PCSK9 Inhibition: Does Lipoprotein Size Matter?

International audienceI n order to assess the risk of cardiovascular diseases in patients, fasting plasma lipids levels are usually measured as total cholesterol, triglycerides, and high-density lipopro-tein cholesterol (HDL-C) and combined to estimate low-density lipoprotein cholesterol (LDL-C) levels using the Friedewald formula. While this indirect measure is strongly correlated with the risk of cardiovascular diseases in many epidemiological studies, it lacks information related to inter-individual differences and patient's pathophysiological status. 1 Indeed, 2 individuals carrying the same amount of LDL-C could display different numbers of LDL particles (LDL-P) or size. As the correlation between LDL-P and risks of cardiovascular diseases may be stronger than LDL-C, the debate persists on the type of measure that could more accurately predict the best prognosis. 2 Such discrepancies seem to be particularly relevant in patients with metabolic syndrome and diabetes. The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as a key factor involved in lipoprotein metabolism regulation since its characterization as the third gene of autosomal-dominant hypercholes-terolemia in 2003 (ADH). 3 PCSK9 acts as a chaperone protein that binds the LDL receptor (LDLR) at the cell membrane and induces LDLR lysosomal degradation rather than recycling. 4 PCSK9 gain-of-function mutations increase LDLR degradation leading to autosomal-dominant hyperc-holesterolemia. 5 The identification of the link between PCSK9 loss-of-function mutations, low level of plasmatic LDL-C, and increased protection against cardiovascular diseases has sustained the concept of PCSK9 inhibition as a new therapeutic strategy in hypercholesterolemia. 6 Among PCSK9 inhibitors, the most advanced ones are based on humanized monoclonal antibodies (mAb) targeting extracel-lular PCSK9 4,7 and 2 of them (alirocumab: Praluent â ; evolocumab: Repatha â) have been recently approved by the U.S. Food and Drug Administration and European Medicines Evaluation Agency. The overall outcome of these studies indicated that PCSK9 mAb injections every 2 to 4 weeks led to up to 60% decrease of plasma LDL-C concentrations, either assessed by indirect calculation or by direct measurement. 7 It should be reminded here that LDL-C estimation with Friedewald calculation underestimates true LDL-C values in the lowest ranges (