Residual Cardiovascular Disease Risk Research Articles

Relative Contributions of Arterial Stiffness and Hypertension to Cardiovascular Disease: The Framingham Heart Study.

BackgroundThe presence and implications of abnormal arterial stiffness, a potential independent predictor of outcomes, in community‐dwelling treated hypertensives is unknown. Furthermore, limited data exist regarding the risk of cardiovascular disease (CVD) associated with arterial stiffness across the entire range of blood pressure.Methods and ResultsWe measured carotid‐femoral pulse wave velocity (PWV) and classical CVD risk factors in 2127 community‐dwelling participants (mean age 60 years, 57% women) of The Framingham Offspring Cohort. The participants were divided into 4 groups according to hypertension (yes/no, defined as blood pressure ≥140/90 mm Hg or use of antihypertensive treatment) and PWV status (high/low based on age‐ and sex‐specific median values) and followed up for CVD events (CVD death, myocardial infarction, unstable angina, heart failure, and stroke). Sixty percent (233 of 390) of controlled and 90% (232 of 258) of uncontrolled treated hypertensives had high PWV. The multivariable‐adjusted risk for CVD events (n=248, median follow‐up 12.6 years) rose from normotension with low PWV (reference) to normotension with high PWV (hazard ratio 1.29, 95% CI 0.83–2.00) and from hypertension with low PWV (hazard ratio 1.54, 95% CI 1.01–2.36) to hypertension with high PWV (hazard ratio 2.25, 95% CI 1.54–3.29).ConclusionsA substantial proportion of treated hypertensives have high arterial stiffness, a finding that may explain some of the notable residual CVD risk associated with even well‐controlled hypertension. High PWV is associated with a trend towards increasing CVD risk in both nonhypertensives and hypertensives, a finding that may support the use of arterial stiffness measurements in both populations.

Abstract 108: Relative Contributions of Arterial Stiffness and Hypertension to CVD Risk: The Framingham Heart Study

Introduction: The presence and implications of abnormal arterial stiffness, a potential independent predictor of outcomes, in community-dwelling treated hypertensives is unknown. Furthermore, limited data exist regarding the risk of cardiovascular disease (CVD) associated with arterial stiffness across the entire range of blood pressure. Methods: We measured carotid-femoral pulse wave velocity (PWV) and classical CVD risk factors in participants of The Framingham Offspring Cohort. The participants were divided into 4 groups according to hypertension (yes/no), and PWV status (high/low based on age- and sex-specific median values) and followed up for CVD events (CVD death, myocardial infarction, unstable angina, heart failure, and stroke). Results: We studied 2127 community-dwelling individuals (60 years, 57% women). 60% (233 of 390) of controlled and 90% (232 of 258) of uncontrolled treated hypertensives had high PWV. The multivariable-adjusted risk for CVD events ( n =248, median follow-up 12.6 years; Figure) rose from normotension with low PWV (reference) to normotension with high PWV (hazard ratio [HR] 1.33, 95% confidence interval [95% CI] 0.86-2.05) and from hypertension with low PWV (HR 1.53, 95% CI 1.00-2.34) to hypertension with high PWV (HR 2.31, 95% CI 1.58-3.36). Conclusions: A substantial proportion of treated hypertensives have high arterial stiffness, a finding that may explain some of the notable residual CVD risk associated in this group. High PWV is associated with a trend towards increasing CVD risk in both non-hypertensives and hypertensives supporting the use of arterial stiffness measurements in both populations.

Abstract 428: Lipoprotein(a) Targeting With RNAi Delivery Platforms in Transgenic Mice and Cynomolgus Monkeys

