Continuous glucose monitoring in adults with type 2 diabetes: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) is increasingly used in the treatment of type 2 diabetes, but the effects on glycaemic control are unclear. The aim of this systematic review and meta-analysis is to provide a comprehensive overview of the effect of CGM on glycaemic control in adults with type 2 diabetes. METHODS: We performed a systematic review using Embase, MEDLINE, Web of Science, Scopus and ClinicalTrials.gov from inception until 2 May 2023. We included RCTs investigating real-time CGM (rtCGM) or intermittently scanned CGM (isCGM) compared with self-monitoring of blood glucose (SMBG) in adults with type 2 diabetes. Studies with an intervention duration <6 weeks or investigating professional CGM, a combination of CGM and additional glucose-lowering treatment strategies or GlucoWatch were not eligible. Change in HbA1c and the CGM metrics time in range (TIR), time below range (TBR), time above range (TAR) and glycaemic variability were extracted. We evaluated the risk of bias using the Cochrane risk-of-bias tool version 2. Data were synthesised by performing a meta-analysis. We also explored the effects of CGM on severe hypoglycaemia and micro- and macrovascular complications. RESULTS: We found 12 RCTs comprising 1248 participants, with eight investigating rtCGM and four isCGM. Compared with SMBG, CGM use (rtCGM or isCGM) led to a mean difference (MD) in HbA1c of -3.43 mmol/mol (-0.31%; 95% CI -4.75, -2.11, p<0.00001, I2=15%; moderate certainty). This effect was comparable in studies that included individuals using insulin with or without oral agents (MD -3.27 mmol/mol [-0.30%]; 95% CI -6.22, -0.31, p=0.03, I2=55%), and individuals using oral agents only (MD -3.22 mmol/mol [-0.29%]; 95% CI -5.39, -1.05, p=0.004, I2=0%). Use of rtCGM showed a trend towards a larger effect (MD -3.95 mmol/mol [-0.36%]; 95% CI -5.46 to -2.44, p<0.00001, I2=0%) than use of isCGM (MD -1.79 mmol/mol [-0.16%]; 95% CI -5.28, 1.69, p=0.31, I2=64%). CGM was also associated with an increase in TIR (+6.36%; 95% CI +2.48, +10.24, p=0.001, I2=9%) and a decrease in TBR (-0.66%; 95% CI -1.21, -0.12, p=0.02, I2=45%), TAR (-5.86%; 95% CI -10.88, -0.84, p=0.02, I2=37%) and glycaemic variability (-1.47%; 95% CI -2.94, -0.01, p=0.05, I2=0%). Three studies reported one or more events of severe hypoglycaemia and macrovascular complications. In comparison with SMBG, CGM use led to a non-statistically significant difference in the incidence of severe hypoglycaemia (RR 0.66, 95% CI 0.15, 3.00, p=0.57, I2=0%) and macrovascular complications (RR 1.54, 95% CI 0.42, 5.72, p=0.52, I2=29%). No trials reported data on microvascular complications. CONCLUSIONS/INTERPRETATION: CGM use compared with SMBG is associated with improvements in glycaemic control in adults with type 2 diabetes. However, all studies were open label. In addition, outcome data on incident severe hypoglycaemia and incident microvascular and macrovascular complications were scarce. REGISTRATION: This systematic review was registered on PROSPERO (ID CRD42023418005).

Retinal microvascular function and incidence and trajectories of clinically relevant depressive symptoms: the Maastricht Study.

BACKGROUND: Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. We investigated the association of retinal microvascular function, a proxy for microvascular function in the brain, with incidence and trajectories of clinically relevant depressive symptoms. METHODS: Longitudinal data are from The Maastricht Study of 5952 participants (59.9 ± 8.5 years/49.7% women) without clinically relevant depressive symptoms at baseline (2010-2017). Central retinal arteriolar equivalent and central retinal venular equivalent (CRAE and CRVE) and a composite score of flicker light-induced retinal arteriolar and venular dilation were assessed at baseline. We assessed incidence and trajectories of clinically relevant depressive symptoms (9-item Patient Health Questionnaire score ⩾10). Trajectories included continuously low prevalence (low, n = 5225 [87.8%]); early increasing, then chronic high prevalence (early-chronic, n = 157 [2.6%]); low, then increasing prevalence (late-increasing, n = 247 [4.2%]); and remitting prevalence (remitting, n = 323 [5.4%]). RESULTS: After a median follow-up of 7.0 years (range 1.0-11.0), 806 (13.5%) individuals had incident clinically relevant depressive symptoms. After full adjustment, a larger CRAE and CRVE were each associated with a lower risk of clinically relevant depressive symptoms (hazard ratios [HRs] per standard deviation [s.d.]: 0.89 [95% confidence interval (CI) 0.83-0.96] and 0.93 [0.86-0.99], respectively), while a lower flicker light-induced retinal dilation was associated with a higher risk of clinically relevant depressive symptoms (HR per s.d.: 1.10 [1.01-1.20]). Compared to the low trajectory, a larger CRAE was associated with lower odds of belonging to the early-chronic trajectory (OR: 0.83 [0.69-0.99]) and a lower flicker light-induced retinal dilation was associated with higher odds of belonging to the remitting trajectory (OR: 1.23 [1.07-1.43]). CONCLUSIONS: These findings support the hypothesis that cerebral microvascular dysfunction contributes to the development of depressive symptoms.

Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model.

AIMS: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. MATERIALS AND METHODS: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. RESULTS: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. CONCLUSIONS: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation.

Age at cardiovascular disease onset, dementia risk, and the role of lifestyle factors.

INTRODUCTION: We first examined the role of age at cardiovascular disease (CVD) onset for incident dementia, and then examined whether lifestyle factors at guideline-recommended levels in individuals with CVD mitigates dementia risk. METHODS: We used population-based data (Whitehall II: n = 10,308/baseline 1985-1988/examinations every 4-5 years). Lifestyle factors (non-smoking, body mass index [BMI], physical activity, diet) were extracted post-CVD. RESULTS: Over a median of 31.6 years, 3275 (32.1%) developed CVD. At age 70, risk of dementia was higher in individuals with CVD onset before (hazard ratio [HR] of incident dementia for participants with CVD before age 60, using participants without CVD at age 70 as the reference: 1.56, 95% confidence interal [CI] 1.18-2.08) but not after 60 years. In participants with CVD, a greater number of lifestyle factors at recommended levels post-CVD was associated with a lower dementia risk (per lifestyle factor at recommended level HR: 0.73, 95% CI 0.59-0.92). DISCUSSION: Our results suggest that early onset CVD is associated with a higher dementia risk at older ages. In those with CVD, the dementia risk was lower if lifestyle factors are at recommended levels following CVD diagnosis. HIGHLIGHTS: CVD in midlife but not in late life is associated with a higher risk of dementia. Dementia risk in CVD patients is lower if their lifestyle factors are at recommended levels. These findings provide evidence to promote CVD prevention in midlife or earlier. Study findings also show the importance of a healthy lifestyle in those with CVD.

Biomarkers of endothelial dysfunction and cognition: A two-step IPD meta-analysis.

INTRODUCTION: This study assessed the association of plasma biomarkers of endothelial dysfunction with cognitive performance and decline. METHODS: Data from 9414 individuals from eight Dutch cohorts were included (Ø  age-range: 57-93 years). Plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin) were combined into a standardized composite score. Cognitive outcomes included executive function, processing speed, immediate and delayed memory, attention, and language. Linear regressions and linear mixed models were run in the individual cohorts and standardized coefficients were subsequently pooled using random-effects meta-analyses. RESULTS: A higher endothelial dysfunction composite score was cross-sectionally associated with worse performance on executive function, processing speed, delayed memory, and attention, but not immediate memory or language (pooled ß-range: -0.04, -0.02). We found no association with change in cognition over time. DISCUSSION: This comprehensive two-step, individual participant data (IPD) meta-analysis showed a small, consistent cross-sectional association between endothelial dysfunction and worse cognitive performance across multiple domains but no support for a longitudinal association. HIGHLIGHTS: Prior evidence on endothelial dysfunction (ED) biomarkers and cognition is conflicting. This two-step, individual participant data (IPD) meta-analysis used data from eight Dutch cohorts. ED was consistently associated with concurrent cognition. ED was not associated with a change in cognition over time. The association of ED with current cognition may be generic.

Thinner inner retinal layers are associated with lower cognitive performance, lower brain volume, and altered white matter network structure-The Maastricht Study.

