The Mechanism of Action of PCSK9 Inhibition and the Truth about Statin Intolerance


The MD Magazine Peer Exchange “Amassing the Clinical Evidence for Optimized Dyslipidemia Management: Vitamin D, Long-Term Statin Outcomes, and PCSK9 Inhibition” features expert insight and analysis of the latest information on managing hypertension and hyperlipidemia, and in-depth discussion on the use of PCSK9 inhibitors in practice.

This Peer Exchange is moderated by Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University and an associate director of surgical intensive care at the New York-Presbyterian Hospital in New York City.

The panelists are:

  • Christie Ballantyne, MD, Co-director of the Lipid Metabolism and Atherosclerosis Clinic at The Methodist Hospital, Director of the Center for Cardiovascular Disease Prevention at the Methodist DeBakey Heart Center, and the Chief of Cardiology at Baylor College of Medicine
  • Keith C. Ferdinand, MD, Immediate Past Chair of the National Forum for Heart Disease and Stroke Prevention, and Professor of Clinical Medicine at the Heart and Vascular Institute at Tulane University School of Medicine
  • Jennifer G. Robinson, MD, MPH, Professor in the Departments of Epidemiology & Medicine and Director of the Prevention Intervention Center, Department of Epidemiology at the College of Public Health, University of Iowa
  • Karol E. Watson, MD, PhD, Professor of Medicine and Cardiology, Co-director of the UCLA Program in Preventive Cardiology, and Director of the UCLA Barbra Streisand Women’s Heart Health Program

Because the PCSK9 inhibitor class is so new, the panel described its mechanism of action for the audience. These are monoclonal antibodies that increase LDL receptor expression on the cell surface. People who are born with loss of function mutations in the PCSK9 gene have inherent PCSK9 inhibition from birth, and it has been found that these individuals have lifelong low LDL levels, according to Watson.

In the ODYSSEY Alternative trial, 42% of patients achieved the LDL treatment goals with PCSK9 inhibition compared with only 4% of patients who used ezetimibe alone. Even though this study was in a statin-intolerant population, one interesting finding was the many patients were actually able to tolerate a moderate (20-mg) dose of atorvastatin. Watson believes that this means clinicians should try to get high-risk patients on statins, because many of them can take them. One explanation for this phenomenon is that the patients were blinded, so they did not know they were receiving a statin, with all of the side effects that are well known already.

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