OSLER and ODYSSEY LONG TERM: PCSK9 inhibitors on the right track of reducing cardiovascular events.

Mohamed Hassan

doi:10.5339/gcsp.2015.20

Abstract

Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors have emerged as a novel treatment option in patients with hypercholesterolemia. Evolocumab and alirocumab have achieved consistent and significant (around 60%) reduction in low-density lipoprotein cholesterol (LDL-C) levels when added to statin therapy in short term studies. The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER), and The Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM) studies are two phase 3, multicentre, randomized, placebo controlled studies that were conducted to evaluate the long term efficacy and safety of evolocumab and alirocumab respectively in reducing lipids and cardiovascular (CV) events. Both studies demonstrated additional 48–53% reduction of CV events when added to statin therapy. Most adverse events occurred with similar frequency in the two groups; however the rate of neurocognitive adverse events was higher with evolocumab and alirocumab than with placebo. These data provide strong support for the notion that lower LDL-C goal is better, and may confirm the role of PCSK9 inhibitors as a new frontier in lipid management. The results of larger long-term outcome studies are still awaited.

Highlights

Evolocumab and alirocumab are monoclonal antibodies that bind to proprotein convertase subtilisin kexin 9 (PCSK9) and inhibit its interaction with LDL receptors
In line with our prior expectations, PCSK inhibition gained further support for possible US Food and Drug Administration (FDA) approval especially in patients with statin intolerance or familial hypercholesterolemia in whom target low-density lipoprotein cholesterol (LDL-C) level could not be achieved by statin therapy
Consistent with the results of previous short-term trials, both evolocumab and alirocumab achieved about 60% reduction from baseline in LDL-C concentration in the longer-term studies

Summary

INTRODUCTION

Evolocumab and alirocumab are monoclonal antibodies that bind to proprotein convertase subtilisin kexin 9 (PCSK9) and inhibit its interaction with LDL receptors. ODYSSEY LONG TERM STUDY The Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM) study was a phase 3, multicentre, randomized, double- blind, placebo-controlled study that has been recently published in the New England Journal of Medicine in March 2014.12 A total of 2341 patients with heterozygous familial hypercholesterolemia, established coronary heart disease (CHD), or CHD risk equivalent (defined as peripheral arterial disease, ischemic stroke, chronic kidney disease, or diabetes mellitus plus two or more additional risk factors [hypertension; ankle –brachial index of # 0.90; microalbuminuria, macroalbuminuria; preproliferative or proliferative retinopathy; or a family history of premature CHD]) were included in the study if they had an LDL-C level $ 70 mg/dL despite receiving maximum tolerated dose of statin therapy. Secondary end-points included the percentage change from baseline in LDL-C level

No at Risk

Findings

DISCUSSION