AHA Journals, Author Interviews, Genetic Research, Heart Disease / 08.03.2021

MedicalResearch.com Interview with: Giordano Bottà, PhD CEO and Co-founder Allelica The Polygenic Risk Score Company MedicalResearch.com: What is the background for this study? Response: Previous research identified that polygenic risk score (PRS) has the highest predictive power compared to other risk factors and identifies individuals with the same risk of those with familial hypercholesterolemia, but are invisible to traditional risk assessment. We explored for the first time the interplay between the main causes of atherosclerosis, LDL cholesterol and PRS.  We were interested in helping cardiologists understand why some individuals have bad arteries full of plaques while others don't in presence of the same LDL levels and no additional risk factors. Our findings explain why this is the case: LDL does not affect everyone the same. We believe that we are at the forefront of a change of paradigm in cardiovascular risk assessment: LDL levels cannot be accessed without considering the genetics of an individual. (more…)
Author Interviews, Heart Disease, Lipids / 01.04.2020

MedicalResearch.com Interview with: Professor F. J. Raal, FRCP, FCP(SA), Cert Endo, MMED, PhD Director, Carbohydrate & Lipid Metabolism Research Unit Professor & Head, Division of Endocrinology & Metabolism, Faculty of Health Sciences, University of the Witwatersrand MedicalResearch.com: What is the background for this study? How does Evinacumab differ from the three drugs used in triple therapy for this severe form of hypercholesterolemia? Response:      Despite available lipid lowering therapies, the vast majority of patients with homozygous familial hypercholesterolemia are unable to achieve desirable LDL-cholesterol levels and remain at high risk for premature atherosclerotic cardiovascular disease. Unlike statins and PCSK9-inhibitors which act mainly by upregulating LDL receptor activity on the cell surface, evinacumab, a monoclonal antibody inhibitor of ANGPTL3, acts independent of the LDL receptor. (more…)
Author Interviews, Lipids, NEJM, Neurological Disorders, Stroke / 18.11.2019

MedicalResearch.com Interview with: Pierre Amarenco, MD Professor and Chairman Paris University, Paris, France INSERM Department of Neurology and Stroke Centre Bichat Hospital Paris, France MedicalResearch.com: What is the background for this study? Response: The rationale of the Treat Stroke to target trial was that after we published the SPARCL trial in 2006 (atorvastatin 80 mg/day vs placebo in patients with stroke) which showed a 16% relative risk reduction of recurrent stroke, we performed several pre specified and post hoc analyses, showing that in SPARCL patients randomized with "atherosclerotic disease" the risk reduction for the primary endpoint was much higher (33%), and in in patients achieving a LDL cholesterol of less than 70 mg/dL as compared to those achieving a LDL cholesterol 100 mg/dL or higher, the risk reduction was 28%. Therefore to confirm this findings, we designed the TST trial, which was an investigator initiated trial funded by the french ministry of health,  and enrolled patients with an ischemic stroke due to atherosclerotic stenosis and randomized them to either a target LDL cholesterol of less than 70 mg/dL or a target LDL cholesterol of 90 to 110 mg/dL. To achieve these goals, the investigators could use any statin available on the market, and titrate the dosage of the statin to get to the assigned target. They could also use ezetimibe on top of statin therapy if a high dosage of statin was not sufficient to get to the target level assigned by randomization. (more…)
AHA Journals, Author Interviews, Heart Disease, Lipids / 17.09.2019

MedicalResearch.com Interview with: Samuel S. Gidding, MD FH Foundation Pasadena, CA MedicalResearch.com: What is the background for this study? Response: Patients with familial hypercholesterolemia are at high risk for atherosclerotic heart disease but little is known about intensification of treatment and event rates in lipid specialty care in the United States. We examined data on 1900 patients, enrolled in the CASCADE FH Registry,sponsored by the Familial Hypercholesterolemia Foundation, to determine if cholesterol lowering therapy increased to improve getting patients to a lower LDL cholesterol and to look at incident cardiac events in tow groups, those with prior heart disease and those without. (more…)
Author Interviews, Heart Disease, Lipids / 18.07.2019

