Background: Cardiovascular-Kidney-Metabolic (CKM) diseases, including coronary heart disease, atherosclerosis, and chronic kidney disease, are significant causes of mortality among diabetic patients. Although diabetes is known to influence these diseases, the underlying biological pathways remain unclear.

Methods: We performed a two-sample Mendelian randomization (MR) analysis to investigate the relationships between type 1 diabetes (T1D), type 2 diabetes (T2D) and CKM traits. Two-step MR analyses were conducted to explore potential pathways involving circulating inflammatory proteins and metabolites. Cross-trait linkage disequilibrium score regression (LDSC) was employed to investigate the genetic association and colocalization analyses were used to assess shared genetic architecture. Additional sensitivity analyses were performed, including exclusion of variants within the major histocompatibility complex/human leukocyte antigen (MHC/HLA) region for T1D.

Results: MR analyses suggested that genetically predicted T2D was associated with increased risks of multiple CKM traits, including coronary heart disease (OR = 1.16, p = 2.01 × 10^-5) and myocardial infarction (OR = 1.17, p = 1.46 × 10^-4), with consistent results across sensitivity analyses. In contrast, initial associations between T1D and CKM diseases were attenuated and no longer statistically significant after excluding variants within the MHC/HLA region, indicating that these associations were largely driven by this immune-related locus. Two-step MR analyses identified several circulating metabolites associated with both T2D and CKM diseases, suggesting that metabolic factors (e.g., 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC) may partially explain the association between T2D and CKM risk (mediation proportions ranging from 4.56% to 29.31%). For T1D, circulating inflammatory proteins and metabolites were also associated with CKM traits; however, these findings are better interpreted as reflecting shared immune and metabolic pathways rather than causal mediation.

Conclusion: Our findings support a potential causal role of T2D in the development of CKM diseases, partly through circulating metabolites. In contrast, the associations observed for T1D appear to be largely driven by the HLA/MHC region and likely reflect shared immune-mediated genetic architectures rather than a direct causal effect. These results provide insight into distinct biological pathways linking different forms of diabetes with CKM diseases.