Background: Meta-analyses of clinical studies have demonstrated that high levels of lipoprotein(a), known as Lp(a), correlate with residual risk of cardiovascular disease (CVD) while Mendelian genetic studies indicate that Lp(a) is an independent cause of CVD. Lp(a) is a complex lipoprotein particle similar in structure to LDL (consisting of cholesterol, triglycerides, phospholipids and apoB-100), but contains the genetically variable liver-expressed protein apo(a). Lp(a) may contribute to atherosclerosis by targeting oxidized phospholipids to vascular injury sites, promoting both inflammation and accumulation of lipids. Methods: RNA interference (RNAi) based approaches for reducing liver apo(a) expression were developed using both a targeted intravenous platform called Dynamic Polyconjugates (DPC) TM and a subcutaneous (SQ) format. The DPC platform comprises an RNAi trigger conjugated to cholesterol, and a hepatocyte-targeted, membrane active peptide to promote endosomal release of the RNAi trigger. The SQ platform is an RNAi trigger targeted to liver by N-acetyl galactosamine in a proprietary format. RNAi activity was assessed in two different humanized transgenic mice and cynomolgus monkeys. Results: In Lp(a) transgenic mice expressing human apo(a) and apoB-100 genes, treatment with a single DPC dose reduced serum Lp(a) by >98% at nadir and >90% for >5 weeks. A single DPC injection in cynomolgus monkeys resulted in >95% reduction in endogenous Lp(a) particles at 5 weeks post injection, without significant changes in toxicity biomarkers. Treatment with a SQ RNAi trigger reduced serum apo(a) in transgenic mice by >90% at nadir, while that in monkeys reached 64% reduction of Lp(a). Additional modifications to the RNAi trigger improved both depth and duration of knockdown in transgenic mice. Conclusion: Long-duration reductions in circulating apo(a) and Lp(a) have been shown with hepatocyte-directed delivery of apo(a)-specific RNAi triggers in mice and monkeys. This represents an intriguing mechanism to evaluate in humans for reducing residual risk of CVD in LDL-controlled individuals with elevated Lp(a).

PCSK9 inhibitors in the prevention of cardiovascular disease.

Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, lack of efficacy and adverse effects mean that a substantial proportion of patients fail to achieve acceptable LDL-C levels with currently available lipid-lowering drugs. Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic strategy to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the receptor for lysosomal degradation. The recognition that inhibition of PCSK9 increases LDL receptor activity has led to the development of a number of approaches to directly target PCSK9. Numerous monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials, involving various patient categories on different background lipid-lowering therapies. Current evidence shows reductions in LDL-C levels of up to 70 % may be achieved with PCSK9 inhibition, independent of background statin therapy. This review examines the most recent evidence and future prospects for the use of PCSK9 inhibitors in the prevention of cardiovascular disease.

Prescription omega-3 fatty acid products: considerations for patients with diabetes mellitus.

Type 2 diabetes mellitus (T2DM) and metabolic syndrome contribute to hypertriglyceridemia, which may increase residual risk of cardiovascular disease in patients with elevated triglyceride (TG) levels despite optimal low-density lipoprotein cholesterol (LDL-C) levels with statin therapy. Prescription products containing the long-chain omega-3 fatty acids (OM3FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are an effective strategy for reducing TG levels. This article provides an overview of prescription OM3FAs, including relevant clinical data in patients with T2DM and/or metabolic syndrome. Prescription OM3FAs contain either combinations of DHA and EPA (omega-3-acid ethyl esters, omega-3-carboxylic acids, omega-3-acid ethyl esters A) or EPA alone (icosapent ethyl). These products are well tolerated and can be used safely with statins. Randomized controlled trials have demonstrated that all prescription OM3FAs produce statistically significant reductions in TG levels compared with placebo; however, differential effects on LDL-C levels have been reported. Products containing DHA may increase LDL-C levels, whereas the EPA-only product did not increase LDL-C levels compared with placebo. Because increases in LDL-C levels may be unwanted in patients with T2DM and/or dyslipidemia, the EPA-only product should not be replaced with products containing DHA. Available data on the effects of OM3FAs in patients with diabetes and/or metabolic syndrome support that these products can be used safely in patients with T2DM and have beneficial effects on atherogenic parameters; in particular, the EPA-only prescription product significantly reduced TG, non-high-density lipoprotein cholesterol, Apo B, remnant lipoprotein cholesterol, and high-sensitivity CRP levels without increasing LDL-C levels compared with placebo. Ongoing studies of the effects of prescription OM3FAs on cardiovascular outcomes will help determine whether these products will emerge as effective add-on options to statin therapy for reduction of residual cardiovascular disease risk.