INTRODUCTION: The retina may provide non-invasive, scalable biomarkers for monitoring cerebral neurodegeneration. METHODS: We used cross-sectional data from The Maastricht study (n = 3436; mean age 59.3 years; 48% men; and 21% with type 2 diabetes [the latter oversampled by design]). We evaluated associations of retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses with cognitive performance and magnetic resonance imaging indices (global grey and white matter volume, hippocampal volume, whole brain node degree, global efficiency, clustering coefficient, and local efficiency). RESULTS: After adjustment, lower thicknesses of most inner retinal layers were significantly associated with worse cognitive performance, lower grey and white matter volume, lower hippocampal volume, and worse brain white matter network structure assessed from lower whole brain node degree, lower global efficiency, higher clustering coefficient, and higher local efficiency. DISCUSSION: The retina may provide biomarkers that are informative of cerebral neurodegenerative changes in the pathobiology of dementia.

Changes in Cardiovascular Health Across Midlife and Late-Life and Magnetic Resonance Imaging Markers of Cerebral Vascular Disease in Late-Life.

BACKGROUND: Cardiovascular health may be used for prevention of cerebral vascular disease; however, data on the association of cardiovascular health across midlife and late-life with late-life cerebral vascular disease are lacking. Our aim was to examine whether midlife or late-life cardiovascular health as well as changes of cardiovascular health within midlife and between midlife and late-life were associated with prevalence of magnetic resonance imaging markers of cerebral vascular disease at late-life. METHODS: Prospective cohort study including 1638 participants from the Atherosclerosis Risk in Communities Study who took part in 2 visits at midlife (mean ages, 53 and 59 years), and a late-life visit (mean age, 76 years). A cardiovascular health Life's Simple 7 score (range, 0-12/0-14, depending on diet availability) including 6 out of 7 items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Participants underwent 3T brain magnetic resonance imaging scans in late-life visit. Outcomes were white matter hyperintensity volume, microbleeds, and lacunar, subcortical, and cortical infarcts at late-life. Linear and logistic regression models were used to assess the associations of cardiovascular health in midlife and late-life, and improvement of cardiovascular health within midlife, and from midlife to late-life with magnetic resonance imaging markers of cerebral vascular disease, adjusting for potential confounders. RESULTS: A higher cardiovascular health in midlife, improvement of cardiovascular health within midlife, higher cardiovascular health at late-life, and improvement of cardiovascular health from midlife to late-life were associated with a lower prevalence of cerebral vascular disease markers. For example, improvement in cardiovascular health (per point) from midlife to late-life was associated with smaller white matter hyperintensity volume (ß, -0.07 [95% CI, -0.10 to -0.04]) and lower odds of microbleeds (odds ratio, 0.93 [0.90-0.97]), lacunar (odds ratio, 0.93 [0.89-0.97]), subcortical (odds ratio, 0.93 [0.89-0.97]), and cortical infarcts (odds ratio, 0.92 [0.87-0.97]). CONCLUSIONS: Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.

The association of white matter connectivity with prevalence, incidence and course of depressive symptoms: The Maastricht Study.

BACKGROUND: Altered white matter brain connectivity has been linked to depression. The aim of this study was to investigate the association of markers of white matter connectivity with prevalence, incidence and course of depressive symptoms. METHODS: Markers of white matter connectivity (node degree, clustering coefficient, local efficiency, characteristic path length, and global efficiency) were assessed at baseline by 3 T MRI in the population-based Maastricht Study (n = 4866; mean ± standard deviation age 59.6 ± 8.5 years, 49.0% women; 17 406 person-years of follow-up). Depressive symptoms (9-item Patient Health Questionnaire; PHQ-9) were assessed at baseline and annually over seven years of follow-up. Major depressive disorder (MDD) was assessed with the Mini-International Neuropsychiatric Interview at baseline only. We used negative binominal, logistic and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle risk factors. RESULTS: A lower global average node degree at baseline was associated with the prevalence and persistence of clinically relevant depressive symptoms [PHQ-9 ⩾ 10; OR (95% confidence interval) per standard deviation = 1.21 (1.05-1.39) and OR = 1.21 (1.02-1.44), respectively], after full adjustment. On the contrary, no associations were found of global average node degree with the MDD at baseline [OR 1.12 (0.94-1.32) nor incidence or remission of clinically relevant depressive symptoms [HR = 1.05 (0.95-1.17) and OR 1.08 (0.83-1.41), respectively]. Other connectivity measures of white matter organization were not associated with depression. CONCLUSIONS: Our findings suggest that fewer white matter connections may contribute to prevalent depressive symptoms and its persistence but not to incident depression. Future studies are needed to replicate our findings.

