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Comment
. 2025 May 1;82(5):439-449.
doi: 10.1001/jamaneurol.2025.0353.

GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias

Huilin Tang  1 , William T Donahoo  2 , Steven T DeKosky  3   4 , Yao An Lee  1 , Pareeta Kotecha  1 , Mikael Svensson  1   5 , Jiang Bian  6 , Jingchuan Guo  1   5
Affiliations
Comment

GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias

Huilin Tang et al. JAMA Neurol. .

Abstract

Importance: The association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) and risk of Alzheimer disease and related dementias (ADRD) remains to be confirmed.

Objective: To assess the risk of ADRD associated with GLP-1RAs and SGLT2is in people with type 2 diabetes (T2D).

Design, setting, and participants: This target trial emulation study used electronic health record data from OneFlorida+ Clinical Research Consortium from January 2014 to June 2023. Patients were 50 years or older with T2D and no prior diagnosis of ADRD or antidementia treatment. Among the 396 963 eligible patients with T2D, 33 858 were included in the GLP-1RA vs other glucose-lowering drug (GLD) cohort, 34 185 in the SGLT2i vs other GLD cohort, and 24 117 in the GLP-1RA vs SGLT2i cohort.

Exposures: Initiation of treatment with a GLP-1RA, SGLT2i, or other second-line GLD.

Main outcomes and measures: ADRD was identified using clinical diagnosis codes. Hazard ratios (HRs) with 95% CIs were estimated using Cox proportional hazard regression models with inverse probability of treatment weighting (IPTW) to adjust for potential confounders.

Results: This study included 33 858 patients in the GLP-1RA vs other GLD cohort (mean age, 65 years; 53.1% female), 34 185 patients in the SGLT2i vs other GLD cohort (mean age, 65.8 years; 49.3% female), and 24 117 patients in the GLP-1RA vs SGLT2i cohort (mean age, 63.8 years; 51.7% female). In IPTW-weighted cohorts, the incidence rate of ADRD was lower in GLP-1RA initiators compared with other GLD initiators (rate difference [RD], -2.26 per 1000 person-years [95% CI, -2.88 to -1.64]), yielding an HR of 0.67 (95% CI, 0.47-0.96). SGLT2i initiators had a lower incidence than other GLD initiators (RD, -3.05 per 1000 person-years [95% CI, -3.68 to -2.42]), yielding an HR of 0.57 (95% CI, 0.43-0.75). There was no difference between GLP-1RAs and SGLT2is, with an RD of -0.09 per 1000 person-years (95% CI, -0.80 to 0.63) and an HR of 0.97 (95% CI, 0.72-1.32).

Conclusion and relevance: In people with T2D, both GLP-1RAs and SGLT2is were statistically significantly associated with decreased risk of ADRD compared with other GLDs, and no difference was observed between both drugs.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Tang reported receiving grants from Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation during the conduct of the study. Dr DeKosky reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study; personal fees from Acumen Pharmaceuticals, Biogen, and Vaccinex for serving as the data and safety monitoring board chair; Cognition Therapeutics for serving on the medical advisory board; Neurotherapeutics for serving as an associate editor; UpToDate for serving as a section editor for dementia; and consulting fees from Eisai, Lilly, Nido Biosciences, and Prevail Therapeutics outside the submitted work. Dr Kotecha reported receiving personal fees from Takeda Pharmaceuticals for serving as an intern in 2023 and Novo Nordisk for serving as a regulatory medical writer from 2021 to 2022 outside the submitted work. No other disclosures were reported.

Comment on

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