Protective effect of antidiabetic drugs against male infertility: evidence from Mendelian randomization

The global prevalence of diabetes has been steadily increasing, with a growing number of younger individuals being affected. Over recent decades, various antidiabetic drugs have been repurposed for treating conditions beyond diabetes. However, the effects of antidiabetic drugs on male infertility (MIF) remain inadequately elucidated. This Mendelian randomization (MR) study aims to clarify the potential impact of antidiabetic drugs on the risk of MIF.

We designed a comprehensive analytical workflow involving two-sample MR and summary-based MR (SMR) to assess the causal relationship between antidiabetic drug targets and MIF. First, instrumental variables were obtained based on HbA1c levels and gene expression levels. Then, MR analysis was performed after selecting positive target genes from four blood glucose level and type 2 diabetes (T2DM) datasets. Finally, we applied SMR analysis to validate and expand upon the previous conclusions. Additionally, sensitivity analyses were conducted to evaluate the robustness of the results.

Seven drug targets associated with five antidiabetic drugs were identified as significantly related to MIF. In the two-sample MR, the following drugs were found to reduce MIF risk through their respective significant targets: metformin (GPD1: IVW OR 0.007, 95% CI 0.000-0.204, P = 0.004), SGLT2 inhibitors (SGLT2i) (SLC5A1: IVW OR 0.048, 95% CI 0.004-0.585, P = 0.017), insulin and its analogs (IGF1R: IVW OR 0.773, 95% CI 0.648-0.922, P = 0.004), and sulfonylureas (TRPM4: IVW OR 0.869, 95% CI 0.766-0.985, P = 0.028; CTPA1: IVW OR 0.838, 95% CI 0.741-0.947, P = 0.005). In SMR analysis, antidiabetic drugs targeting the genes CPE (P = 0.03, HEIDI = 0.970) and TRPM4 (P = 0.028, HEIDI = 0.746) were found to significantly reduce the risk of MIF.

Our study indicates that metformin, SGLT2i, insulin and its analogs, as well as sulfonylureas, may offer potential therapeutic benefits for MIF. Specifically, six antidiabetic drug target genes GPD1, SLC5A1, IGF1R, TRPM4, CPT1 A, and CPE may play a role in the progression of MIF. These findings have significant implications for the development of personalized precision therapies for MIF.