Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial.

BACKGROUND: Hypothalamic obesity resulting from hypothalamic damage might affect melanocortin signalling. We investigated the melanocortin-4 receptor agonist setmelanotide for treatment of hypothalamic obesity. METHODS: This phase 2, open-label, multicentre trial was done in five centres in the USA. Eligible patients were aged between 6 and 40 years with obesity and history of hypothalamic injury or diagnosis of a non-malignant tumour affecting the hypothalamus that was treated with surgery, chemotherapy, or radiation. Setmelanotide was titrated up to a dose of 3·0 mg and administered subcutaneously once a day for a total duration of 16 weeks. The primary endpoint was the proportion of patients with a reduction in BMI of at least 5% from baseline after 16 weeks, compared with a historic control rate of less than 5% in this population. The primary endpoint was analysed using the full analysis set, which includes all patients with baseline data who received at least one dose of setmelanotide. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04725240) and is complete. FINDINGS: Between June 6, 2021, and Jan 13, 2022, 19 patients were screened for inclusion. One patient was excluded, and 18 were enrolled and received at least one dose of setmelanotide. Patients were primarily White (n=14 [78%]) and male (n=11 [61%]). Enrolled patients had a mean age of 15·0 years (SD 5·3) and a mean BMI of 38·0 kg/m2 (SD 6·5). Of 18 patients enrolled, 16 (89%) of 18 patients completed the study and met the primary endpoint of reduction in BMI of at least 5% from baseline after 16 weeks (p<0·0001). The mean reduction in BMI across all patients was 15% (SD 10). A composite proportion of patients had a clinically meaningful change (89%, 90% CI 69-98%; p<0·0001), comprising a reduction in BMI Z score of at least 0·2 points for patients younger than 18 years (92%, 68-100%; p<0·0001) and reduction in bodyweight of at least 5% for patients aged 18 years or older (80%, 34-99%; p<0·0001). Patients aged 12 years or older had a mean reduction in hunger score of 45%. Frequent adverse events included nausea (61%), vomiting (33%), skin hyperpigmentation (33%), and diarrhoea (22%). Of 14 patients who continued treatment in a long-term extension study (NCT03651765), 12 completed at least 12 months of treatment at the time of publication and had a mean change in BMI of -26% (SD 12) from index trial baseline. INTERPRETATION: These findings support setmelanotide as a novel effective treatment of hypothalamic obesity. FUNDING: Rhythm Pharmaceuticals.

Prediction of resting energy expenditure for adolescents with severe obesity: A multi-centre analysis.

BACKGROUND AND OBJECTIVES: Resting energy expenditure (REE) assessments can help inform clinical treatment decisions in adolescents with elevated body mass index (BMI), but current equations are suboptimal for severe obesity. We developed a predictive REE equation for youth with severe obesity and obesity-related comorbidities and compared results to previously published predictive equations. METHODS: Data from indirect calorimetry, clinical measures, and body composition per Dual x-ray absorptiometry (DXA) were collected from five sites. Data were randomly divided into development (N = 438) and validation (N = 118) cohorts. A predictive equation was developed using Elastic Net regression, using sex, race, ethnicity, weight, height, BMI percent of the 95th%ile (BMIp95), waist circumference, hip circumference, waist/hip ratio, age, Tanner stage, fat and fat-free mass. This equation was verified in the validation cohort and compared with 11 prior equations. RESULTS: Data from the total cohort (n = 556, age 15 ± 1.7 years, 77% female, BMIp95 3.3 ± 0.94) were utilized. The best fit equation was REE = -2048 + 18.17 × (Height in cm) - 2.57 × (Weight in kg) + 7.88 × (BMIp95) + 189 × (1 = male, 0 = female), R2 = 0.466, and mean bias of 23 kcal/day. CONCLUSION: This new equation provides an updated REE prediction that accounts for severe obesity and metabolic complications frequently observed in contemporary youth.

Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study.

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

Prevalence of genetic causes of obesity in clinical practice.

