Rachel R. Huxley

Meta-analysis of Cohort and Case-Control Studies of Type-2 Diabetes Mellitus and Risk of Atrial Fibrillation

Atrial fibrillation (AF) is 1 of the most clinically diagnosed cardiac disturbances but little is known about its risk factors. Previous epidemiologic studies have reported on the association between diabetes mellitus (DM) and subsequent risk of AF, with inconsistent results. The aim of this study was to conduct a meta-analysis of published studies to reliably determine the direction and magnitude of any association between DM and AF. A systematic review and meta-analysis was conducted. PubMed and EMBASE were searched to identify prospective cohort and case-control studies that had reported on the association between DM and other measurements of glucose homeostasis with incident AF by April 2010. Studies conducted in primarily high-risk populations and participants in randomized controlled trials were excluded. Seven prospective cohort studies and 4 case-control studies with information on 108,703 cases of AF in 1,686,097 subjects contributed to this analysis. The summary estimate indicated that patients with DM had an approximate 40% greater risk of AF compared to unaffected patients (relative risk [RR] 1.39, 95% confidence interval [CI] 1.10 to 1.75, p for heterogeneity <0.001). After correcting for publication bias, the RR was 1.34 (1.07 to 1.68). Studies that had adjusted for multiple risk factors reported a smaller effect estimate compared to age-adjusted studies (RR 1.24, 95% CI 1.06 to 1.44, vs 1.70, 1.29 to 2.22, p for heterogeneity = 0.053). The population-attributable fraction of AF owing to DM was 2.5% (95% CI 0.1 to 3.9). In conclusion, DM is associated with an increased risk of subsequent AF but the mechanisms that may underpin the relation between DM and AF remain speculative.

Type 2 diabetes, glucose homeostasis and incident atrial fibrillation: the Atherosclerosis Risk in Communities study

Background Type 2 diabetes has been inconsistently associated with the risk of atrial fibrillation (AF) in previous studies that have frequently been beset by methodological challenges. Design Prospective cohort study. Setting The Atherosclerosis Risk in Communities (ARIC) study. Participants Detailed medical histories were obtained from 13 025 participants. Individuals were categorised as having no diabetes, pre-diabetes or diabetes based on the 2010 American Diabetes Association criteria at study baseline (1990–2). Main outcome measures Diagnoses of incident AF were obtained to the end of 2007. Associations between type 2 diabetes and markers of glucose homeostasis and the incidence of AF were estimated using Cox proportional hazards models after adjusting for possible confounders. Results Type 2 diabetes was associated with a significant increase in the risk of AF (HR 1.35, 95% CI 1.14 to 1.60) after adjustment for confounders. There was no indication that individuals with pre-diabetes or those with undiagnosed diabetes were at increased risk of AF compared with those without diabetes. A positive linear association was observed between HbA1c and the risk of AF in those with and without diabetes (HR 1.13, 95% CI 1.07 to 1.20) and HR 1.05, 95% CI 0.96 to 1.15 per 1% point increase, respectively). There was no association between fasting glucose or insulin in those without diabetes, but a significant association with fasting glucose was found in those with the condition. The results were similar in white subjects and African-Americans. Conclusions Diabetes, HbA1c level and poor glycaemic control are independently associated with an increased risk of AF, but the underlying mechanisms governing the relationship are unknown and warrant further investigation.

The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature

Objective To conduct a systematic review in order to (i) summarize the relationship between birthweight and blood pressure, following numerous publications in the last 3 years, (ii) assess whether other measures of size at birth are related to blood pressure, and (iii) study the role of postnatal catch-up growth in predicting blood pressure. Data identification All papers published between March 1996 and March 2000 that examined the relationship between birth weight and systolic blood pressure were identified and combined with the papers examined in a previous review. Subjects More than 444 000 male and female subjects aged 0–84 years of all ages and races. Results Eighty studies described the relationship of blood pressure with birth weight. The majority of the studies in children, adolescents and adults reported that blood pressure fell with increasing birth weight, the size of the effect being approximately 2 mmHg/kg. Head circumference was the only other birth measurement to be most consistently associated with blood pressure, the magnitude of the association being a decrease in blood pressure by approximately 0.5 mmHg/cm. Skeletal and non-skeletal postnatal catch-up growth were positively associated with blood pressure, with the highest blood pressures occurring in individuals of low birth weight but high rates of growth subsequently. Conclusions Both birth weight and head circumference at birth are inversely related to systolic blood pressure. The relationship is present in adolescence but attenuated compared to both the pre- and post-adolescence periods. Accelerated postnatal growth is also associated with raised blood pressure.

