When It Comes to LDL-C, “You Really Can’t Be Too Low”

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

Dr. Marc Sabatine

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.

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Not All HDL Cholesterol is Good – Size Matters

MedicalResearch.com Interview with:

Samar R. El Khoudary, PhD, MPH, BPharm, FAHA Associate Professor, Epidemiology PITT Public Health Epidemiology Data Center University of Pittsburgh Pittsburgh, PA 15260 

Dr. El Khoudary

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. 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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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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Praluent Plus Statins Reduce LDL In High Risk Cardiovascular Patients

MedicalResearch.com Interview with:

VP Head of Cardiovascular Development and Head Global Cardiovascular Medical Affairs Sanofi

Dr. Edelberg

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 

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Cardioprotective Effect of PCSK9 Inhibitors Should Outweigh Potential Harm of Diabetes Risk

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.

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Phase1 Trial Supports PCSK9-Inhibitor Inclisiran For Reducing LDL Cholesterol

MedicalResearch.com Interview with:

Kevin Fitzgerald, Ph.D. Alnylam Pharmaceuticals Cambridge, MA 02142

Dr. Kevin Fitzgerald

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.

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Statins Reduce Inflammation As Well As LDL

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.

Dr. Johan Frostegård

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.

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“Bad Cholesterol” LDL-C Linked to Aortic Valve Disease

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.   Continue reading

Evolocumab Markedly Reduced LDL in Hypercholesterolemia

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.

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Hyperlipidemia: Monoclonal Antibody Successfully Reduced LDL-C in One Year Trial

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.

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