MedicalResearch.com Interview with: Guanmin Chen MD PhD MPH Senior Biostatistician Research Facilitation, Alberta Health Services Adjunct Research Assistant Professor University of Calgary  Co-authors: Guanmin Chen, PhD, MD, MPH, Megan S. Farris, MSc, Tara Cowling, MA, MSc, Stephen M. Colgan, PhD, Pin Xiang, PharmD, Louisa Pericleous, PhD, Raina M. Rogoza, MSc, Ming-Hui Tai, MSc, PhD, and Todd Anderson, MD  MedicalResearch.com: What are the main findings? Response:
  • Atherosclerotic cardiovascular disease (ASCVD) remains a significant cause of morbidity and mortality in Canada (and worldwide). Despite the established benefits of treatment with statins, most Canadians fail to achieve dyslipidemia targets (a risk factor for ASCVD).
  • The objective of this study was to examine current treatment patterns of lipid-lowering therapies for the management of low-density lipoprotein cholesterol (LDL-C) in patients with ASCVD.
  • This was a retrospective cohort study conducted using province-wide administrative health data from Alberta, Canada. Datasets used included health services, pharmaceutical, and laboratory data, in addition to the Alberta population registry. The study population consisted of individuals aged 18 years or older diagnosed with ASCVD between 2011-2015, based on International Classification of Diseases (ICD) codes. The cohort was then restricted to individuals with an initial (index) LDL-C measurement after ASCVD diagnosis and at least one year of pre-index data and one year of follow-up data.
(more…)
Author Interviews, Genetic Research, Heart Disease, JAMA, Lipids / 25.04.2019

MedicalResearch.com Interview with: Florian Kronenberg, MD Division of Genetic Epidemiology Department of Medical Genetics, Molecular and Clinical Pharmacology Medical University of Innsbruck, Innsbruck, Austria MedicalResearch.com: What is the background for this study? Response: Lp(a) is one of the most prevalent lipoprotein risk factors for cardiovascular disease. Roughly 20% of the general Caucasian population have concentrations above 50 mg/dL and the 10% with the highest concentrations have a 2 to 3-fold increased risk for myocardial infarction. There is strong evidence from genetic studies that high Lp(a) concentrations are causally related to cardiovascular outcomes. Until recently there was no drug available which lowers Lp(a) without any effects on other lipoproteins. This has recently changed by the development of drugs that block the production of Lp(a) in an impressive way. These drugs have to be studied in randomized controlled trials whether they not only lower Lp(a) concentrations but also cardiovascular outcomes. For the planning of such studies it is crucial to estimate the amount of Lp(a) lowering required to show a clinical benefit. (more…)
Author Interviews, Brigham & Women's - Harvard, Lipids, Stroke / 16.04.2019

MedicalResearch.com Interview with: Pamela M. Rist, ScD Assistant Professor of Medicine, Harvard Medical School Brigham and Women's Hospital, Division of Preventive Medicine Boston, MA 02215  MedicalResearch.com: What is the background for this study? What are the main findings? Response: Although hypercholesterolemia is a risk factor for ischemic stroke, some prior studies have observed an inverse association between total and low-density lipoprotein (LDL) cholesterol and risk of hemorrhagic stroke.  However, many studies were not able to study this association specifically among women. Our main result was very low levels of low-density lipoprotein (LDL) cholesterol or low levels of triglycerides were associated with an increased risk of hemorrhagic stroke among women. (more…)
Accidents & Violence, Author Interviews, Heart Disease, Inflammation, JACC, Lipids / 18.03.2019

MedicalResearch.com Interview with: Dr. George Dangas MD PhD Professor of Medicine, Cardiology Mount Sinai Health System MedicalResearch.com: What is the background for this study? Response: Widespread use of statins targeted to decrease levels of low density lipoprotein cholesterol (LDL-C) below 70mg/dL are recommended by guidelines. However, residual cholesterol risk may only be one part of the residual risk equation. Indeed, Biological inflammation has long been known as a pathophysiological mechanism of atherosclerosis and the recent CANTOS trial opened new therapeutic perspective by demonstrating that inflammation modulation via selective interleukin-1β inhibition could result in improved diagnosis in patients with coronary artery disease. However, the prevalence and impact of a residual inflammatory biological syndrome in patients with controlled cholesterol risk is unclear. (more…)
Author Interviews, Heart Disease, Imperial College, Lipids, NEJM, Statins / 13.03.2019

MedicalResearch.com Interview with: Prof. Kosh Ray, MB ChB, MD, MPhil Faculty of Medicine, School of Public Health Chair in Public Health (Clinical) Imperial College London MedicalResearch.com: What is the background for this study? What are the main findings? Response: Bempedoic acid is the first in class of a new therapy for lowering LDL cholesterol. This is the largest and longest study to date with this therapy and involved about 2200 pts with patients with either established cardiovascular disease or familial hypercholestrolaemia and in whom LDL was > 70mg/dl or 1.8 mmol/L despite maximally tolerated statins. %0% were on high intensity statins and the majority of the rest on moderate intensity. The aim was to show long term safety 1 year and efficacy at 24 weeks and at 1 year.  (more…)
ALS, Author Interviews, Statins / 15.02.2019

MedicalResearch.com Interview with: Alastair J. Noyce MD, PhD Preventive Neurology Unit, Wolfson Institute of Preventive Medicine Queen Mary University of London, Department of Clinical and Movement Neurosciences, University College London, Institute of Neurology, London UK MedicalResearch.com: What is the background for this study? What are the main findings?  Response: Amyotrophic lateral sclerosis (ALS) or motor neurone disease (MND) is a relentlessly progressive disorder that affects nerves which supply muscles. Over time the nerves die, leading to limb weakness, speech and swallowing problems, and ultimately breathing problems. Patients die on average 3-5 after diagnosis. There is no cure and the underlying disease processes are only understood in part. In this study, we adopted a large-scale approach to exploring causal risk factors for ALS. Causality is important because it implies that if one could modify or induce a change in a risk factor, one would observe a change in the risk of ALS. Observational studies struggle to prove causality definitely. Associations in observational studies can arise because: 1) the risk factor truly changes risk of ALS; or 2) something about ALS changes one’s exposure to the risk factor; or 3) the presence of another factor, which may or may not be known, can induce an association between a risk factor and ALS. Unless scenario 1 represents the truth, then changing the risk factor will not have any effect on risk of ALS. We used a proxy-based approach, known as Mendelian randomisation, to assess hundreds of possible risk factors for ALS for evidence of causality. What emerged from this was a very clear signal linking LDL cholesterol to risk of ALS. (more…)
Author Interviews, Brigham & Women's - Harvard, Heart Disease, JAMA, Lipids / 03.08.2018

MedicalResearch.com Interview with: Marc S. Sabatine, MD, MPH Chairman | TIMI Study Group Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine Brigham and Women's Hospital Professor of Medicine | Harvard Medical School MedicalResearch.com: What is the background for this study? What are the main findings?  Response: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for cardiovascular disease. The initial statin trials studied patients with high levels of LDL-C, and showed a benefit by lowering LDL-C. We and others did studies in patients with so-called “average” levels of LDL-C (120-130 mg/dL), and also showed clinical benefit with lowering. (more…)
AHA Journals, Author Interviews, Heart Disease, Lipids, Menopause, University of Pennsylvania, Women's Heart Health / 19.07.2018

MedicalResearch.com Interview with: Samar R. El Khoudary, Ph.D., M.P.H. BPharm, FAHA Associate Professor Department of Epidemiology University of Pittsburgh Graduate School of Public Health MedicalResearch.com: What is the background for this study? What are the main findings? Response: The background for this study is based on the current measurements used to determine cardiovascular disease risk in postmenopausal women. Higher levels of HDL “good cholesterol” as measured by the widely available clinical test, HDL-Cholesterol, may not always be indicative of a lower risk of cardiovascular disease in postmenopausal women. HDL is a family of particles found in the blood that vary in sizes, cholesterol contents and function. HDL particles can become dysfunctional under certain conditions such as chronic inflammation. HDL has traditionally been measured as the total cholesterol carried by the HDL particles, known as HDL cholesterol. HDL cholesterol, however, does not necessarily reflect the overall concentration, the uneven distribution, or the content and function of HDL particles. We looked at 1,138 women aged 45 through 84 enrolled across the U.S. in the Multi-Ethnic Study of Atherosclerosis (MESA), a medical research study sponsored by the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH). MESA began in 1999 and is still following participants today. We assessed two specific measurements of HDL: the number and size of the HDL particles and total cholesterol carried by HDL particles. Our study also looked at how age when women transitioned into post menopause, and the amount of time since transitioning, may impact the expected cardio-protective associations of HDL measures. Our study points out that the traditional measure of the good cholesterol, HDL cholesterol, fails to portray an accurate depiction of heart disease risk for postmenopausal women. We reported a harmful association between higher HDL cholesterol and atherosclerosis risk that was most evident in women with older age at menopause and who were greater than, or equal to, 10 years into post menopause. In contrast to HDL cholesterol, a higher concentration of total HDL particles was associated with lower risk of atherosclerosis. Additionally, having a high number of small HDL particles was found beneficial for postmenopausal women. These findings persist irrespective of age and how long it has been since women became postmenopausal. On the other hand, large HDL particles are linked to an increased risk of cardiovascular disease close to menopause. Women are subject to a variety of physiological changes in their sex hormones, lipids, body fat deposition and vascular health as they transition through menopause. We are hypothesizing that the decrease of estrogen, a cardio-protective sex hormone, along with other metabolic changes, can trigger chronic inflammation over time, which may alter the quality of HDL particles. Future studies should test this hypothesis. The study findings indicate that measuring size and number of HDL particles can better reflect the well-known cardio-protective features of the good cholesterol in postmenopausal women. (more…)
Author Interviews, Heart Disease, JAMA, Lipids / 17.04.2018

