Introduction: Dementia risk is substantially elevated in patients with diabetes. However, evidence on dementia risk associated with various antidiabetic regimens is still limited. This study aims to comprehensively investigate the risk of dementia and Alzheimer's disease (AD) associated with various antidiabetic classes. Methods: Cochrane Central Register of Controlled Trials, Embase, MEDLINE (PubMed), and Scopus were searched from inception to March 2024 (PROSPERO CRD 42022365927). Observational studies investigating dementia and AD incidences after antidiabetic initiation were identified. Bayesian network meta-analysis was performed to determine dementia and AD risks associated with antidiabetics. Preferred Reporting Items for Systematic Reviews-Network Meta-Analyses (PRISMA-NMA) guidelines were followed. Statistical analysis was performed and updated in November 2023 and March 2024, respectively. Results: A total of 1,565,245 patients from 16 studies were included. Dementia and AD risks were significantly lower with metformin and sodium glucose co-transporter-2 inhibitors (SGLT2i). Metformin displayed the lowest risk of dementia across diverse antidiabetics, whereas α-glucosidase inhibitors demonstrated the highest risk. SGLT2i exhibited the lowest dementia risk across second-line antidiabetics. Dementia risk was significantly higher with dipeptidyl peptidase-4 inhibitor (DPP4i), metformin, sulfonylureas, and thiazolidinediones (TZD) compared to SGLT2i in the elderly (≥75 years). Dementia risk associated with metformin was substantially lower, regardless of diabetic complication status or baseline A1C. Discussion: Metformin and SGLT2i demonstrated lower dementia risk than other antidiabetic classes. Patient-specific factors may affect this relationship and cautious interpretation is warranted as metformin is typically initiated at an earlier stage with fewer complications. Hence, further large-scaled clinical trials are required.
This research was partially supported by National Research Foundation (NRF), grant-funded by Ministry of Education (no. 2021R1I1A1A01044500) and the Ministry of Science and ICT (no. 2021R1C1C1003735) and Ministry of Food and Drug Safety in 2023 (no. 21153MFDS601). The protocol of this network meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD 42022365927). This study does not require approval from Institutional Review Board and consent to participate. All data generated and/or analyzed during the study are included in the previous published articles (and its online supplementary files). No additional datasets were generated during the current study. All authors declare no conflicts of interest. No financial disclosures have been reported by the authors of this paper.YS and JP contributed equally to this work. SS and YJC contributed equally to this work. This research was partially supported by National Research Foundation (NRF) , grant-funded by Ministry of Education [No. 2021R1I1A1A01044500 ] and the Ministry of Science and ICT [No. 2021R1C1C1003735 ] and Ministry of Food and Drug Safety in 2023 [No. 21153MFDS601 ]. All authors declare no conflicts of interest. No financial disclosures have been reported by the authors of this paper. The protocol of this network meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) ( CRD 42022365927 ). This study does not require approval from Institutional Review Board and consent to participate. All data generated and/or analyzed during the study are included in the previous published articles (and its online supplementary files). No additional datasets were generated during the current study.
