Association of moderate and vigorous physical activity with incidence of type 2 diabetes and subsequent mortality: 27 year follow-up of the Whitehall II study

AIMS/HYPOTHESIS: This work examined the role of physical activity in the course of diabetes using data spanning nearly three decades. Our first aim was to examine the long-term association of moderate and vigorous physical activity with incidence of type 2 diabetes. Our second aim was to investigate the association of moderate-to-vigorous physical activity post-diabetes diagnosis with subsequent risk of all-cause and cardiovascular disease mortality. METHODS: A total of 9987 participants from the Whitehall II cohort study free of type 2 diabetes at baseline (1985-1988) were followed for incidence of type 2 diabetes, based on clinical assessments between 1985 and 2016 and linkage to electronic health records up to 31 March 2017. We first examined the association of moderate and vigorous physical activity measured by questionnaire in 1985-1988 (mean age 44.9 [SD 6.0] years; women, 32.7%) with incident type 2 diabetes, using the interval-censored, illness-death model, a competing risk analysis that takes into account both competing risk of death and intermittent ascertainment of diabetes due to reliance on data collection cycles (interval-censored). The second analysis was based on individuals with type 2 diabetes over the follow-up period where we used Cox regression with inverse probability weighting to examine the association of moderate-to-vigorous physical activity after diagnosis of type 2 diabetes with risk of all-cause and cardiovascular disease mortality. RESULTS: Of the 9987 participants, 1553 developed type 2 diabetes during a mean follow-up of 27.1 (SD 6.3) years. Compared with participants who were inactive in 1985-1988, those who undertook any duration of moderate-to-vigorous physical activity had a lower risk of type 2 diabetes (HR 0.85 [95% CI 0.75, 0.97], p = 0.02; analysis adjusted for sociodemographic, behavioural and health-related factors). In 1026 participants with a diagnosis of type 2 diabetes over the follow-up period, data on moderate-to-vigorous physical activity after diabetes diagnosis were available; 165 all-cause deaths and 55 cardiovascular disease-related deaths were recorded during a mean follow-up of 8.8 (SD 6.1) years. In these participants with diabetes, any duration of moderate-to-vigorous physical activity was associated with lower all-cause mortality (HR 0.61 [95% CI 0.41, 0.93], p = 0.02) while the association with cardiovascular mortality was evident only for physical activity undertaken at or above recommendations (≥2.5 h per week of moderate-to-vigorous physical activity or ≥1.25 h per week of vigorous physical activity; HR 0.40 [95% CI 0.16, 0.96], p = 0.04) in fully adjusted models. CONCLUSIONS/INTERPRETATION: Moderate-to-vigorous physical activity plays an important role in diabetes, influencing both its incidence and prognosis. A protective effect on incidence was seen for durations of activity below recommendations and a marginal additional benefit was observed at higher durations. Among individuals with type 2 diabetes, any duration of moderate-to-vigorous physical activity was associated with reduced all-cause mortality while recommended durations of physical activity were required for protection against cardiovascular disease-related mortality. DATA AVAILABILITY: Whitehall II data, protocols and other metadata are available to the scientific community. Please refer to the Whitehall II data sharing policy at https://www.ucl.ac.uk/epidemiology-health-care/research/epidemiology-and-public-health/research/whitehall-ii/data-sharing

Association of daily composition of physical activity and sedentary behaviour with incidence of cardiovascular disease in older adults.

