Effect of secular trends on age-related trajectories of cardiovascular risk factors: the Whitehall II longitudinal study 1985-2009

Secular trends in cardiovascular risk factors have been described, but few studies have examined simultaneously the effects of both ageing and secular trends within the same cohort

Heart Rate and Heart Rate Variability Changes Are Not Related to Future Cardiovascular Disease and Death in People With and Without Dysglycemia: A Downfall of Risk Markers? The Whitehall II Cohort Study

OBJECTIVE: Higher resting heart rate (rHR) and lower heart rate variability (HRV) are associated with increased risk of cardiovascular disease (CVD) and all-cause mortality in people with and without diabetes. It is unknown whether temporal changes in rHR and HRV may contribute to this risk. We investigated associations between 5-year changes in rHR and HRV and risk of future CVD and death, taking into account participants' baseline glycemic state. RESEARCH DESIGN AND METHODS: In this prospective, population-based cohort study we investigated 4,611 CVD-free civil servants (mean [SD] age, 60 [5.9] years; 70% men). We measured rHR and/or six indices of HRV. Associations of 5-year change in 5-min rHR and HRV with fatal and nonfatal CVD and all-cause mortality or the composite of the two were assessed, with adjustments made for relevant confounders. Effect modification by glycemic state was tested. RESULTS: At baseline, 63% of participants were normoglycemic, 29% had prediabetes, and 8% had diabetes. During a median (interquartile range) follow-up of 11.9 (11.4; 12.3) years, 298 participants (6.5%) experienced a CVD event and 279 (6.1%) died of non-CVD-related causes. We found no association between 5-year changes in rHR and HRV and future events. Only baseline rHR was associated with all-cause mortality. A 10 bpm-higher baseline HR level was associated with a 11.4% higher rate of all-cause mortality (95% CI 1.0-22.9%; P = 0.032). Glycemic state did not modify associations. CONCLUSIONS: Changes in rHR and HRV and possibly also baseline values of these measures are not associated with future CVD or death in people with or without dysglycemia

Efficacy and toxicity of adjuvant chemotherapy in elderly patients with colorectal cancer:the ACCORE study

BACKGROUND: Elderly patients with primary colorectal cancer (CRC) are less frequently treated with adjuvant chemotherapy than younger patients due to concerns regarding toxicity and efficiency. We investigated how age, performance status (PS) and comorbidity influence treatment outcomes. PATIENTS AND METHODS: A retrospective single-centre study of 529 patients with stages II–III CRC treated with adjuvant chemotherapy (5-fluorouracil/capecitabine+/÷oxaliplatin) from 2001 to 2011 at Herlev Hospital, Denmark. Baseline characteristics, chemotherapy and outcome were analysed with respect to age after adjusting for PS and comorbidity. RESULTS: Elderly patients (>70 years) had significantly more comorbidity (p<0.001) and poorer PS (p=0.001) than younger patients. Elderly were more frequently treated with single-agent therapy (p=0.001) and at lower initial dose (p<0.001). There was no age-dependent difference in 3-year disease-free survival (DFS; HR 1.09, 95% CI 0.80 to 1.47, p=0.59), in grade 3–5 toxicity (29% vs 28%, p=0.86) or in 10-year CRC mortality (28%, HR 1.07, p=0.71). In elderly patients, a reduction in chemotherapy dose intensity compared with full dose had no impact on DFS or CRC mortality. Elderly patients receiving <50% of planned cycles had shorter DFS (HR=1.78, p=0.020) and higher CRC mortality (HR=2.17, p=0.027) than elderly receiving all cycles. Poor PS in younger and elderly patients was related to shorter DFS (HR=1.95, p=0.002; HR=1.6, p=0.035, respectively) and overall survival (OS; HR=2.28, p<0.001; HR=2.03, p=0.002). Comorbidity in younger patients was significantly related to shorter DFS (HR 2.72, p<0.001), OS (HR 3.16, p<0.001) and higher CRC mortality (HR 2.70, p=0.001). CONCLUSIONS: Choice of regimen, primary dose reduction and given dose intensity in patients treated with adjuvant chemotherapy for CRC were highly dependent on age. However, age had no impact on DFS and CRC mortality. Comorbidity in younger patients and PS in all patients were associated with shorter DFS and higher CRC mortality

Bimodal Distribution of Glucose Is Not Universally Useful for Diagnosing Diabetes

OBJECTIVE—Bimodality in the distribution of glucose has been used to define the cut point for the diagnosis of diabetes. Previous studies on bimodality have primarily been in populations with a high prevalence of type 2 diabetes, including one study in a white Caucasian population. All studies included participants with known diabetes. The aim of this study was to assess whether a bimodal structure is a general phenomenon in fasting plasma glucose (FPG) and 2-h plasma glucose that is useful for deriving a common cut point for diabetes in populations of different origin, both including and excluding known diabetes

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

Moving to an A1C-Based Diagnosis of Diabetes Has a Different Impact on Prevalence in Different Ethnic Groups

