Longitudinal Associations Between Glycemic Status and Cognitive Function in Older Participants at High Risk of Cardiovascular Disease: Two-Year Follow-Up in the PREDIMED-Plus Study
Authors: Martínez Carlos Gómez , Babio Nancy , Julvez Jordi , Tomás Nerea Becerra , González Miguel A. Martínez , Corella Dolores , Castañer Olga , Romaguera Dora , Vioque Jesús , Alonso-Gómez Ángel M. , Wärnberg Julia , Martínez José A. , Serra-Majem Luís , Estruch Ramón , Tinahones Francisco , Lapetra José , Pintó Xavier , Tur Josep A. , Miranda José López , Cavanillas Aurora Bueno , Gaforio José J. , Martín Pilar Matía , Daimiel Lidia , Sánchez Vicente Martín , Vidal Josep , Vázquez Clotilde , Ros Emilio , Dalsgaard Søren , Orea Carmen Sayón , Sorlí José V. , Torre Rafael de la , Abete Itziar , Sierra Lucas Tojal , López Francisco J. Barón , Brufal Noelia Fernández , Konieczna Jadwiga , Ríos Antonio García , Sacanella Emilio , López María R. Bernal , Lozano Jose M. Santos , Razquin Cristina , Sala Andrea Álvarez , Goday Albert , Zulet María de los Á. , Luna Jessica Vaquero , Espino Javier Diez , Cuenca Aida , Aranda Fernando Fernández , Bulló Mònica , Salas-Salvadó Jordi 
Published: August 2021

Abstract
BACKGROUND: Type 2 diabetes was related with larger cognitive decline. However, other glycemic dysregulations showed inconsistent results. Our aim was to examine longitudinal associations between diabetes/glycemic status and cognitive function in older adults with metabolic syndrome. METHODS: We conducted a 2-year prospective cohort study (n=6,874) within the framework of the PREDIMED-Plus study. The participants (with overweight/obesity and metabolic syndrome; mean age 64.9 years; 48.5% women) completed a battery of 8 cognitive tests, and a global cognitive function Z-score (GCF) was estimated. Participants were categorized by diabetes status (no-diabetes, prediabetes, and <5 or ≥5-year diabetes duration), and control. At baseline, insulin resistance (HOMA-IR) and glycated hemoglobin (HbA1c) levels were measured and antidiabetic medications were recorded. Linear and logistic regression models, adjusted by potential confounders, were fitted to assess associations between glycemic status and changes in cognitive function. RESULTS: Prediabetes status was unrelated to cognitive decline. However, compared to participants without diabetes, those with ≥5-year diabetes duration had greater reductions in the GCF (β=-0.11 [95%CI -0.16;-0.06]), processing speed and executive function measurements. Inverse associations were observed between baseline HOMA-IR and changes in the GCF (β=-0.0094 [95%CI -0.0164;-0.0023]), but also between HbA1c levels and changes in the GCF (β=-0.0610 [95%CI -0.0889;-0.0331]), the Mini-Mental test, and other executive function tests. Poor diabetes control was inversely associated with phonologic fluency. Sulfonylureas, but especially insulin use, were related to cognitive decline.CONCLUSIONS: Insulin resistance, diabetes status, longer diabetes duration, poor glycemic control, and insulin treatment were associated with worsening cognitive function at short-term in a population at high cardiovascular risk.TRIAL REGISTRATION: ISRCTN, ISRCTN89898870. Registered 28 May 2014 - Retrospectively registered, http://www.isrctn.com/ISRCTN89898870