LAUSR

PCSK9 Inhibitors, Statins, Low-Density Lipoprotein Cholesterol, Mevalonate Pathway, and Toxicity To the Editor In a study by Koren et al,1 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors exhibited potent and persistent long-term efficacy in reducing low-density lipoprotein (LDL) cholesterol levels. In the 2017 FOURIER trial by Sabatine et al,2 evolocumab demonstrated cardiovascular protection in the absence of significant toxic effects despite very low LDLcholesterol levels.However,thestrongemphasisonverylow circulating LDL cholesterol levels may be an inadequate focus for assessing the adverse effects of PCSK9 inhibitors. Statins reduce intracellular cholesterol (and isoprenoid) availability by inhibiting HMG-CoA reductase (mevalonate pathway).3 Some toxic effects of statins are related to their ability to reduce intracellular cholesterol synthesis.4,5 Conversely, PCSK9 inhibitors do not reduce intracellular cholesterol levels. Indeed, by favoring LDL receptor recycling, PCSK9 inhibitors promote LDL cholesterol dumping into the cells. In addition, the intracellular mevalonate pathway is not affected by PCSK9 inhibition. Therefore, extremely low LDL cholesterol levels may have very different pathophysiological implications if achieved by statins or PCSK9 inhibition. Indeed, extremely low LDL cholesterol seems to be safe in patients exhibiting loss-of-function PSCK9 mutations. PCSK9 inhibition provides a unique way of cardiovascular protection by removing LDL cholesterol where it may be harmful (ie, circulating) while increasing cholesterol availability where it is needed (ie, intracellular). Toxic effects of PCSK9 inhibition must be scrutinized as any other medical intervention. However, focusing on low circulating LDL levels might be unwise.