Aaron S. Kelly

Severe Obesity in Children and Adolescents: Identification, Associated Health Risks, and Treatment Approaches A Scientific Statement From the American Heart Association

Severe obesity afflicts between 4% and 6% of all youth in the United States, and the prevalence is increasing. Despite the serious immediate and long-term cardiovascular, metabolic, and other health consequences of severe pediatric obesity, current treatments are limited in effectiveness and lack widespread availability. Lifestyle modification/behavior-based treatment interventions in youth with severe obesity have demonstrated modest improvement in body mass index status, but participants have generally remained severely obese and often regained weight after the conclusion of the treatment programs. The role of medical management is minimal, because only 1 medication is currently approved for the treatment of obesity in adolescents. Bariatric surgery has generally been effective in reducing body mass index and improving cardiovascular and metabolic risk factors; however, reports of long-term outcomes are few, many youth with severe obesity do not qualify for surgery, and access is limited by lack of insurance coverage. To begin to address these challenges, the purposes of this scientific statement are to (1) provide justification for and recommend a standardized definition of severe obesity in children and adolescents; (2) raise awareness of this serious and growing problem by summarizing the current literature in this area in terms of the epidemiology and trends, associated health risks (immediate and long-term), and challenges and shortcomings of currently available treatment options; and (3) highlight areas in need of future research. Innovative behavior-based treatment, minimally invasive procedures, and medications currently under development all need to be evaluated for their efficacy and safety in this group of patients with high medical and psychosocial risks.

The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity: a randomized, placebo-controlled, clinical trial.

IMPORTANCE Medical treatment options for pediatric obesity remain limited. Glucagon-like peptide-1 (GLP-1) receptor agonists induce weight loss by suppressing appetite and increasing satiety, but few studies have evaluated this therapy as a treatment for obesity. OBJECTIVE To evaluate the effects of exenatide on body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and cardiometabolic risk factors in adolescents with severe obesity. DESIGN Three-month, randomized, double-blind, placebo-controlled, multicenter clinical trial followed by a 3-month open-label extension. SETTING An academic medical center and an outpatient pediatric endocrinology clinic. PATIENTS A total of 26 adolescents (12-19 years of age) with severe obesity (BMI ≥ 1.2 times the 95th percentile or BMI ≥ 35). INTERVENTION All patients received lifestyle modification counseling and were equally randomized to exenatide or placebo injection, twice per day. MAIN OUTCOME MEASURES The primary end point was the mean percent change in BMI measured at baseline and 3 months. Secondary end points included absolute change in BMI, body weight, body fat, blood pressure, hemoglobin A1c, fasting glucose, fasting insulin, and lipids at 3 months. RESULTS Twenty-two patients completed the trial. Exenatide elicited a greater reduction in percent change in BMI compared with placebo (-2.70% [95% CI, -5.02% to -0.37%]; P = .03). Similar findings were observed for absolute change in BMI (-1.13 [95% CI, -2.03 to -0.24]; P = .02) and body weight (-3.26 kg [95% CI, -5.87 to -0.66 kg]; P = .02). Although not reaching the level of statistical significance, reduction in systolic blood pressure was observed with exenatide. During the open-label extension, BMI was further reduced in those initially randomized to exenatide (cumulative BMI reduction of 4%). CONCLUSIONS AND RELEVANCE These results provide preliminary evidence supporting the feasibility, safety, and efficacy of GLP-1 receptor agonist therapy for the treatment of severe obesity in adolescents. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01237197.

Relationships of Cardiac Autonomic Function With Metabolic Abnormalities in Childhood Obesity

Objective: The objective was to examine cardiovascular autonomic (cANS) function and its potential relationships with leptin resistance, insulin resistance, oxidative stress, and inflammation in a pediatric sample with varying levels of obesity.

Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study.

The objective of this pilot study was to evaluate the effects of exenatide on BMI (primary endpoint) and cardiometabolic risk factors in nondiabetic youth with extreme obesity. Twelve children and adolescents (age 9–16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m2) were enrolled in a 6‐month, randomized, open‐label, crossover, clinical trial consisting of two, 3‐month phases: (i) a control phase of lifestyle modification and (ii) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase‐order (i.e., starting with control or drug therapy) then crossed‐over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance tests (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3‐, and 6‐months. The mean change over each 3‐month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (−1.7 kg/m2, 95% confidence interval (CI) (−3.0, −0.4), P = 0.01), body weight (−3.9 kg, 95% CI (−7.11, −0.69), P = 0.02), and fasting insulin (−7.5 mU/l, 95% CI (−13.71, −1.37), P = 0.02). Significant improvements were observed for OGTT‐derived insulin sensitivity (P = 0.02) and β‐cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well‐tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well‐controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.

