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

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.