HDL therapies — past, present and future

For a number of years, high-density lipoprotein (HDL) has been recognized to have an athero-protective role by promoting reverse lipid transport, a process facilitating the cholesterol efflux from atherosclerotic plaques in the artery wall and its elimination by the liver via biliary excretion. On the contrary, low-density lipoprotein (LDL) particles carry cholesterol to the organs and tissues where it can be used to produce hormones or maintain cell metabolism. When an imbalance develops, as a result of either an excess level of cholesterol associated with LDL (LDL-C) or a less effective cholesterol elimination by HDL (HDL-C), this causes an excess of cholesterol to be transported to the tissues and promotes the deposition of cholesterol. This often occurs in the artery walls, particularly in the coronary arteries. There is no approved medical treatment for directly suppressing or treating the atherosclerotic plaque once it is formed. Epidemiological studies have shown that the risk of developing cardio-vascular disease (CVD) is higher in patients with low levels of HDL-C regardless of LDL-C levels, even in patients optimally treated with LDL-C-lowering therapies. These data highlight that low HDL-C and low HDL particle number is an important target of therapies aiming to reduce the residual risk of CVD.

Abstract 16001: Relationship Between Serum n-3 to n-6 Poly-unsaturated Fatty Acid Ratios and Coronary Plaque Components Identified by iMap-Intravascular Ultrasound in Patients With Stable Angina Pectoris

Background: Residual risk of cardiovascular disease exists even in patients achieving low-density lipoprotein cholesterol (LDL-C) goals. A low value of serum eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio is well known to be associated with cardiovascular events. However, the association between serum EPA/AA ratio and coronary plaque components has not been fully investigated. Purpose: We evaluated the relationships between serum EPA/AA ratio and coronary plaque morphology on iMap-intravascular ultrasound (IVUS) which is a 40 MHz IVUS tissue characteristic system. Methods: We investigated 80 consecutive coronary culprit lesions with stable angina pectoris (SAP) patients, who underwent pre-intervention iMap-IVUS. All patients were divided into two groups; groups with higher values of the median EPA/AA ratio and lower values of the median EPA/AA ratio. We assessed the relationship between the two groups. Results: Median values of EPA, AA and EPA/AA ratio were 67.5 (44.3-100.3) μg/ml, 174.2 (145.5-202.9) μg/ml, and 0.38 (0.23-0.60). Patients in lower EPA/AA ratio group (<0.38) showed younger age (65±11 vs 70±6, p=0.02), more OMI patients (40 vs 18%, p=0.03), higher value of LDL-C (94.5±29.3 vs 80.9±26.5 mg/dl, p=0.03), lower ejection fraction (61.4±8.8 vs 65.4±7.2%, p=0.04), greater lesion plaque area (11.5±4.4 vs 9.6±4.4 mm2, p<0.05), compared with higher EPA/AA ratio group. In multivariate analysis, LDL-C value was an independent predictor of lower EPA/AA ratio (odds ratio 1.02, 95% confidence interval 1.00-1.04, p= 0.04). In lower LDL-C group (<70 mg/dl), EPA/AA inversely correlated with %-necrotic area and volume (r=-0.56, p=0.004, and r=-0.54, p=0.01), and positively correlated with %-fibrotic area and volume (r=0.57, p=0.003, and r=0.54, p=0.01), although EPA/AA ratio did not correlate with plaque components in higher LDL-C groups. In lower LDL-C group, for prediction of the highest %-necrotic volume tertile (>42.1%), cut-off value of EPA/AA ratio was 0.20 (sensitivity 50%, specificity 94%, area under the curve 0.77, p=0.02). Conclusion: serum EPA/AA ratio may be related to plaque components at the culprit site in SAP patients with low LDL-C values.

PCSK9 inhibition: the way forward in the treatment of dyslipidemia.

Barely a decade after the discovery of the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and its recognition as a key player in cholesterol metabolism, PCSK9 inhibition is now considered an exciting approach in the reduction of residual risk of cardiovascular disease. The progress from PCSK9 discovery to the development of targeted treatment has been unprecedented in terms of scale and speed. The first suggestion of a link between PCSK9 and hypercholesterolemia was published in 2003; a decade later, two meta-analyses of clinical trials comparing anti-PCSK9 treatment to placebo or ezetimibe, including >10,000 hypercholesterolemic individuals, were published. Currently, three PCSK9 inhibitors are being evaluated in clinical outcome trials and the results will determine the future of these lipid-lowering therapies by establishing their clinical efficacy in terms of cardiovascular event reduction, safety, and the consequences of prolonged exposure to very low levels of LDL-cholesterol. Irrespective of their outcomes, the exceptionally rapid development of these drugs exemplifies how novel technologies, genetic validation, and rapid clinical progression provide the tools to expedite the development of new drugs.

