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Physiologically, in the presence of an intracellular deficit of cholesterol, the LDLR synthesis, expression and function increases, thus uptaking, introducing and providing cholesterol to the cell. This process is counter-regulated by PCSK9 expression, the protease inducing LDLR proteolysis, thereby limiting its function maintaining a constant cholesterol intracellular concentration. Accordingly, the balance or Yin-Yang between PCSK9 and LDLR directly regulates the intracellular concentration of cholesterol and indirectly has a high impact on circulating LDL-cholesterol. This article reviews the brief and amazing recent history with PCSK9 inhibition from basic science to current clinical recommendations for MAbs-PCSK9. In 2003 and 2005, respectively, the pcsk9 gene mutations, determinants of the “gain of function” of PCSK9 and severe hypercholesterolemia, and the pcsk9 gene mutations with “loss of function” of PCSK9, determinants of hypocholesterolemia were described; subsequently, in 2006, the association between the PCSK9 gene mutations and the “loss of function” of PCSK9 with hypocholesterolemia and reduction of up to 88% for the risk of a coronary event in the “mutant” population versus the control population was published. In 2009, the effect of a “full human” monoclonal antibody vs PCSK9 in mice and non-human primates was first reported; MAbs-PCSK9, AMG-145 and REGN-727, produced in cynomolgus monkeys a doubling in the number of LDLR and an average 75% reduction in circulating LDL-cholesterol. In 2012, the first phase I studies with Evolocumab and Alirocumab versus placebo were reported; these programs informed very significant reductions in LDL-cholesterol in healthy subjects and patients with familial and non-familial hypercholesterolemia treated without/with statins; in both programs, tolerability and safety of MAbs were similar to placebo. With this evidence, the Phase II and III investigations with MAbsPCSK9 initiated; four years after, pending the results of ongoing studies of cardiovascular outcomes and long-term safety (ODYSSEY-Outcomes with Alirocumab and FOURIER with Evolocumab), the OSLER trial with Evolocumab and the ODYSSEY-Long Term trial with Alirocumab, together with some recent meta-analysis of MAbs-PCSK9 allows us to establish the following scenario: MAbs-PCSK9 Evolocumab and Alirocumab have a positive and significant impact on LDL-cholesterol, other apo-B100 lipoproteins -including Lp(a)-, overall mortality and myocardial infarction; all the aforementioned with a safety profile and tolerability very favorable. In the same scenario, the recently published GLAGOV trial demonstrates for the first time that the addition of a non-statin therapy -Evolocumab-, to the optimal treatment with statins is associated with atheroregression. Beyond currently approval indications by regulatory agencies, taking account of high cost of PCSK9 inhibitors and financial restraints within healthcare budgets, by now and before definitive evidence publication, the MAbs-PCSK9 are recommended in six clinical scenarios analyzed in this paper. However, even though it is irrefutable that the MAbs-PCSK9 showed great efficiency in reducing atherogenic lipoproteins and insinuated a promising reduction in overall mortality and myocardial infarction, the certainty of the net benefit that this therapeutic strategy adds to the optimal current treatment with statins and other non-statin lipid-lowering drugs will be conclusive when results of the two currently ongoing “ad hoc” programs with Evolocumab and Alirocumab are available. Finally, preliminary results with PCSK9-mRNA interference with Inclisiran are presented.

PCSK9 Inhibition-Reaching Physiologic LDL-C Levels “Endo, Goldstein and Brown’s Dream is Coming True”