The High-Density Lipoprotein Puzzle Why Classic Epidemiology, Genetic Epidemiology, and Clinical Trials Conflict?
01 May 2016-Arteriosclerosis, Thrombosis, and Vascular Biology (Lippincott Williams & WilkinsHagerstown, MD)-Vol. 36, Iss: 5, pp 777-782
TL;DR: In this paper, the authors investigated the relationship between HDL cholesterol and the future risk of myocardial infarction and found that statin therapy interferes with ATP-binding cassette transporter-mediated macrophage cholesterol efflux via miR33 and thus may diminish certain HDL functional properties.
Abstract: Classical epidemiology has established the incremental contribution of the high-density lipoprotein (HDL) cholesterol measure in the assessment of atherosclerotic cardiovascular disease risk; yet, genetic epidemiology does not support a causal relationship between HDL cholesterol and the future risk of myocardial infarction. Therapeutic interventions directed toward cholesterol loading of the HDL particle have been based on epidemiological studies that have established HDL cholesterol as a biomarker of atherosclerotic cardiovascular risk. However, therapeutic interventions such as niacin, cholesteryl ester transfer protein inhibitors increase HDL cholesterol in patients treated with statins, but have repeatedly failed to reduce cardiovascular events. Statin therapy interferes with ATP-binding cassette transporter-mediated macrophage cholesterol efflux via miR33 and thus may diminish certain HDL functional properties. Unraveling the HDL puzzle will require continued technical advances in the characterization and quantification of multiple HDL subclasses and their functional properties. Key mechanistic criteria for clinical outcomes trials with HDL-based therapies include formation of HDL subclasses that improve the efficiency of macrophage cholesterol efflux and compositional changes in the proteome and lipidome of the HDL particle that are associated with improved antioxidant and anti-inflammatory properties. These measures require validation in genetic studies and clinical trials of HDL-based therapies on the background of statins.
Citations
More filters
TL;DR: The cross-talk between adipocytes and HDL related to cardiovascular disease is summarized, new insights of the potential mechanism underlying obesity and HDL dysfunction are focused on and adipose tissue is targeted for the treatment of HDL metabolism in obesity.
Abstract: Obesity is the most common nutritional disorder worldwide and is associated with dyslipidemia and atherosclerotic cardiovascular disease. The hallmark of dyslipidemia in obesity is low high density lipoprotein (HDL) cholesterol (HDL-C) levels. Moreover, the quality of HDL is also changed in the obese setting. However, there are still some disputes on the explanations for this phenomenon. There is increasing evidence that adipose tissue, as an energy storage tissue, participates in several metabolism activities, such as hormone secretion and cholesterol efflux. It can influence overall reverse cholesterol transport and plasma HDL-C level. In obesity individuals, the changes in morphology and function of adipose tissue affect plasma HDL-C levels and HDL function, thus, adipose tissue should be the main target for the treatment of HDL metabolism in obesity. In this review, we will summarize the cross-talk between adipocytes and HDL related to cardiovascular disease and focus on the new insights of the potential mechanism underlying obesity and HDL dysfunction.
65 citations
TL;DR: The genetic basis of extreme HDL-C concentrations encountered clinically is frequently polygenic, with contributions from both rare large-effect and common small-effect variants.
49 citations
TL;DR: Dyslipidemia, especially increased LDL-c and triglyceride levels, continues to play a significant role in CV risk, and the combination of genetic testing and counseling is important in the management of patients with dys Lipidemia of genetic etiology.
Abstract: The cardiovascular (CV) risk related to lipid disorders is well established and is based on a robust body of evidence from well-designed randomized clinical trials, as well as prospective observational studies. In the last two decades, significant advances have been made in understanding the genetic basis of dyslipidemias. The present review is intended as a comprehensive discussion of current knowledge about the genetics and pathophysiology of disorders that predispose to dyslipidemia. We also focus on issues related to statins and the proprotein convertase subtilisin/kexin type 9 (PCSK9) and some of its polymorphisms, as well as new cholesterol-lowering medications, including PCSK9 inhibitors. Cholesterol is essential for the proper functioning of several body systems. However, dyslipidemia—especially elevated low-density lipoprotein (LDL-c) and triglyceride levels, as well as reduced lipoprotein lipase activity—is associated with an increased risk of coronary artery disease (CAD). High-density lipoprotein (HDL-c), however, seems to play a role as a risk marker rather than as a causal factor of the disease, as suggested by Mendelian randomization studies. Several polymorphisms in the lipoprotein lipase locus have been described and are associated with variations in the activity of this enzyme, producing high concentrations of triglycerides and increased risk of CAD. Dyslipidemia, especially increased LDL-c and triglyceride levels, continues to play a significant role in CV risk. The combination of genetic testing and counseling is important in the management of patients with dyslipidemia of genetic etiology. Strategies focused on primary prevention can offer an opportunity to reduce CV events.
