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
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 may produce clinical benefits, such as reductions in the rates of cardiac death or myocardial infarction. (See "Low density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors".)
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]. Blocking 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.
Another potential method of interfering with PCSK9 is to block its synthesis, which is dependent on messenger RNA. A study of a small interfering RNA (siRNA) molecule, which can direct sequence-specific degradation of messenger RNA for PCSK9, is ongoing. In a phase 1 dose-escalation study of healthy adult volunteers with serum LDL-C levels of ≥3 mmol/L (116 mg/dL) who received a single dose of one such siRNA (ALN-PCS), treatment with the highest dose lead to a 70 percent mean reduction in circulating PCSK9 and a mean 40 percent reduction in LDL-C from baseline relative to placebo . (See 'Current investigation' below.)
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- MECHANISM OF ACTION
- CLINICAL EFFECT
- Neurocognitive toxicity
- Muscle toxicity
- Hepatitis C virus (HCV) infectivity
- Colon tumors
- Insulin resistance and diabetes
- Drug interactions
- ADVERSE EFFECTS
- Renal and hepatic impairment
- APPROVED INDICATIONS
- CURRENT INVESTIGATION