---
title: "Antidiabetic Regimens and Risk of Cognitive Disorders in Type 2 Diabetes: Retrospective Cohort Fin"
id: "pubmed-42636218"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42636218"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42636218/"
doi: "10.1371/journal.pone.0356138"
published_at: "2026-08-24T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Antidiabetic Regimens and Risk of Cognitive Disorders in Type 2 Diabetes: Retrospective Cohort Fin
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42636218
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42636218/)
- **DOI:** [10.1371/journal.pone.0356138](https://doi.org/10.1371%2Fjournal.pone.0356138)
- **Published At:** 2026-08-24T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- This retrospective cohort study evaluated associations between commonly used **antidiabetic** regimens and incident cognitive disorders in adults with **type 2 diabetes** using TriNetX US electronic health records (2010–2024). - The study population included 1,528,885 adults aged 40–69 years with at least 1 year of follow-up; mean age was 58 years and 49.2% were women. - Patients were grouped by initial and continued treatment: **metformin only** (reference), metformin plus **DPP-4 inhibitors**, metformin plus **GLP-1 receptor agonists**, metformin plus **SGLT-2 inhibitors**, and **insulin monotherapy**. - Primary outcomes were incident mild cognitive disorder, Alzheimer disease, and vascular dementia identified by ICD-10 codes. - Propensity score matching was used to balance covariates; Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Landmark analyses stratified follow-up shorter and longer than 5 years. - Compared with metformin only, metformin plus **GLP-1 receptor agonists** was associated with lower incidence of vascular dementia (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). - Metformin plus **SGLT-2 inhibitors** was associated with reduced vascular dementia risk (HR 0.68; 95% CI 0.54–0.87) but not with Alzheimer disease or mild cognitive disorder in the reported results. - **Insulin monotherapy** was associated with higher incidence across outcomes: vascular dementia (HR 3.27; 95% CI 3.03–3.52), mild cognitive disorder (HR 1.71; 95% CI 1.56–1.87), and Alzheimer disease (HR 1.56; 95% CI 1.32–1.84). - The authors conclude that combining metformin with GLP-1 receptor agonists or SGLT-2 inhibitors was associated with lower risk of some cognitive outcomes, while insulin monotherapy was associated with increased risk. - The abstract does not report details on specific covariates included in propensity matching, absolute incidence rates, subgroup analyses, or causal inference statements beyond associations.
## Clinical Analysis & Structured Key Points
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Antidiabetic medications and risk of cognitive disorders in type 2 diabetes: A retrospective cohort study [Ahmad Basil Nasir](https://pubmed.ncbi.nlm.nih.gov/?term=Nasir+AB&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Yassine Kilani](https://pubmed.ncbi.nlm.nih.gov/?term=Kilani+Y&cauthor_id=42636218)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-2 "Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Mohammad Aldiabat](https://pubmed.ncbi.nlm.nih.gov/?term=Aldiabat+M&cauthor_id=42636218)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-3 "Department of Internal Medicine, Washington University, Saint Louis, Missouri, United States of America."), [Omar Abdelghany](https://pubmed.ncbi.nlm.nih.gov/?term=Abdelghany+O&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Youssef Hafez](https://pubmed.ncbi.nlm.nih.gov/?term=Hafez+Y&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Nitin Desai](https://pubmed.ncbi.nlm.nih.gov/?term=Desai+N&cauthor_id=42636218)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-2 "Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Mahmoud Y Madi](https://pubmed.ncbi.nlm.nih.gov/?term=Madi+MY&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Francis G Wade](https://pubmed.ncbi.nlm.nih.gov/?term=Wade+FG&cauthor_id=42636218)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-2 "Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Kamran Qureshi](https://pubmed.ncbi.nlm.nih.gov/?term=Qureshi+K&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Lewis J Frey](https://pubmed.ncbi.nlm.nih.gov/?term=Frey+LJ&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-4 "Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.")[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-5 "VA St. Louis Healthcare System, St. Louis, Missouri, United States of America."), [Adam D Farmer](https://pubmed.ncbi.nlm.nih.gov/?term=Farmer+AD&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-4 "Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Wing-Kin Syn](https://pubmed.ncbi.nlm.nih.gov/?term=Syn+WK&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-4 "Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.")