Abstract
The use of statins as the primary therapy for reducing low-density lipoprotein cholesterol has raised concerns regarding their potential side effects in increasing the risk of type 2 diabetes (T2D). However, the underlying mechanism remains largely unknown. In this study, we utilized multi-omics molecular signatures to unravel the etiology of statin-induced T2D. Through systematic screening of 102 gut microbial features, 40 blood metabolites, and 131 circulating proteins in East Asians and Europeans, we identified a set of blood metabolites and proteins potentially influenced by genetically proxied statin use. Notably, Mendelian randomization analyses provided evidence that elevated circulating levels of gastric inhibitory polypeptide (GIP) were associated with an increased risk of T2D. This association between genetically proxied statin use and GIP was consistently observed across East Asian and European populations, highlighting the pivotal role of GIP in modulating the risks of statin-induced T2D. Furthermore, this study established an extensive atlas of multi-omics molecular signatures associated with statin-induced T2D, offering valuable insights for prioritizing intervention targets.