43 citations
TL;DR: The findings support future investigations into pharmacologic targeting of lipoproteins beyond LDL-C, such as triglyceride-rich lipopoteins, to reduce residual risk for ASCVD among individuals with CKD.
39 citations
TL;DR: This review highlights manuscripts published in ATVB within the past 2 years, focusing on novel pathways that might contribute to vascular complications of diabetes mellitus, which is a major healthcare problem that needs to find solutions to.
Abstract: The global prevalence of diabetes mellitus among adults has risen from 4.7% in 1980 to 8.5% in 2014, increasing the number of adults with diabetes mellitus to a staggering 422 million worldwide, according to the World Health Organization. For comparison, this number is larger than the total population of the United States. Diabetes mellitus not only reduces quality of life and life expectancy, but is also a major cause of several microvascular complications and macrovascular complications that lead to blindness, renal failure, myocardial infarction, stroke, and the necessity to amputate limbs. The burden of diabetes mellitus–associated complications worldwide is therefore a major healthcare problem that we urgently need to find solutions to. In this context, a large body of research has been devoted to identifying risk factors of vascular complications of diabetes mellitus with the goal of improving prevention of these complications. Such research has revealed that vascular complications of diabetes mellitus are associated with multiple risk factors—including dyslipidemia, hypertension, smoking, age, metabolic control, and systemic inflammation—and that the relative contribution of these risk factors is likely to vary depending on the type of diabetes mellitus and what risk factors are present in a given subject. Other research is aimed at finding novel and reliable biomarkers for vascular complications of diabetes mellitus and novel targets for treatment. In this review, we highlight manuscripts published in ATVB within the past 2 years, focusing on novel pathways that might contribute to vascular complications of diabetes mellitus. This work ranges from experiments on isolated cells to animal models of diabetes mellitus to studies in humans.
Elevated blood glucose is a hallmark of all types of diabetes mellitus, which include type 1 diabetes mellitus, type 2 diabetes mellitus, diabetes mellitus characterized by aspects of both type 1 and type 2 diabetes mellitus, gestational diabetes …
38 citations
References
More filters
The Heart Research Institute1, St Bartholomew's Hospital2, Karolinska Institutet3, University of Amsterdam4, Pierre-and-Marie-Curie University5, Autonomous University of Madrid6, Columbia University7, Université de Montréal8, University of California, San Francisco9, Pfizer10, University of Wisconsin-Madison11
TL;DR: Although there was evidence of an off-target effect of torcetrapib, it cannot rule out adverse effects related to CETP inhibition, and the trial was terminated prematurely because of an increased risk of death and cardiac events.
Abstract: Background Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib. Methods We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina. Results At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both compari...
2,832 citations
TL;DR: Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter, there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels.
Abstract: Background In patients with established cardiovascular disease, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein (LDL) cholesterol levels with statin therapy. It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein (HDL) cholesterol is superior to simvastatin alone in reducing such residual risk. Methods We randomly assigned eligible patients to receive extended-release niacin, 1500 to 2000 mg per day, or matching placebo. All patients received simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an LDL cholesterol level of 40 to 80 mg per deciliter (1.03 to 2.07 mmol per liter). The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. Results A total of 3414 patients were randomly assigned to receive niacin (1718) or placebo (1696). The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter), lowered the triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter), and lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter). The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P=0.79 by the log-rank test). Conclusions Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol and triglyceride levels. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; AIM-HIGH ClinicalTrials.gov number, NCT00120289.).
2,535 citations
TL;DR: Lid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.