MedicalResearch.com Interview with: 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. (more…)
Author Interviews, Lipids, Sanofi / 29.11.2017

MedicalResearch.com Interview with: 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. (more…)
Author Interviews, Columbia, Heart Disease, Lipids / 13.09.2017

MedicalResearch.com Interview with: Dr. Jay Edelberg MD, PhD VP Head of Cardiovascular Development and Head Global Cardiovascular Medical Affairs Sanofi  MedicalResearch.com: What should readers take away from the data that Sanofi and Regeneron is presenting at ESC Congress 2017?    Response: This year at European Society of Cardiology (ESC,) we are pleased to present analyses that further demonstrate additional efficacy and tolerability of Praluent (alirocumab). While statins remain the first-line treatment, Praluent has shown a consistent benefit as an additional therapy to high-intensity statins in patients with clinical atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH), allowing many patients to achieve low-density lipoprotein (LDL) cholesterol levels previously considered unattainable in this patient population. Our data further emphasize the need for additional cholesterol-lowering options in these high cardiovascular (CV) risk patient populations, including individuals living with diabetes.   (more…)
Author Interviews, Genetic Research, Lipids, NEJM / 01.12.2016

MedicalResearch.com Interview with: Brian A. Ference, M.D Division of Cardiovascular Medicine Wayne State University School of Medicine Detroit, MI MedicalResearch.com: What are the main findings? Response: Lifelong exposure to modestly lower plasma LDL-C levels caused by rare loss-of-function mutations in the PCSK9 gene is associated with a substantially lower lifetime risk of developing cardiovascular disease. This discovery motivated the development of monoclonal antibodies directed against PCSK9 which have now been shown to reduce plasma LDL-C levels by 50-60%. The cardiovascular medicine community is early anticipating the results of two large cardiovascular outcome trials that will determine if lowering LDL-C levels by inhibiting PCSK9 will reduce the risk of cardiovascular events. Because monoclonal antibodies and other therapies directed against PCSK9 are designed to recapitulate the phenotype of PCSK9 loss-of-function mutations, we reasoned that it may be possible to anticipate the efficacy and safety results of the ongoing cardiovascular outcome studies by more precisely characterizing the effect of genetic variants in the PCSK9 gene on the risk of both cardiovascular events and new onset diabetes. To do this, we a constructed genetic score consisting of multiple independently inherited variants in the PCK9 gene to create an instrument that mimics the effect of PCSK9 inhibitors. We then compared the effect of genetic variants that mimic the effect of PCSK9 inhibitors with the effect of genetic variants in the HMGCR gene that mimic the effect of statins to make inferences about the likely effect of PCSK9 inhibitors on the risk of cardiovascular events and new onset diabetes as compared to treatment with a statin. (more…)
Author Interviews, Heart Disease, Lipids, NEJM, Pharmacology / 14.11.2016

MedicalResearch.com Interview with: Kevin Fitzgerald, Ph.D. Alnylam Pharmaceuticals Cambridge, MA 02142 MedicalResearch.com: What is the background for this study? Response: Inclisiran (ALN-PCSsc) is a subcutaneously administered RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia. The Phase 1 trial of inclisiran was conducted in the U.K. as a randomized, single-blind, placebo controlled, single ascending-and multi-dose, subcutaneous dose-escalation study in 69 volunteer subjects with elevated baseline LDL-C (≥ 100 mg/dL). The primary objective of the study was to evaluate the safety, side effect profile, and pharmacodynamics effects of inclisiran. (more…)
AHA Journals, Author Interviews, Heart Disease, Lipids / 28.09.2016

MedicalResearch.com Interview with: Dr. Johan Frostegård MD PhD Professor of medicine Karolinska Institutet's Institute of Environmental Medicine and Consultant at Karolinska University Hospital's Emergency Clinic MedicalResearch.com: What is the background for this study? What are the main findings? Response: Statins are one of the worlds most sold medications, which has generated large profits, but also, in my opinion, helped many people. Still, side effects are much discussed after more than 2 decades of use, as exemplified by a current debate between Lancet and BMJ (the former has the opinion that side effects are not major issues, but the latter do not agree). Also the exact role of LDL (low density lipoprotein, also known as the ”bad cholesterol”) as a risk factor is discussed, and can vary, according to many researchers. LDL levels are important among middle aged persons, especially men, as a risk markers for cardiovascular disease, especially myocardial infarction. LDL is most likely less important as a risk factor in individuals above 60 years of age, and also among women – as compared to middle aged men. (more…)
Author Interviews, Heart Disease, JAMA, Lipids / 29.10.2014

