Key aspects of PCSK9 inhibition beyond LDL loweringRamin-Mangata, Stéphane*; Blanchard, Valentin*; Lambert, GillesCurrent Opinion in Lipidology: December 2018 - Volume 29 - Issue 6 - p 453–458 doi: 10.1097/MOL.0000000000000551 THERAPY AND CLINICAL TRIALS: Edited by Erik S.G. Stroes and Gerald F. Watts Abstract Author InformationAuthors Article MetricsMetrics Purpose of review Our primary objective is to review the most recent findings on the biology of PCSK9 and on two key aspects of PCSK9 inhibition beyond LDL control of great clinical relevance: the regulation of lipoprotein (a) circulating levels by PCSK9 inhibitors and the putative diabetogenic effects of these novel therapies. Recent findings The reality of two distinct extracellular and intracellular pathways by which PCSK9 decreases the abundance of the LDLR at the surface of many cell types, most importantly hepatocytes, has recently been established. In contrast, the exact mechanisms by which PCSK9 inhibitors lower the circulating levels of lipoprotein (a) remain a point of major dispute. Despite strong indications from genetic studies that PCSK9 inhibition should increase diabetes risk, no such effect has been observed in clinical trials, and in-vitro and in-vivo studies do not clarify this issue. Summary The trafficking pathways by which PCSK9 enhance LDLR degradation via the endolysosomal extracellular route or via the Golgi–lysosomal intracellular route remain to be fully elucidated. The mechanisms by which PCSK9 inhibitors reduce lipoprotein (a) also merit additional research efforts. The role of PCSK9 on glucose metabolism should likewise be studied in depth. Laboratoire Inserm UMR 1188, DéTROI, Université de La Réunion, Sainte-Clotilde, France Correspondence to Gilles Lambert, PhD, Inserm UMR 1188, Plateforme CYROI, 2 Rue Maxime Rivière, 97490 Sainte Clotilde, France. Tel: +33 262 692 437 708; fax: +33 262 262 938 237; e-mail: firstname.lastname@example.org Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.