PCSK9 inhibitors: Pharmacology, adverse effects, and use
- John JP Kastelein, MD, PhD, FESC
John JP Kastelein, MD, PhD, FESC
- Professor of Medicine
- Academic Medical Center, University of Amsterdam
- Amsterdam, the Netherlands
- Erik SG Stroes, MD, PhD
Erik SG Stroes, MD, PhD
- Professor of Medicine
- Academic Medical Center
- University of Amsterdam
- Lotte CA Stiekema, MD
Lotte CA Stiekema, MD
- Academic Medical Center
- Robert S Rosenson, MD
Robert S Rosenson, MD
- Section Editor — Lipids
- Professor of Medicine
- Mount Sinai School of Medicine
- Director, Cardiometabolic Disorders
- Mount Sinai Heart
Proprotein convertase subtilisin/kexin type 9 inhibitors have been approved by regulatory agencies for the treatment of individuals with inadequately treated levels of low density lipoprotein-cholesterol (LDL-C). They are capable of lowering LDL-C by as much as 60 percent in patients on statin therapy. In addition, they produce clinical benefits, such as reductions in the rates of stroke or myocardial infarction.
This topic will focus on information the clinician might need when considering using these drugs. The potential indications for the use of these drugs are discussed separately. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Third line treatment' and "Treatment of drug-resistant hypercholesterolemia", section on 'PCSK9 antibodies'.)
MECHANISM OF ACTION
Proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme (serine protease) encoded by the PCSK9 gene, is predominantly produced in the liver [1-3]. PCSK9 binds to the low density lipoprotein receptor (LDL-R) on the surface of hepatocytes, leading to the degradation of the LDL-R and higher plasma LDL-cholesterol (LDL-C) levels [4,5]. Antibodies to PCSK9 interfere with its binding of the LDL-R leading to higher hepatic LDL-R expression and lower plasma LDL-C levels (figure 1) .
There are several strategies to lower free plasma PCSK9, including antisense, silencing ribonucleic acid (RNA), and monoclonal antibody strategies. PCSK9-antibodies are the first of these therapies approved for clinical use. These antibodies are specific for PCSK9 and do not bind to other members of the PCSK enzyme family [7,8].
Alirocumab and evolocumab are fully humanized monoclonal antibodies that bind free plasma PCSK9, promoting degradation of this enzyme [9-12]. As a result, less free PCSK9 is available in plasma to bind to LDL-R. This results in a higher fraction of LDL-R recycling towards the hepatocyte surface. As a direct consequence, the liver has the capacity to remove more LDL-C from the circulation, resulting in lower LDL-C plasma levels.
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- MECHANISM OF ACTION
- CLINICAL EFFECT
- Absorption, distribution, and onset
- Metabolism and clearance
- - Hepatic impairment
- - Renal impairment
- Drug interactions
- ADVERSE EFFECTS
- Immunologic and allergic effects
- Neurocognitive toxicity
- Muscle toxicity
- Hepatitis C virus (HCV) infectivity
- Colon tumors
- Insulin resistance and diabetes
- APPROVED INDICATIONS
- ONGOING INVESTIGATION
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS