Abstract
BACKGROUND: Patients with diabetes mellitus (DM) are at increased risk for Clostridioides difficile (C. difficile) infection (CDI), in part due to frequent exposure to antibiotics-particularly broad-spectrum agents-which represents the most important modifiable risk factor for CDI. OBJECTIVE: To systematically evaluate the impact of DM on the incidence and recurrence risk of CDI, explore underlying mechanisms, and provide evidence-based guidance for prevention and control in high-risk populations. METHODS: A systematic search was conducted in PubMed, Embase, and Web of Science to identify cohort and case-control studies reporting on the association between diabetes and the risk or outcomes of CDI. The ROBINS-I tool was used for risk of bias assessment. Random-effects models were applied to pool odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses, sensitivity analyses, and cumulative meta-analyses were performed. The quality of evidence for the primary outcomes was graded according to the GRADE approach. The study protocol was registered in PROSPERO (registration number: CRD420251128182). RESULTS: A total of 12 international studies (including 8 reporting recurrence outcomes) and covering more than 3. 5 million participants from North America, Europe, and East Asia were included. Meta-analysis showed that diabetes significantly increased the risk of CDI (OR=1. 46, 95% CI: 1. 20-1. 77), as well as the risk of recurrence (OR=3. 11, 95% CI: 1. 98-4. 87). Subgroup and sensitivity analyses yielded consistent results, and cumulative meta-analysis indicated that effect sizes became stable over time. Mechanistic analyses suggested that immune dysfunction, gut microbiota imbalance, and exposure to high-risk medications were key contributing factors. Based on GRADE assessment, the quality of evidence for the primary outcomes was moderate, with a low risk of publication bias. CONCLUSION: Diabetes is an independent risk factor for both CDI and its recurrence. It is recommended that clinicians strengthen CDI risk assessment and integrated prevention strategies for patients with diabetes, with a focus on optimizing antibiotic stewardship, reducing unnecessary broad-spectrum antibiotic use, and microbiota-targeted interventions. High-quality prospective studies are needed to further improve prevention strategies and elucidate underlying mechanisms.