Background: While obesity is common in the United States, monogenic obesity is rare, accounting for approximately 5% of individuals with obesity. New targeted therapies for genetic forms of obesity are available but there is limited guidance on who requires testing. The aims of this study were to evaluate the prevalence of potentially clinically significant variants among individuals in Pediatric Endocrinology or Medical Weight Center clinics at a single center and to identify clinical characteristics that may make genetic obesity more likely. Methods: Children and adults who had a genetic test for obesity, Uncovering Rare Obesity Gene panel, ordered during routine clinic visits from December 2019 to March 2021 were identified. Results: Of the 139 patients with testing ordered, 117 had available results and clinical data. Over 40% (52/117, 44%) had at least one positive result (variant) with a variant that is considered pathogenic, likely pathogenic, or a variant of uncertain significance. No association was detected between age, sex, race, and body mass index (BMI) or BMI z-score with a variant. Twenty-six individuals (22%) had one or more variants in genes associated with Bardet Biedl Syndrome, and 8 (6.8%) of them had pathogenic variants, higher than expected. Conclusion: Overall, clinical suspicion for genetic obesity is important in determining who requires genetic testing but no clinical factors were found to predict results. While obesity is multifactorial, novel medications for genetic forms of obesity indicate the need for evidence-based guidelines for who requires genetic testing for obesity.

Risk Factors for Progression to Type 2 Diabetes in a Pediatric Prediabetes Clinic Population.

Background: Pediatric type 2 diabetes (T2D) is increasing in prevalence, yet it is unclear what definition of pediatric prediabetes predicts progression to T2D. Strategies are needed to better identify at risk individuals who could benefit from early intervention. Methods: Retrospective chart review of a pediatric prediabetes clinic over 7 years. Inclusion criteria include hemoglobin A1c (HbA1C) and ≥1 glucose from oral glucose tolerance test. Exclusion criteria include type 1 diabetes, maturity onset diabetes of the young, or T2D on initial visit. Results: A total of 552 patients were included, 6.5% (n = 36) progressed to T2D over 2.4 ± 1.5 years. At initial visit, T2D progressors had a higher body mass index (38.6 ± 6.5 vs 34.2 ± 8.4 kg/m2, P = .002), HbA1C (6.0 ± 0.3%, vs 5.7± 0.3, P < .001), 2-hour glucose (141 ± 28 vs 114 ± 29 mg/dL, P < .001), and C-peptide (4.8 vs 3.6 ng/mL, P = .001). Fasting glucose was not significantly different. In a multivariable model, male sex (hazard ratio [HR], 2.4; P = .012), initial visit HbA1C (HR, 1.3 per 0.1% increase; P < .001), and 2-hour glucose level (HR, 1.2 per 10 mg/dL increase; P = .014) were all predictive of T2D progression. Patients who progressed to T2D had an increase in body mass index of 4.2 kg/m2 and children consistently taking metformin took longer to progress (43 ± 21 vs 26 ± 16 months; P = .016). Discussion: A total of 6.5% of patients with prediabetes developed T2D over a 7-year period. Initial visit laboratory values and weight trajectory may allow for risk stratification, whereas fasting plasma glucose is less helpful. Weight stabilization and metformin therapy could be important interventions for diabetes prevention in children.

Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. OBJECTIVE: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. METHODS: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. RESULTS: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). CONCLUSION: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

Approach to the Patient With Hypothalamic Obesity.

Hypothalamic obesity (HO) is defined as abnormal weight gain due to physical destruction of the hypothalamus. Suprasellar tumors, most commonly craniopharyngiomas, are a classic cause of HO. HO often goes unnoticed initially as patients, families, and medical teams are focused on oncologic treatments and management of panhypopituitarism. HO is characterized by rapid weight gain in the first year after hypothalamic destruction followed by refractory obesity due to an energy imbalance of decreased energy expenditure without decreased food intake. Currently available pharmacotherapies are less effective in HO than in common obesity. While not a cure, dietary interventions, pharmacotherapy, and bariatric surgery can mitigate the effects of HO. Early recognition of HO is necessary to give an opportunity to intervene before substantial weight gain occurs. Our goal for this article is to review the pathophysiology of HO and to discuss available treatment options and future directions for prevention and treatment.

Prolonged lapses between pediatric and adult care are associated with rise in HbA1c and inpatient days among patients with type 1 diabetes.

