Sex-specific associations of adiposity with cardiometabolic traits in the UK: A multi-life stage cohort study with repeat metabolomics.

BACKGROUND: Sex differences in cardiometabolic disease risk are commonly observed across the life course but are poorly understood and may be due to different associations of adiposity with cardiometabolic risk in females and males. We examined whether adiposity is differently associated with cardiometabolic trait levels in females and males at 3 different life stages. METHODS AND FINDINGS: Data were from 2 generations (offspring, Generation 1 [G1] born in 1991/1992 and their parents, Generation 0 [G0]) of a United Kingdom population-based birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). Follow-up continues on the cohort; data up to 25 y after recruitment to the study are included in this analysis. Body mass index (BMI) and total fat mass from dual-energy X-ray absorptiometry (DXA) were measured at mean age 9 y, 15 y, and 18 y in G1. Waist circumference was measured at 9 y and 15 y in G1. Concentrations of 148 cardiometabolic traits quantified using nuclear magnetic resonance spectroscopy were measured at 15 y, 18 y, and 25 y in G1. In G0, all 3 adiposity measures and the same 148 traits were available at 50 y. Using linear regression models, sex-specific associations of adiposity measures at each time point (9 y, 15 y, and 18 y) with cardiometabolic traits 3 to 6 y later were examined in G1. In G0, sex-specific associations of adiposity measures and cardiometabolic traits were examined cross-sectionally at 50 y. A total of 3,081 G1 and 4,887 G0 participants contributed to analyses. BMI was more strongly associated with key atherogenic traits in males compared with females at younger ages (15 y to 25 y), and associations were more similar between the sexes or stronger in females at 50 y, particularly for apolipoprotein B-containing lipoprotein particles and lipid concentrations. For example, a 1 standard deviation (SD) (3.8 kg/m2) higher BMI at 18 y was associated with 0.36 SD (95% confidence interval [CI] = 0.20, 0.52) higher concentrations of extremely large very-low-density lipoprotein (VLDL) particles at 25 y in males compared with 0.15 SD (95% CI = 0.09, 0.21) in females, P value for sex difference = 0.02. By contrast, at 50 y, a 1 SD (4.8 kg/m2) higher BMI was associated with 0.33 SD (95% CI = 0.25, 0.42) and 0.30 SD (95% CI = 0.26, 0.33) higher concentrations of extremely large VLDL particles in males and females, respectively, P value for sex difference = 0.42. Sex-specific associations of DXA-measured fat mass and waist circumference with cardiometabolic traits were similar to findings for BMI and cardiometabolic traits at each age. The main limitation of this work is its observational nature, and replication in independent cohorts using methods that can infer causality is required. CONCLUSIONS: The results of this study suggest that associations of adiposity with adverse cardiometabolic risk begin earlier in the life course among males compared with females and are stronger until midlife, particularly for key atherogenic lipids. Adolescent and young adult males may therefore be high priority targets for obesity prevention efforts.

Health care utilization and the associated costs attributable to cardiovascular disease in Ireland: a cross-sectional study.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality and disability globally. We examined healthcare service utilization and costs attributable to CVD in Ireland in the period before the introduction of a major healthcare reform in 2016. METHODS: Secondary analysis of data from 8 113 participants of the first wave of The Irish Longitudinal Study on Ageing. CVD was defined as having a self-reported doctor's diagnosis of myocardial infarction, angina, heart failure, stroke, atrial fibrillation or transient ischaemic attack. Participants self-reported the utilization of healthcare services in the year preceding the interview. Negative binomial regression with average marginal effects (AME) was used to estimate the incremental number of general practitioner (GP) and outpatient department (OPD) visits, accident and emergency department attendances and hospitalisations in population with CVD relative to population without CVD. We calculated the corresponding costs at individual and population levels, by gender and age groups. RESULTS: The prevalence of CVD was 18.2% (95% CI: 17.3, 19.0) Participants with CVD reported higher utilization of all healthcare services. In adjusted models, having CVD was associated with incremental 1.19 (95% CI: 0.99, 1.39) GP and 0.79 (95% CI: 0.65, 0.93) OPD visits. There were twice as many incremental hospitalisations in males with CVD compared to females with CVD (AME (95% CI): 0.20 (0.16, 0.23) vs 0.10 (0.07, 0.14)). The incremental cost of healthcare service use in population with CVD was an estimated €352.2 million (95% CI: €272.8, €431.7), 93% of which was due to use of secondary care services. CONCLUSION: We identified substantially increased use of healthcare services attributable to CVD in Ireland. Continued efforts aimed at CVD primary prevention and management are required.

Mitochondrial DNA haplogroups and trajectories of cardiometabolic risk factors during childhood and adolescence: A prospective cohort study.

BACKGROUND: Mitochondria are organelles responsible for converting glucose into energy. Mitochondrial DNA is exclusively maternally inherited. The role of mitochondrial DNA haplogroups in the aetiology of cardiometabolic disease risk is not well understood. METHODS: Sex-specific associations between common European mitochondrial DNA haplogroups (H, U, J, T, K, V, W, I and X) and trajectories of cardiometabolic risk factors from birth to 18 years were examined in a prospective cohort. Cardiometabolic risk factors measured from birth/mid-childhood to 18 years included body mass index (BMI), fat and lean mass, systolic and diastolic blood pressure, pulse rate, high-density lipoprotein cholesterol (HDL-c), non-HDL-c and triglycerides. Fractional polynomial and linear spline multilevel models explored the sex-specific association between haplogroups and risk factor trajectories. RESULTS: Among a total of 7,954 participants with 79,178 repeated measures per outcome, we found no evidence that haplogroups U, T, J, K and W were associated with cardiometabolic risk factors compared to haplogroup H. In females, haplogroup V was associated with 4.0% (99% CI: -7.5, -0.6) lower BMI at age one but associations did not persist at age 18. Haplogroup X was associated with 1.3kg (99% CI: -2.5, -0.2) lower lean mass at age 9 which persisted at 18. Haplogroup V and X were associated with 9.3% (99% CI: -0.4, 19.0) and 16.4% (99% CI: -0.5,33.3) lower fat mass at age 9, respectively, although confidence intervals spanned the null and associations did not persist at 18. In males, haplogroup I was associated with 2.4% (99% CI: -0.5, 5.3) higher BMI at age 7; widening to 5.1% (99% CI: -0.5, 10.6) at 18 with confidence intervals spanning the null. CONCLUSIONS: Our study demonstrated little evidence of sex-specific associations between mitochondrial DNA haplogroups and cardiometabolic risk factors.

Application of multilevel linear spline models for analysis of growth trajectories in a cohort with repeat antenatal and postnatal measures of growth: a prospective cohort study.

OBJECTIVES: To model trajectories of antenatal and postnatal growth using linear spline multilevel models. DESIGN: Prospective cohort study. SETTING: Maternity hospital in Dublin, Ireland. PARTICIPANTS: 720-759 mother-child pairs from the ROLO study (initially a randomised control trial of a low glycaemic index diet in pregnancy to prevent recurrence of macrosomia [birth weight >4 kg]). PRIMARY OUTCOMES: Trajectories of growth from 20 weeks gestation (abdominal circumference [AC], head circumference [HC] and weight) or birth (length/height) to 5 years. RESULTS: Over 50% of women had third-level education and 90% were of white ethnicity. Women were a mean (SD) age of 32 years (4.2) at recruitment. The best fitting model for AC, HC and weight included a model with 5 linear spline periods. The best fitting models for length/height included a model with 3 linear spline periods from birth to 6 months, 6 months to 2 years and 2 years to 5 years. Comparison of observed and predicted values for each model demonstrated good model fit. For all growth measures, growth rates were generally fastest in pregnancy or immediately post partum (for length/height), with rates of growth slowing after birth and becoming slower still as infancy and childhood progressed. CONCLUSION: We demonstrate the application of multilevel linear spline models for examining growth trajectories when both antenatal and postnatal measures of growth are available. The approach may be useful for cohort studies or randomised control trials with repeat prospective assessments of growth.

Associations between maternal metabolic parameters during pregnancy and fetal and child growth trajectories from 20 weeks' gestation to 5 years of age: Secondary analysis from the ROLO longitudinal birth cohort study.

OBJECTIVE: To examine the association between maternal metabolic parameters in pregnancy and growth trajectories up to 5 years of age. METHODS: Data from mother-child pairs who participated in the ROLO study, a randomized trial examining the impact of a low glycaemic index diet on the recurrence of macrosomia, were analysed. Fetal and child growth trajectories were developed from longitudinal measurements from 20 weeks gestation up to 5 years of age. We examined associations between maternal fasting glucose, insulin, HOMA-IR and leptin, taken in early pregnancy (14-16 weeks) and late pregnancy (28 weeks), and weight (kg) and abdominal circumference (cm) trajectories using linear spline multilevel models. RESULTS: We found no strong evidence of associations between any maternal metabolic parameters and fetal to childhood weight and abdominal circumference trajectories from 20 weeks gestation to 5 years. CONCLUSION: In a cohort of women with obesity with infants at risk of macrosomia, maternal metabolic markers were not strongly associated with trajectories of weight or abdominal circumference from 20 weeks gestation to 5 years of age.

Childhood socioeconomic position and sex-specific trajectories of metabolic traits across early life: prospective cohort study.

BACKGROUND: Socioeconomic inequalities in cardiovascular disease risk begin early in life and are more pronounced in females than males later in life. Causal atherogenic traits explaining this are not well understood. We explored sex-specific associations between childhood socioeconomic position (SEP) and molecular measures of systemic metabolism across early life. METHODS: Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort in southwest England. Pregnant women with an expected delivery date between 1991 and 1992 were invited to participate. Maternal education was the primary indicator of SEP. Concentrations of 148 metabolic traits from targeted metabolomics (nuclear magnetic resonance spectroscopy) from research clinics at ages 7, 15, 18 and 25 years were analysed. The sex-specific slope index of inequality (SII) in trajectories of metabolic traits was estimated using multilevel models. FINDINGS: Total number of participants included was 6537 (12,543 repeated measures). Lower maternal education was associated with more adverse levels of several atherogenic lipids and key metabolic traits among females at age 7 years, but not males. For instance, SII for very small very-low-density lipoprotein (VLDL) concentrations was 0.16SD (95% CI: 0.01, 0.30) among females and -0.02SD (95% CI: -0.16, 0.13) among males. Between 7 and 25 years, inequalities widened among females and emerged among males particularly for VLDL particle concentrations, apolipoprotein-B concentrations, and inflammatory glycoprotein acetyls. For instance, at 25 years, SII for very small VLDL concentrations was 0.36SD (95% CI: 0.20, 0.52) and 0.22SD (95% CI: 0.04, 0.40) among females and males respectively. INTERPRETATION: Prevention of socioeconomic inequalities in cardiovascular disease risk requires a life course approach beginning at the earliest opportunity, especially among females. FUNDING: The UK Medical Research Council and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). KON is supported by a Health Research Board (HRB) of Ireland Investigator Led Award (ILP-PHR-2022-008). JB, GDS and KT work in a unit funded by the UK MRC (MC_UU_00011/1 and MC UU 00011/3) and the University of Bristol. OR is supported by a UKRI Future Leaders Fellowship (MR/S03532X/1). These funding sources had no role in the design and conduct of this study. This publication is the work of the authors and KON will serve as guarantor for the contents of this paper.

Puberty Timing and Sex-Specific Trajectories of Systolic Blood Pressure: a Prospective Cohort Study.

BACKGROUND: Sex differences in systolic blood pressure (SBP) emerge during adolescence but the role of puberty is not well understood. We examined sex-specific changes in SBP preceding and following puberty and examined the impact of puberty timing on SBP trajectories in females and males. METHODS: Trajectories of SBP before and after puberty and by timing of puberty in females and males in a contemporary birth cohort study were analyzed. Repeated measures of height from age 5 to 20 years were used to identify puberty timing (age at peak height velocity). SBP was measured on ten occasions from 3 to 24 years (N participants, 4062; repeated SBP measures, 29 172). Analyses were performed using linear spline multilevel models based on time before and after puberty and were adjusted for parental factors and early childhood factors. RESULTS: Mean age at peak height velocity was 11.7 years (SD, 0.8) for females and 13.6 years (SD, 0.9) for males. Males had faster rates of increase in SBP before puberty leading to 10.19 mm Hg (95% CI, 6.80-13.57) higher mean SBP at puberty which remained similar at 24 years (mean difference, 11.43 mm Hg [95% CI, 7.22-15.63]). Puberty timing was associated with small transient differences in SBP trajectories postpuberty in both sexes and small differences at 24 years in females only. CONCLUSIONS: A large proportion of the higher SBP observed in males compared with females in early adulthood is accrued before puberty. Interventions targeting puberty timing are unlikely to influence SBP in early adulthood.

Impact of population distribution shifts in sugar-sweetened beverage consumption on type II diabetes incidence in Ireland.

PURPOSE: We simulate population shifts in the distribution of sugar-sweetened beverage (SSB) consumption and address previous methodological limitations to provide valid and reliable estimates of the potential impact of public health interventions on type II diabetes incidence in Ireland. METHODS: A comparative risk assessment was conducted, using distribution shift calculations to estimate potential impact fractions (PIFs) for percentage reductions in SSB consumption. Data from the Survey of Lifestyle, Attitudes and Nutrition was analyzed. Individual risk of developing type II diabetes was estimated using a risk prediction algorithm. PIFs were calculated using risk estimates, changes in SSB consumption, and an appropriately specified relative risk. The impact of a 20% levy on SSBs was explored. Monte-Carlo simulation with 150,000 iterations estimated uncertainty intervals (UIs). PIFs were applied to 2016 census data, estimating the absolute incident cases that may potentially be avoided through reduced SSB consumption. RESULTS: Of the 7272 Survey of Lifestyle, Attitudes and Nutrition participants, 53.3% consumed SSBs. The 10-year rate of type II diabetes was estimated at 4.3% (95% confidence interval: 4.2%, 4.4%). Simulating a 100% reduction in SSB consumption, the population attributable fraction was 1.8% (95%UI: 0.1%, 3.3%). Population shifts in consumption after a 20% levy results in a PIF of 0.37% (95%UI: 0.02%, 0.7%). We estimate 135,850 incident type II diabetes cases over a 10-year period. Of these, 2446 (95% UI: 136, 4483) cases may be attributable to SSB consumption. CONCLUSIONS: Overcoming previous methodological limitations, unbiased estimates demonstrate that a population shift in SSB consumption can potentially play a role in the primary prevention of type II diabetes.

Trends in national pharmaceutical expenditure on diabetes in Ireland 2011-2015: a repeated cross-sectional study.

OBJECTIVES: To explore trends in pharmaceutical expenditure on diabetes between 2011 and 2015, describing trends in expenditure on blood glucose-lowering medications and estimating the effect of cost-containment measures implemented during this time. DESIGN: Repeated cross-sectional study of national pharmacy claims data in Ireland. PARTICIPANTS: Patients' dispensed items used in the treatment or management of diabetes. PRIMARY AND SECONDARY OUTCOMES: Total expenditure associated with diabetes was calculated by extracting data on all diabetes-related items dispensed to eligible patients. Costs were categorised into two groups. Diabetes-specific items include items used directly in diabetes treatment (WHO-Anatomical Therapeutic Chemical (ATC): A10, V07, V04) and diabetes-related include all other condition-related items (WHO-ATC: B01, C, H04, N03, N06). The impacts of two specific cost-containment measures, co-payments and reference pricing, were assessed using segmented linear regression analyses of interrupted time-series. RESULTS: Total expenditure varied over the study period, peaking at €216 994 441 in 2012. Expenditure on diabetes-specific items increased steadily by 18% reaching €153 621 477 in 2015, with blood glucose-lowering medications accounting for 73% of this increase. During the same period, expenditure on diabetes-related items decreased by 32% to €50 835 856. The introduction of reference pricing for atorvastatin in November 2013 resulted in immediate costs savings of €2.4 million per yearly quarter (level-change p<0.001). CONCLUSIONS: The increasing expenditure on blood glucose-lowering medications negates the effect of recent cost-containment measures, presenting a significant challenge for the provision of diabetes care. Innovative policies are required to ensure high-quality diabetes care can be provided at an equitable, affordable and sustainable rate.

Unmet need for bariatric surgery.

INTRODUCTION: With the rising prevalence of severe obesity and type 2 diabetes (T2D), bariatric surgery offers a clinical and cost-effective treatment for carefully selected patients. Despite this, the provision of surgical services varies significantly between countries. OBJECTIVE: To inform health service planning by estimating the number of people who would potentially benefit from bariatric surgery. SETTING: Nationally representative sample of community-dwelling older adults. METHODS: We applied two separate evidence-based criteria sets for eligibility for bariatric surgery. For the first set of criteria, we considered those with body mass index≥40 kg/m2 or≥35 kg/m2 and one or more of the following: T2D, hypertension, previous myocardial infarction, or sleep apnea. For the second set of criteria, we considered patients with T2D and body mass index≥35 kg/m2, with one or more of the following: previous myocardial infarction, elevated urine albumin-creatinine ratio, retinopathy, neuropathy, or peripheral vascular disease. Prevalence estimates were applied to census figures for 2011, estimating absolute numbers meeting the criteria. RESULTS: Among adults aged≥50 years, 7.97% (95% confidence interval [CI]: 7.23, 8.78), representing 92,573 people (95% CI: 83,978, 101,981), met criteria one and 0.97% (95% CI: 0.73, 1.28), representing 11,231 people (95% CI: 8471, 14,890), met criteria two. With fewer than 1/100,000 population publicly funded surgeries taking place annually, current service provision meets much less than 0.1% of the need. CONCLUSIONS: While many adults who fulfill the eligibility criteria for bariatric surgery may not want or require it, the current level of need for bariatric surgical services is not being met. A strategy to develop and expand the provision of bariatric care is urgently needed.