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
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.
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.
Objective To compare markers of cardiovascular health in youth diagnosed with attention deficit hyperactivity disorder (ADHD) by the use of stimulant medication with healthy controls. Study design ...Children and adolescents (n = 85; mean age 11.2 ± 2.8 years; 66 boys) diagnosed with ADHD using a stimulant and 53 siblings without ADHD (mean age 11.1 ± 3.8 years; 28 boys) were included in this cross-sectional study. Measured variables included blood pressure, heart rate (HR), HR variability: SD of the RR interval and low frequency to high frequency ratio, carotid-radial pulse wave velocity, carotid artery augmentation index (AIx), radial artery AIx, brachial artery flow-mediated dilation, and digital reactive hyperemic index. Results Compared with control patients, participants with ADHD had greater resting systolic blood pressure (3.9 mm Hg, 95% CI 1.2-6.7, P = .005), diastolic blood pressure (5.5 mm Hg, 95% CI 3.2-7.8, P < .001), HR (9.2 beats/min, 95% CI 6.0-12.3, P < .001), low frequency to high frequency ratio (0.55, 95% CI 0.22-0.89, P = .001), carotid AIx (7.2%, 95% CI 1.9-12.5, P = .008), and pulse wave velocity (0.36 m/s, 95% CI −0.05, 0.78, P = .089), and lower SD of the RR interval (−33.7 milliseconds, 95% CI −46.1, −21.3, P < .001). Neither flow-mediated dilation nor reactive hyperemic index was significantly different. Conclusions Children and adolescents being treated with a stimulant medication for ADHD exhibited signs of altered cardiac autonomic function, characterized by increased sympathetic tone, and showed evidence of arterial stiffening.
Most studies in adults suggest that acute glucose consumption induces a transient impairment in endothelial function. We hypothesized that obese youth would demonstrate reduced endothelial function ...and increased inflammation and oxidative stress following acute glucose ingestion and that transient elevations in plasma glucose would correlate with endothelial dysfunction, inflammation, and oxidative stress. Thirty‐four obese (BMI ≥95th percentile) children and adolescents (age 12.4 ± 2.6 years; BMI = 37.9 ± 6.7 kg/m2; 50% females) underwent measurement of endothelial function (reactive hyperemic index (RHI)), glucose, insulin, C‐reactive protein (CRP), interleukin‐6 (IL‐6), circulating oxidized low‐density lipoprotein (oxLDL), and myeloperoxidase (MPO) in a fasting state and at 1‐ and 2‐h following glucose ingestion. Repeated measures ANOVA with Tukey post‐tests and Pearson correlations were performed. Glucose and insulin levels significantly increased at 1‐ and 2‐h (all P values < 0.001). Compared to baseline, there were no statistically significant differences in 1‐ and 2‐h RHI, CRP, IL‐6, and oxLDL. However, MPO significantly decreased at the 1‐ (P < 0.05) and 2‐h (P < 0.001) time points. At the 1‐h time point, glucose level was significantly inversely correlated with RHI (r = −0.40, P < 0.05) and at the 2‐h time point, glucose level was positively correlated with MPO (r = 0.40, P < 0.05). An acute oral glucose load does not reduce endothelial function or increase levels of inflammation or oxidative stress in obese youth. However, associations of postprandial hyperglycemia with endothelial function and oxidative stress may have implications for individuals with impaired glucose tolerance or frank type 2 diabetes.
Background
Although coronary artery pathology is a prominent feature of mucopolysaccharidosis (MPS), it may be underestimated by coronary angiography because of its diffuse nature. It is also ...generally assumed that cardiovascular risk is increased in MPS and reduced following hematopoietic stem cell transplantation (HSCT) or enzyme replacement therapy (ERT), but this has never been formally evaluated. Non-invasive methods of assessing vascular endothelial function may provide a measure of cardiovascular risk in MPS. We evaluated endothelial function, using digital reactive hyperemia, in youth with MPS and in healthy controls.
Methods
Digital reactive hyperemic index (RHI) was measured in 12 children and adolescents (age 10.3 ± 3.9 years old; 11 boys) with treated MPS and nine age- and gender-matched (11.4 ± 4.0; 8 boys) healthy controls. An independent t-test was used to compare RHI between individuals with MPS and controls.
Results
Children and adolescents with MPS (MPS type II: N = 5; type I: N = 4; type VI: N = 3) whether treated by HSCT (N = 4) or ERT (N = 8) had significantly lower RHI compared to controls (MPS 1.22 ± 0.19 vs. controls 1.46 ± 0.32, p < 0.05).
Conclusion
These preliminary findings suggest that children and adolescents with treated MPS have significantly poorer endothelial function when compared to healthy controls. Further investigation into the utility of endothelial function for risk stratification and the long term implications of reduced endothelial function in MPS is warranted.
Pathological mechanisms of how childhood obesity leads to increased risk of cardiovascular disease (CVD) are not fully characterized. Oxidative-stress-related enzymes, such as xanthine oxidase (XO), ...have been linked to obesity, endothelial dysfunction, and CVD in adults, but little is known about this pathway in children. The aim of this study was to determine whether differential XO activity is associated with endothelial dysfunction, CVD risk factors, or cytokine levels.