[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#full-view-affiliation-6 "Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country \(UPV/EHU\), Vizcaya, Spain.") Affiliations Expand ### Affiliations * 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. * 2 Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. * 3 Department of Internal Medicine, Washington University, Saint Louis, Missouri, United States of America. * 4 Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. * 5 VA St. Louis Healthcare System, St. Louis, Missouri, United States of America. * 6 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Vizcaya, Spain. * PMID: **42636218** * DOI: [ 10.1371/journal.pone.0356138 ](https://doi.org/10.1371/journal.pone.0356138) Item in Clipboard # Antidiabetic medications and risk of cognitive disorders in type 2 diabetes: A retrospective cohort study Ahmad Basil Nasir et al. PLoS One. 2026. Show details Display options Display options Format Abstract PubMed PMID PLoS One Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22PLoS+One%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22PLoS+One%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42636218/) . 2026 Aug 24;21(8):e0356138. doi: 10.1371/journal.pone.0356138. eCollection 2026. ### Authors [Ahmad Basil Nasir](https://pubmed.ncbi.nlm.nih.gov/?term=Nasir+AB&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Yassine Kilani](https://pubmed.ncbi.nlm.nih.gov/?term=Kilani+Y&cauthor_id=42636218)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-2 "Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Mohammad Aldiabat](https://pubmed.ncbi.nlm.nih.gov/?term=Aldiabat+M&cauthor_id=42636218)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-3 "Department of Internal Medicine, Washington University, Saint Louis, Missouri, United States of America."), [Omar Abdelghany](https://pubmed.ncbi.nlm.nih.gov/?term=Abdelghany+O&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Youssef Hafez](https://pubmed.ncbi.nlm.nih.gov/?term=Hafez+Y&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Nitin Desai](https://pubmed.ncbi.nlm.nih.gov/?term=Desai+N&cauthor_id=42636218)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-2 "Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Mahmoud Y Madi](https://pubmed.ncbi.nlm.nih.gov/?term=Madi+MY&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Francis G Wade](https://pubmed.ncbi.nlm.nih.gov/?term=Wade+FG&cauthor_id=42636218)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-2 "Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Kamran Qureshi](https://pubmed.ncbi.nlm.nih.gov/?term=Qureshi+K&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Lewis J Frey](https://pubmed.ncbi.nlm.nih.gov/?term=Frey+LJ&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-4 "Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.")[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-5 "VA St. Louis Healthcare System, St. Louis, Missouri, United States of America."), [Adam D Farmer](https://pubmed.ncbi.nlm.nih.gov/?term=Farmer+AD&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-4 "Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America."), [Wing-Kin Syn](https://pubmed.ncbi.nlm.nih.gov/?term=Syn+WK&cauthor_id=42636218)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-1 "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-4 "Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.")[ 6 ](https://pubmed.ncbi.nlm.nih.gov/42636218/#short-view-affiliation-6 "Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country \(UPV/EHU\), Vizcaya, Spain.") ### Affiliations * 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. * 2 Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. * 3 Department of Internal Medicine, Washington University, Saint Louis, Missouri, United States of America. * 4 Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America. * 5 VA St. Louis Healthcare System, St. Louis, Missouri, United States of America. * 6 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Vizcaya, Spain. * PMID: **42636218** * DOI: [ 10.1371/journal.pone.0356138 ](https://doi.org/10.1371/journal.pone.0356138) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract **Objective:** 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. **Design, setting, and participants:** This retrospective cohort study used the TriNetX US Collaborative Network of electronic health records from 2010 to 2024. Adults aged 40-69 years with type 2 diabetes and at least 1 year of follow-up were included. Propensity score matching was applied to balance covariates. **Exposure:** Patients were classified into 5 treatment groups: metformin only (reference), metformin plus DPP-4 inhibitors, metformin plus GLP-1 receptor agonists, metformin plus SGLT-2 inhibitors, and insulin monotherapy. Exposure was defined by first recorded prescription and continued use during follow-up. **Main outcomes and measures:** Primary outcomes were incident mild cognitive disorder, Alzheimer disease, and vascular dementia, identified using ICD-10 codes. Hazard ratios with 95% confidence intervals were estimated from Cox proportional hazards models, with landmark analyses for follow-up shorter and longer than 5 years. **Results:** Among 1,528,885 adults with type 2 diabetes (mean age, 58 years; 49.2% women), GLP-1 receptor agonists plus metformin were associated with lower incidence of vascular dementia (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). SGLT-2 inhibitors plus metformin reduced vascular dementia risk (HR, 0.68; 95% CI, 0.54-0.87) but not other outcomes. Insulin monotherapy was associated with higher incidence of vascular dementia (HR, 3.27; 95% CI, 3.03-3.52), mild cognitive disorder (HR, 1.71; 95% CI, 1.56-1.87), and Alzheimer disease (HR, 1.56; 95% CI, 1.32-1.84). **Conclusions and relevance:** GLP-1 receptor agonists and SGLT-2 inhibitors combined with metformin were associated with reduced risk of cognitive decline. Insulin monotherapy was associated with higher incid
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