Abstract: CONTEXT: Associations of major lipids and apolipoproteins with the risk of vascular disease have not been reliably quantified. OBJECTIVE: To assess major lipids and apolipoproteins in vascular risk. DESIGN, SETTING, AND PARTICIPANTS: Individual records were supplied on 302,430 people without initial vascular disease from 68 long-term prospective studies, mostly in Europe and North America. During 2.79 million person-years of follow-up, there were 8857 nonfatal myocardial infarctions, 3928 coronary heart disease [CHD] deaths, 2534 ischemic strokes, 513 hemorrhagic strokes, and 2536 unclassified strokes. MAIN OUTCOME MEASURES: Hazard ratios (HRs), adjusted for several conventional factors, were calculated for 1-SD higher values: 0.52 log(e) triglyceride, 15 mg/dL high-density lipoprotein cholesterol (HDL-C), 43 mg/dL non-HDL-C, 29 mg/dL apolipoprotein AI, 29 mg/dL apolipoprotein B, and 33 mg/dL directly measured low-density lipoprotein cholesterol (LDL-C). Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. RESULTS: The rates of CHD per 1000 person-years in the bottom and top thirds of baseline lipid distributions, respectively, were 2.6 and 6.2 with triglyceride, 6.4 and 2.4 with HDL-C, and 2.3 and 6.7 with non-HDL-C. Adjusted HRs for CHD were 0.99 (95% CI, 0.94-1.05) with triglyceride, 0.78 (95% CI, 0.74-0.82) with HDL-C, and 1.50 (95% CI, 1.39-1.61) with non-HDL-C. Hazard ratios were at least as strong in participants who did not fast as in those who did. The HR for CHD was 0.35 (95% CI, 0.30-0.42) with a combination of 80 mg/dL lower non-HDL-C and 15 mg/dL higher HDL-C. For the subset with apolipoproteins or directly measured LDL-C, HRs were 1.50 (95% CI, 1.38-1.62) with the ratio non-HDL-C/HDL-C, 1.49 (95% CI, 1.39-1.60) with the ratio apo B/apo AI, 1.42 (95% CI, 1.06-1.91) with non-HDL-C, and 1.38 (95% CI, 1.09-1.73) with directly measured LDL-C. Hazard ratios for ischemic stroke were 1.02 (95% CI, 0.94-1.11) with triglyceride, 0.93 (95% CI, 0.84-1.02) with HDL-C, and 1.12 (95% CI, 1.04-1.20) with non-HDL-C. CONCLUSION: Lipid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.
2,196 citations
University of Pennsylvania1, Broad Institute2, Harvard University3, Boston University4, National Institutes of Health5, Lund University6, University of Copenhagen7, University of Texas Health Science Center at Houston8, deCODE genetics9, Queen Mary University of London10, University of Lübeck11, Glenfield Hospital12, University of Leicester13, University of Oxford14, University of Cambridge15, University of Ottawa16, University of Iceland17, Population Health Research Institute18, McGill University19, Vanderbilt University20, University of Missouri–Kansas City21, University of Münster22, University of Verona23, Queen's University Belfast24, MedStar Washington Hospital Center25, GlaxoSmithKline26, University of Helsinki27, Karolinska Institutet28, University of Mainz29, Utrecht University30, University of Groningen31, University of Michigan32, United States Department of Agriculture33, Centro Nacional de Investigaciones Cardiovasculares34, University of North Carolina at Chapel Hill35, University of Regensburg36, Katholieke Universiteit Leuven37, University of Edinburgh38, University of Kiel39, University of Leeds40, Aarhus University41, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico42, University of Washington43, Wellcome Trust Sanger Institute44
TL;DR: In this paper, a Mendelian randomisation analysis was performed to compare the effect of HDL cholesterol, LDL cholesterol, and genetic score on risk of myocardial infarction.
Abstract: Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. – ¹³) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10
1,878 citations
University of Colorado Denver1, Linköping University2, Hoffmann-La Roche3, Houston Methodist Hospital4, The Heart Research Institute5, Saint Louis University6, University of Oslo7, University of Glasgow8, University of Adelaide9, Cedars-Sinai Medical Center10, Montreal Heart Institute11, Mayo Clinic12
TL;DR: In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events.
Abstract: Background In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. Methods We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. Results At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 ...
1,773 citations