability worldwide. Its economic burden is enormous, and the estimated direct and indirect costs of the disease in 2006 exceeded $400 billion. Low-density lipoprotein cholesterol is recognized as a major cause of coronary heart disease and other clinical forms of atherosclerotic disease, and an elevated low-density lipoprotein cholesterol level remains the primary target of lipid-lowering therapy. Recent retrospective evidence points to deficiencies in the management of patients with atherosclerosis in the clinical practice setting. Enhancing awareness of the need to monitor and treat dyslipidemia in atherosclerosis, and of the benefits of such treatment reported in recent studies, may help to narrow this treatment gap. This review will examine the development of atherosclerosis and the role atherosclerosis plays in the underlying pathophysiology of CV disease. Imaging methods for assessing progression of atherosclerosis and new recommendations for risk-reduction therapy in patients with established atherosclerotic vascular disease are discussed. Emphasis is on newer data regarding the effect of statins in retarding progression of atherosclerosis or even inducing regression of atherosclerosis.

The association between low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and the development of coronary heart disease (CHD) is well established. The management of CHD has traditionally focused on the reduction of LDL cholesterol or on the total lipid profile. Yet, treatment strategies for reducing risk in CHD also requires a focus on increasing low HDL cholesterol, as LDL cholesterol reduction alone is insufficient in preventing CHD events. This article reviews the strategies for targeting HDL cholesterol to optimize outcomes in CHD.

Background: Lowering the dietary glycemic load and increasing protein intake may be advantageous for weight management., Objective: This randomized controlled trial was designed to evaluate the effects of an ad libitum reduced-glycemic-load (RGL) diet on body weight, body composition, and cardiovascular disease (CVD) risk markers in overweight and obese adults during an initial weight-loss phase (12 wk) and a weight-loss maintenance phase (weeks 24-36)., Design: Subjects were assigned to RGL (n = 43) or low-fat, portion-controlled (control; n = 43) diet groups. The RGL group was instructed to eat until satisfied, maintaining a low carbohydrate intake during weeks 0-2 and adding low-glycemic-index carbohydrate thereafter. Control subjects were instructed to reduce fat intake and decrease portion sizes, with a targeted energy deficit of 500 to 800 kcal/d., Results: The RGL group had lost significantly more weight than did the control group at week 12 (-4.9 and -2.5 kg, respectively; P = 0.002), but the 2 groups did not differ significantly at week 36 (-4.5 and -2.6 kg, respectively; P = 0.085). Changes in fat mass differed between the groups at week 12 (-1.9 and -0.9 kg, respectively; P = 0.016) but not at week 36 (-2.0 and -1.3 kg, respectively; P = 0.333). At the end of the study, no differences were found in responses for CVD risk markers except a larger mean change in HDL cholesterol in the RGL group than in the control group (3.8 and 1.9 mg/dL, respectively; P = 0.037)., Conclusion: These findings provide evidence that an ad libitum RGL diet is a reasonable alternative to a low-fat, portion-controlled eating plan for weight management.

Background: Type 2 diabetes (T2DM) is a major risk factor for developing cardiovascular disease (CVD). The growing epidemic of T2DM has contributed to CVD becoming the leading cause of morbidity and mortality in the United States., Objective: To review the pathophysiology of CVD; to demonstrate the interrelatedness of CVD, the metabolic syndrome, and T2DM; and to discuss treatment options that may reduce the risk of CVD in patients with T2DM., Summary: Recent data from the International Diabetes Federation show that the worldwide prevalence of T2DM is much higher than previously estimated. Managing patients with T2DM continues to severely burden the U.S. health care system. Furthermore, most costs associated with managing these patients are associated with treating CVD complications. Studies have shown that several agents can decrease the risk of CVD in patients with T2DM., Conclusions: To combat the diabetes epidemic, clinicians should treat patients with T2DM and prediabetes early and aggressively to control their metabolic disturbances and reduce the risk of CVD. Diet, exercise, and several pharmacologic agents have been shown to reduce the risk of CVD.

It is well established that aggressive risk factor modification results in improved cardiovascular disease (CVD) outcomes. Yet, patients with type 2 diabetes mellitus have a much higher baseline risk for cardiovascular events. As type 2 diabetes and hypertension commonly coexist, achieving recommended targets for diabetes, hypertension, and CVD requires aggressive management. Global risk reduction with aggressive low-density lipoprotein reduction and through the additional normalization of glucose levels and blood pressure can help to reduce absolute risk in this very high-risk population.