Fasting plasma samples were obtained from obese (BMI ≥ 95th percentile; n = 20) and age- and gender-matched healthy weight (BMI > 5th and < 85th percentile; n = 22) children and adolescents (mean age, 12 ± 3 years) to quantify XO activity. In addition, fasting cholesterol, insulin, glucose, blood pressure, endothelial function, and cytokine levels were assessed.
We observed a 3.8-fold increase in plasma XO activity in obese, compared to healthy weight, children (118 ± 21 vs. 31 ± 9 nU/mg of protein; p < 0.001). Plasma XO activity was correlated with BMI z-score (r = 0.41), waist circumference (r = 0.41), high-density lipoprotein cholesterol (r = -0.32), oxidized low-density lipoprotein (r = 0.57), adiponectin (r = -0.53), and monocyte chemotactic protein-1 (r = -0.59).
XO activity is highly elevated in obese children and correlates with CVD risk factors, suggesting that XO may play a role in increasing cardiovascular risk early in life in the context of obesity.
Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but coronary artery disease (CAD) and cardiovascular complications cause mortality in a high percentage of patients. Non-invasive ...measures of sub-clinical atherosclerosis, such as carotid intima–media thickness (cIMT) and arterial stiffness, may be useful for prediction of CAD outcomes in MPS patients.
The aim of the study was to determine if cIMT and arterial stiffness are abnormal in MPS I and II patients compared to healthy controls.
MPS patients underwent carotid artery ultrasonography, and electronic wall-tracking software was used to measure cIMT, carotid artery cross-sectional compliance (cCSC), cross-sectional distensibility (cCSD), and incremental elastic modulus (cIEM). Control data from healthy subjects were obtained from a different study that utilized identical testing within the same laboratory.
A total of 406 healthy controls and 25 MPS patients (16 MPS I, 9 MPS II) were studied. All MPS patients had or were receiving treatment: 15 patients (6 MPS I, 9 MPS II) were receiving enzyme replacement therapy (ERT), 9 patients (all MPS I) had received hematopoietic stem cell transplant (HSCT), and 1 patient with MPS I had received HSCT and was receiving enzyme replacement therapy (ERT). MPS patients had significantly higher mean (±SD) cIMT (0.56±0.05mm) compared to controls (0.44±0.04mm; adjusted p<0.001). MPS patients also had increased stiffness compared to controls, showing significantly lower cCSC (0.14±0.09mm2/mmHg versus 0.16±0.05mm2/mmHg; adjusted p=0.019), and higher cIEM (1362±877mmHg versus 942±396mmHg; adjusted p<0.001). cCSD in MPS patients was lower than that of controls (29.7±16.4% versus 32.0±8.2%) but was not statistically significant; p=0.12. Among MPS patients, cCSD showed a significant association with cIMT (p=0.047), while the association between cIEM and cIMT approached significance (p=0.077). No significant differences were observed in cIMT, cCSD, cCSC, and cIEM between MPS I and MPS II patients.
Despite treatment, MPS patients had higher cIMT compared to healthy controls, indicating this marker of sub-clinical atherosclerosis may be a useful predictor of CAD outcomes. The association of arterial stiffness measures with cIMT suggests that mechanical and structural changes may occur in concert among MPS patients. Although yet to be confirmed, increased cIMT and arterial stiffness in MPS I and II patients may be a consequence of inflammatory signaling pathways triggered by heparan or dermatan sulfate-derived oligosaccharides. Prospective, longitudinal studies will need to be performed in order to evaluate the usefulness of these carotid measurements as predictors of adverse CAD outcomes in MPS patients.
•Carotid artery structure and function were studied in 25 MPS I and II patients.•MPS patients had significantly higher carotid intima–media thickness versus controls.•MPS patients demonstrated increased carotid stiffness versus controls.•MPS carotid intima–media thickness was positively associated with carotid stiffness.•No differences seen in carotid intima–media thickness or stiffness between MPSs I and II
Objective We characterized the state of the vascular endothelium in pediatric obesity by comparing circulating endothelial cell (CEC) number and activation phenotype in severely obese children to ...that of normal weight, overweight, and obese children. Study design We used immunohistochemical examination of buffy-coat smears to enumerate CEC and immunofluorescence microscopy to quantify activated CEC in 107 children and adolescents. Normal weight (body mass index BMI <85th percentile; n = 40), overweight (BMI 85th-<95th percentile; n = 17), and obese (BMI 95th-<99th percentile; n = 23) participants were recruited from a longitudinal study. Severely obese (BMI ≥99th percentile; n = 27) participants were recruited from a pediatric obesity clinic. Group means (adiposity; systolic blood pressure SBP quartiles) were compared with general linear models, adjusted for sex, age, and race. With Pearson correlations, we characterized relations of CEC with cardiovascular risk factors. Results Activated CEC increased across BMI groups ( P < .002) and SBP quartiles ( P < .05). CEC number and activated CEC were highest in the severely obese group. CEC number was significantly associated with SBP, diastolic blood pressure, and triglycerides level. Activated CEC were significantly associated with SBP and high-density lipoprotein cholesterol levels. Conclusions The vascular endothelium was activated in relation to excess adiposity, particularly in severely obese children, and to elevated SBP in children and adolescents.
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