This study aimed (1) to investigate the causal mechanisms of DPP4 gene expression at the mRNA level on CVDs, including all-cause heart failure (HF), atrial fibrillation (AF), myocardial infarction (MI), and stroke in a European population; (2) to assess the direct effect of DPP4 at the mRNA level on CVD, which is independent of type-2 diabetes; and (3) to explore the causality of DPP4 inhibition on CVDs and type-2 diabetes. This evidence concerns the gene DPP4 and type 2 diabetes mellitus.