Variability in benefit from intensive insulin therapy on cardiovascular events in individuals with type 1 diabetes: A post hoc analysis of the DCCT/EDIC study.

AIM: To evaluate presence of treatment effect heterogeneity of intensive insulin therapy (INT) on occurrence of major adverse cardiovascular events (MACE) in individuals with type 1 diabetes. METHODS: In participants from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, individual treatment effect of INT (≥3 daily insulin injections/insulin pump therapy) versus conventional therapy (once/twice daily insulin) on the risk of MACE was estimated using a penalized Cox regression model including treatment-by-covariate interaction terms. RESULTS: In 1441 participants, 120 first MACE events were observed and 1279 individuals (89%) were predicted to benefit from INT with regard to MACE risk reduction. The study population was divided into four groups based on predicted treatment effect: one group with no predicted benefit and three tertiles with predicted treatment benefit. The median absolute reduction in 30-year risk of MACE across groups of predicted treatment effect ranged from -0.2% (i.e. risk increase; interquartile range [IQR] -0.1% to -0.3%) in the group with no predicted benefit to 6.6% (i.e. risk reduction; IQR 3.8%-10.9%; number needed to treat 15) in the highest tertile of predicted benefit. The observed benefit of preventing microvascular complications was stable across all subgroups of predicted MACE benefit. CONCLUSIONS: Although INT reduces the risk of MACE in the majority of individuals with type 1 diabetes, benefit varies substantially. These individual differences in the effect of INT underline the necessity for a better understanding of the individual response to intensive treatment.

Ultrasensitive Troponin I and Incident Cardiovascular Disease.

BACKGROUND: To examine the association of ultrasensitive cTnI (cardiac troponin I) with incident cardiovascular disease events (CVDs) in the primary prevention setting. METHODS: cTnI was analyzed in the baseline plasma (2008-2012) of CVD-free volunteers from the Paris Prospective Study III using a novel ultrasensitive immunoassay (Simoa Troponin-I 2.0 Kit, Quanterix, Lexington) with a limit of detection of 0.013 pg/mL. Incident CVD hospitalizations (coronary heart disease, stroke, cardiac arrhythmias, deep venous thrombosis or pulmonary embolism, heart failure, or arterial aneurysm) were validated by critical review of the hospital records. Hazard ratios were estimated per log-transformed SD increase of cTnI in Cox models using age as the time scale. RESULTS: The study population includes 9503 participants (40% women) aged 59.6 (6.3) years. cTnI was detected in 99.6% of the participants (median value=0.63 pg/mL, interquartile range, 0.39-1.09). After a median follow-up of 8.34 years (interquartile range, 8.0-10.07), 516 participants suffered 612 events. In fully adjusted analysis, higher cTnI (per 1 SD increase of log cTnI) was significantly associated with CVD events combined (hazard ratio, 1.18 [1.08-1.30]). Among all single risk factors, cTnI had the highest discrimination capacity for incident CVD events (C index=0.6349). Adding log cTnI to the SCORE 2 (Systematic Coronary Risk Evaluation) risk improved moderately discriminatory capacity (C index 0.698 versus 0.685; bootstrapped C index difference: 0.0135 [95% CI, 0.0131-0.0138]), and reclassification of the participants (categorical net reclassification index, 0.0628 [95% CI, 0.023-0.102]). Findings were consistent using the US pooled cohort risk equation. CONCLUSIONS: Ultrasensitive cTnI is an independent marker of CVD events in the primary prevention setting.

Association of change in cardiovascular risk factors with incident dementia.