AIM: To quantify the association between the duration of the pediatric-to-adult care transfer with glycemic control among patients with type 1 diabetes (T1D). METHODS: This retrospective cohort study included patients with T1D who completed transfer between pediatric and adult diabetes clinics at a single academic medical center between 2004 and 2020. The primary exposure was time from the last pediatric to first adult diabetes care encounter. The primary outcome was the average HbA1c in the first year after entry into adult care. RESULTS: A total of 449 patients (mean age at transfer 19.8yrs, 51.7 % male) were included for analysis. Transfer required a median of nearly 5 months (196 days; IQR:93-251) and in adjusted and unadjusted models was strongly associated with increased HbA1c within 1 year of transfer (0.19 %, 2 mmol/mol; 95 %CI:0.04 %-0.33 %) for each 6 months of latency. In secondary analyses, transfer latency also exhibited a significant association with days spent hospitalized (IRR 1.23 per 6 months; 95 %CI:1.08-1.33). CONCLUSIONS: Our findings isolate and quantify the impact of prolonged lapses in care associated with the pediatric-to-adult care transfer. These findings underscore the need for providers and healthcare systems to improve this care transition in order to improve outcomes for this vulnerable patient population.

The Coronavirus Disease 2019 Pandemic is Associated with a Substantial Rise in Frequency and Severity of Presentation of Youth-Onset Type 2 Diabetes.

OBJECTIVES: To evaluate the frequency and severity of new cases of youth-onset type 2 diabetes in the US during the first year of the pandemic compared with the mean of the previous 2 years. STUDY DESIGN: Multicenter (n = 24 centers), hospital-based, retrospective chart review. Youth aged ≤21 years with newly diagnosed type 2 diabetes between March 2018 and February 2021, body mass index ≥85th percentile, and negative pancreatic autoantibodies were included. Demographic and clinical data, including case numbers and frequency of metabolic decompensation, were compared between groups. RESULTS: A total of 3113 youth (mean [SD] 14.4 [2.4] years, 50.5% female, 40.4% Hispanic, 32.7% Black, 14.5% non-Hispanic White) were assessed. New cases of type 2 diabetes increased by 77.2% in the year during the pandemic (n = 1463) compared with the mean of the previous 2 years, 2019 (n = 886) and 2018 (n = 765). The likelihood of presenting with metabolic decompensation and severe diabetic ketoacidosis also increased significantly during the pandemic. CONCLUSIONS: The burden of newly diagnosed youth-onset type 2 diabetes increased significantly during the coronavirus disease 2019 pandemic, resulting in enormous strain on pediatric diabetes health care providers, patients, and families. Whether the increase was caused by coronavirus disease 2019 infection, or just associated with environmental changes and stressors during the pandemic is unclear. Further studies are needed to determine whether this rise is limited to the US and whether it will persist over time.

The Efficacy, Safety, and Pharmacology of a Ghrelin O-Acyltransferase Inhibitor for the Treatment of Prader-Willi Syndrome.

CONTEXT: Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG. OBJECTIVE: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients. METHODS: A double-blind, placebo-controlled, phase 2 crossover study was conducted with 2 active treatment periods of 28 days in 19 patients (aged 16-65 years; body mass index (BMI) ≥ 28) with genetically confirmed PWS. The study took place in 7 hospital-based study centers in the United States and Canada. Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods. The Hyperphagia Questionnaire for Clinical Trials and Caregiver Global Impression of Change were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates. RESULTS: Treatment resulted in statistically significant differences compared to placebo in plasma AG (P = .0002), UAG (P = .0488), and AG/UAG (P = .0003). GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not statistically significantly change in response to treatment. Less than half of patients reported a treatment-emergent adverse event (TEAE). No deaths, serious adverse events, or severe TEAEs were reported. CONCLUSION: GLWL-01 is safe and well tolerated. Pharmacological parameters confirmed the inhibition of GOAT following administration of GLWL-01. Patients' eating behaviors, BMI, blood glucose, and total cholesterol, among other similar measures, were not modified.

Energy balance in hypothalamic obesity in response to treatment with a once-weekly GLP-1 receptor agonist.

