Incidence of dementia in patients with type 2 diabetes using SGLT2 inhibitors versus GLP-1 receptor agonists or DPP-4 inhibitors: A systematic review and meta-analysis of cohort studies

Abstract

Background

Individuals with type 2 diabetes mellitus (T2DM) have a higher incidence of dementia than those without the disease, possibly due to overlapping pathophysiological mechanisms. While glycemic control is essential to reduce dementia risk, recent studies suggest that newer antidiabetic agents, SGLT2i, GLP-1 RA, and DPP-4i, may offer neuroprotective effects.

Objective

To investigate the incidence of dementia in T2DM patients treated with SGLT2i compared to GLP-1 RA or DPP-4i.

Methods

A systematic search of PubMed, Embase, and Cochrane databases was conducted for cohort studies published up to June 2025 that assessed dementia incidence in T2DM patients using SGLT2i versus DPP-4i or GLP-1 RA. Risk ratios (RRs) were calculated using the Mantel-Haenszel random-effects model, with variance estimated via restricted maximum likelihood in R version 4.3.0.

Results

Ten studies met inclusion criteria. Four compared SGLT2i with GLP-1 RA, and seven with DPP-4i; one study contributed to both comparisons. The pooled RR for dementia in SGLT2i versus GLP-1 RA users was 0.91 (95% CI: 0.73–1.12; p < 0.003; I² = 78.7%). When comparing SGLT2i to DPP-4i, the RR was 0.39 (95% CI: 0.28–0.56; p < 0.00001; I² = 96.4%).

Conclusions

Use of SGLT2i was associated with a lower risk of dementia compared to DPP-4i, with no significant difference observed when compared to GLP-1 RA.