Comparative Effects of SGLT2 Inhibitors and Incretin-Based Therapies on Dementia Risk in Type 2 Diabetes: A Systematic Review and Meta-analysis

Kirim Song^1,2Jiwon Choi¹Dayeon Jeong^1,3Dongyun Shin¹Young-Mi Ah⁴Ki Young Lee^5,6Kyung Hee Choi^7,8*

• ¹Gachon University College of Pharmacy, Incheon, Republic of Korea
• ²Department of Pharmacy, Chonnam National University Hwasun Hospital, Hwasun-gun, Republic of Korea
• ³Department of Pharmacy, Samsung Medical Center, Gangnam-gu, Republic of Korea
• ⁴Yeungnam University College of Pharmacy, Gyeongsan-si, Republic of Korea
• ⁵Department of Internal Medicine, Gachon University Gil Medical Center, Namdong-gu, Republic of Korea
• ⁶Department of Internal Medicine,, Gachon University School of Medicine, Incheon, Republic of Korea
• ⁷College of Pharmacy, Gachon University, Incheon, Republic of Korea
• ⁸Department of Pharmacy, Gachon University Gil Medical Center, Namdong-gu, Republic of Korea

Background: Antidiabetic drugs lower blood glucose levels and may also have neuroprotective and vascular protection effects. In particular, sodium–glucose cotransporter 2 inhibitors (SGLT2is) and incretin mimetics have demonstrated dementia-reducing effects. We evaluated whether SGLT2is reduce dementia risk compared with incretin mimetics in patients with type 2 diabetes (T2D). Methods: Systematic review and meta-analysis were performed by searching the PubMed, Embase, and Cochrane Library databases through February 2025. Both randomized trials and cohort studies were identified and qualitatively assessed, but only cohort studies were included in the quantitative meta-analysis. We also compared the effects of SGLT2is with those of dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1RA) on dementia incidence. Results: Nine studies were identified for analysis. Compared with incretin mimetics, SGLT2is significantly reduced the overall dementia risk [hazard ratio (HR) 0.82, 95% CI: 0.73-0.91], and SGLT2is had stronger effects than DPP-4i (HR 0.67, 95% CI: 0.59-0.77) and GLP-1RA (HR 0.93, 95% CI: 0.86-1.00). SGLT2i also reduced the risks of vascular dementia and Alzheimer's disease (HR 0.49, 95% CI: 0.35–0.70 vs. HR 0.68, 95% CI: 0.52–0.88, respectively). The results of subgroup analyses revealed increased benefits for patients aged older than 65 years. Empagliflozin was the most consistently protective among the SGLT2i agents. Conclusion: SGLT2is may provide neuroprotective benefits beyond glycemic control in patients with T2D, particularly in older populations at higher risk of cognitive decline. These findings support consideration of SGLT2is as a preferred therapeutic option for patients with T2D at increased risk of dementia, although randomized controlled trials would further strengthen this evidence base.