BACKGROUND/OBJECTIVES: Hypothalamic obesity (HO) frequently occurs following suprasellar tumors from a combination of decreased energy expenditure and increased energy intake. Glucagon-like peptide-1 receptor agonist (GLP1RA) therapy is associated with increased satiety and energy expenditure. We hypothesized GLP1RA therapy in patients with HO would cause both lower energy intake and increased energy expenditure. SUBJECTS/METHODS: Forty-two patients aged 10-26 years (median 16 years) with HO with suprasellar tumors were randomized to GLP1RA (exenatide extended release once-weekly, ExQW, n = 23) or placebo (n = 19). Thirty seven (81%) patients completed the 36-week double-blind placebo-controlled trial. Total energy expenditure (TEE) was measured with doubly labeled water, physical activity was assessed with actigraphy, and intake was estimated with ad libitum buffet meal. Results are presented as adjusted mean between-group difference. RESULTS: As compared with treatment with placebo, treatment with ExQW was associated with decreased energy intake during a buffet meal (-1800 kJ (-430 kcal), 95% CI -3 184 to -418 kJ, p = 0.02). There were no significant differences in physical activity between groups. ExQW (vs. placebo) treatment was associated with a decrease in TEE (-695 kJ/day (-166 kcal/day), 95% CI -1 130 to -264 kJ/day, p < 0.01, adjusted for baseline TEE). The treatment effect was still significant after further adjustment for change in body composition (-372 kJ/day (-89 kcal/day), 95% CI -699 to -42 kJ/day, p = 0.04) or change in leptin (-695 kJ/day (-166 kcal/day), 95% CI -1 130 to -264 kJ/day, p < 0.01). This decrease in TEE occurred despite an increase in lean mass and fat mass (1.7 vs. 1.3 kg lean mass, p = 0.88 and 1.5 vs. 4.6 kg fat mass, p = 0.04, ExQW vs. placebo). CONCLUSIONS: Treatment with a GLP1RA was associated with a decrease in food intake but also a decrease in TEE that was disproportionate to change in body composition.

Phentermine/Topiramate for the Treatment of Adolescent Obesity.

BACKGROUND: Antiobesity medication may be useful for the treatment of pediatric obesity, yet few safe and effective options exist. We evaluated phentermine/topiramate (PHEN/TPM) for weight management in adolescents with obesity. METHODS: This 56-week, randomized, double-blind trial enrolled adolescents 12 to less than 17 years of age with obesity. Participants were randomly assigned 1:1:2 to receive either placebo (n=56), mid-dose PHEN/TPM (7.5 mg/46 mg; n=54), or top-dose PHEN/TPM (15 mg/92 mg; n=113), respectively. All participants received lifestyle therapy. The primary end point was mean percent change in body-mass index (BMI) from randomization to week 56. RESULTS: Participants had a mean (±SD) age of 14.0±1.4 years and a mean (±SD) BMI of 37.8±7.1 kg/m2; 54.3% were female. The primary end point of percent change in BMI at week 56 showed differences from placebo of -10.44 percentage points (95% CI, -13.89 to -6.99; P<0.001) and -8.11 percentage points (95% CI, -11.92 to -4.31; P<0.001) for the top and mid doses of PHEN/TPM, respectively. Differences from placebo in percent change in triglycerides nominally favored PHEN/TPM (mid dose, -21%; 95% CI, -40 to -2; and top dose, -21%; 95% CI, -38 to -4), as did differences in percent change in high-density lipoprotein cholesterol (HDL-C) (mid dose, 10%; 95% CI, 3 to 18; and top dose, 9%; 95% CI, 2 to 15). The incidence of participants reporting at least one adverse event was 51.8%, 37.0%, and 52.2% in the placebo, mid-dose, and top-dose groups, respectively. Serious adverse events were reported for two participants in the top-dose group. CONCLUSIONS: PHEN/TPM at both the mid and top doses offered a statistically significant reduction in BMI and favorably impacted triglyceride and HDL-C levels in adolescents with obesity. (Funded by VIVUS LLC, with project support provided by Covance LLC; ClinicalTrials.gov number, NCT03922945.).

Calcitriol and Levothyroxine Dosing for Patients With Pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is a rare hormone resistance syndrome caused by mutations in GNAS. This cross-sectional study investigated whether PHP patients with parathyroid hormone (PTH), thyrotropin (thyroid stimulating hormone; TSH), and free thyroxine (T4) levels at goal required higher doses of levothyroxine and calcitriol than recommended by current guidelines to overcome mineral ion abnormalities due to hormone resistance. Baseline demographic and clinical data of participants enrolled in PHP research studies between 2012-2021 were collected via retrospective chart review. Longitudinally, data were recorded at a maximum frequency of once a year starting at 1 year of age. The PTH at goal (PAG) group was defined as PTH < 150 pg/mL and calcium ≥ 8.4 mg/dL, and the TSH and free T4 at goal (TAG) group was defined as TSH < 5 mIU/L and free T4 ≥ 0.8 ng/dL. The PAG group (n = 74) was prescribed higher calcitriol doses than the PTH not at goal (PNAG) group (n = 50) (0.9 ±â€…1.1 vs 0.5 ±â€…0.9 mcg/day, P = 0.04) and 21% of individual patients were prescribed ≥ 1.5 mcg of calcitriol daily. This remained true after normalization for body weight (0.013 ±â€…0.015 vs 0.0067 ±â€…0.0095 mcg/kg/day, P = 0.008). There was no statistically significant difference in levothyroxine dosing between the TAG group (n = 122) and TSH and free T4 not at goal (TNAG) group (n = 45) when normalized for weight (2.0 ±â€…0.7 vs 1.8 ±â€…0.7 mcg/kg/day, P = 0.2). More than one-third of patients with PHP had PTH levels not at goal and some patients required calcitriol doses ≥ 1.5 mcg/day to meet current treatment goals.

