GLP-1 RAs More Effective Than Metformin for Reducing Dementia Risk in T2DM

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may be more effective than metformin for reducing the risk of dementia in patients with type 2 diabetes, according to findings from a recent study.1

Leveraging a decade of data from the TriNetX database for adults with type 2 diabetes who initiated either GLP-1 RAs or metformin as first-line therapy, the study found GLP-1 RAs significantly reduced the risk of overall dementia—particularly Alzheimer’s disease and non-vascular dementias—compared with metformin. Notably, GLP-1 RAs also provided substantial reductions in all-cause mortality, further supporting the early use of GLP-1 RAs in patients with type 2 diabetes at risk of cognitive decline.1

Previous research has indicated a heightened risk of developing dementia among individuals with type 2 diabetes, with dementia risk increasing the longer a person has diabetes and the more severe it is.2 While both GLP-1 RAs and metformin have both demonstrated potential neuroprotective effects in type 2 diabetes, no head-to-head real-world comparisons have evaluated their relative efficacy in preventing dementia.1

“Given the significant clinical and societal burden of T2DM-related dementia, determining which therapy— GLP-1 RAs or metformin—provides superior protection against cognitive decline is crucial,” senior author Jiaqiang Zhang, of the department of anesthesiology and perioperative medicine at Zhengzhou University, and colleagues wrote.1 “Clarifying this therapeutic distinction will offer crucial guidance for clinicians, policymakers, and researchers, potentially reshaping dementia prevention strategies in T2DM management.”

To assess the comparative effectiveness of GLP-1 RAs and metformin in reducing dementia risk, investigators conducted a retrospective cohort study using data from TriNetX for adults with type 2 diabetes who initiated either GLP-1 RAs or metformin as first-line therapy between November 2004 and November 2024. The index date was defined as the earliest prescription date post-diagnosis, with ≥ 24 months of follow-up required. Investigators employed 1:1 propensity score matching to balance baseline characteristics between patients on GLP-1 RAs and patients on metformin.1

The primary outcome was the incidence of overall dementia, defined as the first occurrence of a diagnosis of vascular dementia, Alzheimer’s disease, unspecified dementia, or dementia associated with other diseases. Secondary outcomes included the incidence of specific dementia subtypes and all-cause mortality.1

To address potential biases from pre-existing or undiagnosed dementia and to allow sufficient time for the therapeutic effects of the medications to manifest, investigators applied a 6-month washout period. Follow-up began on day 181 after the index date and continued until the first occurrence of an outcome, loss to follow-up, or the conclusion of the study period.1

Among 87,229 matched patients per cohort, GLP-1 RA use was associated with a significantly reduced risk of overall dementia (adjusted hazard ratio [aHR], 0.90; 95% CI, 0.85-0.95), Alzheimer’s disease (aHR, 0.88; 95% CI, 0.83-0.94), and non-vascular dementias (aHR, 0.75; 95% CI, 0.70-0.81) compared with metformin. However, no significant difference was observed for vascular dementia. Further analysis revealed the all-cause mortality rate was notably reduced in the GLP-1 RA group (aHR, 0.89; 95% CI, 0.81-0.95).1

Subgroup analyses showed consistent benefit across age and sex. Investigators noted the benefits were most pronounced in patients aged ≥60 years, with significant reductions noted in those 60–79 years of age (aHR, 0.85; 95% CI, 0.80-0.90) and ≥ 80 years of age (aHR, 0.80; 95% CI, 0.74-0.88). Additionally, while both sexes benefitted, investigators pointed out females had a slightly lower aHR (0.83; 95% CI, 0.79-0.89) compared with males (0.90; 95% CI, 0.84-0.97).1

“Given the increasing global burden of diabetes-related cognitive decline and the lack of head-to-head comparisons between GLP-1 RAs and metformin, our findings provide actionable insights for clinical decision-making and may inform future guidelines. Additionally, the study underscores the importance of tailoring therapeutic strategies to optimize both metabolic and neuroprotective outcomes in high-risk T2DM populations,” investigators concluded.1 “Further randomized controlled trials are warranted to confirm these findings and evaluate the long-term cognitive benefits of GLP-1 RAs.”

References

1. Sun M, Wang X, Lu Z, et al. Evaluating GLP-1 receptor agonists versus metformin as first-line therapy for reducing dementia risk in type 2 diabetes. BMJ Open Diab Res Care 2025;13:e004902. doi:10.1136/ bmjdrc-2025-004902

2. Alzheimer’s Society. Diabetes and the risk of dementia. August 2024. Accessed July 22, 2025. https://www.alzheimers.org.uk/about-dementia/managing-the-risk-of-dementia/reduce-your-risk-of-dementia/diabetes