PCSK9 Inhibiting Monoclonal Antibodies

Low-density lipoprotein cholesterol (LDL-C), a component of dyslipidemia, is a modifiable risk factor for cerebrovascular disease including ischemic stroke and TIAs. The current guidelines recommend the use of lipid-lowering medications to reduce the risk of stroke among patients with ischemic stroke or TIA presumed to be of atherosclerotic origin. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, in addition to healthy lifestyle modifications are a mainstay in the treatment of hyperlipidemia and stroke risk reduction. However, there are limitations to statins use. Some patients, despite being on maximum doses of high-intensity statins in conjunction with other lipid-lowering medications like ezetimibe, continue to have persistently elevated LDL-C levels, while a subset of patients is unable to tolerate statins due to their adverse effects, namely statin-induced myopathy. A relatively new class of monoclonal antibodies have been developed that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein involved in lipid metabolism, and can address therapeutic limitations in this subset of patients. A second class of drugs using small interfering RNA that lower PCSK9 are also currently under active investigation. This chapter will focus on PCSK9 inhibitors by discussing pharmacology, clinical trials with a focus on stroke outcomes, and clinical use in practice.