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. 2025 Jun;21(6):e70313.
doi: 10.1002/alz.70313.

Heterogeneous treatment effects of GLP-1RAs and SGLT2is on risk of Alzheimer's disease and related dementia in patients with type 2 diabetes: Insights from a real-world target trial emulation

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

Heterogeneous treatment effects of GLP-1RAs and SGLT2is on risk of Alzheimer's disease and related dementia in patients with type 2 diabetes: Insights from a real-world target trial emulation

Huilin Tang et al. Alzheimers Dement. 2025 Jun.

Abstract

Introduction: This study assessed the heterogeneous treatment effects (HTEs) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) on the risk of Alzheimer's disease and related dementias (ADRD).

Methods: This target trial emulation study included adults (≥ 50 years) with type 2 diabetes (T2D) and newly prescribed a GLP-1RA, SGLT2i, or other second-line glucose-lowering drugs (GLDs). A doubly robust learning approach was deployed to estimate the risk difference (RD) of ADRD and identify key subgroups.

Results: Both GLP-1RAs (RD, -1.5%) and SGLT2is (-1.7%) were associated with a reduced ADRD risk compared to other GLDs. Key subgroups were determined based on cardiovascular disease (CVD), cerebrovascular disease (CeVD), chronic kidney disease, and Hispanic ethnicity. Patients with CVD and CeVD had the greatest benefits from GLP-1RAs (-4.8%) and SGLT2is (-4.6%). No overall difference was observed between GLP-1RAs and SGLT2i.

Discussion: These findings suggest the importance of personalized treatment in diabetes management regarding ADRD risk.

Highlights: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were associated with a decreased risk of Alzheimer's disease and related dementias (ADRD), while the protective association varied across subgroups defined by cardiovascular disease (CVD), cerebrovascular disease (CeVD), and chronic kidney disease (CKD). Similarly, sodium-glucose cotransporter-2 inhibitors (SGLT2is) were associated with a decreased risk of ADRD, with the protective association varying among subgroups defined by CVD, CeVD, and Hispanic ethnicity. There was no difference between GLP-1RAs and SGLT2is in the risk of ADRD.

Keywords: Alzheimer's disease and related dementias; GLP‐1RAs; SGLT2is; type 2 diabetes.

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Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Predicted individualized treatment effect (ITE, treatment effect on person level) of GLP‐1RA vs. other GLDs (A), SGLT2is vs. other GLDs (B), and GLP‐1RA vs. SGLT2i on the risk of developing ADRD. The predicted ITE is presented as RD in the risk of ADRD between groups (Y‐axis). The predicted ITE is stratified into deciles (X‐axis). ADRD, Alzheimer's disease and related dementias; CeVD, cerebrovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; GLDs, glucose‐lowering drugs; GLP‐1RA, glucagon‐like peptide‐1 receptor agonists; RD, risk difference; SGLT2i, sodium‐glucose cotransporter 2 inhibitors.
FIGURE 2
FIGURE 2
A single decision tree was developed to identify the absolute risk change in risk of ADRD between GLP‐1RA and other GLDs (A), between SGLT2i and other GLDs (B), and between GLP‐1RAs and SGLT2is (C) in people with T2D. Negative values indicate reduced absolute risk of ADRD, whereas positive values indicate increased absolute risk of ADRD. ADRD, Alzheimer's disease and related dementias; GLDs, glucose‐lowering drugs; GLP‐1RA, glucagon‐like peptide‐1 receptor agonists; SGLT2i, sodium‐glucose cotransporter 2 inhibitors; T2D, type 2 diabetes.
FIGURE 3
FIGURE 3
Sensitivity analyses of absolute RD for ADRD for GLP‐1RA vs. other GLDs(A), SGLT2i vs. other GLDs(B), and GLP‐1RA vs. SGLT2is(C) in the overall population and subgroups identified using a single decision tree model. *no HTE subgroups were identified. ADRD, Alzheimer's disease and related dementias; CI, confidence interval; CKD, chronic kidney disease; CeVD, cerebrovascular disease; GLDs, glucose‐lowering drugs; RD, risk difference; SGLT2is, sodium‐glucose cotransporter 2 inhibitors.
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References

    1. Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Kaabi JA. Epidemiology of type 2 diabetes – Global Burden of Disease And Forecasted Trends. J Epidemiol Glob Health. 2020;10(1):107. doi:10.2991/jegh.k.191028.001 - DOI - PMC - PubMed
    1. Livingston G, Huntley J, Liu KY, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet Standing Commission. Lancet. 2024;404(10452):572‐628. doi:10.1016/S0140-6736(24)01296-0 - DOI - PubMed
    1. Kale MB, Bhondge HM, Wankhede NL, et al. Navigating the intersection: diabetes and Alzheimer's intertwined relationship. Ageing Res Rev. 2024;100:102415. doi:10.1016/j.arr.2024.102415 - DOI - PubMed
    1. Braunwald E. Gliflozins in the management of cardiovascular disease. N Engl J Med. 2022;386(21):2024‐2034. doi:10.1056/NEJMra2115011 - DOI - PubMed
    1. Heerspink HJL, Perkins BA, Fitchett DH, Husain M, Cherney DZI. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134(10):752‐772. doi:10.1161/CIRCULATIONAHA.116.021887 - DOI - PubMed

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