Background: Existing observational studies yielded mixed results between cognitive and dementia outcomes and newer glucose-lowering drugs (GLDs) , i.e., dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) , and sodium-glucose co-transporter-2 (SGLT2) inhibitors, while individual randomized trials have inadequate power to examine such an effect. Thus, we aimed to evaluate the effect of these newer GLDs on the risk of dementia by performing a meta-analysis of randomized outcome trials.

Methods: We included published randomized placebo-controlled cardiovascular and renal outcome trials that evaluated DPP-4 inhibitors, GLP-1RAs, and SGLT2 inhibitors and reported dementia events. The study outcomes were all-cause dementia and vascular dementia, extracted from We calculated pooled odds ratios (OR) and 95% CIs using the Peto method.

Results: We included 21 trials involving 1all-cause dementia cases (including 22 vascular dementia cases) among 167,5patients with or without type 2 diabetes over a median follow-up of 2.2 years. Neither DPP-4 inhibitors (OR, 0.65 [0.33-1.29]) , GLP-1RAs (OR, 0.88 [0.51-1.52]) , or SGLT2 inhibitors (OR, 1.22 [0.54-2.74]) were significantly associated with all-cause dementia incidence. For vascular dementia, compared with placebo, SGLT2 inhibitors were significantly associated with a decreased risk (OR, 0.[0.02-0.66]) , while DPP-4 inhibitors (OR, 0.67 [0.12-3.85]) and GLP-1RAs (OR, 0.37 [0.12-1.14]) did not significantly decrease the risk. No evidence of statistical heterogeneity or publication bias was detected in the meta-analysis (p >0.05) .

Conclusion: SGLT2 inhibitors may have a beneficial effect on lowering the vascular dementia risk, thus may be a drug repurposing signal. Nevertheless, future randomized controlled trials and/or comparative effectiveness studies using real-world data are warranted to further confirm our conclusion.


H.Tang: None. S.Niu: None. J.D.Brown: None. J.Wei: None. A.G.Winterstein: Consultant; Genentech, Inc., Research Support; Merck & Co., Inc. J.Bian: None. J.Guo: None.

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