PCSK9 inhibitors and diabetes mellitus

Czech version

Authors: Branislav Vohnout ^1,2,3; Jana Lisičanová ³; Andrea Havranová ⁴
Authors‘ workplace: Ústav výživy, FO a ZOŠ a Koordinačné centrum pre familiárne hyperlipoproteinémie, Slovenská zdravotnícka univerzita v Bratislave, Slovenská republika ¹; Ústav epidemiológie LF UK v Bratislave, Slovenská republika ²; Diabetologická ambulancia Diabeda s. r. o., Bratislava, Slovenská republika ³; Ústav klinického a translačného výskumu, Biomedicínske centrum Slovenskej akadémie vied, Bratislava, Slovenská republika ⁴
Published in: Vnitř Lék 2018; 64(12): 1186-1189
Category:

Overview

Proproteinconvertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor (LDLR) expression. Anti-PCSK9 monoclonal antibody (MAb) therapy reduces LDL-cholesterol (LDL-C) by ~60 % and reduces also the risk of major adverse cardiovascular events. Mendelian randomisation studies showed that patients carrying loss-of-function PCSK9 genetic variants display lower LDL-C and have an increased risk of developing type 2 diabetes (T2DM). Randomized controlled trials with anti-PCSK9 MAbs however showed no effect on the risk. A possible explanation of the discrepancy is that the deficiency of locally but not circulating PCSK9 is responsible for increased LDLR expression in pancreatic islets, which results in cholesterol accumulation and B-cell dysfunction. Thus PCSK9 lowering therapy with MAb targeting mainly circulating PCSK9 might have a limited impact on LDLR expression in pancreatic cells and on the risk of T2DM. Long-term clinical trials are however needed to confirm it.

Key words:

diabetes mellitus – LDL receptor – PCSK9

Sources

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