The Causal Mechanism Between the Dipeptidyl Peptidase‐4, Heart Failure, and Other Cardiovascular Diseases: A Mendelian Randomization and Mediation Study

<b>Aims:</b> Dipeptidyl peptidase-4 (DPP4) inhibitors are commonly used to treat type 2 diabetes. However, the causality of it on cardiovascular diseases (CVDs) is controversial. 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. <b>Methods:</b> Utilizing DPP4 and CVD summary statistics from eQTLGen Consortium, GTEx Portal, and UK Biobank, we applied weak IV and pleiotropy robust Mendelian randomization methods (MR-RAPS, GRAPPLE, BESIDE-MR, debiased IVW) and mediation analysis to assess the causal impact of DPP4 at the mRNA level on CVD and the direct effect of DPP4 at the mRNA level on CVD, not mediated by diabetes. The causality of DPP4 inhibition on CVD was also evaluated. <b>Results:</b> MR-RAPS suggested a potential causal relationship between increased DPP4 at the mRNA levels and HF (0.031 [95% CI, 0.06-0.56; <i>p</i>=0.014]). However, there was limited evidence that increased DPP4 levels affect AF, MI, or stroke. Other analyses corroborated these findings. Mediation analysis indicated a direct effect of DPP4 at the mRNA level on HF, while debiased IVW showed limited evidence for a causal effect of DPP4 inhibition on CVDs, possibly due to low statistical power. <b>Conclusions:</b> Mendelian randomization analyses support the cardiovascular safety of DPP4 inhibitors in managing type 2 diabetes, with little evidence for DPP4-mediated cardiovascular harm, reinforcing their appropriateness for clinical use in European populations. Additionally, if DPP4 inhibition affects cardiovascular outcomes, it may not do so through glycemic control, such as HbA1c reduction.