Cardiovascular Disease Risk Factors in Youth With Diabetes Mellitus A Scientific Statement From the American Heart Association

The rates of both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are increasing in youth.1 In the past 10 years, guidelines for the identification and management of cardiovascular disease (CVD) risk factors in youth with diabetes mellitus have been published by multiple professional organizations, including the American Diabetes Association (ADA),2,3 the American Heart Association (AHA),4,5 the American Academy of Pediatrics,6 the International Society of Pediatric and Adolescent Diabetes (ISPAD),7 and the Pediatric Cardiovascular Risk Reduction Initiative.8 This scientific statement summarizes and interprets these guidelines and new developments in the field in the past decade and outlines future research and clinical needs to improve cardiovascular health and risk factor management in youth with diabetes mellitus. Additional goals for this statement are to increase awareness of CVD risk factors and their identification, prevention, and treatment and to improve cardiovascular health in youth with diabetes mellitus by encouraging advancement in research and clinical care, including understanding and implementing current CVD guidelines. Improving cardiovascular health in youth with diabetes mellitus has important public health implications; therefore, this statement aims to reach healthcare providers in diabetes mellitus, cardiology, and related fields. (Note: The sections within this scientific statement are organized by diabetes mellitus type, when possible, with brief summary statements concluding each section. Multiple definitions for CVD are used in the cited articles. Readers of this statement should include risk factors, surrogate markers, and end-organ damage under this umbrella term of CVD.) ### Type 1 Diabetes Mellitus Multiple studies document an increase of 2% to 5% annually in the incidence of T1DM worldwide.9 The SEARCH for Diabetes in Youth (SEARCH) study estimated that there were 166 018 to 179 388 youth with T1DM in the United States in 2010.1 Worldwide, rates of T1DM differ …

Effects of Exenatide vs. Metformin on endothelial function in obese patients with pre-diabetes: a randomized trial

BackgroundGlucagon like peptide-1 (GLP-1) receptor agonist treatment may improve endothelial function via direct and indirect mechanisms. We compared the acute and chronic effects of the GLP-1 receptor agonist exenatide vs. metformin on endothelial function in patients with obesity and pre-diabetes.MethodsWe performed a randomized, open-label, clinical trial in 50 non-diabetic individuals (mean age 58.5 ± 10.0; 38 females) with abdominal obesity and either impaired fasting glucose, elevated HbA1c, or impaired glucose tolerance (IGT) who were randomized to receive 3-months of exenatide or metformin. Microvascular endothelial function, assessed by digital reactive hyperemia (reactive hyperemic index: RHI), C-reactive protein (CRP), circulating oxidized LDL (oxLDL), and vascular cell adhesion molecule-1 (VCAM-1) were measured at baseline and 3-months. Seven subjects with IGT participated in a sub-study comparing the effects of pre-administration of exenatide and metformin on postprandial endothelial function.ResultsThere were no differences for the change in RHI (Δ exenatide: 0.01 ± 0.68 vs. Δ metformin: -0.17 ± 0.72, P = 0.348), CRP, oxLDL, or VCAM-1 between exenatide and metformin treatment. Triglycerides were reduced more with exenatide compared to metformin (Δ exenatide: -25.5 ± 45.7 mg/dL vs. Δ metformin: -2.9 ± 22.8 mg/dL, P = 0.032). In the sub-study, there was no difference in postprandial RHI between exenatide and metformin.ConclusionsThree months of exenatide therapy had similar effects on microvascular endothelial function, markers of inflammation, oxidative stress, and vascular activation, as metformin, in patients with obesity and pre-diabetes.Clinical trials registrationThis study is registered on http://www.clinicaltrials.gov/:NCT00546728

Rosiglitazone improves endothelial function and inflammation but not asymmetric dimethylarginine or oxidative stress in patients with type 2 diabetes mellitus

We compared the vascular effects of rosiglitazone versus glyburide and evaluated asymmetric dimethylarginine (ADMA) and oxidative stress as potential mechanisms associated with changes in vascular health in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to 6 months of either rosiglitazone (n = 20) or glyburide (n = 16) in addition to metformin. The following variables were measured pre- and post-treatment: glucose, insulin, homeostasis model assessment (HOMA), hemoglobin A1c (HbA1c), C-peptide, blood pressure, lipids, C-reactive protein (CRP), ADMA, 8-isoprostane, oxidized LDL cholesterol, brachial artery flow-mediated dilation (FMD), endothelium-independent dilation (EID), and brachial and carotid artery stiffness. Rosiglitazone and glyburide treatment resulted in significant and equivalent decreases in glucose (p < 0.0001) and HbA1c (p < 0.0001), with a trend toward decreased HOMA (p = 0.09). Rosiglitazone significantly decreased C-peptide (p < 0.01) with a strong trend toward decreased fasting insulin (p = 0.05). Rosiglitazone reduced CRP compared with glyburide (p = 0.001), but no differences were observed between groups for ADMA or the markers of oxidative stress. Rosiglitazone significantly improved FMD (p < 0.05) with trends toward improvements in carotid artery distension (p = 0.099) and distensibility (p = 0.078). In conclusion, compared with glyburide, rosiglitazone improves endothelial function and CRP in patients with T2DM. These improvements are not associated with reductions in ADMA or markers of oxidative stress.