Racial and Ethnic Disparities in Comorbidities in Youth With Type 2 Diabetes in the Pediatric Diabetes Consortium (PDC).

BACKGROUND: Type 2 diabetes in the U.S. is more prevalent in youth of minority racial-ethnic background, but disparities in health outcomes have not been examined in this population. RESEARCH DESIGN AND METHODS: We examined racial-ethnic differences in the initial presentation and subsequent comorbidities in 1,217 youth with type 2 diabetes (63% girls) enrolled in the Pediatric Diabetes Consortium (PDC) Registry from February 2012 to June 2018. Demographic and clinical data were collected from medical records and participant self-report. RESULTS: Overall, the mean age at presentation was 13.4 ± 2.4 years, and BMI was 35.0 ± 9.4 kg/m2. HbA1c was higher and C-peptide was lower in non-Hispanic Black (NHB) and Hispanic (H) youth compared with non-Hispanic White (NHW) youth. NHB were three times as likely to present in diabetic ketoacidosis (19%) versus NHW (6.3%) and H (7.5%), and NHB and H both had a worse HbA1c trajectory compared with NHW peers. Microalbuminuria was documented in 11%, hypertension in 34%, and dyslipidemia in 42% of Registry participants, with no significant difference among racial-ethnic groups. Nonalcoholic fatty liver disease (NAFLD) was diagnosed in 9% and 11% of H and NHW, respectively, versus 2% in NHB. CONCLUSIONS: NHB and H youth with type 2 diabetes presented with worse metabolic control and had persistently worse HbA1c trajectories compared with NHW. Comorbidities exist in a large percentage of these youth independent of race-ethnicity, except for NAFLD being less prevalent in NHB. Greater efforts are needed to mitigate racial-ethnic disparities at diagnosis and in the management of youth with type 2 diabetes.

MRI measures of hypothalamic injury are associated with glucagon-like peptide-1 receptor agonist treatment response in people with hypothalamic obesity.

AIM: To evaluate whether neuroimaging-delineated regions of hypothalamic injury are associated with a differential treatment response to a glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with hypothalamic obesity (HO). MATERIALS AND METHODS: We performed a prespecified secondary analysis of a randomized, multicentre, double-blind, placebo-controlled trial of people aged 10-25 years with hypothalamic injury and HO randomized to the GLP-1RA exenatide once-weekly (ExQW) or placebo for 36 weeks. Subjects underwent MRI prior to enrolment and the degree of hypothalamic damage was assessed using an integrative hypothalamic lesion score (HLS). Mammillary body (MB) damage was specifically determined. The main clinical endpoints were % change in body mass index (BMI) and change in % body fat. Nested ANCOVA models including a treatment × imaging measure interaction were compared using partial F-tests to assess whether the effect of ExQW treatment differed by severity of hypothalamic damage. RESULTS: Complete data were available in 35/42 randomized participants (placebo, n = 15; ExQW, n = 20). ExQW-treated patients with worse HLS or bilateral MB damage had greater reductions in % body fat at 36 weeks (interaction coefficient estimates for HLS: -0.9%, 95% CI -1.6% to -0.2%, p = .02; for MB damage: -7.4%, 95% CI -10.1% to -4.7%, p < .001, respectively) but not for BMI % change. Similarly, patients with more damaged and smaller MB cross-sectional areas had greater reductions in % body fat following ExQW (interaction coefficient estimate 0.3%, 95% CI 0.2%-0.4%, p < .001). CONCLUSIONS: In people with HO, greater hypothalamic damage as determined by MRI, in particular MB injury, is associated with greater reductions in adiposity following GLP-1RA treatment.

Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants.

BACKGROUND/OBJECTIVES: Melanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus. SUBJECTS/METHODS: The sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping. RESULTS: Targeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m2. In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 (P = 5.36 × 10-25, Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties (P = 6.23 × 10-08, Beta = -0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI. CONCLUSIONS: MC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.