INTRODUCTION: We evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk. METHODS: Two longitudinal population-based studies were used: Atherosclerosis Risk in Communities (ARIC) (n = 11,460/visits at ages 54 and 60), and Age, Gene/Environment Susceptibility (AGES)-Reykjavik (n = 3907/visit at age 51). A cardiovascular health score (range 0-12/0-14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Cardiovascular health was defined as low (score 0-4/0-5), intermediate (5-7/6-9), or high (8-12/10-14). Incident dementia was ascertained through linkage to health records and with neuropsychological examinations. RESULTS: Midlife high compared to low cardiovascular health (hazard ratios [HRs]: for ARIC: 0.60 [95% confidence interval: 0.52, 0.69]); for AGES-Reykjavik: 0.83 [0.66, 0.99] and improvement of cardiovascular health score within midlife (HR per one-point increase: ARIC: 0.94 [0.92, 0.96]) were associated with lower dementia risk. DISCUSSION: Better cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk. HIGHLIGHTS: Cardiovascular health and dementia were studied in two large cohort studies. Better cardiovascular health at midlife relates to lower dementia risk. Improvement of cardiovascular health within midlife relates to lower dementia risk. Promotion of cardiovascular health at midlife can help to reduce dementia risk.

Retinal Microvascular Caliber and Incident Depressive Symptoms: The Multi-Ethnic Study of Atherosclerosis.

Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. The retina allows for visualization of a microvascular bed that shares similarities with the cerebral microvasculature. We investigated the associations between baseline retinal arteriolar and venular calibers (central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE), respectively) and incident depressive symptoms in the Multi-Ethnic Study of Atherosclerosis (MESA). We used longitudinal data on 4,366 participants (mean age = 63.2 years; 48.5% women, 28.4% Black) without baseline depressive symptoms. Depressive symptoms, defined as Center for Epidemiologic Studies Depression Scale score ≥16 and/or use of antidepressant medication, were determined between 2002 and 2004 (baseline; MESA visit 2) and at 3 follow-up examinations conducted every 1.5-2 years thereafter. Fundus photography was performed at baseline. After a mean follow-up period of 6.1 years, 21.9% (n = 958) had incident depressive symptoms. After adjustment for sociodemographic, lifestyle, and cardiovascular factors, a 1-standard-deviation larger baseline CRVE was associated with a higher risk of depressive symptoms (hazard ratio = 1.10, 95% confidence interval: 1.02, 1.17), and a 1-standard-deviation larger baseline CRAE was not statistically significantly associated with incident depressive symptoms (hazard ratio = 1.04, 95% confidence interval: 0.97, 1.11). In this study, larger baseline CRVE, but not CRAE, was associated with a higher incidence of depressive symptoms.

Interplay of White Matter Hyperintensities, Cerebral Networks, and Cognitive Function in an Adult Population: Diffusion-Tensor Imaging in the Maastricht Study.

Background Lesions of cerebral small vessel disease, such as white matter hyperintensities (WMHs) in individuals with cardiometabolic risk factors, interfere with the trajectories of the white matter and eventually contribute to cognitive decline. However, there is no consensus yet about the precise underlying topological mechanism. Purpose To examine whether WMH and cognitive function are associated and whether any such association is mediated or explained by structural connectivity measures in an adult population. In addition, to investigate underlying local abnormalities in white matter by assessing the tract-specific WMH volumes and their tract-specific association with cognitive function. Materials and Methods In the prospective type 2 diabetes-enriched population-based Maastricht Study, structural and diffusion-tensor MRI was performed (December 2013 to February 2017). Total and tract-specific WMH volumes; network measures; cognition scores; and demographic, cardiovascular, and lifestyle characteristics were determined. Multivariable linear regression and mediation analyses were used to investigate the association of WMH volume, tract-specific WMH volumes, and network measures with cognitive function. Associations were adjusted for age, sex, education, diabetes status, and cardiovascular risk factors. Results A total of 5083 participants (mean age, 59 years ± 9 [standard deviation]; 2592 men; 1027 with diabetes) were evaluated. Larger WMH volumes were associated with stronger local (standardized ß coefficient, 0.065; P < .001), but not global, network efficiency and lower information processing speed (standardized ß coefficient, -0.073; P < .001). Moreover, lower local efficiency (standardized ß coefficient, -0.084; P < .001) was associated with lower information processing speed. In particular, the relationship between WMHs and information processing speed was mediated (percentage mediated, 7.2% [95% CI: 3.5, 10.9]; P < .05) by the local network efficiency. Finally, WMH load was larger in the white matter tracts important for information processing speed. Conclusion White matter hyperintensity volume, local network efficiency, and information processing speed scores are interrelated, and local network properties explain lower cognitive performance due to white matter network alterations. © RSNA, 2020 Online supplemental material is available for this article.

Association Between Age at Diabetes Onset and Subsequent Risk of Dementia.