PCSK9 inhibitors: Novel therapeutic agents for the treatment of hypercholesterolemia

Reducing plasma levels of low-density lipoprotein cholesterol (LDL-c) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, a substantial proportion of patients fail to achieve acceptable LDL-c levels with currently available lipid-lowering drugs. Over the last decade, inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) has emerged as a promising target to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the LDL receptor for lysosomal degradation. Inhibition of PCSK9 increases expression of the LDL receptor. This observation has led to the development of a number of approaches to directly target PCSK9. Three monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials involving various patient categories on different background lipid lowering therapies. Current evidence shows reductions in LDL cholesterol levels of up to 70%, independent of background statin therapy. The results of phase 3 trials will demonstrate the long-term efficacy and safety of PCSK9 inhibition, and will indicate whether LDL-c lowering induced by this novel approach translates into beneficial effects on CVD outcome.

Abstract 127: Effects of miR-33 Antagonism on Glucose and Triglyceride Metabolism in Nonhuman Primates.

Elevated plasma low-density lipoprotein (LDL) and decreased high-density lipoprotein (HDL) cholesterol levels increase the risk of cardiovascular disease (CVD). While strategies to lower LDL cholesterol have been successful in reducing CVD-related mortality, there is still an unmet need for developing therapies to reduce the residual risk of atherosclerotic CVD. Plasma HDL cholesterol levels are inversely correlated with CVD risk and thus novel therapies to increase plasma HDL cholesterol levels have garnered much attention in recent years. MicroRNA-33a and b (miR-33a/b) are intronically-encoded microRNAs residing in the sterol response element binding protein genes SREBF2 and SREBF1 and suppress the expression of the genes involved in cholesterol efflux and fatty acid oxidation. Recent studies show that antagonism of miR-33 results in increased ABCA1expression and elevated plasma HDL levels in both mice and nonhuman primates. However, findings in mice suggest that long term miR-33 antagonism may lead to hepatic steatosis and increased production of very low-density lipoprotein (VLDL), the precursor to proatherogenic LDL. In the current study, cynomolgus monkeys were fed a high carbohydrate diet plus Kool Aid prior to administration of antisense oligonucleotides (ASOs) specific for miR-33a/b. As expected, miR-33 antagonism resulted in elevated plasma total cholesterol levels, predominantly due to increased HDL. No differences in plasma LDL or triglycerides were observed between treatment groups. MiR-33a/b antagonism had no effect on VLDL triglyceride secretion rates. Anti-miR-33 treatment did not promote hepatic lipid accumulation or adversely affect liver transaminase levels. Glucose tolerance tests revealed no differences in either plasma glucose or insulin levels in response to miR-33a/b antagonism. These findings suggest that anti-miR-33 therapy raises HDL cholesterol without negatively impacting either triglyceride or glucose homeostasis in nonhuman primates.

Role for combination therapy in diabetic dyslipidemia.

Individuals with type 2 diabetes mellitus have a high residual risk of cardiovascular disease (CVD) despite maximal statin therapy and lifestyle interventions. In addition, adults with diabetes frequently exhibit the pattern of elevated triglycerides, small dense LDL, and reduced levels of high density lipoprotein cholesterol (HDL), also known as diabetic dyslipidemia. The role of combination therapy with an additional agent such as niacin, ezetimibe, fenofibrate, and n-3 fatty acids have been extensively studied with disappointing results. Review of key trials assessing benefit of combination therapy to reduce CVD risk from dyslipidemia is performed. While combination therapy frequently results in an improvement in lipid profile, to date, no consistent improvement in clinical outcomes has been observed. Therefore, current guidelines do not recommend combination therapy in individuals with diabetes, highlighting the role of intensifying statin therapy and lifestyle interventions. The recently released The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE IT) demonstrated a small but significant improvement in clinical endpoints with addition of ezetimibe to statins in high-risk patients. Although this trial was not specifically targeted towards patients with diabetes, the results may influence the future role of a combination therapy in such a population.

Apolipoprotein C-III: a potent modulator of hypertriglyceridemia and cardiovascular disease.