Birth weight and risk of type 2 diabetes: A systematic review

CONTEXT Low birth weight is implicated as a risk factor for type 2 diabetes. However, the strength, consistency, independence, and shape of the association have not been systematically examined. OBJECTIVE To conduct a quantitative systematic review examining published evidence on the association of birth weight and type 2 diabetes in adults. DATA SOURCES AND STUDY SELECTION Relevant studies published by June 2008 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1950), and Web of Science (from 1980), with a combination of text words and Medical Subject Headings. Studies with either quantitative or qualitative estimates of the association between birth weight and type 2 diabetes were included. DATA EXTRACTION Estimates of association (odds ratio [OR] per kilogram of increase in birth weight) were obtained from authors or from published reports in models that allowed the effects of adjustment (for body mass index and socioeconomic status) and the effects of exclusion (for macrosomia and maternal diabetes) to be examined. Estimates were pooled using random-effects models, allowing for the possibility that true associations differed between populations. DATA SYNTHESIS Of 327 reports identified, 31 were found to be relevant. Data were obtained from 30 of these reports (31 populations; 6090 diabetes cases; 152 084 individuals). Inverse birth weight-type 2 diabetes associations were observed in 23 populations (9 of which were statistically significant) and positive associations were found in 8 (2 of which were statistically significant). Appreciable heterogeneity between populations (I(2) = 66%; 95% confidence interval [CI], 51%-77%) was largely explained by positive associations in 2 native North American populations with high prevalences of maternal diabetes and in 1 other population of young adults. In the remaining 28 populations, the pooled OR of type 2 diabetes, adjusted for age and sex, was 0.75 (95% CI, 0.70-0.81) per kilogram. The shape of the birth weight-type 2 diabetes association was strongly graded, particularly at birth weights of 3 kg or less. Adjustment for current body mass index slightly strengthened the association (OR, 0.76 [95% CI, 0.70-0.82] before adjustment and 0.70 [95% CI, 0.65-0.76] after adjustment). Adjustment for socioeconomic status did not materially affect the association (OR, 0.77 [95% CI, 0.70-0.84] before adjustment and 0.78 [95% CI, 0.72-0.84] after adjustment). There was no strong evidence of publication or small study bias. CONCLUSION In most populations studied, birth weight was inversely related to type 2 diabetes risk.

Body-mass index and all-cause mortality: Individual-participant-data meta-analysis of 239 prospective studies in four continents.

Summary Background Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. Methods Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4–14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5–<25·0 kg/m2. Findings All-cause mortality was minimal at 20·0–25·0 kg/m2 (HR 1·00, 95% CI 0·98–1·02 for BMI 20·0–<22·5 kg/m2; 1·00, 0·99–1·01 for BMI 22·5–<25·0 kg/m2), and increased significantly both just below this range (1·13, 1·09–1·17 for BMI 18·5–<20·0 kg/m2; 1·51, 1·43–1·59 for BMI 15·0–<18·5) and throughout the overweight range (1·07, 1·07–1·08 for BMI 25·0–<27·5 kg/m2; 1·20, 1·18–1·22 for BMI 27·5–<30·0 kg/m2). The HR for obesity grade 1 (BMI 30·0–<35·0 kg/m2) was 1·45, 95% CI 1·41–1·48; the HR for obesity grade 2 (35·0–<40·0 kg/m2) was 1·94, 1·87–2·01; and the HR for obesity grade 3 (40·0–<60·0 kg/m2) was 2·76, 2·60–2·92. For BMI over 25·0 kg/m2, mortality increased approximately log-linearly with BMI; the HR per 5 kg/m2 units higher BMI was 1·39 (1·34–1·43) in Europe, 1·29 (1·26–1·32) in North America, 1·39 (1·34–1·44) in east Asia, and 1·31 (1·27–1·35) in Australia and New Zealand. This HR per 5 kg/m2 units higher BMI (for BMI over 25 kg/m2) was greater in younger than older people (1·52, 95% CI 1·47–1·56, for BMI measured at 35–49 years vs 1·21, 1·17–1·25, for BMI measured at 70–89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46–1·56, vs 1·30, 1·26–1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. Interpretation The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. Funding UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.

Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775 385 individuals and 12 539 strokes

BACKGROUND Diabetes mellitus is a major cause of death and disability worldwide and is a strong risk factor for stroke. Whether and to what extent the excess risk of stroke conferred by diabetes differs between the sexes is unknown. We did a systematic review and meta-analysis to estimate the relative effect of diabetes on stroke risk in women compared with men. METHODS We systematically searched PubMed for reports of prospective, population-based cohort studies published between Jan 1, 1966, and Dec 16, 2013. Studies were selected if they reported sex-specific estimates of the relative risk (RR) for stroke associated with diabetes, and its associated variability. We pooled the sex-specific RRs and their ratio comparing women with men using random-effects meta-analysis with inverse-variance weighting. FINDINGS Data from 64 cohort studies, representing 775,385 individuals and 12,539 fatal and non-fatal strokes, were included in the analysis. The pooled maximum-adjusted RR of stroke associated with diabetes was 2·28 (95% CI 1·93-2·69) in women and 1·83 (1·60-2·08) in men. Compared with men with diabetes, women with diabetes therefore had a greater risk of stroke--the pooled ratio of RRs was 1·27 (1·10-1·46; I(2)=0%), with no evidence of publication bias. This sex differential was seen consistently across major predefined stroke, participant, and study subtypes. INTERPRETATION The excess risk of stroke associated with diabetes is significantly higher in women than men, independent of sex differences in other major cardiovascular risk factors. These data add to the existing evidence that men and women experience diabetes-related diseases differently and suggest the need for further work to clarify the biological, behavioural, or social mechanisms involved. FUNDING None.

Absolute and Attributable Risks of Atrial Fibrillation in Relation to Optimal and Borderline Risk Factors The Atherosclerosis Risk in Communities (ARIC) Study

Background— Atrial fibrillation (AF) is an important risk factor for stroke and overall mortality, but information about the preventable burden of AF is lacking. The aim of this study was to determine what proportion of the burden of AF in blacks and whites could theoretically be avoided by the maintenance of an optimal risk profile. Methods and Results— This study included 14 598 middle-aged Atherosclerosis Risk in Communities (ARIC) Study cohort members. Previously established AF risk factors, namely high blood pressure, elevated body mass index, diabetes mellitus, cigarette smoking, and prior cardiac disease, were categorized into optimal, borderline, and elevated levels. On the basis of their risk factor levels, individuals were classified into 1 of these 3 groups. The population-attributable fraction of AF resulting from having a nonoptimal risk profile was estimated separately for black and white men and women. During a mean follow-up of 17.1 years, 1520 cases of incident AF were identified. The age-adjusted incidence rates were highest in white men and lowest in black women (7.45 and 3.67 per 1000 person-years, respectively). The overall prevalence of an optimal risk profile was 5.4% but varied according to race and gender: 10% in white women versus 1.6% in black men. Overall, 56.5% of AF cases could be explained by having ≥1 borderline or elevated risk factors, of which elevated blood pressure was the most important contributor. Conclusion— As with other forms of cardiovascular disease, more than half of the AF burden is potentially avoidable through the optimization of cardiovascular risk factors levels.

