PCSK9 Inhibitors Are a Safe Alternative to Statins

Robert S. Rosenson, MD
Icahn School of Medicine at Mount Sinai, New York

Rosenson RS. PCSK9 inhibitors are a safe alternative to statins [published online April 3, 2019]. Cardiology Consultant.


As I explained in my previous commentary,1 down-titrating or discontinuing a statin after a myocardial infarction (MI)—may be due to adverse muscle events—can have a major negative impact on a patient’s health. It is imperative that a patient finds a statin he or she can tolerate.

But what if a patient cannot achieve a low low-density lipoprotein cholesterol (LDL-C) on a statin that they can tolerate?

There are several options. One such option is adding ezetimibe, and another is considering a PCSK9 inhibitor. Both of these non-statin agents have far fewer adverse muscle events than statins, and they have favorable outcomes in patients with coronary heart disease when added to statin therapy, be it post-acute coronary syndrome or in patients with stable coronary heart disease.

There have been several trials that have evaluated PCSK9 inhibitors in patients with statin adverse muscle events. The most important of these trials was the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3) trial.2 This was a randomized, double-blind, placebo-controlled crossover study design that included participants who had experienced adverse muscle events on 3 statins or atorvastatin, 10 mg, plus 1 other statin. The LDL-C had to exceed the value recommended in the Adult Treatment Panel III guidelines,3 so individuals with coronary heart disease who had an LDL-C level greater than 70 mg/dL or high-risk individuals with an LDL-C level greater than or equal to 100 mg/dL were considered.

In the first part of the trial, known as Part A, participants were randomly assigned to either atorvastatin, 20 mg, or a placebo. If the participant correctly identified that he or she was on atorvastatin, he or she was allowed to continue into the second part of the trial. But since this was a crossover study design, all the participants received atorvastatin, 20 mg, or placebo and then switched for the second part of Part A.

In Part B of the trial, study participants were randomly assigned 2 to 1 to receive either a PCSK9 inhibitor or ezetimibe, and their symptoms were evaluated. The main results were that there was marked reduction in LDL-C with the inhibitor, and this therapy resulted in fewer discontinuations than seen even with ezetimibe in study participants who had failed or experienced adverse muscle events on atorvastatin, 20 mg, daily.

A second notable study is a parallel arm study known as Odyssey Alternative.4 In this trial, which was a running phase, study participants were randomly assigned to ezetimibe or alirocumab. As compared with statin therapy, the PCSK9 inhibitor was better tolerated than ezetimibe.

We have 2 important trials—and other trials such as GAUSS-1 and GAUSS-2—that provide the database that PCSK9 inhibitors may be a useful alternative therapy to lower LDL-C in high-risk individuals who are unable to tolerate statins at the doses needed to effectively lower their LDL cholesterol.


The Mechanisms of Muscle Events

In a study led by Elam and colleagues that was published in PLOS One,5 the researchers performed skeletal muscle biopsies on participants with muscle statin intolerance and determined that some participants had activation of a certain gene cluster that is associated with myalgia while some participants had activation of a different gene cluster that is associated with myopathy. Other participants had both myalgia and myopathy and so might have had more than 1 gene network activated.

This data is intriguing and provides the justification for understanding precise mechanisms that contribute to or cause the adverse muscle event is necessary. The study’s findings can also aid in determining whether the symptoms patients report are those of adverse muscle events—the patient may have a genetic susceptibility that precludes them from tolerating statins at all or tolerating the doses of statins needed to achieve lower LDL-C.

Looking ahead, we are currently working in the area of metabolomics to identify how a branched amino acid metabolism can influence some of the manifestations of statin muscle symptoms.

Robert S Rosenson, MD, is Professor of Medicine at the Icahn School of Medicine at Mount Sinai - New York, where he serves as Director of Cardiometabolic Disorders. He is a Fellow of the American Heart Association Council on Epidemiology and Prevention; Fellow of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Fellow of the American College of Cardiology; Fellow of the European Society of Cardiology; and a past Fellow of the American College of Chest Physicians (inactive).



  1. Rosenson RS. The importance of identifying muscle events in statin users [published online April 3, 2019]. Cardiology Consultant.
  2. Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, et al; GAUSS-3 Investigators. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. 2016;315(15):1580-1590.
  3. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation. 2018;106(25):3143.
  4. Moriarty PM, Thompson PD, Cannon CP, et al; ODYSSEY ALTERNATIVE Investigators. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758-769.
  5. Elam MB, Majumdar G, Mozhui K, et al. Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge. PLoS One. 2017;12(8):e0181308.