The development of CETP (cholesteryl ester transfer protein) inhibitors has had a long and difficult course with 3 compounds failing in phase III clinical trials. Finally, the REVEAL (Randomized ...Evaluation of the Effects of Anacetrapib through Lipid modification) trial has shown that the CETP inhibitor anacetrapib decreased coronary heart disease when added to statin therapy. Although the result is different to earlier studies, this is likely related to the size and duration of the trial. The benefit of anacetrapib seems to be largely explained by lowering of non-HDL-C (high-density lipoprotein cholesterol), rather than increases in HDL-C. Although the magnitude of benefit for coronary heart disease appeared to be moderate, in part this may have reflected aspects of the trial design. Anacetrapib treatment was associated with a small increase in blood pressure, but was devoid of major side effects and was also associated with a small reduction in diabetes mellitus. Treatment with CETP inhibitors, either alone or in combination with statins, could provide another option for patients with coronary disease who require further reduction in LDL (low-density lipoprotein) and non-HDL-C.
Dyslipidemia is a risk factor for atherosclerotic cardiovascular disease (ASCVD). Abundant data indicate that low-density lipoproteins (LDL) are causal for ASCVD; a new class of LDL-lowering ...medicines, the PCSK9 inhibitors, will address much unmet medical need. Human genetics suggest that triglyceride-rich lipoproteins (TRL) are pro-atherogenic and have pointed to a number of protein regulators of lipoprotein lipase activity that are candidates for therapeutic targeting. Finally, high-density lipoprotein (HDL) cholesterol does not appear to be causally associated with protection from ASCVD, reinforced by the failure of three CETP inhibitors in CV outcome trials, but HDL function remains of interest.
Targeting plasma lipids is a mainstay of preventing and treating cardiovascular disease. This Review discusses the new class of PCSK9 inhibitors and approaches in development to reduce triglycerides. Three CETP inhibitors have failed in phase 3 trials, bringing into question HDL-C as a therapeutic target.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
HDL metabolism represents a major target for the development of therapies intended to reduce the risk of atherosclerotic cardiovascular disease. HDL metabolism is complex and involves dissociation of ...HDL apolipoprotein and HDL cholesterol metabolism. Advances in our understanding of the molecular regulation of HDL metabolism, macrophage cholesterol efflux, and HDL function will lead to a variety of novel therapeutics.
HDL and cardiovascular disease Rader, Daniel J, Prof; Hovingh, G Kees, MD
The Lancet (British edition),
08/2014, Volume:
384, Issue:
9943
Journal Article
Peer reviewed
Summary The cholesterol contained within HDL is inversely associated with risk of coronary heart disease and is a key component of predicting cardiovascular risk. However, despite its properties ...consistent with atheroprotection, the causal relation between HDL and atherosclerosis is uncertain. Human genetics and failed clinical trials have created scepticism about the HDL hypothesis. Nevertheless, drugs that raise HDL-C concentrations, cholesteryl ester transfer protein inhibitors, are in late-stage clinical development, and other approaches that promote HDL function, including reverse cholesterol transport, are in early-stage clinical development. The final chapters regarding the effect of HDL-targeted therapeutic interventions on coronary heart disease events remain to be written.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Familial hypercholesterolemia (FH) is a dominantly inherited genetic disorder affecting approximately 1 in 250 individuals. FH cascade testing strategies incorporating genetic testing results when ...available or low-density lipoprotein cholesterol (LDL-C) when genetic testing results are not available are cost-effective for identifying new cases of FH. Cascade screening for FH is an evidence -based intervention which can reduce the burden of morbidity and mortality from accelerated atherosclerotic cardiovascular disease (ASCVD) in populations.
Abstract Abdominal obesity contributes to insulin resistance, a metabolic abnormality linked to the development of type 2 diabetes mellitus and cardiovascular disease (CVD). Insulin resistance ...generally precedes the development of type 2 diabetes. Currently, an estimated 10 million US adults have diabetes and another 25 million have impaired glucose tolerance (IGT), an intermediate step between insulin resistance and diabetes. The pathophysiologic mechanisms known to increase CVD risk in individuals with insulin resistance include formation of advanced glycation end products, hypertension, proinflammatory and prothrombotic states, and dyslipidemia (i.e., low levels of high-density lipoprotein cholesterol, increased levels of triglycerides, small, dense low-density lipoprotein cholesterol particles, apoplipoprotein B, and inflammation). The increased flux of free fatty acids from adipose tissue to the liver promotes dyslipidemia. Insulin resistance and impaired glucose tolerance are associated with increased CVD risk. Individuals with coexisting metabolic syndrome and diabetes have the highest prevalence rates of CVD. The Nurses’ Health Study showed that CVD risk was elevated even before the development of diabetes compared with women who never developed diabetes. Lifestyle modification is recommended as the first-line treatment for obesity and its metabolic sequelae. Pharmacotherapy may be useful in patients for whom nonpharmacologic approaches alone are ineffective or insufficient. Primary care physicians play a critical role in the early identification and treatment of patients at increased risk for the development of type 2 diabetes and CVD because of their obesity and associated complications.
Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height ...within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation.
In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio OR 1.34; 95% CI 1.29 to 1.40; p = 5 × 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations.
In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.
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Using a polygenic score of DNA sequence polymorphisms, the authors of this study quantified genetic risk and assessed four healthy lifestyle factors. Among participants at high genetic risk, a ...healthy lifestyle was associated with a reduced risk of coronary disease.
Both genetic and lifestyle factors are key drivers of coronary artery disease, a complex disorder that is the leading cause of death worldwide.
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A familial pattern in the risk of coronary artery disease was first described in 1938 and was subsequently confirmed in large studies involving twins and prospective cohorts.
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Since 2007, genomewide association analyses have identified more than 50 independent loci associated with the risk of coronary artery disease.
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These risk alleles, when aggregated into a polygenic risk score, are predictive of incident coronary events and provide a continuous and quantitative measure of genetic susceptibility.
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Atherosclerosis is characterized by the thickening of the arterial wall and is the primary cause of coronary artery disease and cerebrovascular disease, two of the most common causes of illness and ...death worldwide. Clinical trials have confirmed that certain lipoproteins and the renin-angiotensin-aldosterone system are important in the pathogenesis of atherosclerotic cardiovascular disease, and that interventions targeted towards these are beneficial. Furthermore, efforts to understand how risk factors such as high blood pressure, dysregulated blood lipids and diabetes contribute to atherosclerotic disease, as well as to understand the molecular pathogenesis of atherosclerotic plaques, are leading to new targets for therapy.
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Pathophysiological, epidemiological, and genetic studies provide strong evidence that lipoprotein(a) Lp(a) is a causal mediator of cardiovascular disease (CVD) and calcific aortic valve disease ...(CAVD). Specific therapies to address Lp(a)-mediated CVD and CAVD are in clinical development. Due to knowledge gaps, the National Heart, Lung, and Blood Institute organized a working group that identified challenges in fully understanding the role of Lp(a) in CVD/CAVD. These included the lack of research funding, inadequate experimental models, lack of globally standardized Lp(a) assays, and inadequate understanding of the mechanisms underlying current drug therapies on Lp(a) levels. Specific recommendations were provided to facilitate basic, mechanistic, preclinical, and clinical research on Lp(a); foster collaborative research and resource sharing; leverage expertise of different groups and centers with complementary skills; and use existing National Heart, Lung, and Blood Institute resources. Concerted efforts to understand Lp(a) pathophysiology, together with diagnostic and therapeutic advances, are required to reduce Lp(a)-mediated risk of CVD and CAVD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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