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RESEARCH PRODUCT

Metformin Use and Cognitive Function in Older Adults With Type 2 Diabetes Following a Mediterranean Diet Intervention

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Background 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. Study resulting from the following grants: SLT006/17/00246, SLT002/16/00045 and SLT006/17/00077 funded by the Department of Health of the Generalitat de Catalunya by the calls Acció instrumental de programes de recerca orientats en l'àmbit de la recerca i la innovació en salut and Pla estratègic de recerca i innovació en salut (PERIS). We thank CERCA Programme/Generalitat de Catalunya for institutional support. This project was funded by Instituto de Salud Carlos III (ISCIII), the Spanish Government Official Agency for funding biomedical research-with competitive grants leaded by JS-S and Josep Vidal for the periods 2014–2016, 2015–2017, 2017–2019, and 2018–2020, through the Fondo de Investigación para la Salud (FIS), which is co-funded by the European Regional Development Fund, ERDF, a way to build Europe) [grants: PI13/00233, PI13/00728, PI13/01123, PI13/00462, PI16/00533, PI16/00366, PI16/01094, PI16/00501, PI17/01167, PI19/00017, PI19/00781, PI19/01032, PI19/00576]; the Especial Action Project entitled: Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus grant to JS-S; the European Research Council [Advanced Research Grant 2014–2019; agreement #340918] granted to Miguel Ángel Martínez-González; the Recercaixa (number 2013ACUP00194) grant to JS-S. This research was also partially funded by EU-H2020 Grants (Eat2beNICE/H2020-SFS-2016-2; Ref 728018; and PRIME/H2020-SC1-BHC-2018-2020; Ref: 847879), Grant PROMETEO/2017/017 (Generalitat Valenciana) and Grant FEA/SEA 2017 for Primary Care Research. This work is also partially supported by ICREA under the ICREA Academia programme. This work was supported by grants from DIUE de la Generalitat de Catalunya 2017 SGR 138 from the Departament d'Economia i Coneixement de la Generalitat de Catalunya (Spain). NS-D has received the FI 2021 predoctoral grant (FI_B2021/00104) from the Agency for Management of University and Research Grants (AGAUR) of the Generalitat de Catalunya. CV-A was supported by a predoctoral Grant of the Ministerio de Educación, Cultura y Deporte (FPU16/01453). AA-S has received a post-doctoral grant from the Consellería de Innovación, Ciencia y Sociedad Digital, Generalitat Valenciana, Valencia (APOSTD/2020/003). The Physiopathology of Obesity and Nutrition Networking Biomedical Research Center (CIBEROBN) is an initiative of ISCIII.