Long-term Cardiometabolic Outcomes Research Articles

Metformin co-commencement at time of antipsychotic initiation for attenuation of weight gain: a systematic review and meta-analysis.

Antipsychotic medications are associated with weight gain and metabolic derangement. However, comprehensive evidence for the efficacy of co-commenced pharmacological treatments to mitigate initial weight gain is limited. Metformin has been shown to be effective in reducing weight among people on antipsychotic medications who are already overweight, but the potential benefits of metformin co-commencement in mitigating antipsychotic-induced weight gain has not been systematically reviewed. We conducted a systematic review of PubMed, EMBASE, PsychInfo, CINAHL, the Cochrane database, and China National Knowledge Infrastructure from inception to 18 November 2023. We undertook a meta-analysis of concomitant commencement of metformin versus placebo for attenuation of weight gain and metabolic syndrome for people with schizophrenia commencing a new antipsychotic. Fourteen studies from Australia, United States, Venezuela, and China with 1126 participants were included. We found that metformin was superior to placebo in terms of attenuating weight gain (-3.12 kg, 95% CI -4.22 to -2.01 kg). Metformin also significantly attenuated derangement of fasting glucose levels, total cholesterol, and total triglyceride levels. Sensitivity analysis on study quality, duration, and antipsychotic agent did not impact the results. Meta-analysis was also conducted on adverse drug reactions (ADR) reported in each study which showed no significant difference in ADR incidence between metformin and placebo groups. Subgroup analysis on antipsychotic-naïve participants and participants switching to new antipsychotic did not impact the results. Metformin led to statistically significant and clinically meaningful attenuation of weight gain as well as attenuation of several other metabolic parameters when commenced concomitantly with antipsychotic medications. Co-commencement of metformin with antipsychotic medications, where tolerated, should be considered in the clinical setting with aim to improve long-term cardiometabolic outcomes for patients with long-term need of antipsychotic treatments.

Incidence of cardiometabolic outcomes among people living with HIV-1 initiated on integrase strand transfer inhibitor versus non-integrase strand transfer inhibitor antiretroviral therapies: a retrospective analysis of insurance claims in the United States.

Integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART) has been associated with weight gain, though there is limited information on associations between ART-related weight gain and cardiometabolic outcomes among people living with HIV-1 (PLWH). We, therefore, evaluated risks of incident cardiometabolic outcomes following INSTI versus non-INSTI-based ART initiation in the United States. We conducted a retrospective study using IBM MarketScan Research Databases (12 August 2012-31 January 2021). Treatment-naïve PLWH initiating ART (index date) on/after 12 August 2013 (approval date of the first second-generation INSTI, dolutegravir) were included and censored at regimen switch/discontinuation, end of insurance eligibility or end of data availability. We used inverse probability of treatment weights constructed with baseline (12 months pre-index) characteristics to account for differences between INSTI- and non-INSTI-initiating cohorts. Doubly robust hazard ratios (HRs) obtained from weighted multivariable Cox regression were used to compare time to incident cardiometabolic outcomes (congestive heart failure [CHF], coronary artery disease, myocardial infarction, stroke/transient ischemic attack, hypertension, type II diabetes, lipid disorders, lipodystrophy and metabolic syndrome) by INSTI-initiation status. Weighted INSTI (mean age = 39 years, 23% female, 70% commercially insured, 30% Medicaid insured) and non-INSTI (mean age = 39 years, 24% female, 71% commercially insured, 29% Medicaid insured) cohorts included 7059 and 7017 PLWH, respectively. The most common INSTI-containing regimens were elvitegravir-based (43.4%), dolutegravir-based (33.3%) and bictegravir-based (18.4%); the most common non-INSTI-containing regimens were darunavir-based (31.5%), rilpivirine-based (30.4%) and efavirenz-based (28.3%). Mean±standard deviation follow-up periods were 1.5±1.5 and 1.1±1.2 years in INSTI- and non-INSTI-initiating cohorts, respectively. INSTI initiators were at a clinically and significantly increased risk of experiencing incident CHF (HR = 2.12, 95% confidence interval [CI] = 1.08-4.05; p = 0.036), myocardial infarction (HR = 1.79, 95% CI = 1.03-5.65; p = 0.036) and lipid disorders (HR = 1.26, 95% CI = 1.04-1.58; p = 0.020); there was no evidence of an increased risk for other individual or composite outcomes. Over a short average follow-up period of <2 years, INSTI use among treatment-naïve PLWH was associated with an increased risk of several cardiometabolic outcomes, such as CHF, myocardial infarction and lipid disorders, compared to non-INSTI use. Further research accounting for additional potential confounders and with longer follow-up is warranted to more accurately and precisely quantify the impact of INSTI-containing ART on long-term cardiometabolic outcomes.

Study protocol for a Developmental Epidemiological Study of Children born through Reproductive Technologies (DESCRT).

The primary objective of this study is to determine what parental factors or specific ART may influence the risk for adverse cardiometabolic outcomes among children so conceived and their parents. The secondary objective of this study is to prospectively examine the effects of infertility or ART on the intrauterine environment, obstetric and neonatal outcomes. Pregnancies conceived with ART are at an increased risk of being affected by adverse obstetric and neonatal outcomes when compared to spontaneously conceived (SC) pregnancies among fertile women. Small cohort studies have suggested ART-conceived children may have a higher risk of long-term cardiometabolic disturbances as well. Currently, few studies have compared long-term cardiometabolic outcomes among ART-conceived children and non-IVF treated (NIFT) children, to children conceived spontaneously to parents with infertility (subfertile parents). The Developmental Epidemiological Study of Children born through Reproductive Technologies (DESCRT) is a prospective cohort study that aims to: establish a biobank and epidemiological cohort of children born to subfertile or infertile parents who either conceived spontaneously (without assistance) or used reproductive technologies to conceive (all offspring were from couples assessed and/or treated in the same institute); prospectively examine the effects of infertility or ART on the intrauterine environment, obstetric and neonatal outcomes; and determine what parental factors or ART may influence the cardiometabolic risk of children so conceived. Pregnancies and resultant children will be compared by mode of conception, namely offspring that were conceived without medical assistance or SC or following NIFT, IVF with fresh embryo transfer or frozen embryo transfer (FET), and by fertilization method (conventional versus ICSI). DESCRT has a Child group evaluating long-term outcomes of children as well as a Pregnancy group that will compare obstetric and neonatal outcomes of children conceived since the commencement of the study. Recruitment started in May of 2017 and is ongoing. When the study began, we estimated that ∼4000 children would be eligible for enrollment. Eligible participants are first-trimester pregnancies (Pregnancy group) or children (Child group) born to parents who were evaluated at an infertility center in the University of California, San Francisco, CA, USA who were SC or conceived after reproductive treatments (NIFT, IVF ± ICSI, FET). Children in the Child group were conceived at UCSF and born from 2001 onwards. In the Pregnancy group, enrollment began in November of 2017.The primary outcome is the cardiometabolic health of offspring in the Child group, as measured by blood pressure and laboratory data (homeostatic model assessment for insulin resistance (HOMA-IR), oral glucose disposition). There are several secondary outcome measures, including: outcomes from parental survey response (assessing parent/child medical history since delivery-incidence of cardiometabolic adverse events), anthropomorphic measurements (BMI, waist circumference, skinfold thickness), and laboratory data (liver enzymes, lipid panel, metabolomic profiles). In the Pregnancy group, outcomes include laboratory assessments (bhCG, maternal serum analytes, soluble fms-like tyrosine kinase-1 (sFLT-1), and placental growth factor (PlGF)) and placental assessments (placental volume in the second and third trimester and placental weight at delivery). Importantly, aliquots of blood and urine are stored from parents and offspring as part of a biobank. The DESCRT cohort is unique in two ways. First, there is an extensive amount of clinical and laboratory treatment data: parental medical history and physical examination at the time of treatment, along with ovarian reserve and infertility diagnosis; and treatment specifics: for example, fertilization method, culture O2 status, embryo quality linked to each participant. These reproductive data will aid in identifying explanatory variables that may influence the primary cardiometabolic outcomes of the offspring-and their parents. Second, the DESCRT control group includes pregnancies and children SC from parents with subfertility, which may help to assess when infertility, as opposed to reproductive treatments, may be affecting offspring cardiometabolic health. This study is funded by the National Institutes of Health NICHD (1R01HD084380-01A1). A.J.A. is a shareholder in Carrot and consultant for Flo Health. The other authors have no conflicts of interest. NCT03799107. 10 January 2019. 10 May 2017.

Mapping the Evidence on Human Milk Fortification and Cardiovascular Risk Factors and Outcomes among Low Birth Weight Infants: A Scoping Review

Introduction: Preterm and low birth weight infants receiving a diet of human milk require fortification with protein, carbohydrates, vitamins, and minerals due to missed growth and nutrient accretion that would otherwise occur in utero. Although rapid catch-up growth improves anthropometric and neurodevelopmental indices, research has suggested that accelerated postnatal growth may be associated with poor long-term cardiometabolic outcomes. Methods: We conducted a scoping review to map the evidence on human milk fortification and cardiometabolic risk factors and outcomes among low birth weight infants. We searched Ovid Medline, Ovid Embase, CINAHL, and Web of Science from inception to June 2021 and examined grey literature for relevant referenced articles. Studies were included if they were a primary study focused on fortified human milk and cardiometabolic risk factors or outcomes among low birth weight infants. A modified version of the Cochrane Collaboration Randomized Controlled Trial data collection form guided data collection. We conducted a narrative synthesis of the results structured around the Population, Concept, Context framework. Results: We included 19 articles (14 randomized controlled trials, three quasi-randomized trials and two cohort studies) on cardiometabolic risk factors among 1,955 low birth weight infants who received fortified human milk. None of the included studies addressed long-term cardiometabolic outcomes. Body weight was the most examined risk factor in all included studies, with 13 studies observing benefit from human milk fortification. Two studies linked rapid growth with cardiometabolic risk factors. Discussion: The focus across the 19 included studies was the anthropometric advantages of fortified HM among LBW infants. A meta-analysis was not performed for this review, but if completed may yield a different inference. Conclusion: Limited evidence is available regarding the long-term cardiometabolic outcomes among low birth weight infants who received fortified human milk. Existing literature is focused on the short-term anthropometric benefits of fortification post-hospital discharge. Yet, some reports have linked rapid early postnatal growth with the development of cardiometabolic risk factors later in life. Future studies should explore the long-term cardiometabolic outcomes among low birth weight infants with the goal of optimizing anthropometric and brain growth while minimizing long-term cardiometabolic risk.

Association between self-reported physical activity and indicators of cardiovascular risk in community-dwelling older adults with hypertension in Korea: A cohort study.

The prevalence of hypertension has increased with the rise in the elderly population, and high blood pressure is a major cause of cardiovascular disease. Physical activity is an important strategy for preventing cardiovascular disease. The study aimed to explore the association between physical activity and cardiovascular risk indicators in community-dwelling older adults with hypertension.This study is a secondary data analysis of a prospective longitudinal study using data from the Elderly Cohort Database of the National Health Insurance Service in South Korea between 2002 and 2013. Participants included 10,588 older adults (≥60 years) with hypertension. Data assessing self-reported physical activity and directly measured blood pressure, fasting blood glucose, body mass index, and total cholesterol levels throughout the 12-year study were extracted from the original database and analyzed. Participants were categorized into 4 groups based on the reported changes in physical activity over time: Group I (Maintaining No Physical Activity Group), II (Changing from No Physical Activity to Physical Activity Group), III (Changing from Physical Activity to No Physical Activity Group), and IV (Maintaining Physical Activity Group). Cox proportional hazard model was used to confirm the risk of cardiovascular indicators over time in each group.Participants’ mean age was 64.2 years in the initial year of 2002. The number of participants in Groups I, II, III, and IV was 4032, 2697, 1919, and 1940, respectively. Group IV showed a significant decline in risk for uncontrolled hypertension compared to Group I (hazard ratio = 0.87, 95% confidence interval [0.800–0.948]). Group II showed a significant decrease in risk for uncontrolled diabetes compared to Group I (hazard ratio = 0.94, 95% confidence interval [0.888–0.999]).The findings indicated that physical activity is a significant factor associated with indicators of cardiovascular risk in older people with high blood pressure. Healthcare providers should be aware of the importance of older adults’ physical activity and encourage them to perform and maintain it steadily for better long-term cardio-metabolic outcomes.