Importance: Trends in type 2 diabetes show an increase in prevalence along with younger age of onset. While vascular complications of early-onset type 2 diabetes are known, the associations with dementia remains unclear. Objective: To determine whether younger age at diabetes onset is more strongly associated with incidence of dementia. Design, Setting, and Participants: Population-based study in the UK, the Whitehall II prospective cohort study, established in 1985-1988, with clinical examinations in 1991-1993, 1997-1999, 2002-2004, 2007-2009, 2012-2013, and 2015-2016, and linkage to electronic health records until March 2019. The date of final follow-up was March 31, 2019. Exposures: Type 2 diabetes, defined as a fasting blood glucose level greater than or equal to 126 mg/dL at clinical examination, physician-diagnosed type 2 diabetes, use of diabetes medication, or hospital record of diabetes between 1985 and 2019. Main Outcomes and Measures: Incident dementia ascertained through linkage to electronic health records. Results: Among 10 095 participants (67.3% men; aged 35-55 years in 1985-1988), a total of 1710 cases of diabetes and 639 cases of dementia were recorded over a median follow-up of 31.7 years. Dementia rates per 1000 person-years were 8.9 in participants without diabetes at age 70 years, and rates were 10.0 per 1000 person-years for participants with diabetes onset up to 5 years earlier, 13.0 for 6 to 10 years earlier, and 18.3 for more than 10 years earlier. In multivariable-adjusted analyses, compared with participants without diabetes at age 70, the hazard ratio (HR) of dementia in participants with diabetes onset more than 10 years earlier was 2.12 (95% CI, 1.50-3.00), 1.49 (95% CI, 0.95-2.32) for diabetes onset 6 to 10 years earlier, and 1.11 (95% CI, 0.70-1.76) for diabetes onset 5 years earlier or less; linear trend test (P < .001) indicated a graded association between age at onset of type 2 diabetes and dementia. At age 70, every 5-year younger age at onset of type 2 diabetes was significantly associated with an HR of dementia of 1.24 (95% CI, 1.06-1.46) in analyses adjusted for sociodemographic factors, health behaviors, and health-related measures. Conclusions and Relevance: In this longitudinal cohort study with a median follow-up of 31.7 years, younger age at onset of diabetes was significantly associated with higher risk of subsequent dementia.

Depression, antidepressants and low hemoglobin level in the Paris Prospective Study III: A cross-sectional analysis.

Anemia is known to be associated with depression both in community and clinical populations. However, it is still unknown if this association depends or not on antidepressant intake. We investigated the respective association of depression and antidepressant intake with low hemoglobin level in a large community-based cohort. In 8640 volunteers aged 50 to 75 recruited between June 2008 and June 2012 in Paris (France), we assessed hemoglobin levels (g/dl), depressive symptoms and antidepressant intake. We examined the association of both depression and antidepressant intake with hemoglobin level, adjusting for numerous socio-demographic and health variables. We also assessed the association with specific antidepressant classes. Depression and antidepressant intake were independently associated with lower hemoglobin level (ß = -0.074; p = .05 and ß = -0.100; p = .02 respectively in the fully-adjusted model). Regarding antidepressant classes, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) intake were associated with lower hemoglobin level (ß = -0.11; p = .01). To conclude, both depression and antidepressant intake were associated with lower hemoglobin level. In particular, as SSRI or SNRIs intake was also related to lower hemoglobin level, these classes should be used with caution in depressed individuals at risk for anemia.

Sleep apnoea is associated with hearing impairment: The Paris prospective study 3.

OBJECTIVES: Hearing impairment (HI) is a leading impairment worldwide, and identifying modifiable risk factors of HI may have major public health implications. The aim of this study was to investigate the association between obstructive sleep apnoea (OSA) and HI. DESIGN: Observational longitudinal study (the Paris Prospective Study 3). SETTING: Population-based. PARTICIPANTS: Volunteers aged 50-75 years and consulting at a preventive medical centre were included between 2008 and 2012. 6797 participants were included in the present analysis. MAIN OUTCOME MEASURES: Audiometry testing was performed in both ears in all participants, and HI was defined by a pure-tone average (PTA) >25 decibels (dB) hearing level in the better ear. RESULTS: Obstructive sleep apnoea (estimated by the Berlin questionnaire) was present in 18.6% (n = 1267) and HI in 13.9% (n = 947) of the participants. Mean age was 59.5 years (SD 6.2) and 63.5% were male (n = 4317). In multiple logistic regression modelling, OSA was significantly associated with a 1.21-increased odds of HI (95% confidence interval 1.01-1.44). Several sensitivity analyses supported this finding. CONCLUSION: Obstructive sleep apnoea is associated with a 21% increased odds of HI. These results support active screening of HI in subjects with OSA, and future studies should evaluate whether the treatment of OSA can delay the onset of HI.

