Antidiabetic medications and risk of cognitive disorders in type 2 diabetes: A retrospective cohort study
Ahmad Basil Nasir, Yassine Kilani, Mohammad Aldiabat, Omar Abdelghany, Youssef Hafez, Nitin Desai, Mahmoud Y. Madi, Francis G. Wade, Kamran Qureshi, Lewis J. Frey, Adam D. Farmer, Wing-Kin Syn
Abstract
To evaluate the associations between commonly used antidiabetic regimens and incidence of mild cognitive disorder, Alzheimer disease, and vascular dementia in adults with type 2 diabetes.
Introduction
Diabetes is a chronic progressive condition projected to affect more than 1.3 billion people worldwide by 2050 [1,2]. Type 2 diabetes mellitus (T2DM) nearly doubles the risk of cognitive decline, including mild cognitive disorder (MCD), Alzheimer disease (AD), and vascular dementia (VD) [3].
Materials and methods
This retrospective cohort study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. We conducted a retrospective cohort study using the TriNetX US Collaborative Network, which contains deidentified electronic health records from more than 118 million patients across 69 health care organizations.
Results
Of 51,859,560 patient records screened, 1,528,885 adults aged 40–69 years with type 2 diabetes were eligible (mean age, 58 years; 49.2% women). Treatment groups included 446,109 receiving metformin only, 43,519 receiving metformin plus DPP-4 inhibitors, 115,362 receiving metformin plus GLP-1 receptor agonists, 59,691 receiving metformin plus SGLT-2 inhibitors, and 368,668 receiving insulin monotherapy.
Discussion
In this cohort of more than 1.5 million adults with type 2 diabetes, use of GLP-1 receptor agonists plus metformin was associated with lower incidence of vascular dementia, mild cognitive disorder, and Alzheimer disease. SGLT-2 inhibitors plus metformin were associated with reduced risk of vascular dementia only, and DPP-4 inhibitors showed no significant associations.
Conclusion
This study highlights the differential cognitive outcomes associated with various antidiabetic medications in patients with type 2 diabetes. GLP-1 receptor agonists combined with metformin were associated with reduced risk across all three outcomes — mild cognitive disorder, Alzheimer disease, and vascular dementia.
Citation: Nasir AB, Kilani Y, Aldiabat M, Abdelghany O, Hafez Y, Desai N, et al. (2026) Antidiabetic medications and risk of cognitive disorders in type 2 diabetes: A retrospective cohort study. PLoS One 21(8): e0356138. https://doi.org/10.1371/journal.pone.0356138
Editor: Tomislav Bulum, Medical School, University of Zagreb, CROATIA
Received: November 10, 2025; Accepted: July 30, 2026; Published: August 24, 2026
Copyright: © 2026 Nasir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