Impact of maternal prenatal stress by glucocorticoids on metabolic and cardiovascular outcomes in their offspring: A systematic scoping review.

Background“Stress” is an emerging problem in our society, health care system as well as patient care, worldwide. Especially by focusing on pre-gestational, gestational but also lactation phases “stress” is to be considered as an own trans-generational risk factor which is associated with adverse metabolic as well cardiovascular outcomes in mothers and their children. Hence, the maternal hypothalamic-pituitary-adrenotrophic (HPA) axis may be stimulated by various “stress” mechanisms as well as risk factors leading to an adverse in utero environment, e.g. by excess exposure of glucocorticoids, contributing to cardio-metabolic disorders in mothers and their offspring.ObjectiveTo review the evidence of in utero programming by focusing on the impact of maternal “stress”, on adverse cardio-metabolic outcomes on their offspring later in life, by identifying underlying (patho-) physiological mechanisms (1) as well as adverse short and long-term cardio-metabolic outcomes (2).MethodsWe conducted a systematic scoping review to identify publications systematically including reviews, interventional, observational, experimental studies as well as human and animal model studies. MEDLINE (PubMed) and EMBASE databases and reference lists were searched. Peer-reviewed articles from January 2000 until August 2020 were included.ResultsOverall, n = 2.634 citations were identified, n = 45 eligible studies were included and synthesized according to their key findings. In brief, maternal hypothalamic-pituitary-adrenotrophic (HPA) axis might play a key role modifying in utero milieu leading to cardio-metabolic diseases in the offspring later in life. However, maternal risk factor “stress”, is clearly linked to adverse cardio-metabolic offspring outcomes, postnatally, such as obesity, hyperglycemia, insulin resistance, diabetes mellitus (DM), Metabolic Syndrome (MetS), cardiovascular disease (CD), hypertension, restricted fetal growth as well as reduced birth, adrenal, and pancreas weights.ConclusionsWomen who experienced “stress” as risk factor, as well as their offspring, clearly have a higher risk of adverse short- as well as long-term cardio-metabolic outcomes. Future research work is needed to understand complex transgenerational mechanisms.

Vitamin D status in infancy and cardiometabolic health in adolescence

Vitamin D deficiency is associated with obesity-related conditions, but the role of early life vitamin D status on the development of obesity is poorly understood. We assessed whether serum 25-hydroxyvitamin D [25(OH)D] at age 1 y was related to metabolic health through adolescence. We quantified serum 25(OH)D in samples obtained at age 1 y from 306 participants in a cohort study in Santiago, Chile. Anthropometry was performed at ages 5, 10, and 16/17 y. At 16/17 y, we determined body composition using DXA and quantified metabolic parameters in a blood sample. We examined the associations of infancy 25(OH)D with BMI-for-age z-score (BMIZ) at ages 5, 10, and 16/17 y; with percentage fat and percentage lean body mass at age 16/17 y; and with a metabolic syndrome (MetS) score and its components at age 16/17 y. Infancy 25(OH)D was inversely associated with BMIZ in childhood. Every 25-nmol/L difference in 25(OH)D was related to an adjusted 0.11 units lower BMIZ at age 5 y (95% CI: -0.20, -0.03; P=0.01) and a 0.09 unit lower BMIZ change from ages 1 to 5 y (95% CI: -0.17, -0.01; P=0.02). Also, every 25-nmol/L 25(OH)D in infancy was associated with an adjusted 1.3 points lower percentage body fat mass (95% CI: -2.2, -0.4; P=0.005) and an adjusted 0.03 units lower MetS score (95% CI: -0.05, -0.01; P=0.01) at age 16/17 y, through inverse associations with waist circumference and the HOMA-IR. Serum 25(OH)D at age 1 y is inversely associated with childhood BMIZ, percentage body fat at age 16/17 y, and a MetS score at age 16/17 y. Intervention studies are warranted to examine the effects of vitamin D supplementation in early life on long-term cardiometabolic outcomes.

Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis

Background Metformin is increasingly offered as an acceptable and economic alternative to insulin for treatment of gestational diabetes mellitus (GDM) in many countries. However, the impact of maternal metformin treatment on the trajectory of fetal, infant, and childhood growth is unknown. Methods and findings PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov, and the Cochrane database were systematically searched (from database inception to 26 February 2019). Outcomes of GDM-affected pregnancies randomised to treatment with metformin versus insulin were included (randomised controlled trials and prospective randomised controlled studies) from cohorts including European, American, Asian, Australian, and African women. Studies including pregnant women with pre-existing diabetes or non-diabetic women were excluded, as were trials comparing metformin treatment with oral glucose-lowering agents other than insulin. Two reviewers independently assessed articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Outcome measures were parameters of fetal, infant, and childhood growth, including weight, height, BMI, and body composition. In total, 28 studies (n = 3,976 participants) met eligibility criteria and were included in the meta-analysis. No studies reported fetal growth parameters; 19 studies (n = 3,723 neonates) reported measures of neonatal growth. Neonates born to metformin-treated mothers had lower birth weights (mean difference −107.7 g, 95% CI −182.3 to −32.7, I2 = 83%, p = 0.005) and lower ponderal indices (mean difference −0.13 kg/m3, 95% CI −0.26 to 0.00, I2 = 0%, p = 0.04) than neonates of insulin-treated mothers. The odds of macrosomia (odds ratio [OR] 0.59, 95% CI 0.46 to 0.77, p < 0.001) and large for gestational age (OR 0.78, 95% CI 0.62 to 0.99, p = 0.04) were lower following maternal treatment with metformin compared to insulin. There was no difference in neonatal height or incidence of small for gestational age between groups. Two studies (n = 411 infants) reported measures of infant growth (18–24 months of age). In contrast to the neonatal phase, metformin-exposed infants were significantly heavier than those in the insulin-exposed group (mean difference 440 g, 95% CI 50 to 830, I2 = 4%, p = 0.03). Three studies (n = 520 children) reported mid-childhood growth parameters (5–9 years). In mid-childhood, BMI was significantly higher (mean difference 0.78 kg/m2, 95% CI 0.23 to 1.33, I2 = 7%, p = 0.005) following metformin exposure than following insulin exposure, although the difference in absolute weights between the groups was not significantly different (p = 0.09). Limited evidence (1 study with data treated as 2 cohorts) suggested that adiposity indices (abdominal [p = 0.02] and visceral [p = 0.03] fat volumes) may be higher in children born to metformin-treated compared to insulin-treated mothers. Study limitations include heterogeneity in metformin dosing, heterogeneity in diagnostic criteria for GDM, and the scarcity of reporting of childhood outcomes. Conclusions Following intrauterine exposure to metformin for treatment of maternal GDM, neonates are significantly smaller than neonates whose mothers were treated with insulin during pregnancy. Despite lower average birth weight, metformin-exposed children appear to experience accelerated postnatal growth, resulting in heavier infants and higher BMI by mid-childhood compared to children whose mothers were treated with insulin. Such patterns of low birth weight and postnatal catch-up growth have been reported to be associated with adverse long-term cardio-metabolic outcomes. This suggests a need for further studies examining longitudinal perinatal and childhood outcomes following intrauterine metformin exposure. This review protocol was registered with PROSPERO under registration number CRD42018117503.

Abstract P054: The Benefits Of Physical Activity On Cardiovascular Indicators In Community-dwelling Hypertensive Older Adults: A Nationwide Health Examination Cohort Data In Korea

