Metformin Shows Inconsistent Results for Alzheimer's Prevention

Metformin, a drug primarily used for the treatment of diabetes, has been thought to provide clinical benefits extending to neurodegenerative conditions, including Alzheimer's disease (AD). Results published in Cureus showed that metformin may not be the optimal pharmacologic agent for patients with diabetes who are trying to target neurodegeneration as their primary concern.¹

New research shows metformin's inconsistent neuroprotective effects against Alzheimer's, challenging its role in diabetes management for cognitive health. | Image Credit: Valdemar - stock.adobe.com

“Metformin's use for DM treatment is generally considered to be a first-line option due to affordability, accessibility, and effectiveness in lowering A1C, as evidenced here with patients having taken metformin having reduced values when compared to sulfonylureas and short-acting insulins with differences of 0.1% and 0.56%, respectively,” the study authors wrote.¹

In Frontiers in Neuroscience, investigators conducted a systematic review and meta-analysis to determine if metformin can prevent cognitive dysfunction, with results showing that the occurrence of cognitive decline decreased for patients with diabetes, but only for the prevention of dementia and not AD. Further, from the authors of a study in Neurobiology of Aging, metformin use did correlate to slower decline on a score of global cognition compared with patients who did not use metformin. However, when examining any diabetes medication, there was no association observed for diabetes medication and cognitive function compared with no diabetes medication.^2,3

In the current study, investigators compared metformin, glucagon-like peptide-1s (GLP-1s), insulin, and sulfonylureas for hemoglobin A_1c, AD development, and mortality. Then, investigators compared the protective value of metformin for patients with diabetes compared to those without diabetes. Data was included from TriNetX, with investigators including patients who were documented to take one of the drug classes of interest. Patients were older than 50 years.¹

Analysis group A included metformin compared with GLP-1s, group B included metformin and sulfonylureas, group C included metformin and short-acting insulin, and group D included metformin users with diabetes and metformin users without diabetes. The results showed a significantly higher risk of AD for analysis A, metformin compared with GLP1s, and there was no statistically significant difference for analysis B or analysis C. As for patients with and without diabetes, the risk of patients with diabetes developing AD who were taking metformin was higher than those without, according to the study authors.¹

As for mortality, analysis A indicated statistically insignificant risk differences, and groups B and C demonstrated lower mortality risk. For patients with and without diabetes, the mortality risk was insignificant. When looking at hemoglobin A_1c, the investigators found that patients taking metformin had a value of 6.53% compared with GLP-1s having 6.28%. Further, for metformin and sulfonylureas, the hemoglobin A_1c values were 6.58% and 6.68%, respectively, and for metformin and short-acting insulins, the values were 6.60% and 7.16%, respectively.¹

“Metformin's neuroprotective effects against AD, compared to other treatments, were inconsistent,” the authors concluded. “There was no comparison between analyses A-C, in which metformin demonstrated a protective effect against neurologic decline based on the incidence of an AD diagnosis.”

READ MORE: Diabetes Resource Center

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REFERENCES

1. DiGiovanni A, Shehaj A, Millar D, Tse C, Rizk E. Utility of Pharmacological Agents for Diabetes Mellitus in the Prevention of Alzheimer's Disease: Comparison of Metformin, Glucagon-Like Peptide-1 (GLP-1) Agonists, Insulin, and Sulfonylureas. Cureus. 2025;17(7):e87350. Published 2025 Jul 5. doi:10.7759/cureus.87350

2. Zhang JH, Zhang XY, Sun YQ, Lv RH, Chen M, Li M. Metformin use is associated with a reduced risk of cognitive impairment in adults with diabetes mellitus: A systematic review and meta-analysis. Front Neurosci. 2022;16:984559. Published 2022 Aug 25. doi:10.3389/fnins.2022.984559

3. Sood A, Capuano AW, Wilson RS, et al. Metformin, age-related cognitive decline, and brain pathology. Neurobiol Aging. 2024;133:99-106. doi:10.1016/j.neurobiolaging.2023.10.005