LPA Gene Variants Linked To Cardiac Events Despite Statins

MedicalResearch.com Interview with:

Wei-Qi Wei, MD, PhD Assistant Professor Department of Biomedical Informatics Vanderbilt University Nashville, TN 37203

Dr. Wei-Qi Wei

Wei-Qi Wei, MD, PhD
Assistant Professor
Department of Biomedical Informatics
Vanderbilt University
Nashville, TN 37203

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The study was motived by the clinical observation that some patients develop coronary heart disease events despite taking statins, one of our most effective drugs to reduce cardiovascular risk. We collected data within the eMERGE network of people taking statins and monitored them for development of coronary heart disease events over time.  We  conducted a genome-wide association study of those with events compared to those without events.

Our results showed that single nucleotide polymorphisms (SNPs) on the LPA gene were associated with a significantly increased risk of coronary heart disease events. Individuals with the variant were 50% more likely to have an event. More importantly, even among patients who achieved ideal on-treatment LDL cholesterol levels (<70 mg/dL), the association remained statistically significant.

We then did a phenome-wide association study to see if other diseases or conditions were associated with these LPAvariants. The major associated conditions were all cardiovascular. This sort of study can highlight potential other indications for a drug targeting this pathway and suggest potential adverse events that might be experienced from targeting this pathway. Clearly, more and larger studies will be needed to truly understand the potential risks and benefits of a future drug targeting this pathway.  Continue reading

Patients With Highest LDL Levels Benefit Most From Lipid-Lowering Drugs

MedicalResearch.com Interview with:

Dr. Jennifer Robinson, MD MPH professor of epidemiology, University of Iowa College of Public Health. CREDIT Tom Langdon

Dr. Robinson

Dr. Jennifer Robinson, MD MPH
Professor, Departments of Epidemiology & Medicine
Director, Prevention Intervention Center
Department of Epidemiology
University of Iowa

MedicalResearch.com: What is the background for this study?

Response: Compared to previous placebo-controlled statin trials, the FOURIER trial where all patients were on high or moderate intensity statin, had no reduction in cardiovascular or total mortality and the reduction in cardiovascular events was less than expected.  However, other PCSK9 inhibitor trials performed in populations with higher baseline low density lipoprotein cholesterol (LDL-C) had cardiovascular risk reductions similar to that in the statin trails.

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Very High ‘Good Cholesterol’ HDL Linked To Increased Risk of Infections

MedicalResearch.com Interview with:

Børge G. Nordestgaard, MD, DMSc Professor, University of Copenhagen Chief Physician, Dept. Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital, Denmark

Prof. Nordestgaard

Børge G. Nordestgaard, MD, DMSc
Professor, University of Copenhagen
Chief Physician, Dept. Clinical Biochemistry
Herlev and Gentofte Hospital
Copenhagen University Hospital, Denmark 

MedicalResearch.com: What is the background for this study?

Response: For decades research into the role and function of high-density lipoprotein (HDL) has revolved around the believe that HDL protects against atherosclerotic cardiovascular disease. However, results from large genetic studies and from large randomized clinical trials with HDL cholesterol elevating drugs have all indicated that there is no causal association between HDL cholesterol and risk of atherosclerotic cardiovascular disease.

Given the hitherto strong focus on cardiovascular disease, little is known about the possible role of HDL in other aspects of human health and disease. Preclinical evidence has indicated that HDL might be of importance for normal function of the immune system and susceptibility to infectious disease, but it had never previously been investigated if levels of HDL cholesterol is associated with the risk of infectious disease in individuals from the general population. In the present study we tested this hypothesis in more than 100.000 Danes from the population at large.

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Statins: Large Disparity Between US/Canadian/UK and European Guidelines

MedicalResearch.com Interview with:

Borge G. Nordestgaard,

Borge G. Nordestgaard

Børge G. Nordestgaard, MD, DMSc
Department of Clinical Biochemistry
Herlev and Gentofte Hospital, Copenhagen University Hospital
Herlev, Denmark

MedicalResearch.com: What is the background for this study?

Response: Five major organizations recently published guidelines for using statins to prevent atherosclerotic cardiovascular disease  — the American College of Cardiology/American Heart Association (ACC/AHA) in 2013, the United Kingdom’s National Institute for Health and Care Excellence (NICE) in 2014, and in 2016 the Canadian Cardiovascular Society (CCS), the US Preventive Services Task Force (USPSTF), and the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS). We applied these five guidelines to a contemporary study cohort of 45,750 40-75 year olds from the Copenhagen General Population Study.

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Frequent Take-Out Food Linked To Increased Cholesterol and Obesity in Children

MedicalResearch.com Interview with:

Dr. Angela S Donin Population Health Research Institute, St George’s University of London, London, UK

Dr. Donin

Dr. Angela S Donin
Population Health Research InstituteSt George’s
University of London
London, UK 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There are increasing numbers of takeaway outlets, particularly in deprived neighbourhoods. This is driving an increase in consumption of takeaway meals, which previous evidence has shown is linked to higher risks of heart disease, type 2 diabetes and obesity. Little is known about the dietary and health impact of high consumption of takeaway foods in children.

This research found children who regularly ate takeaway meals had higher body fat and cholesterol compared to children who rarely ate take away meals, they also had overall poorer diet quality.

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Praluent May Reduce Need For Apheresis In Some Patients With Familial Hypercholesterolemia

MedicalResearch.com Interview with:

Dr. Jay Edelberg VP Head of CV Development and Head Global CV Medical Affairs

Dr. Edelberg

Dr. Jay Edelberg MD, PhD
VP Head of CV Development and
Head Global CV Medical Affairs
Sanofi 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Patients with heterozygous familial hypercholesterolemia (HeFH) are often not able to achieve their target low-density lipoprotein cholesterol (LDL-C) levels, and some may require lipoprotein apheresis (LA) to lower their “bad cholesterol.” Apheresis is a procedure similar to kidney dialysis, where bad cholesterol is mechanically removed from the blood. It is an invasive, expensive, and time-consuming treatment for patients, as well as physicians.