Circulating oxidized LDL and inflammation in extreme pediatric obesity.

Oxidative stress and inflammation have not been well‐characterized in extreme pediatric obesity. We compared levels of circulating oxidized low‐density lipoprotein (oxLDL), C‐reactive protein (CRP), and interleukin‐6 (IL‐6) in extremely obese (EO) children to normal weight (NW) and overweight/obese (OW/OB) children. OxLDL, CRP, IL‐6, BMI, blood pressure, and fasting glucose, insulin, and lipids were obtained in 225 children and adolescents (age 13.5 ± 2.5 years; boys 55%). Participants were classified into three groups based on gender‐ and age‐specific BMI percentile: NW (<85th, n = 127), OW/OB (85th– <1.2 times the 95th percentile, n = 64) and EO (≥1.2 times the 95th percentile or BMI ≥35 kg/m2, n = 34). Measures were compared across groups using analysis of covariance, adjusted for gender, age, and race. Blood pressure, insulin, and lipids worsened across BMI groups (all P < 0.0001). OxLDL (NW: 40.8 ± 9.0 U/l, OW/OB: 45.7 ± 12.1 U/l, EO: 63.5 ± 13.8 U/l) and CRP (NW: 0.5 ± 1.0 mg/l, OW/OB: 1.4 ± 2.9 mg/l, EO: 5.6 ± 4.9 mg/l) increased significantly across BMI groups (all groups differed with P < 0.01). IL‐6 was significantly higher in EO (2.0 ± 0.9 pg/ml) compared to OW/OB (1.3 ± 1.2 pg/ml, P < 0.001) and NW (1.1 ± 1.0 pg/ml, P < 0.0001) but was not different between NW and OW/OB. Extreme pediatric obesity, compared to milder forms of adiposity and NW, is associated with higher levels of oxidative stress and inflammation, suggesting that markers of early cardiovascular disease and type 2 diabetes mellitus are already present in this young population.

Cardiovascular risk and insulin resistance in childhood cancer survivors

OBJECTIVE Increased cardiovascular (CV) risk has been reported in adults who are childhood cancer survivors (CCS). We sought to determine the emergence of CV risk factors in CCS while still children. STUDY DESIGN CCS in remission ≥5 years from cancer diagnosis (n=319, age=14.5 years) and their siblings (control subjects, n=208, age=13.6 years) participated in this cross-sectional study of CV risk, which included physiologic assessment of insulin sensitivity/resistance (hyperinsulinemic euglycemic clamp). Adjusted comparisons between CCS major diagnoses (leukemia [n=110], central nervous system tumors [n=82], solid tumors [n=127]) and control subjects were performed with linear regression for CV risk factors and insulin sensitivity. RESULTS Despite no significant differences in weight and body mass index, CCS had greater adiposity (waist [73.1 versus 71.1 cm, P=.02]; percent fat [28.1 versus 25.9%, P=.007]), lower lean body mass (38.4 versus 39.9 kg, P=.01) than control subjects. After adjustment for adiposity, CCS had higher total cholesterol level (154.7 versus 148.3 mg/dL, P=.004), low-density lipoprotein cholesterol level (89.4 versus 83.7 mg/dL, P=.002), and triglyceride level (91.8 versus 84 mg/dL, P=.03) and were less insulin sensitive (insulin stimulated glucose uptake, measure of insulin resistance, adjusted for lean body mass 12.1 versus 13.4 mg/kg/min, P=.002) than control subjects. CONCLUSIONS CCS have greater CV risk than healthy children. Because CV risk factors track from childhood to adulthood, early development of altered body composition and decreased insulin sensitivity in CCS may contribute significantly to their risk of early CV morbidity and mortality.

Relation of circulating oxidized LDL to obesity and insulin resistance in children

Kelly AS, Jacobs DR Jr, Sinaiko AR, Moran A, Steffen LM, Steinberger J. Relation of circulating oxidized LDL to obesity and insulin resistance in children.