Drug targets for lipid modification and risk of type 2 diabetes: a cis-Mendelian randomization study.

Abstract

Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) is the cornerstone in the prevention of coronary artery disease (CAD) but may also increase risk of type 2 diabetes (T2D). A comprehensive examination of the genetic evidence of T2D related side-effects of all current lipid-modifying drugs, including those in development, has not yet been performed. This cis-Mendelian randomization study used individual level data from the UK Biobank, Lifelines, and publicly available genome-wide association data. We identified loci that are either targeted directly with drugs, or alternatively, targeting their gene products (mRNA and/or protein). Included are, in alphabetical order, the loci ACLY, ANGPTL3, ANGPTL4, APOB, APOC3, CETP, HMGCR, LDLR, LIPG, LPA, MTTP, NPC1L1, and PCSK9. We used cis-genetic instruments weighted for LDL-C, HDL-C, triglycerides, and apolipoproteins as downstream proxies for the drug targets. Main outcomes were prevalent and incident T2D, with CAD as a contrast outcome. Lipid modification through HMGCR is predicted to reduce CAD risk and increase T2D risk. Modification through targeting APOC3, LDLR, LPA, MTTP, NPC1L1, and PCSK9 is predicted to reduce CAD risk without a change in T2D risk. Modification through ANGPTL4 and CETP is predicted to reduce risk of both CAD and T2D. For ACLY, ANGPTL3, APOB, and LIPG, we found evidence for neither CAD nor T2D. This study provides genetic evidence for variation in diabetes-related side-effects of different lipid-modifying drugs, with potential relevance for future clinical trials and individual treatment decisions.