Co-administration of cyclosporine and ticagrelor may lead to a higher exposure to cyclosporine: a case report of a 49-year-old man.

ADVERSE EVENT: A drug interaction leading to higher exposure to cyclosporine. DRUGS IMPLICATED: Cyclosporine and ticagrelor. THE PATIENT: A 49-year-old man with a stable renal graft, managed with cyclosporine with stable trough blood concentrations for several years, was treated with ticagrelor for unstable angina pectoris. EVIDENCE THAT LINKS THE DRUG TO THE EVENT: The timeline was consistent with the appearance of an interaction, the interaction was confirmed by an increase in trough concentration of cyclosporine, and there were no alternative causes that by themselves could have caused the increase in cyclosporine exposure. MANAGEMENT: Cessation of ticagrelor. MECHANISM: Inhibition of CYP3A4 and P-glycoprotein by ticagrelor. IMPLICATIONS FOR THERAPY: Clinicians should be aware of this potential interaction as ticagrelor is frequently prescribed in individuals using cyclosporine. Close monitoring of cyclosporine serum concentrations is warranted to avoid overdosing of cyclosporine. A pharmacokinetic study is needed to further examine the probable interaction between cyclosporine and ticagrelor.

Association of Change in Cardiovascular Risk Factors With Incident Cardiovascular Events.

Importance: There is consistent evidence of the association between ideal cardiovascular health and lower incident cardiovascular disease (CVD); however, most studies used a single measure of cardiovascular health. Objective: To examine how cardiovascular health changes over time and whether these changes are associated with incident CVD. Design, Setting, and Participants: Prospective cohort study in a UK general community (Whitehall II), with examinations of cardiovascular health from 1985/1988 (baseline) and every 5 years thereafter until 2015/2016 and follow-up for incident CVD until March 2017. Exposures: Using the 7 metrics of the American Heart Association (nonsmoking; and ideal levels of body mass index, physical activity, diet, blood pressure, fasting blood glucose, and total cholesterol), participants with 0 to 2, 3 to 4, and 5 to 7 ideal metrics were categorized as having low, moderate, and high cardiovascular health. Change in cardiovascular health over 10 years between 1985/1988 and 1997/1999 was considered. Main Outcome and Measure: Incident CVD (coronary heart disease and stroke). Results: The study population included 9256 participants without prior CVD (mean [SD] age at baseline, 44.8 [6.0] years; 2941 [32%] women), of whom 6326 had data about cardiovascular health change. Over a median follow-up of 18.9 years after 1997/1999, 1114 incident CVD events occurred. In multivariable analysis and compared with individuals with persistently low cardiovascular health (consistently low group, 13.5% of participants; CVD incident rate per 1000 person-years, 9.6 [95% CI, 8.4-10.9]), there was no significant association with CVD risk in the low to moderate group (6.8% of participants; absolute rate difference per 1000 person-years, -1.9 [95% CI, -3.9 to 0.1]; HR, 0.84 [95% CI, 0.66-1.08]), the low to high group, (0.3% of participants; absolute rate difference per 1000 person-years, -7.7 [95% CI, -11.5 to -3.9]; HR, 0.19 [95% CI, 0.03-1.35]), and the moderate to low group (18.0% of participants; absolute rate difference per 1000 person-years, -1.3 [95% CI, -3.0 to 0.3]; HR, 0.96 [95% CI, 0.80-1.15]). A lower CVD risk was observed in the consistently moderate group (38.9% of participants; absolute rate difference per 1000 person-years, -4.2 [95% CI, -5.5 to -2.8]; HR, 0.62 [95% CI, 0.53-0.74]), the moderate to high group (5.8% of participants; absolute rate difference per 1000 person-years, -6.4 [95% CI, -8.0 to -4.7]; HR, 0.39 [95% CI, 0.27-0.56]), the high to low group (1.9% of participants; absolute rate difference per 1000 person-years, -5.3 [95% CI, -7.8 to -2.8]; HR, 0.49 [95% CI, 0.29-0.83]), the high to moderate group (9.3% of participants; absolute rate difference per 1000 person-years, -4.5 [95% CI, -6.2 to -2.9]; HR, 0.66 [95% CI, 0.51-0.85]), and the consistently high group (5.5% of participants; absolute rate difference per 1000 person-years, -5.6 [95% CI, -7.4 to -3.9]; HR, 0.57 [95% CI, 0.40-0.80]). Conclusions and Relevance: Among a group of participants without CVD who received follow-up over a median 18.9 years, there was no consistent relationship between direction of change in category of a composite metric of cardiovascular health and risk of CVD.