Objective: To compare screen detected diabetes prevalence and the degree of diagnostic agreement by ethnicity with the current OGTT-based and newly proposed HbA<SUB>1c</SUB>-based diagnostic criteria. Research design and methods: Six studies (1999-2009) from Denmark, United Kingdom, Australia, Greenland, Kenya, and India were tested for the probability of an HbA<SUB>1c</SUB> ≥ 6.5% among diabetes cases based on an OGTT. The difference in probability between centers was analyzed by logistic regression adjusting for relevant confounders. Results: Diabetes prevalence was lower with the HbA<SUB>1c</SUB>-based diagnostic criteria in four out of six studies. The probability of an HbA<SUB>1c</SUB> ≥ 6.5% among OGTT-diagnosed cases ranged widely (17.0 to 78.0%) by study center. Differences in diagnostic agreement between ethnic sub-groups in the United Kingdom study were of the same magnitude as between-country comparisons. Conclusions: A shift to an HbA<SUB>1c</SUB>-based diagnosis for diabetes will have substantially different consequences for diabetes prevalence across ethnic groups and populations

Body mass index trajectories in early childhood in relation to cardiometabolic risk profile and body composition at 5 years of age

BACKGROUND: Both impaired and accelerated postnatal growth have been associated with adult risks of obesity and cardiometabolic diseases, like type 2 diabetes and cardiovascular disease. However, the timing of the onset of cardiometabolic changes and the specific growth trajectories linking early growth with later disease risks are not well understood. OBJECTIVES: The aim of this study was to identify distinct trajectories of BMI growth from 0 to 5 y and examine their associations with body composition and markers of cardiometabolic risk at age 5 y. METHODS: In a prospective birth cohort study of 453 healthy and term Ethiopian children with BMIs assessed a median of 9 times during follow-up, we identified subgroups of distinct BMI trajectories in early childhood using latent class trajectory modeling. Associations of the identified growth trajectories with cardiometabolic markers and body composition at 5 y were analyzed using multiple linear regression analyses in 4 adjustment models for each outcome. RESULTS: We identified 4 heterogeneous BMI growth trajectories: stable low BMI (19.2%), normal BMI (48.8%), rapid catch-up to high BMI (17.9%), and slow catch-up to high BMI (14.1%). Compared with the normal BMI trajectory, children in the rapid catch-up to high BMI trajectory had higher triglycerides (TGs) (range of β-coefficients in Models 1-4: 19-21%), C-peptides (23-25%), fat masses (0.48-0.60 kg), and fat-free masses (0.50-0.77 kg) across the 4 adjustment models. Children in the stable low BMI trajectory had lower LDL cholesterol concentrations (0.14-0.17 mmol/L), HDL cholesterol concentrations (0.05-0.09 mmol/L), fat masses (0.60-0.64 kg), and fat-free masses (0.35-0.49 kg), but higher TGs (11-13%). CONCLUSIONS: The development of obesity and cardiometabolic risks may be established already in early childhood; thus, our data provide a further basis for timely interventions targeted at young children from low-income countries with unfavorable growth patterns. The birth cohort was registered at ISRCTN as ISRCTN46718296

Risk of Cardiovascular Disease and Death in Individuals With Prediabetes Defined by Different Criteria: The Whitehall II Study

OBJECTIVE: We compared the risk of cardiovascular disease (CVD) and all-cause mortality in subgroups of prediabetes defined by fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), or HbA1c. RESEARCH DESIGN AND METHODS: In the Whitehall II cohort, 5,427 participants aged 50–79 years and without diabetes were followed for a median of 11.5 years. A total of 628 (11.6%) had prediabetes by the World Health Organization (WHO)/International Expert Committee (IEC) criteria (FPG 6.1–6.9 mmol/L and/or HbA1c 6.0–6.4%), and 1,996 (36.8%) by the American Diabetes Association (ADA) criteria (FPG 5.6–6.9 mmol/L and/or HbA1c 5.7–6.4%). In a subset of 4,730 individuals with additional measures of 2hPG, 663 (14.0%) had prediabetes by 2hPG. Incidence rates of a major event (nonfatal/fatal CVD or all-cause mortality) were compared for different definitions of prediabetes, with adjustment for relevant confounders. RESULTS: Compared with that for normoglycemia, incidence rate in the context of prediabetes was 54% higher with the WHO/IEC definition and 37% higher with the ADA definition (P < 0.001) but declining to 17% and 12% after confounder adjustment (P ≥ 0.111). Prediabetes by HbA1c was associated with a doubling in incidence rate for both the IEC and ADA criteria. However, upon adjustment, excess risk was reduced to 13% and 17% (P ≥ 0.055), respectively. Prediabetes by FPG or 2hPG was not associated with an excess risk in the adjusted analysis. CONCLUSIONS: Prediabetes defined by HbA1c was associated with a worse prognosis than prediabetes defined by FPG or 2hPG. However, the excess risk among individuals with prediabetes is mainly explained by the clustering of other cardiometabolic risk factors associated with hyperglycemia