Introduction: Diabetes, kidney disease, and cardiovascular disease have complex interactions and coexistences that significantly worsen a patient’s overall health. Previous research results have shown that SGLT2i hypoglycemic drugs can not only effectively control blood sugar in diabetic patients but also protect the kidneys and heart. This study further focuses on diabetic patients with kidney disease to explore the effectiveness of using SGLT2i hypoglycemic drugs in avoiding heart-related complications or death. Methods: This is a multicenter retrospective cohort study using the Taipei Medical University Clinical Research Database (TMUCRD) as the data source. This study selected patients who suffered from both type 2 diabetes and chronic kidney disease from 1 January 2008 to 31 December 2020, as the research team. Integrated or separate 4-point major adverse cardiovascular events (4P-MACE) and mortality were the outcomes of this study. The Kaplan-Meier curves method and Cox proportional hazard regression analysis were used to explore the association between each influencing factor and the outcome. Results: A total of 5,005 patients with type 2 diabetes and CKD were included in this study, of which 524 patients were stably treated with SGLT2i, 3,952 patients were treated with DPP4i, and 529 patients were treated with TZD. The results showed that the SGLT2i user group had a significantly lower risk of 4P-MACE compared with the SGLT2i nonuser group (hazard ratio [HR]: 0.68, 95% CI [0.49, 0.95], p = 0.024). The SGLT2i group had a significantly lower risk of cardiovascular mortality compared with the DPP4i and TZD groups (HR: 0.37, 95% CI [0.21, 0.65], p < 0.001; HR: 0.42, 95% CI [0.20, 0.90], p = 0.025). Conclusion: This study found that for patients with both diabetes and kidney disease, SGLT2i is a better option than other oral hypoglycemic medications because it can significantly avoid the occurrence of heart-related complications. The results of this study can be used as a reference for clinical medication selection practice.

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