Metformin Use Is Associated With Better Cognitive Performance in Older Adults With Type 2 Diabetes: Exploratory Analysis of Vitamin B12 and Methylmalonic Acid Pathways in NHANES 2011–2014
5 affiliations
- 1Neurobiology of Nutrition Laboratory, Department of Nutritional Sciences College of Health & Human Sciences, Texas Tech University Lubbock Texas USA
- 2Department of Internal Medicine Babol University of Medical Sciences Babol Iran
- 3Human Molecular Aging Center, Texas Tech University Lubbock Texas USA
- 4Center of Excellence for Translational Neuroscience & Therapeutics, Texas Tech University Health Sciences Center Lubbock Texas USA
- 5Center of Excellence for Integrated Health, Texas Tech University Health Sciences Center Lubbock Texas USA
Abstract
Aims: Metformin, the first‐line treatment for Type 2 diabetes mellitus (T2DM), may be neuroprotective but also lowers serum vitamin B12 by ~19%, raising concern that B12 depletion could offset this benefit. We used modern exploratory causal mediation methods in a nationally representative sample to test whether vitamin B12 and methylmalonic acid (MMA) mediate the metformin–cognition association.
Materials and Methods: We analysed NHANES 2011–2014 data from 587 adults aged ≥ 60 years with T2DM (408 metformin users, 179 users of other non‐insulin antidiabetics), using an active‐comparator design. The primary outcome was the Digit Symbol Substitution Test (DSST). Exploratory mediation analysis across four frameworks (bootstrap, parallel mediation, structural equation modeling, weighted quantile sum regression) tested whether B12 and MMA mediate the metformin–cognition association, supplemented by sensitivity, quantile regression, causal forest and Bayesian analyses.
Results: Metformin users had lower serum B12 (569.3 vs. 825.3 pg/mL; p = 0.026) but better cognitive performance (DSST 47.5 vs. 39.5; p < 0.001). Fully adjusted regression showed a 3.75‐point higher DSST score with metformin (95% CI −0.06 to 7.55; p = 0.053), significant under multiple imputation (β = 3.49; p = 0.006). Across mediation frameworks, 95.1% of the effect was direct and B12/MMA‐independent. Benefit was concentrated in adults aged 60–69 years (interaction p = 0.003) and lower DSST quantiles.
Conclusions: Metformin is associated with better cognition in older T2DM adults. The association was not statistically explained by B12 or MMA. The benefit was concentrated in younger‐old and cognitively vulnerable subgroups.
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BibTeX
@article{fotros2026metformin,
title = {{Metformin Use Is Associated With Better Cognitive Performance in Older Adults With Type 2 Diabetes: Exploratory Analysis of Vitamin B12 and Methylmalonic Acid Pathways in NHANES 2011–2014}},
author = {Danial Fotros and Hanieh Sakhdari and Andrew C. Shin},
journal = {Diabetes, Obesity \& Metabolism},
year = {2026},
month = sep,
doi = {10.1111/dom.71396},
url = {https://doi.org/10.1111/dom.71396},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Metformin Use Is Associated With Better Cognitive Performance in Older Adults With Type 2 Diabetes: Exploratory Analysis of Vitamin B12 and Methylmalonic Acid Pathways in NHANES 2011–2014
AU - Danial Fotros
AU - Hanieh Sakhdari
AU - Andrew C. Shin
PY - 2026
DA - 2026/09/28
JO - Diabetes, Obesity & Metabolism
DO - 10.1111/dom.71396
UR - https://doi.org/10.1111/dom.71396
AB - Aims: Metformin, the first‐line treatment for Type 2 diabetes mellitus (T2DM), may be neuroprotective but also lowers serum vitamin B12 by ~19%, raising concern that B12 depletion could offset this benefit. We used modern exploratory causal mediation methods in a nationally representative sample to test whether vitamin B12 and methylmalonic acid (MMA) mediate the metformin–cognition association. Materials and Methods: We analysed NHANES 2011–2014 data from 587 adults aged ≥ 60 years with T2DM (408 metformin users, 179 users of other non‐insulin antidiabetics), using an active‐comparator design. The primary outcome was the Digit Symbol Substitution Test (DSST). Exploratory mediation analysis across four frameworks (bootstrap, parallel mediation, structural equation modeling, weighted quantile sum regression) tested whether B12 and MMA mediate the metformin–cognition association, supplemented by sensitivity, quantile regression, causal forest and Bayesian analyses. Results: Metformin users had lower serum B12 (569.3 vs. 825.3 pg/mL; p = 0.026) but better cognitive performance (DSST 47.5 vs. 39.5; p < 0.001). Fully adjusted regression showed a 3.75‐point higher DSST score with metformin (95% CI −0.06 to 7.55; p = 0.053), significant under multiple imputation (β = 3.49; p = 0.006). Across mediation frameworks, 95.1% of the effect was direct and B12/MMA‐independent. Benefit was concentrated in adults aged 60–69 years (interaction p = 0.003) and lower DSST quantiles. Conclusions: Metformin is associated with better cognition in older T2DM adults. The association was not statistically explained by B12 or MMA. The benefit was concentrated in younger‐old and cognitively vulnerable subgroups.
SN - 1462-8902
SN - 1463-1326
ER -