Abstract
The reduction of circulating low-density lipoprotein-cholesterol (LDL-C) is a primary target in cardiovascular risk reduction due to its well-established benefits in terms of decreased mortality. Despite the use of statin therapy, 10%–20% of high- and very-high-risk patients do not reach their LDL-C targets. There is an urgent need for improved strategies to manage dyslipidemia, especially among patients with homozygous familial hypercholesterolemia, but also in patients with established cardiovascular disease who fail to achieve LDL goals despite combined statin, ezetimibe, and PCSK9 inhibitor (PCSK9i) therapy. Inclisiran is a disruptive, first-in-class small interfering RNA (siRNA)-based therapeutic developed for the treatment of hypercholesterolemia that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) synthesis, thereby upregulating the number of LDL receptors on the hepatocytes, thus lowering the plasma LDL-C concentration. Inclisiran decreases the LDL-C levels by over 50% with one dose every 6 months, making it a simple and well-tolerated treatment strategy. In this review, we summarize the general information regarding (i) the role of LDL-C in atherosclerotic cardiovascular disease, (ii) data regarding the role of PCSK9 in cholesterol metabolism, (iii) pleiotropic effects of PCSK9, and (iv) the effects of PCSK9 silencing. In addition, we focus on inclisiran, in terms of its (i) mechanism of action, (ii) biological efficacy and safety, (iii) results from the ORION trials, (iv) benefits of its combination with statins, and (v) its potential future role in atherosclerotic cardiovascular disease.
Highlights
Cholesterol is one of the major components of cellular membranes, which plays an important role in hormone and bile acid synthesis [1]
We summarize the general information regarding (i) the role of lowdensity lipoprotein-cholesterol (LDL-C) in atherosclerotic cardiovascular disease (ASCVD), (ii) data regarding the role of proprotein convertase subtilisin–kexin type 9 (PCSK9) in cholesterol metabolism, (iii) pleiotropic effects of PCSK9, and (iv) the effects of PCSK9 silencing
PCSK9 protein has an impact on the metabolism of triglyceride-rich lipoprotein (TRL)—highly atherogenic particles associated with the initiation and propagation of atherosclerosis
Summary
Cholesterol is one of the major components of cellular membranes, which plays an important role in hormone and bile acid synthesis [1]. For secondary prevention in very-high-risk patients and for very-high-risk familial hypercholesterolemia (FH) patients who do not reach their LDL-C targets on the maximum tolerated doses of statin and ezetimibe, a combination with a proprotein convertase subtilisin/kexin type inhibitor (PCSK9i) is recommended [8]. The clinical benefits of evolocumab were assessed in the FOURIER trial, where evolocumab lowered LDL-C levels by 59% and reduced the risk of cardiovascular death, myocardial infarction (MI), or stroke by 20%, compared with a placebo. The clinical advantages of alirocumab were evaluated in the ODYSSEY Outcomes trial, where alirocumab lowered the LDL-C levels by 57% and reduced the risk of cardiovascular death, MI, stroke, and hospitalization for unstable angina by 15%, compared with the placebo [11]. We focus on inclisiran, discussing (i) its mechanism of action, (ii) its biological efficacy and safety, (iii) results from the ORION trials, (iv) benefits of its combination with statins, and (v) its potential future role in ASCVD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