BACKGROUND: Moderate-to-vigorous physical activity (MVPA) is proposed as key for cardiovascular diseases (CVD) prevention. At older ages, the role of sedentary behaviour (SB) and light intensity physical activity (LIPA) remains unclear. Evidence so far is based on studies examining movement behaviours as independent entities ignoring their co-dependency. This study examines the association between daily composition of objectively-assessed movement behaviours (MVPA, LIPA, SB) and incident CVD in older adults. METHODS: Whitehall II accelerometer sub-study participants free of CVD at baseline (N = 3319, 26.7% women, mean age = 68.9 years in 2012-2013) wore a wrist-accelerometer from which times in SB, LIPA, and MVPA during waking period were extracted over 7 days. Compositional Cox regression was used to estimate the hazard ratio (HR) for incident CVD for daily compositions of movement behaviours characterized by 10 (20 or 30) minutes greater duration in one movement behaviour accompanied by decrease in another behaviour, while keeping the third behaviour constant, compared to reference composition. Analyses were adjusted for sociodemographic, lifestyle, cardiometabolic risk factors and multimorbidity index. RESULTS: Of the 3319 participants, 299 had an incident CVD over a mean (SD) follow-up of 6.2 (1.3) years. Compared to daily movement behaviour composition with MVPA at recommended 21 min per day (150 min/week), composition with additional 10 min of MVPA and 10 min less SB was associated with smaller risk reduction - 8% (HR, 0.92; 95% CI, 0.87-0.99) - than the 14% increase in risk associated with a composition of similarly reduced time in MVPA and more time in SB (HR, 1.14; 95% CI, 1.02-1.27). For a given MVPA duration, the CVD risk did not differ as a function of LIPA and SB durations. CONCLUSIONS: Among older adults, an increase in MVPA duration at the expense of time in either SB or LIPA was found associated with lower incidence of CVD. This study lends support to public health guidelines encouraging increase in MVPA or at least maintain MVPA at current duration

Adiposity, obesity, and arterial aging: longitudinal study of aortic stiffness in the Whitehall II cohort

We sought to determine whether adiposity in later midlife is an independent predictor of accelerated stiffening of the aorta. Whitehall II study participants (3789 men; 1383 women) underwent carotid-femoral applanation tonometry at the mean age of 66 and again 4 years later. General adiposity by body mass index, central adiposity by waist circumference and waist:hip ratio, and fat mass percent by body impedance were assessed 5 years before and at baseline. In linear mixed models adjusted for age, sex, ethnicity, and mean arterial pressure, all adiposity measures were associated with aortic stiffening measured as increase in pulse wave velocity (PWV) between baseline and follow-up. The associations were similar in the metabolically healthy and unhealthy, according to Adult Treatment Panel-III criteria excluding waist circumference. C-reactive protein and interleukin-6 levels accounted for part of the longitudinal association between adiposity and PWV change. Adjusting for chronic disease, antihypertensive medication and risk factors, standardized effects of general and central adiposity and fat mass percent on PWV increase (m/s) were similar (0.14, 95% confidence interval: 0.05-0.24, P=0.003; 0.17, 0.08-0.27, P<0.001; 0.14, 0.05-0.22, P=0.002, respectively). Previous adiposity was associated with aortic stiffening independent of change in adiposity, glycaemia, and lipid levels across PWV assessments. We estimated that the body mass index-linked PWV increase will account for 12% of the projected increase in cardiovascular risk because of high body mass index. General and central adiposity in later midlife were strong independent predictors of aortic stiffening. Our findings suggest that adiposity is an important and potentially modifiable determinant of arterial aging

Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study

Objective: Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional. Design and methods: We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers. Results: Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin. Conclusions: Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function

Oxidative-Nitrative Stress and Poly (ADP-Ribose) Polymerase Activation 3 Years after Pregnancy

Background: Oxidative-nitrative stress and poly (ADP-ribose) polymerase activation have been previously observed in healthy and gestational diabetic pregnancies, and they were also linked to the development of metabolic diseases. The aim of the present study was to examine these parameters and their correlation to known metabolic risk factors following healthy and gestational diabetic pregnancies. // Methods: Fasting and 2 h postload plasma total peroxide level, protein tyrosine nitration, and poly (ADP-ribose) polymerase activation were measured in circulating leukocytes three years after delivery in women following healthy, “mild” (diet-treated) or “severe” (insulin-treated) gestational diabetic pregnancy during a standard 75 g OGTT. Nulliparous women and men served as control groups. // Results: Fasting plasma total peroxide level was significantly elevated in women with previous pregnancy (B = 0.52 ± 0.13; p < 0 001), with further increase in women with insulin-treated gestational diabetes (B=0 36 ± 0 17; p < 0 05) (R2 = 0 419). Its level was independently related to previous pregnancy (B=0 47 ± 0 14; p < 0 01) and current CRP levels (B=0 06 ± 0 02; p < 0 05) (R2 = 0 306). // Conclusions: Elevated oxidative stress but not nitrative stress or poly (ADP-ribose) polymerase activation can be measured three years after pregnancy. The increased oxidative stress may reflect the cost of reproduction and possibly play a role in the increased metabolic risk observed in women with a history of severe gestational diabetes mellitus

