Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study

Background: Type 2 diabetes increases the risk for dementia, but whether it affects cognition before old age is unclear. We investigated whether duration of diabetes in late midlife and poor glycaemic control were associated with accelerated cognitive decline. Methods: 5653 participants from the Whitehall II cohort study (median age 54·4 years [IQR 50·3-60·3] at first cognitive assessment), were classified into four groups: normoglycaemia, prediabetes, newly diagnosed diabetes, and known diabetes. Tests of memory, reasoning, phonemic and semantic fluency, and a global score that combined all cognitive tests, were assessed three times over 10 years (1997-99, 2002-04, and 2007-09). Mean HbA1c was used to assess glycaemic control during follow-up. Analyses were adjusted for sociodemographic characteristics, health-related behaviours, and chronic diseases. Findings: Compared with normoglycaemic participants, those with known diabetes had a 45% faster decline in memory (10 year difference in decline -0·13 SD, 95% CI -0·26 to -0·00; p=0·046), a 29% faster decline in reasoning (-0·10 SD, -0·19 to -0·01; p=0·026), and a 24% faster decline in the global cognitive score (-0·11 SD, -0·21 to -0·02; p=0·014). Participants with prediabetes or newly diagnosed diabetes had similar rates of decline to those with normoglycaemia. Poorer glycaemic control in participants with known diabetes was associated with a significantly faster decline in memory (-0·12 [-0·22 to -0·01]; p=0·034) and a decline in reasoning that approached significance (-0·07 [-0·15 to 0·00]; p=0·052). Interpretation: The risk of accelerated cognitive decline in middle-aged patients with type 2 diabetes is dependent on both disease duration and glycaemic control. Funding: US National Institutes of Health, UK Medical Research Council. © 2013 Elsevier Ltd. All rights reserved

Multicentre, interventional, single-arm study protocol of telemonitored circadian rhythms and patient-reported outcomes for improving mFOLFIRINOX safety in patients with pancreatic cancer (MultiDom, NCT04263948)

Introduction: Circadian clocks regulate cellular proliferation and drug effects. Tolerability and/or efficacy of anticancer therapies have been improved by their administration according to circadian rhythms, while being predicted by circadian robustness. The combination of leucovorin, fluorouracil, irinotecan and oxaliplatin (mFOLFIRINOX) is a standard treatment for pancreatic ductal adenocarcinoma (PDAC), that generates grades 3–4 adverse events in the majority of patients and an estimated 15%–30% emergency admission rate. The MultiDom study evaluates whether mFOLFIRINOX safety can be improved using a novel circadian-based telemonitoring-telecare platform in patients at home. The detection of early warning signals of clinical toxicities could guide their early management, possibly preventing emergency hospital admissions. Methods and analysis: This multicentre, interventional, prospective, longitudinal, single-arm study hypothesises that the mFOLFIRINOX-related emergency admission rate will be 5% (95% CI 1.7% to 13.7%), among 67 patients with advanced PDAC. Study participation is 7 weeks for each patient, including a reference week before chemotherapy onset and 6 weeks afterwards. Accelerometry and body temperature are measured q1-min using a continuously worn telecommunicating chest surface sensor, daily body weight is self-measured with a telecommunicating balance and 23 electronic patient-reported outcomes (e-PROs) are self-rated using a tablet. Hidden Markov model, spectral analyses and other algorithms automatically compute physical activity, sleep, temperature, body weight change, e-PRO severity and 12 circadian sleep/activity parameters, including the dichotomy index I<O (% activity ‘in-bed’ below median activity ‘out-of-bed’), once to four times daily. Health professionals access visual displays of near-real time parameter dynamics and receive automatic alerts, with trackable digital follow-up. Ethics and dissemination: The study has been approved by the National Agency for Medication and Health Product Safety (ANSM) and Ethics Committee West V (2 July 2019; third amendment, 14 June 2022). The data will be disseminated at conferences and in peer-reviewed journals and will support large-scale randomised evaluation. Trial registration numbers: NCT04263948 and ID RCB-2019-A00566-51

Determinants of Cognitive Decline in Aging : Role of Type 2 Diabetes and Antidiabetic Medications

