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

🥈 Top 2% JournalMay 31, 2025Alzheimer's & dementia : the journal of the Alzheimer's Association

Different effects of two diabetes drug types on Alzheimer's and related dementia risk in people with type 2 diabetes

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Abstract

GLP-1 receptor agonists and SGLT2 inhibitors are associated with a 1.5% and 1.7% reduced risk of Alzheimer's disease and related dementias, respectively.

Both GLP-1 receptor agonists and SGLT2 inhibitors showed a reduced risk of Alzheimer's disease and related dementias compared to other glucose-lowering drugs.
Patients with cardiovascular disease and cerebrovascular disease experienced the greatest reduction in risk, with GLP-1RAs showing a reduction of -4.8% and -4.6%.
No significant difference in ADRD risk was observed between GLP-1 receptor agonists and SGLT2 inhibitors.

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INTRODUCTION: This study assessed the (HTEs) of (GLP-1RAs) and (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.

Key numbers

-1.5%

Absolute Risk Reduction of with GLP-1RAs

Compared to other glucose-lowering drugs.

-1.7%

Absolute Risk Reduction of with

Compared to other glucose-lowering drugs.

-4.8%

Risk Reduction in Patients with and for GLP-1RAs

Among patients with both and .

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Abstract

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