The Phase III ESCAPE clinical study looked at the potential effect of LA on total Praluent, free and total PCSK9 concentrations, as well as the combined pharmacodynamics effect of total Praluent on LDL-C-lowering.

Praluent levels remained unaffected by apheresis, and Praluent consistently suppressed free PCSK9 levels in patients with HeFH, regardless of LA treatment. This analysis further confirms clinical ESCAPE data that Praluent can be used in conjunction with LA and may reduce or potentially eliminate the need for LA in some patients.

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Lack of Response to LDL-Lowering Praluent Rare

MedicalResearch.com Interview with:

Dr. Jay Edelberg VP Head of CV Development and Head Global CV Medical Affairs

Dr. Edelberg

Dr. Jay Edelberg MD, PhD
VP Head of CV Development and
Head Global CV Medical Affairs
Sanofi

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Clinical trials of lipid-lowering therapies (LLTs), including statins, often report variations in treatment response regarding effects on low density-lipoprotein cholesterol (LDL-C) levels, although LDL-C reductions are fairly consistent between trials. Praluent is generally well tolerated, however hyporesponsiveness exists in few patients.

Potential causes for variation in patient responsiveness to Praluent include lack of receipt of active study drug, changes in concurrent LLTs, inaccurate or unrepresentative baseline lipid levels, concurrent acute-phase illness, and biological nonresponsiveness.

This analysis evaluated patients pooled from 10 ODYSSEY trials to assess characteristics of patients with hyporesponsiveness to Praluent, defined as <15% LDL-C reduction from baseline at all analyzed time points.

Overall, only 1% of patients (n=33) had <15% LDL-C reduction at all time points. Prolonged hyporesponsiveness to Praluent was rarely associated with Praluent antidrug antibodies. Of the 33 patients with <15% LDL-C reduction at all study timepoints, 27 had undetectable or missing alirocumab levels, absence of pharmacokinetics analyses, or early treatment discontinuation.

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Cellular Protein Nrf1 Protects Against Fatty Liver

MedicalResearch.com Interview with:

Gokhan S. Hotamisligil MD PhD

Dr. Hotamisligil

Gokhan S. Hotamisligil MD PhD
J.S. Simmons Professor of Genetics and Metabolism
Chair, Department of Genetics and Complex Diseases
Department of Genetics and Complex Diseases
Department of Nutrition
Harvard Stem Cell Institute

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Cholesterol is often considered a ‘bad’ nutrient, as it has been strongly linked to a cluster of metabolic diseases. In reality however, cholesterol is absolutely vital for the health of all animal cells, serves as an essential building block for all membranes and precursor for essential molecules.  It usually only becomes toxic when cells are exposed to high levels or free forms of cholesterol or when it is stored in excess.

The reasons why cholesterol over-accumulates or causes excessive damage in cells of some people is not entirely clear, as cells are normally should be able to remove such excesses, and there remains key mechanistic gaps in our understanding of how cells control the molecular process of sensing excess cholesterol, engage ways of removal and launch countermeasures to defend their integrity. Filling this gap may reveal a new path toward alleviating the burden of cholesterol-related diseases.

To this end, we identified a new signal pathway mediated by a protein called Nrf1, which enables cells to know when to remove cholesterol, thereby preventing excess cholesterol storage. We show that Nrf1 directly senses cholesterol in a strategic subcellular compartment called the endoplasmic reticulum and coordinates an adaptive and defensive responses that protects the cells and promotes the removal of cellular cholesterol. Continue reading

LPA Gene Variant May Help Identify Increased Risk of Aortic Stenosis 

MedicalResearch.com Interview with:

Aortic Stenosis Blaus Image Wikipedia

Aortic Stenosis Blaus Image Wikipedia

Hao Yu Chen, MSc
Department of Medicine
McGill University
Montreal, Quebec, Canada
Senior author: George Thanassoulis, MD, MSc

MedicalResearch.com: What is the background for this study?

Response: Aortic stenosis, a narrowing of the main valve of the heart, is the most common type of valve disease in the US. Present in more than 2.5 million individuals in North America, aortic stenosis can lead to heart failure and death. However, there is little known about the causes of aortic stenosis and how it should be treated.

Previously, we have demonstrated that variants of the gene LPA are associated with the development of aortic stenosis. A better understanding of how this region contributes to aortic stenosis could identify higher-risk individuals and inform the development of new medical therapies for aortic stenosis.  Continue reading

Hormones Affect Carotid Plaque Stability and Stroke Vulnerability

MedicalResearch.com Interview with:

Marija Glisic Epidemiology, Erasmus MC

Marija Glisic

Marija Glisic
Epidemiology, Erasmus MC 

MedicalResearch.com: What is the background for this study?

Response: Carotid atherosclerosis is one of most important risk factors for developing stroke. Carotid atherosclerotic plaques characterized by lipid core presence and intraplaque haemorrhage are considered to be unstable, and therefore more prone to rupture and lead to consequent stroke. Sex differences have been observed in carotid plaque composition as well as in stroke incidence. Sex hormones, particularly estrogen and testosterone actions are suggested to underlie the observed sex differences in atherosclerosis. Experimental evidence suggests a direct action of estradiol and testosterone on the vascular system, affecting various mechanisms that may impact plaque composition and subsequently stroke risk.

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