Purpose: The aim of this study was to explore the effects of physical activity on cardiovascular indicators in community-dwelling hypertensive older adults. Methods: This study was a longitudinal study using the Elderly Cohort Database of National Health Insurance Service in Korea between 2002 and 2013. Participants were 10,588 older adults with hypertension. The author extracted variables of physical activity, blood pressure, blood glucose, body mass index, and total cholesterol levels for 11 years from the database. Participants were divided into 4 groups according to the changes in physical activity performance over time in 2013; Group I (totally inactive), II (inactive to active), III (active to inactive), and IV (totally active). Cox proportional hazard model was used to confirm the risk of cardiovascular indicators over time in each group. Results: Participants’ mean age was 64.2 years in the initial year of 2002. The number of participants in Groups I, II, III, and IV was 4032, 2697, 1919, and 1940, respectively. As a result, Group IV had a significantly decreased risk for uncontrolled hypertension by 13% compared to Group I (HR = 0.87, 95% CI = 0.800-0.948). Also, Group II showed a significantly decreased risk for uncontrolled diabetes by 6% compared to Group I (HR = 0.94, 95% CI = 0.888-0.999). Conclusion: Physical activity is one of the most important non-pharmacological and self-management intervention that can be easily applied to older adults with hypertension. It is considered that the continuous performance of physical activity can significantly lower the long-term cardiometabolic risks in older adults. Healthcare providers should be aware of the importance of the physical activity of older adults and encourage them to perform and maintain it steadily for better long-term cardiometabolic outcomes.

Long-term cardio-metabolic outcomes in patients with classical congenital adrenal hyperplasia: is the risk real?

Data on the long-term cardio-metabolic outcomes classical congenital adrenal hyperplasia (CAH) patients have been published with controversial results. Conventional treatment recommends hydrocortisone during childhood; and short and/or long-acting glucocorticoid during adulthood, associated or not with mineralocorticoid, in an attempt to simulate normal cortisol secretion and to normalize androgen excess. However, the balance between glucocorticoid over or undertreatment is very challenging, and patients frequently oscillate between hypercortisolism or hyperandrogenism. Considering these data, we reviewed the frequency of metabolic syndrome components and other cardiovascular risk factors in CAH. Several studies reported increased prevalence obesity, abnormal body composition, increased homeostasis model assessment of insulin resistance and blood pressure levels in CAH patients. However, the evidence quality is still low, because most studies used different glucocorticoid regimes and had heterogeneous goals for hormonal control. Despite the above-mentioned scenario of increased frequency of some cardiovascular surrogate markers in patients, most cohorts comprised young adults, and it is not known if patients will present high frequency of cardiovascular disease in the future. Prospective randomized studies comparing different glucocorticoid regimens should establish the real role of glucocorticoid and androgens on metabolic/cardiovascular profile.

Effect of sildenafil citrate treatment in the eNOS knockout mouse model of fetal growth restriction on long-term cardiometabolic outcomes in male offspring.

Fetal growth restriction (FGR) is associated with an increased risk of hypertension, insulin resistance, obesity and cardiovascular disease in adulthood. Currently there are no effective treatments to reverse the course of FGR. This study used the eNOS knockout mouse (eNOS-/-), a model of FGR, to determine the ability of sildenafil, a potential new treatment for FGR, to improve cardiovascular and metabolic outcomes in adult offspring following a complicated pregnancy. Pregnant eNOS-/- and C57BL/6J control dams were randomised to sildenafil treatment (0.2 mg/ml in drinking water) or placebo at day 12.5 of gestation until birth. After weaning, male offspring were randomised to either a high fat (HFD; 45% kcal from fat) or normal chow diet (ND), and raised to either postnatal day 90 or 150. Growth and body composition, glucose tolerance, insulin resistance, systolic blood pressure and vascular function were analysed at both time-points. eNOS-/- offspring were significantly smaller than their C57BL/6J controls at weaning and P90 (p < 0.01); at P150 they were a similar weight. Total adipose tissue deposition at P90 was significantly increased only in eNOS-/- mice fed a HFD (p < 0.001). At P150 both C57BL/6J and eNOS-/- offspring fed a HFD demonstrated significant adipose tissue deposition (p < 0.01), regardless of maternal treatment. Both diet and maternal sildenafil treatment had a significant effect on glucose tolerance. Glucose tolerance was significantly impaired in eNOS-/- mice fed a HFD (p < 0.01); this was significant in offspring from both sildenafil and vehicle treated mothers at P90 and P150. Glucose tolerance was also impaired in C57BL/6J mice fed a HFD at both P90 and P150 (p < 0.01), but only in those also exposed to sildenafil. In these C57BL/6J mice, sildenafil was associated with impaired insulin sensitivity at P90 (p = 0.020) but increased insulin resistance at P150 (p = 0.019). Exposure to sildenafil was associated with a significant increase in systolic blood pressure in eNOS-/- mice compared with their C57BL/6J diet controls at P150 (p < 0.05). Exposure to sildenafil had differing effects on vascular function in mesenteric arteries; it increased vasodilation in response to ACh in C57BL/6J mice, but was associated with a more constrictive phenotype in eNOS-/- mice. eNOS-/- mice demonstrate a number of impaired outcomes consistent with programmed cardiometabolic disease, particularly when faced with the 'second hit' of a HFD. Exposure to sildenafil treatment during pregnancy did not increase fetal growth or significantly improve adult metabolic or cardiac outcomes. Maternal sildenafil treatment was, however, associated with small impairments in glucose handling and an increase in blood pressure. This study highlights the importance of understanding the long-term effects of treatment during pregnancy in offspring from both complicated and healthy control pregnancies.

Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk

BackgroundLoss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. ObjectivesThe goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. MethodsWhole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. ResultsAmong 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)—Asn51Ser, Ala411Thr, and His615Gln—had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: −8.0; 95% confidence interval [CI]: −12.7 to −3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = −16.3; 95% CI: −36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = −3.2; 95% CI: −6.4 to −0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). ConclusionsFunctionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.

The Pune Rural Intervention in Young Adolescents (PRIYA) study: design and methods of a randomised controlled trial

BackgroundThe Pune Maternal Nutrition Study (PMNS) was established to prospectively study the relationship of maternal nutrition to fetal growth and later cardiometabolic risk in the offspring. High homocysteine and low vitamin B12 levels in pregnancy predicted lower birthweight and higher insulin resistance at 6 years in the offspring. B12 deficiency was widespread in this population, due to low dietary intake. We therefore commenced a community-based intervention study with the underlying hypothesis that vitamin B12 supplementation of adolescent members of the PMNS cohort will improve birth weight, B12 status, and reduce future diabetes risk, in their offspring.MethodsThe individually randomised controlled trial commenced in September 2012, with boys and girls randomized into 3 groups, to receive daily for at least 3 years or until the birth of their first child: 1) vitamin B12 2 μg; or 2) vitamin B12 2 μg plus multiple micronutrients (MMN) plus 20 g of milk powder or 3) placebo. Iron and folic acid is given to all participants. Compliance is assessed by monthly supplement counts. Adverse events are recorded using a standardised questionnaire. The primary outcome is cord blood B12 concentration; based on 180–200 pregnancies in the girls, the study has ~80% power to detect a 0.5 SD change in newborn B12, in the B12 supplementation groups compared with controls, at the 5% significance level. Primary analysis will be by intention to treat.DiscussionOur study tests a primordial prevention strategy through an intergenerational intervention started pre-conceptionally in both boys and girls using physiological doses of micronutrients to improve immediate pregnancy-related and long-term cardio metabolic outcomes. The results will have significant public health implications in a setting with widespread B12 deficiency but relative folate sufficiency. The randomised controlled trial design allows us to be confident that our findings will be causally relevant.Trial registrationISRCTN 32921044, applied on 14/09/2012. CTRI 2012/12/003212, registered on 02/12/2012. Retrospectively registered.

Pregnancy Interventions or Behaviors and Cardiometabolic Biomarkers: a Systematic Review

While normal pregnancy is characterized by changes in serum glucose and lipid levels, overweight and obese women exhibit marked alterations in the trajectory of these changes. Reviews have been published assessing the efficacy of behavioral interventions for weight management during pregnancy. No reviews, however, have examined the metabolic impact of such lifestyle changes/behaviors. We conducted this systematic review summarizing evidence to July 2015 from both trials and observational studies examining the impact of lifestyle interventions or healthy behaviors (diet and/or exercise) among pregnant women on cardiometabolic biomarkers measured during pregnancy. We found that studies are conflicting and have small sample sizes. A better understanding of the underlying mechanisms that may mediate the effects of nutrition and physical activity on gestational weight gain, pregnancy complications, and long-term cardiometabolic outcomes is needed with particular focus on high-risk groups of overweight and obese women.