Chen Che-Kai, Kuo Chang-Fu, Chang Yu-Jing, Zhang Weiya, Doherty Michael, Chang Ming-Ling, Chen Tsung-Hsing
Center for Artificial Intelligence in Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
School of Medicine, Chang Gung University, Taoyuan, Taiwan.
Int J Endocrinol. 2025 Aug 26;2025:2357272. doi: 10.1155/ije/2357272. eCollection 2025.
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. 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. MR-RAPS suggested a potential causal relationship between increased DPP4 at the mRNA levels and HF (0.031 [95% CI, 0.06-0.56; =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. 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.
二肽基肽酶 -4（DPP4）抑制剂常用于治疗2型糖尿病。然而，其与心血管疾病（CVD）之间的因果关系存在争议。本研究旨在：（1）在欧洲人群中，研究DPP4基因在mRNA水平的表达对CVD的因果机制，包括全因心力衰竭（HF）、心房颤动（AF）、心肌梗死（MI）和中风；（2）评估DPP4在mRNA水平对CVD的直接作用，该作用独立于2型糖尿病；（3）探究DPP4抑制对CVD和2型糖尿病的因果关系。利用来自eQTLGen联盟、GTEx门户和英国生物银行的DPP4和CVD汇总统计数据，我们应用弱IV和多效性稳健孟德尔随机化方法（MR - RAPS、GRAPPLE、BESIDE - MR、去偏IVW）和中介分析，以评估DPP4在mRNA水平对CVD的因果影响以及DPP4在mRNA水平对CVD的直接作用（非由糖尿病介导）。还评估了DPP4抑制对CVD的因果关系。MR - RAPS表明，mRNA水平DPP4升高与HF之间存在潜在因果关系（0.031 [95% CI，0.06 - 0.56；P = 0.014]）。然而，仅有有限证据表明DPP4水平升高会影响AF、MI或中风。其他分析证实了这些发现。中介分析表明DPP4在mRNA水平对HF有直接作用，而去偏IVW显示DPP4抑制对CVD有因果作用的证据有限，可能是由于统计效力较低。孟德尔随机化分析支持DPP4抑制剂在治疗2型糖尿病时的心血管安全性，几乎没有证据表明DPP4介导心血管损害，这进一步证明了其在欧洲人群中临床应用的合理性。此外，如果DPP4抑制影响心血管结局，可能并非通过血糖控制（如降低糖化血红蛋白）来实现。