Ethnic comparisons of the cross‐sectional relationships between measures of body size with diabetes and hypertension

Recent estimates indicate that two billion people are overweight or obese and hence are at increased risk of cardiovascular disease and its comorbidities. However, this may be an underestimate of the true extent of the problem, as the current method used to define overweight may lack sensitivity, particularly in some ethnic groups where there may be an underestimate of risk. Measures of central obesity may be more strongly associated with cardiovascular risk, but there has been no systematic attempt to compare the strength and nature of the associations between different measures of overweight with cardiovascular risk across ethnic groups. Data from the Obesity in Asia Collaboration, comprising 21 cross‐sectional studies in the Asia‐Pacific region with information on more than 263 000 individuals, indicate that measures of central obesity, in particular, waist circumference (WC), are better discriminators of prevalent diabetes and hypertension in Asians and Caucasians, and are more strongly associated with prevalent diabetes (but not hypertension), compared with body mass index (BMI).

The burden of blood pressure-related disease: a neglected priority for global health

The importance of high blood pressure as a major cause of common serious diseases has been recognized in most Western countries for ≈50 years. Before that, malignant hypertension was a frequent reason for hospital admission and a common cause of death.1 Safe and effective antihypertensive drugs were first developed in the 1960s and were shown to dramatically improve the prognosis associated with malignant hypertension.2,3 Over the next few decades, the widespread use of an expanding armamentarium of blood pressure–lowering drugs to patients at risk of malignant hypertension effectively eradicated this condition from most developed countries. Subsequently, the provision of blood pressure–lowering treatments to a much broader group of patients at risk of serious cardiovascular diseases, such as stroke and coronary heart disease, among whom blood pressure levels were often only modestly elevated, contributed importantly to the declines in stroke and coronary disease deaths rates experienced by most Western populations.4 However, the situation in higher-income countries stands in stark contrast to that experienced by their lower-income neighbors. The overall burden of blood pressure–related diseases is rapidly rising in countries such as India and China as a consequence of the aging population, increasing urbanization, and increases in age-specific rates of conditions such as stroke.5,6 Even war-torn countries and those ravaged by HIV/AIDS, such as some in sub-Saharan Africa, incur a huge burden of blood pressure–related diseases. In several such populations, cerebral hemorrhage is the leading cause of death in adults.7 Although safe and effective antihypertensive treatment could be provided in these regions with a range of generic products from <1 cent per person per day, the reality is that most people for whom such drugs are clearly indicated receive no treatment whatsoever. In this regard, the antihypertensive care available for a large proportion of the world’s population …

Sociodemographic Correlates of the Increasing Trend in Prevalence of Gestational Diabetes Mellitus in a Large Population of Women Between 1995 and 2005

OBJECTIVE—Gestational diabetes mellitus (GDM) is an increasingly prevalent risk factor for the development of type 2 diabetes in the mother and is responsible for morbidity in the child. To better identify women at risk of developing GDM we examined sociodemographic correlates and changes in the prevalence of GDM among all births between 1995 and 2005 in Australias largest state. RESEARCH DESIGN AND METHODS—A computerized database of all births (n = 956,738) between 1995 and 2005 in New South Wales, Australia, was used in a multivariate logistic regression that examined the association between sociodemographic characteristics and the occurrence of GDM. RESULTS—Between 1995 and 2005, the prevalence of GDM increased by 45%, from 3.0 to 4.4%. Women born in South Asia had the highest adjusted odds ratio (OR) of any region (4.33 [95% CI 4.12–4.55]) relative to women born in Australia. Women living in the three lowest socioeconomic quartiles had higher adjusted ORs for GDM relative to women in the highest quartile (1.54 [1.50–1.59], 1.74 [1.69–1.8], and 1.65 [1.60–1.70] for decreasing socioeconomic status quartiles). Increasing age was strongly associated with GDM, with women aged >40 years having an adjusted OR of 6.13 (95% CI 5.79–6.49) relative to women in their early 20s. Parity was associated with a small reduced risk. There was no association between smoking and GDM. CONCLUSIONS—Maternal age, socioeconomic position, and ethnicity are important correlates of GDM. Future culturally specific interventions should target prevention of GDM in these high-risk groups.