Le déclin des performances cognitives au cours du vieillissement représente une problématique majeure dans le contexte actuel de vieillissement de la population. Le processus de vieillissement cognitif est complexe et multifactoriel. Dans la première partie de nos travaux, nous nous sommes intéressés particulièrement au rôle du diabète de type 2 dans le déclin des fonctions cognitives à partir des données longitudinales de la cohorte Whitehall II. Les performances cognitives ont été évaluées à travers une batterie de tests neuropsychologiques chez des individus âgés de 45 à 70 ans lors du premier passage de tests cognitifs. Nous avons ainsi observé que le diabète de type 2 à l'inclusion dans l'étude était associée à de moins bonnes performances cognitives et à un déclin cognitif plus important au cours du suivi, en particulier chez des patients diabétiques de type 2 de longue date. Nous avons observé une relation entre le mauvais équilibre glycémique et le déclin accéléré des fonctions cognitives. Dans la deuxième partie de ce travail de thèse, nous nous sommes intéresses au rôle potentiellement protecteur des médicaments antidiabétiques sur le déclin cognitif dans le cadre d'une méta-analyse des essais contrôles randomisés. Les résultats de la méta-analyse indiquent que le contrôle glycémique strict n'est pas associé à une diminution du risque de déclin cognitif chez les patients diabétiques de type 2. Nos résultats sont en faveur d'une contribution du diabète de type 2 diagnostiqué en milieu de vie au déclin des fonctions cognitives et participent à une meilleure compréhension de ce processus.Cognitive decline represents a major issue given the current context of population aging. The cognitive aging process is complex and multifactorial. In first part of our work, we addressed in particular the contribution of type 2 diabetes to cognitive decline, based on longitudinal data from the Whitehall 2 study. Cognitive function was assessed through a battery of neuropsychological tests in participants aged 45 to 70 years old at the beginning of cognitive testing. We observed that baseline type 2 diabetes was associated with lower cognitive performance at baseline and greater decline over follow-up, particularly in patients with longer duration of type 2 diabetes. We observed a relationship between poor glycemic control and faster cognitive decline. In second part of our work, we were interested in the potentially protective role of antidiabetic medications on cognitive decline in a meta-analysis of randomized controlled trials. The meta-analysis indicated that intensive glycemic control was not associated with slower cognitive decline. Our results support the hypothesis of a contribution of type 2 diabetes to cognitive decline in midlife and contribute to improve our understanding of this process

Déterminants du déclin cognitif au cours du vieillissement : rôle du diabète de type 2 et des médicaments antidiabétiques

Cognitive decline represents a major issue given the current context of population aging. The cognitive aging process is complex and multifactorial. In first part of our work, we addressed in particular the contribution of type 2 diabetes to cognitive decline, based on longitudinal data from the Whitehall 2 study. Cognitive function was assessed through a battery of neuropsychological tests in participants aged 45 to 70 years old at the beginning of cognitive testing. We observed that baseline type 2 diabetes was associated with lower cognitive performance at baseline and greater decline over follow-up, particularly in patients with longer duration of type 2 diabetes. We observed a relationship between poor glycemic control and faster cognitive decline. In second part of our work, we were interested in the potentially protective role of antidiabetic medications on cognitive decline in a meta-analysis of randomized controlled trials. The meta-analysis indicated that intensive glycemic control was not associated with slower cognitive decline. Our results support the hypothesis of a contribution of type 2 diabetes to cognitive decline in midlife and contribute to improve our understanding of this process.Le déclin des performances cognitives au cours du vieillissement représente une problématique majeure dans le contexte actuel de vieillissement de la population. Le processus de vieillissement cognitif est complexe et multifactoriel. Dans la première partie de nos travaux, nous nous sommes intéressés particulièrement au rôle du diabète de type 2 dans le déclin des fonctions cognitives à partir des données longitudinales de la cohorte Whitehall II. Les performances cognitives ont été évaluées à travers une batterie de tests neuropsychologiques chez des individus âgés de 45 à 70 ans lors du premier passage de tests cognitifs. Nous avons ainsi observé que le diabète de type 2 à l'inclusion dans l'étude était associée à de moins bonnes performances cognitives et à un déclin cognitif plus important au cours du suivi, en particulier chez des patients diabétiques de type 2 de longue date. Nous avons observé une relation entre le mauvais équilibre glycémique et le déclin accéléré des fonctions cognitives. Dans la deuxième partie de ce travail de thèse, nous nous sommes intéresses au rôle potentiellement protecteur des médicaments antidiabétiques sur le déclin cognitif dans le cadre d'une méta-analyse des essais contrôles randomisés. Les résultats de la méta-analyse indiquent que le contrôle glycémique strict n'est pas associé à une diminution du risque de déclin cognitif chez les patients diabétiques de type 2. Nos résultats sont en faveur d'une contribution du diabète de type 2 diagnostiqué en milieu de vie au déclin des fonctions cognitives et participent à une meilleure compréhension de ce processus