Work Disability among Employees with Diabetes: Latent Class Analysis of Risk Factors in Three Prospective Cohort Studies

BACKGROUND: Studies of work disability in diabetes have examined diabetes as a homogeneous disease. We sought to identify subgroups among persons with diabetes based on potential risk factors for work disability. METHODS: Participants were 2,445 employees with diabetes from three prospective cohorts (the Finnish Public Sector study, the GAZEL study, and the Whitehall II study). Work disability was ascertained via linkage to registers of sickness absence and disability pensions during a follow-up of 4 years. Study-specific latent class analysis was used to identify subgroups according to prevalent comorbid disease and health-risk behaviours. Study-specific associations with work disability at follow-up were pooled using fixed-effects meta-analysis. RESULTS: Separate latent class analyses for men and women in each cohort supported a two-class solution with one subgroup (total n = 1,086; 44.4%) having high prevalence of chronic somatic diseases, psychological symptoms, obesity, physical inactivity and abstinence from alcohol and the other subgroup (total n = 1,359; 55.6%) low prevalence of these factors. In the adjusted meta-analyses, participants in the 'high-risk' group had more work disability days (pooled rate ratio = 1.66, 95% CI 1.38-1.99) and more work disability episodes (pooled rate ratio = 1.33, 95% CI 1.21-1.46). These associations were similar in men and women, younger and older participants, and across occupational groups. CONCLUSIONS: Diabetes is not a homogeneous disease in terms of work disability risk. Approximately half of people with diabetes are assigned to a subgroup characterised by clustering of comorbid health conditions, obesity, physical inactivity, abstinence of alcohol, and associated high risk of work disability; the other half to a subgroup characterised by a more favourable risk profile

Oxidative-Nitrative Stress and Poly (ADP-Ribose) Polymerase Activation 3 Years after Pregnancy

Background: Oxidative-nitrative stress and poly (ADP-ribose) polymerase activation have been previously observed in healthy and gestational diabetic pregnancies, and they were also linked to the development of metabolic diseases. The aim of the present study was to examine these parameters and their correlation to known metabolic risk factors following healthy and gestational diabetic pregnancies. Methods: Fasting and 2 h postload plasma total peroxide level, protein tyrosine nitration, and poly (ADP-ribose) polymerase activation were measured in circulating leukocytes three years after delivery in women following healthy, "mild" (diet-treated) or "severe" (insulin-treated) gestational diabetic pregnancy during a standard 75 g OGTT. Nulliparous women and men served as control groups. Results: Fasting plasma total peroxide level was significantly elevated in women with previous pregnancy (B = 0.52 +/- 0.13; p < 0.001), with further increase in women with insulin-treated gestational diabetes (B = 0.36 +/- 0.17; p < 0.05) (R(2) = 0.419). Its level was independently related to previous pregnancy (B = 0.47 +/- 0.14; p < 0.01) and current CRP levels (B = 0.06 +/- 0.02; p < 0.05) (R(2) = 0.306). Conclusions: Elevated oxidative stress but not nitrative stress or poly (ADP-ribose) polymerase activation can be measured three years after pregnancy. The increased oxidative stress may reflect the cost of reproduction and possibly play a role in the increased metabolic risk observed in women with a history of severe gestational diabetes mellitus

Association between change in cardiovascular risk scores and future cardiovascular disease: analyses of data from the Whitehall II longitudinal, prospective cohort study

