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

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.