George Thanassoulis, MD MSc FRCP(C) Director, Preventive and Genomic Cardiology FRQ-S Clinician-Scientist/Chercheur-Boursier Clinicien Assistant Professor of Medicine, McGill University McGill University Health Center Montreal, QCMedicalResearch.com Interview with: George Thanassoulis, MD MSc FRCP(C) Director, Preventive and Genomic Cardiology FRQ-S Clinician-Scientist/Chercheur-Boursier Clinicien Assistant Professor of Medicine, McGill University McGill University Health Center Montreal, QC Medical Research: What is the background for this study? What are the main findings? Dr. Thanassoulis: Although LDL-C (i.e. bad cholesterol) has been linked with aortic valve disease in several prior reports, randomized trials to lower cholesterol in aortic valve disease were not effective suggesting that cholesterol may not be important in valve disease. To address this, we performed a Mendelian randomization study, that showed that a genetic predisposition to LDL-C, was associated with both calcium deposits on the aortic valve and aortic stenosis (I.e. Valve narrowing).  These results can be viewed as the effect of a life-long increase in LDL-C on the incidence of aortic valve disease and suggest that increases in LDL-C cause aortic stenosis.   (more…)
Author Interviews, General Medicine, Lancet, Lipids / 02.10.2014

Professor F. J. Raal FRCP, FRCPC, FCP(SA), Cert Endo, MMED, PhD Director, Carbohydrate & Lipid Metabolism Research Unit Professor & Head, Division of Endocrinology & Metabolism Faculty of Health Sciences, University of the Witwatersrand Johannesburg Hospital Johannesburg South AfricaMedicalResearch.com Interview with: Professor F. J. Raal FRCP, FRCPC, FCP(SA), Cert Endo, MMED, PhD Director, Carbohydrate & Lipid Metabolism Research Unit Professor & Head, Division of Endocrinology & Metabolism Faculty of Health Sciences, University of the Witwatersrand Johannesburg Hospital Johannesburg South Africa Medical Research: What are the main findings of the study? Dr. Raal: Heterozygous familial hypercholesterolaemia (HeFH)  is one of the most common inherited disorder in man affects between 1:250 to 1:300 persons worldwide. Thus, there are likely more than 3 million patients with heterozygous familial hypercholesterolaemia in the United States and Europe alone. The RUTHERFORD-2 study was a large world-wide multinational study  of the use of the PCSK9-inhibitor, evolocumab, in over 300 patients with heterozygous familial hypercholesterolaemia (HeFH). Evolocumab administered either 140 mg biweekly or 420 mg monthly as a subcutaneous injection, much like an insulin injection, was well tolerated with minimal side effects,  and markedly reduced levels of LDL cholesterol or “bad cholesterol”  by over 60% compared to placebo. (more…)
Author Interviews, Lipids, NEJM, Statins / 31.03.2014

Evan A. Stein, M.D., Ph.D. FRCP(C), FCAP Metabolic and Atherosclerosis Research Center Cincinnati, OH 45225,MedicalResearch.com Interview with: Evan A. Stein, M.D., Ph.D. FRCP(C), FCAP Metabolic and Atherosclerosis Research Center Cincinnati, OH 45225,   MedicalResearch.com: What are the main findings of the study? Dr. Stein: The study which is the first 52 week randomized double blind trial of a PCSK9 to report results (all others have been 12 weeks) demonstrated that the excellent LDL-C reductions of 55-60% seen at 12 weeks are maintained through 52 weeks, with no fall off in patient compliance, tolerability of efficacy. It also demonstrated that with longer treatment no new or unexpected side effects. The study also had a unique design in that prior to randomization to the PCSK9 inhibitor (evolocumab) or placebo patients had a run in period during which time they were assigned, based on NCEP-ATP III criteria, to appropriated background therapy which ranged from diet only, to atorvastatin 10 mg a day, to atorvatatin 80 mg a day or atorvastatin 80 mg a day plus ezetimibe - reflecting how these patients are treated in practice. Only then if their LDL-C was still above 75 mg/dL were they randomized into the treatment part of the study with the new drug. The study showed that irrespective of background therapy the reduction with evolocumab was consistent. (more…)