Repurposing Antidiabetic Drugs for Cerebrovascular Diseases: Causal Evidence from Drug Target Mendelian Randomization and Colocalization

Abstract

Cerebrovascular diseases have caused substantial social and economic burdens, and new treatment methods are urgently needed. Evaluating the feasibility of the use of antidiabetic drugs for treating cerebrovascular diseases is meaningful in this field. We designed a comprehensive study process that includes two-sample Mendelian randomization (MR), which uses genetic proxies for antidiabetic drug targets, summary-based MR (SMR) for mRNAs, and colocalization for drug target genes to assess their causal relationships with 10 cerebrovascular disease phenotypes. Seven of the eight main types of clinical antidiabetic drugs were identified, yielding eleven potential drug targets. Our study observed that sulfonylureas (KCNJ11) and metformin (GPD1) reduce the risk of stroke and that TZDs (PPARG) reduce the risk of hippocampal perivascular spaces. In addition, sulfonylureas can reduce the risk of certain cerebral small vessel disease. These results show that antidiabetic drugs have hypoglycemic properties and affect cerebrovascular health. Our study supports repurposing antidiabetic drugs as disease-modifying therapies to improve cerebrovascular health. Future research should focus on studying the role of drugs in different phenotypes of cerebrovascular diseases and explore the potential molecular mechanisms to analyze further the potential effects of antidiabetic drugs on cerebrovascular diseases.

Keywords: Antidiabetic drugs; Cerebrovascular diseases; Colocalization; Drug targets; Gene expression; Mendelian randomization.