The purpose of this article is to summarize the recent epidemiological, basic science, and pharmaceutical research linking apolipoprotein C-III (apoC-III) with the development and treatment of cardiovascular disease (CVD). ApoC-III is an important emerging target linking hypertriglyceridemia with CVD. ApoC-III is a potent modulator of many established CVD risk factors, and is found on chylomicrons, very-low density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles. Recent studies show that in humans, apoC-III levels are an independent risk factor for CVD, and its presence on lipoproteins may promote their atherogenicity. This year, two large-scale epidemiological studies have linked mutations in apoC-III with increased incidence of CVD and hypertriglyceridemia. ApoC-III raises plasma triglycerides through inhibition of lipoprotein lipase, stimulation of very-low density lipoprotein secretion, and is a novel factor in modulating intestinal triglyceride trafficking. ApoC-III also stimulates inflammatory processes in the vasculature and the pancreas. The combination of raising plasma triglycerides and independently stimulating inflammatory processes makes apoC-III a valuable target for reducing the residual CVD risk in patients already on statin therapy, or for whom triglycerides are poorly controlled. Clinical trials on apoC-III antisense oligonucleotides are in progress. ApoC-III is a potent direct modulator of established CVD risk factors: plasma triglycerides and inflammation. Recent findings show that changes in apoC-III levels are directly associated with changes in cardiovascular risk and the atherogenicity of the lipoproteins on which apoC-III resides. Emerging roles of apoC-III include a role in directing the atherogenicity of high-density lipoprotein, intestinal dietary triglyceride trafficking, and modulating pancreatic β-cell survival. The combination of these roles makes apoC-III an important therapeutic target for the management and prevention of CVD.

Interferon-γ: Promising therapeutic target in atherosclerosis.

Atherosclerosis is a chronic inflammatory disorder of the vasculature and is the primary cause of cardiovascular disease (CVD). CVD is currently the world's leading cause of death and the numbers are predicted to rise further because of a global increase in risk factors such as diabetes and obesity. Current therapies such as statins have had a major impact in reducing mortality from CVD. However, there is a marked residual CVD risk in patients on statin therapy. It is therefore important to understand the molecular basis of this disease in detail and to develop alternative novel therapeutics. Interferon-γ (IFN-γ) is a pro-inflammatory cytokine that is often regarded as a master regulator of atherosclerosis development. IFN-γ is able to influence several key steps during atherosclerosis development, including pro-inflammatory gene expression, the recruitment of monocytes from the blood to the activated arterial endothelium and plaque stability. This central role of IFN-γ makes it a promising therapeutic target. The purpose of this editorial is to describe the key role IFN-γ plays during atherosclerosis development, as well as discuss potential strategies to target it therapeutically.

Type 2 diabetes mellitus, metabolic syndrome, and mixed dyslipidemia: how similar, how different, and how to treat?

Individuals with mixed atherogenic dyslipidemia, type 2 diabetes mellitus (T2DM), and metabolic syndrome are at high risk of developing cardiovascular disease (CVD) and can often benefit greatly from preventive lifestyle and medical interventions. These conditions typically co-exist in an individual, and the lipid profiles associated with them have several features in common. The worldwide prevalence of T2DM, atherogenic dyslipidemia, and metabolic syndrome is increasing, particularly in southern Asia and the Middle East. Statins can lower low-density lipoprotein-cholesterol and reduce the risk of CVD in these high-risk individuals, but there is a residual risk of CVD associated with additional lipid abnormalities, such as high levels of triglycerides and low levels of high-density lipoprotein cholesterol. These abnormalities are commonly found in patients with T2DM and metabolic syndrome. Additional lipid-modifying therapies that target these abnormalities, such as fibrates and omega-3 polyunsaturated fatty acids, may be able to improve lipid profiles and further reduce the risk of CVD in these patients.

Residual Cardiovascular Risk in Diabetic Patients: The Role of Fibrate Statin Combination

Patients with Type 2 diabetes mellitus (T2DM) have increased cardiovascular disease (CVD) risk. The use of statins significantly reduces the rate of CVD events but many T2DM patients, especially those with mixed dyslipidaemia (MD), have residual CVD risk. The use of fibrates, which improve triglyceride and high-density lipoprotein cholesterol levels, is beneficial for the treatment of patients with MD. Evidence from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study showed a possible beneficial effect on CVD events of the addition of fenofibrate (FF) to statin treatment in patients with T2DM and atherogenic MD. Furthermore, FF has been associated with slowing of the progression of early diabetic retinopathy. The combination of statin with a fibrate may improve the residual CVD risk and microvascular complications of patients with T2DM. However, trials specifically designed to assess the effects of fibrate-statin combination on cardiovascular outcomes in patients with T2DM are missing.