Associations between arterial stiffness, depressive symptoms and cerebral small vessel disease: cross-sectional findings from the AGES-Reykjavik Study.

BACKGROUND: Arterial stiffness may contribute to depression via cerebral microvascular damage, but evidence for this is scarce. We therefore investigated whether arterial stiffness is associated with depressive symptoms and whether cerebral small vessel disease contributes to this association. METHODS: This cross-sectional study included a subset of participants from the AGES-Reykjavik study second examination round, which was conducted from 2007 to 2011. Arterial stiffness (carotid-femoral pulse wave velocity [CFPWV]), depressive symptoms (15-item geriatric depression scale [GDS-15]) and cerebral small vessel disease (MRI) were determined. Manifestations of cerebral small vessel disease included higher white matter hyperintensity volume, subcortical infarcts, cerebral microbleeds, Virchow-Robin spaces and lower total brain parenchyma volume. RESULTS: We included 2058 participants (mean age 79.6 yr; 59.0% women) in our analyses. Higher CFPWV was associated with a higher GDS-15 score, after adjustment for potential confounders (ß 0.096, 95% confidence interval [CI] 0.005-0.187). Additional adjustment for white matter hyperintensity volume or subcortical infarcts attenuated the association between CFPWV and the GDS-15 score, which became nonsignificant (p > 0.05). Formal mediation tests showed that the attenuating effects of white matter hyperintensity volume and subcortical infarcts were statistically significant. Virchow-Robin spaces, cerebral microbleeds and cerebral atrophy did not explain the association between CFPWV and depressive symptoms. LIMITATIONS: Our study was limited by its cross-sectional design, which precludes any conclusions about causal mediation. Depressive symptoms were assessed by a self-report questionnaire. CONCLUSION: Greater arterial stiffness is associated with more depressive symptoms; this association is partly accounted for by white matter hyperintensity volume and subcortical infarcts. This study supports the hypothesis that arterial stiffness leads to depression in part via cerebral small vessel disease.

Associations of plasma NfL, GFAP, and t-tau with cerebral small vessel disease and incident dementia: longitudinal data of the AGES-Reykjavik Study.

We investigated the associations of plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (t-tau) with markers of cerebral small vessel disease (SVD) and with incident dementia. We also investigated whether associations of NfL, GFAP, and t-tau with incident dementia were explained by SVD. Data are from a random subsample (n = 1069) of the population-based AGES-Reykjavik Study who underwent brain MRI and in whom plasma NfL, GFAP, and t-tau were measured at baseline (76.1 ± 5.4 years/55.9% women/baseline 2002-2006/follow-up until 2015). A composite SVD burden score was calculated using white matter hyperintensity volume (WMHV), subcortical infarcts, cerebral microbleeds, and large perivascular spaces. Dementia was assessed in a 3-step process and adjudicated by specialists. Higher NfL was associated with a higher SVD burden score. Dementia occurred in 225 (21.0%) individuals. The SVD burden score significantly explained part of the association between NfL and incident dementia. WMHV mostly strongly contributed to the explained effect. GFAP was not associated with the SVD burden score, but was associated with WMHV, and WMHV significantly explained part of the association between GFAP and incident dementia. T-tau was associated with WMHV, but not with incident dementia. In conclusion, the marker most strongly related to SVD is plasma NfL, for which the association with WMHV appeared to explain part of its association with incident dementia. This study suggests that plasma NfL may reflect the contribution of co-morbid vascular disease to dementia. However, the magnitude of the explained effect was relatively small, and further research is required to investigate the clinical implications of this finding.