PCSK9 inhibitors for treating hypercholesterolemia

ABSTRACT

Introduction: Scientific evidence on subjects treated with statin or other lipid-lowering treatments has established that treatments aiming to lower low-density lipoprotein cholesterol (LDL-C) can reduce atherosclerosis. PCSK9 inhibitors (PCSK9-i), thanks to their efficacy in reducing LDL-C constitute a further step in the treatment of dyslipidemia and cardiovascular (CV) diseases.

Areas covered: The purpose of this narrative review is to summarize the current knowledge of PCSK9-i, with particular regard to pharmacodynamic, pharmacokinetic, and clinical data on evolocumab and alirocumab.

Expert opinion: PCSK9-I are effective in reducing atherosclerotic events through their significant LDL-C-lowering action similarly to statins. Furthermore, these drugs can be considered safe and well-tolerated. However, some controversies remain with regard to their efficacy in reducing mortality and the paucity of data on both pleiotropic effects and long-term safety of these drugs. However, future studies will focus on understanding the effects of very low cholesterol levels on health. At present, we know that the genetic model of PCSK9 deficiency is characterized by very low LDL-C levels without particular health problems. Yet, we do not know the effect of prolonged PCSK9 inhibition induced by antibody action during the lifetime of normal subjects.

KEYWORDS:

• PCSK9 inhibitors
• LDL-C
• lipid-lowering drugs
• hypercholesterolemia

Article highlights

• Dyslipidemia and LDL-C are well-known modifiable CV risk factors for acute coronary syndromes (ACS).

• The discovery that PCSK9 interacts with LDL receptor constituted a further step forward in the comprehension of the pathophysiology of dyslipidemia and laid the groundwork for the concept that limiting PCSK9 action could be a successful strategy for the management of hypercholesterolemic patients.

• The efficacy of evolocumab and alirocumab, two PCSK9-I, in reducing LDL-C has been confirmed in several phase III trials, except for patients affected by Homozygous Familial Hypercholesterolemia (Ho-FH) with receptor-negative mutations.

• In clinical trials, they reduce LDL-C levels of about 60% without being influenced by the background lipid-lowering therapy.

• Several pooled analyses, systematic reviews, and meta-analyses of phase II and III studies on these drugs have been performed. Overall, the rate of adverse events (AEs) leading to treatment discontinuation was similar in PCSK9-I groups and in control groups.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One referee has received honoraria from Sanofi. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.