Combination of Statin Plus Renin Angiotensin System Inhibition for the Prevention or the Treatment of Atherosclerotic Cardiovascular Disease

Statins effectively reduce cardiovascular disease (CVD) morbidity and mortality. However, even after low-density lipoprotein cholesterol goal attainment there is a residual CVD risk. To reduce this risk, combining statins with drugs acting on the renin-angiotensin system (RAS) was investigated. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE), Japanese Coronary Artery Disease (JCAD), Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and The Assessing the Treatment Effect in Metabolic Syndrome Without Perceptible Diabetes (ATTEMPT) trials suggest that the statin plus RAS inhibition combination reduces CVD events more than a statin alone and considerably more than RAS inhibition alone. This benefit seems to be related to effects on endothelial function, vascular inflammation and the initiation, progression and rupture of atheromatous plaques. These effects are, at least in part, driven by mediators, the microRNAs (miRs), that are implicated in the pathogenesis and clinical manifestations of atherosclerosis (e.g. restoration of endothelial function and attenuation of vascular inflammation). Some miRs are favourably affected by statins and others by RAS inhibition. There is a miR family (miR-146a/b), related to coronary artery plaque destabilization that is beneficially affected by both statins and RAS inhibition. Statins and RAS inhibition combination should be routinely prescribed in high risk patients with CVD, hypertension, obesity, metabolic syndrome, and/or diabetes to maximize clinical benefit.

Cholesterol removal from plaques and elimination from the body: change in paradigm to reduce risk for heart disease

Accumulation of lipid-laden macrophage foam cells in arterial wall is the hallmark of atherosclerosis, the underlying cause of cardiovascular disease (CVD). Increased uptake of cholesteryl ester-rich modified low-density lipoprotein (LDL) is thought to be responsible for lipid accumulation and strong inverse correlation exists between plasma LDL and CVD. However, despite reaching the target LDL levels significant residual risk for CVD remains. Furthermore, current therapeutic strategies do not lead to regression of existing plaques. This review discusses a change in paradigm emphasizing the importance of removal of cholesterol from macrophage foam cells and final elimination of cholesterol from the body. Intracellular processes involved in this process are described to provide insight into the development of new therapies for CVD.

Role of selective peroxisome proliferator‐activated receptor modulators in managing cardiometabolic disease: tale of a roller‐coaster

AbstractAtherogenic dyslipidaemia is a hypertriglyceridaemic phenotype, associated with increased plasma concentrations of small, dense low‐density lipoprotein (sdLDL) particles, triglyceride‐rich lipoproteins (TRLs) and non‐high‐density lipoprotein cholesterol (non‐HDL‐C), and low HDL particles. Atherogenic dyslipidaemia commonly accompanies several metabolic disorders including type 2 diabetes, metabolic syndrome, non‐alcoholic fatty liver disease (NAFLD) and obesity, and increases the risk of cardiovascular disease (CVD). Statins significantly lower plasma LDL‐cholesterol and CVD risk, but their efficacy in correcting hypertriglyceridaemia is limited. Untreated hypertriglyceridaemia may partly account for residual risk of CVD in patients on statin treatment. Activators of peroxisome proliferator‐activated receptor (PPAR) α are more effective in correcting TRL and HDL metabolism than statins. A dual PPARα/δ agonist (GFT‐505) may have additional benefits on hepatic insulin sensitivity, steatosis and fibrosis. Selective PPAR modulators (SPPARMs) have the potential of increasing therapeutic specificity, while reducing unwanted off‐target effects. This review provides a summary of findings from randomized controlled trials of the efficacy of fenofibrate (as the most widely used PPARα agonist) and novel selective PPARα (ABT‐335 and k‐877), PPARα/δ (GFT‐505), PPARδ (MBX‐8025 and GW501516) and PPARγ (INT131) agonists in the treatment of atherogenic dyslipidaemia and NAFLD.

Lipoprotein(a) Concentrations, Rosuvastatin Therapy, and Residual Vascular Risk

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

Lipoprotein(a)

Lipoprotein(a)