Soldevila-Domenech, NataliaCuenca Royo, Aida Ma, 1981-Babio, NancyForcano, LauraNishi, StephanieVintró Alcaraz, CristinaGómez Martínez, CarlosJiménez Murcia, SusanaFernández-Carrión, RebecaGomis González, Maria, 1988-Alvarez-Sala, AndreaCarlos, SilviaPintó Sala, XavierCorella, DoloresDíez Espino, JavierCastañer, OlgaFernández Aranda, FernandoSalas Salvadó, JordiTorre Fornell, Rafael de la2021-11-122021-11-122021Soldevila-Domenech N, Cuenca-Royo A, Babio N, Forcano L, Nishi S, Vintró-Alcaraz C, Gómez-Martínez C, Jiménez-Murcia S, Fernández-Carrión R, Gomis-González M, Alvarez-Sala A, Carlos S, Pintó X, Corella D, Díez-Espino J, Castañer O, Fernández-Aranda F, Salas-Salvadó J, de la Torre R. Metformin use and cognitive function in older adults with type 2 diabetes following a mediterranean diet intervention. Front Nutr. 2021;8:742586. DOI: 10.3389/fnut.2021.7425862296-861Xhttp://hdl.handle.net/10230/48958Background and Purpose: Both adherence to the Mediterranean diet (MedDiet) and the use of metformin could benefit the cognitive performance of individuals with type 2 diabetes, but evidence is still controversial. We examined the association between metformin use and cognition in older adults with type 2 diabetes following a MedDiet intervention. Methods: Prospective cohort study framed in the PREDIMED-Plus-Cognition sub-study. The PREDIMED-Plus clinical trial aims to compare the cardiovascular effect of two MedDiet interventions, with and without energy restriction, in individuals with overweight/obesity and metabolic syndrome. The present sub-study included 487 cognitively normal subjects (50.5% women, mean ± SD age of 65.2 ± 4.7 years), 30.4% of them (N = 148) with type 2 diabetes. A comprehensive battery of neurocognitive tests was administered at baseline and after 1 and 3 years. Individuals with type 2 diabetes that exhibited a good glycemic control trajectory, either using or not using metformin, were compared to one another and to individuals without diabetes using mixed-effects models with inverse probability of treatment weights. Results: Most subjects with type 2 diabetes (83.1%) presented a good and stable glycemic control trajectory. Before engaging in the MedDiet intervention, subjects using metformin scored higher in executive functions (Cohen's d = 0.51), memory (Cohen's d = 0.38) and global cognition (Cohen's d = 0.48) than those not using metformin. However, these differences were not sustained during the 3 years of follow-up, as individuals not using metformin experienced greater improvements in memory (β = 0.38 vs. β = 0.10, P = 0.036), executive functions (β = 0.36 vs. β = 0.02, P = 0.005) and global cognition (β = 0.29 vs. β = -0.02, P = 0.001) that combined with a higher MedDiet adherence (12.6 vs. 11.5 points, P = 0.031). Finally, subjects without diabetes presented greater improvements in memory than subjects with diabetes irrespective of their exposure to metformin (β = 0.55 vs. β = 0.10, P < 0.001). However, subjects with diabetes not using metformin, compared to subjects without diabetes, presented greater improvements in executive functions (β = 0.33 vs. β = 0.08, P = 0.032) and displayed a higher MedDiet adherence (12.6 points vs. 11.6 points, P = 0.046). Conclusions: Although both metformin and MedDiet interventions are good candidates for future cognitive decline preventive studies, a higher adherence to the MedDiet could even outweigh the potential neuroprotective effects of metformin in subjects with diabetes.application/pdfeng© 2021 Soldevila-Domenech, Cuenca-Royo, Babio, Forcano, Nishi, Vintró-Alcaraz, Gómez-Martínez, Jiménez-Murcia, Fernández-Carrión, Gomis-González, Alvarez-Sala, Carlos, Pintó, Corella, Díez-Espino, Castañer, Fernández-Aranda, Salas-Salvadó and de la Torre. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.info:eu-repo/semantics/articlehttp://dx.doi.org/10.3389/fnut.2021.742586Mediterranean dietCognitionMetabolic syndromeMetforminNutritionObesityOverweightType 2 diabetesinfo:eu-repo/semantics/openAccess