BACKGROUND: Evaluation of cardiovascular disease risk in primary care, which is recommended every 5 years in middle-aged and older adults (typical age range 40-75 years), is based on risk scores, such as the European Society of Cardiology Systematic Coronary Risk Evaluation (SCORE) and American College of Cardiology/American Heart Association Atherosclerotic Cardiovascular Disease (ASCVD) algorithms. This evaluation currently uses only the most recent risk factor assessment. We aimed to examine whether 5-year changes in SCORE and ASCVD risk scores are associated with future cardiovascular disease risk. METHODS: We analysed data from the Whitehall II longitudinal, prospective cohort study for individuals with no history of stroke, myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, definite angina, heart failure, or peripheral artery disease. Participants underwent clinical examinations in 5-year intervals between Aug 7, 1991, and Dec 6, 2016, and were followed up for incident cardiovascular disease until Oct 2, 2019. Levels of, and 5-year changes in, cardiovascular disease risk were assessed using the SCORE and ASCVD risk scores and were analysed as predictors of cardiovascular disease. Harrell's C index, continuous net reclassification improvement, the Akaike information criterion, and calibration analysis were used to assess whether incorporating change in risk scores into a model including only a single risk score assessment improved the predictive performance. We assessed the levels of, and 5-year changes in, SCORE and ASCVD risk scores as predictors of cardiovascular disease and disease-free life-years using Cox proportional hazards and flexible parametric survival models. FINDINGS: 7574 participants (5233 [69·1%] men, 2341 [30·9%] women) aged 40-75 years were included in analyses of risk score change between April 24, 1997, and Oct 2, 2019. During a mean follow-up of 18·7 years (SD 5·5), 1441 (19·0%; 1042 [72·3%] men and 399 [27·7%] women) participants developed cardiovascular disease. Adding 5-year change in risk score to a model that included only a single risk score assessment improved model performance according to Harrell's C index (from 0·685 to 0·690, change 0·004 [95% CI 0·000 to 0·008] for SCORE; from 0·699 to 0·700, change 0·001 [0·000 to 0·003] for ASCVD), the Akaike information criterion (from 17 255 to 17 200, change -57 [95% CI -97 to -13] for SCORE; from 14 739 to 14 729, change -10 [-28 to 7] for ASCVD), and the continuous net reclassification index (0·353 [95% CI 0·234 to 0·447] for SCORE; 0·232 [0·030 to 0·344] for ASCVD). Both favourable and unfavourable changes in SCORE and ASCVD were associated with cardiovascular disease risk and disease-free life-years. The associations were seen in both sexes and all age groups up to the age of 75 years. At the age of 45 years, each 2-unit improvement in risk scores was associated with an additional 1·3 life-years (95% CI 0·4 to 2·2) free of cardiovascular disease for SCORE and an additional 0·9 life-years (95% CI 0·5 to 1·3) for ASCVD. At age 65 years, this same improvement was associated with an additional 0·4 life-years (95% CI 0·0 to 0·7) free of cardiovascular disease for SCORE and 0·3 life-years (95% CI 0·1 to 0·5) for ASCVD. These models were developed into an interactive calculator, which enables estimation of the number of cardiovascular disease-free life-years for an individual as a function of two risk score measurements. INTERPRETATION: Changes in the SCORE and ASCVD risk scores over time inform cardiovascular disease risk prediction beyond a single risk score assessment. Repeat data might allow more accurate cardiovascular risk stratification and strengthen the evidence base for decisions on preventive interventions. FUNDING: UK Medical Research Council, British Heart Foundation, Wellcome Trust, and US National Institute on Aging

Association between systolic blood pressure and dementia in the Whitehall II cohort study: role of age, duration, and threshold used to define hypertension

Aims: To examine associations of diastolic and systolic blood pressure (SBP) at age 50, 60, and 70 years with incidence of dementia, and whether cardiovascular disease (CVD) over the follow-up mediates this association. // Methods and results: Systolic and diastolic blood pressure were measured on 8639 persons (32.5% women) from the Whitehall II cohort study in 1985, 1991, 1997, and 2003. Incidence of dementia (n dementia/n total = 385/8639) was ascertained from electronic health records followed-up until 2017. Cubic splines using continuous blood pressure measures suggested SBP ≥130 mmHg at age 50 but not at age 60 or 70 was associated with increased risk of dementia, confirmed in Cox regression analyses adjusted for sociodemographic factors, health behaviours, and time varying chronic conditions [hazard ratio (HR) 1.38; 95% confidence interval (95% CI) 1.11, 1.70]. Diastolic blood pressure was not associated with dementia. Participants with longer exposure to hypertension (SBP ≥ 130 mmHg) between mean ages of 45 and 61 years had an increased risk of dementia compared to those with no or low exposure to hypertension (HR 1.29, 95% CI 1.00, 1.66). In multi-state models, SBP ≥ 130 mmHg at 50 years of age was associated with greater risk of dementia in those free of CVD over the follow-up (HR 1.47, 95% CI 1.15, 1.87). // Conclusion: Systolic blood pressure ≥130 mmHg at age 50, below the conventional ≥140 mmHg threshold used to define hypertension, is associated with increased risk of dementia; in these persons this excess risk is independent of CVD