GLP-1–Metformin Therapy Linked to Fewer Cognitive Disorders

Glucagon-like peptide-1 (GLP-1) receptor agonists combined with metformin were associated with lower incidence of vascular dementia, mild cognitive disorder, and Alzheimer disease than metformin alone among adults aged 40 to 69 years with type 2 diabetes, according to a retrospective cohort study published in PLOS ONE.

The analysis used TriNetX US Collaborative Network records from 2010 through 2024. It included 1,528,885 adults with at least 1 year of follow-up; mean age was 58 years, and 49.2% were women. Investigators compared metformin only with metformin plus dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin plus GLP-1 receptor agonists, metformin plus sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and insulin monotherapy. Comparisons used 1:1 propensity score matching.

Among 102,399 patients in each matched group, GLP-1 receptor agonists plus metformin were associated with lower incidence of vascular dementia (hazard ratio [HR], 0.46; 95% CI, 0.37-0.57), mild cognitive disorder (HR, 0.79; 95% CI, 0.66-0.95), and Alzheimer disease (HR, 0.46; 95% CI, 0.31-0.70). The associations were consistent across follow-up intervals shorter than 5 years and 5 years or longer.

During follow-up shorter than 5 years, SGLT-2 inhibitors plus metformin were associated with lower vascular-dementia incidence (HR, 0.68; 95% CI, 0.54-0.87) among 58,327 matched patients, but not with mild cognitive disorder or Alzheimer disease. DPP-4 inhibitors plus metformin had no significant association with any of the 3 outcomes. Insulin monotherapy was associated with higher incidence of vascular dementia (HR, 3.27), mild cognitive disorder (HR, 1.71), and Alzheimer disease (HR, 1.56) among 333,153 matched patients during this interval.

The observational design precluded causal conclusions, and the investigators emphasized residual confounding, particularly confounding by indication for insulin. Other limitations were diagnostic-code reliance, unverified adherence and exposure duration, and restriction to US adults aged 40 to 69 years. Competing risks were not modeled, and median follow-up was shorter with insulin than metformin alone (303 vs 612 days), further complicating interpretation.

Source: Nasir AB, Kilani Y, Aldiabat M, et al. Antidiabetic medications and risk of cognitive disorders in type 2 diabetes: a retrospective cohort study. PLoS One. 2026;21(8):e0356138. doi:10.1371/journal.pone.0356138