Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors: Shaping the future after the further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER) trial

Abstract

Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have been shown to decrease low-density lipoprotein cholesterol (LDL-C) levels by about 60% on top of statin therapy [1]. Apart from LDL-C, PCSK9 inhibitors also increase high-density lipoprotein cholesterol (HDL-C) and reduce triglycerides (TGs), non-HDL-C and lipoprotein (a) [Lp(a)] levels, potentially lowering residual cardiovascular (CV) risk [2,3]. In terms of safety, PCSK9 inhibitors did not increase the risk for severe adverse events, stroke, musculoskeletal side effects or neurocognitive disorders, as supported in a recent meta-analysis [4]. However, there have been reports on a potential adverse impact on neurocognitive function in 2 large trials [5,6] although this has not been confirmed yet (see below).Currently, there are 2 available PCSK9 inhibitors: evolocumab and alirocumab that have been approved by both the Food and Drug Administration (FDA) and the European Medicine Agency (EMA). The development of bococizumab, another PCSK9 inhibitor, was discontinued, mainly based on a significant attenuation of its LDL-C-lowering effect over time, possibly due to the development of antidrug antibodies [7]. It should be noted that bococizumab is a murine-derived, humanized monoclonal antibody whereas the other 2 drugs (i.e. evolocumab and alirocumab) are fully human monoclonal antibodies; this difference may explain the higher immunogenicity associated with bococizumab [8].With regard to CV outcomes, evolocumab was shown to significantly reduce the rate of CV events at 1 year [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.28 to 0.78; p = 0.003)] in a prespecified exploratory analysis of 2 previous open-label, randomized, controlled trials [the Open-Label Study of Long-Term Evaluation against LDL Cholesterol 1 (OSLER-1) and OSLER-2] [6]. Similarly, alirocumab significantly decreased the rate of major adverse CV events at 78 weeks compared with placebo (HR, 0.52; 95% CI, 0.31 to 0.90; p = 0.02) in a post-hoc analysis of a previous phase 3, randomized, placebo-controlled, double-blind study [i.e. the Long-term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients with Hypercholesterolemia Not Adequately Controlled with Their Lipid Modifying Therapy (ODYSSEY LONG TERM) [5]].

Lipid-lowering therapy and renin-angiotensin-aldosterone system inhibitors in the era of the COVID-19 pandemic

“…In COVID-19-positive patients, the majority of baseline CVD is of atherosclerosis origin, with the worst prognosis for patients being at the high, and especially very high and extremely high, risk of CVD [16]; thus, intensive LLT with statins and/or fixed combination with ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors seems to be critical. Indeed, we should do our best to maximally improve therapy adherence and thus have a better prognosis for the infected CVD patients [44,45]. In this context, there are no premises that PCSK9 inhibitors, because they are monoclonal antibodies (in relation to the above-mentioned high cytokine storm during infection), should be discontinued.…”

Effect of alirocumab and evolocumab on all-cause mortality and major cardiovascular events: A meta-analysis focusing on the number needed to treat

“…This study also aids with the cost-effectiveness analysis of drugs (51)(52)(53). When two PCSK9 inhibitors became commercially available in 2015, they did improve the clinical prognosis for secondary prevention, but the annual retail cost was nearly $14,000.…”

Lipid-lowering Drugs and Neurocognitive Function: A Systematic Review

“…Two mAbs for LDL-C reduction, evolocumab and alirocumab, have been permitted by both the FDA and European Medicines Agency and both have affirmed a notable ability in reducing LDL-C along with a promising safety profile (6). Additionally, according to the Further Cardiovascular Outcomes Research that reported the PCSK9 inhibition in patients with elevated risk trial (7), patients presenting high cardiovascular risk were investigated at first. Evolocumab has been proven to decrease cardiovascular episodes.…”