A phase 3 randomized clinical trial using a once-weekly glucagon-like peptide-1 receptor agonist in adolescents and young adults with hypothalamic obesity.

AIM: To evaluate the efficacy, safety and tolerability of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with hypothalamic obesity (HO). MATERIALS AND METHODS: A two-arm, randomized, multicentre, double-blind, placebo-controlled trial was conducted in 10- to 25-year-olds with hypothalamic injury following intracranial tumour and HO. Participants were randomized to once-weekly subcutaneous injections of a GLP-1 RA exenatide 2 mg (ExQW) or placebo for 36 weeks. The primary efficacy endpoint was 36-week % change in body mass index (BMI). Secondary outcomes included change in body composition (by dual energy x-ray absorptiometry). RESULTS: Forty-two participants were randomized to ExQW (n = 23) or placebo (n = 19). Participants were 5 ± 2 years (mean ± SD) postdiagnosis and development of HO (BMI 37.3 ± 7.1 kg/m2 ). In intention-to-treat analysis, the effect of 36-week ExQW vs. placebo on % Δ BMI was not significant (estimated treatment difference -1.7 ± 1.8%, 95% CI -4.1 to 0.6%, P = .40); however, total body fat mass was reduced (estimated treatment difference -3.1 ± 1.4 kg, 95% CI -5.7 to -0.4 kg, P = .02). There was a significant reduction in waist circumference (estimated effect of treatment -3.5 [95% CI -5.5 to -1.6] cm, P = .004). All patients treated with placebo increased % of adipose tissue, while 50% treated with ExQW had reductions (P < .001). Mean HbA1c, glucose tolerance and serum lipids did not change significantly with therapy. ExQW was well tolerated. The most frequent adverse events were transient gastrointestinal disturbances (ExQW vs. placebo: nausea 6/23 vs. 3/18, vomiting 4/23 vs. 4/18 and diarrhoea 7/23 vs. 3/18). CONCLUSIONS: GLP-1 RAs are a promising and safe treatment to improve or stabilize HO in children and young adults.

Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients.

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.

A Clinic-based Approach to Diagnosis and Management of Prediabetes in High-risk Children and Adolescents.

BACKGROUND: Type 2 diabetes (T2D) in youth is increasing in prevalence. Diabetes screening is recommended for at-risk youth but best-practice strategies for management of pediatric prediabetes are unknown. This study leverages a pediatric prediabetes clinic to assess identification of high-risk patients, the rate of clinic follow-up and progression to T2D in youth over time. METHODS: Retrospective chart review of children referred to a single center for evaluation of prediabetes over a 3-year period. Measurements included hemoglobin A1c (HbA1C) and oral glucose tolerance testing. Patients were classified as normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or T2D based on 2019 American Diabetes Association criteria. Patients classified as IGT/T2D were prescribed metformin. RESULTS: Of the 254 patients included; 25.6% had IGT and 6.7% had T2D. The IGT/T2D groups were older and more obese than the NGT group. There was a moderate correlation between HbA1C and fasting glucose (r = 0.59, P < 0.001); HbA1C and 2-hour glucose (r = 0.63, P < 0.001). Over the 3-year study, 52 of 82 patients with IGT/T2D (63%) returned for follow-up. Four patients regained NGT; 3 of those had isolated impaired fasting glucose (100 to 102 mg/dL). Three patients (4.6%) progressed from IGT to T2D over an average of 13 ±â€…6.2 months. In those patients, body mass index had increased 1.7 ±â€…2.3 kg/m2 from baseline. CONCLUSIONS: A pediatric prediabetes clinic may allow for identification of high-risk youth but lost to follow-up rates are high. Continued weight gain is a risk factor for progression to T2D and effective weight management programs are needed.

Trends in pediatric obesity management, a survey from the Pediatric Endocrine Society Obesity Committee.

Background In the United States, 18.5% of children are obese. Dietary and lifestyle modifications are key, but often ineffective. There are limited approved pediatric pharmacotherapies. The objective of this study was to evaluate current treatment practices for pediatric obesity among members of the Pediatric Endocrine Society (PES, n = 1300) and the Pediatric Obesity Weight Evaluation Registry (POWER, n = 42) consortium. Methods A 10-question online survey on treatment of children with obesity in clinical practice was conducted. Results The response rates were 19% for PES and 20% for POWER members. The majority were female (65%) and board certified in pediatric endocrinology (81%). Most practitioners saw 5-10 patients with obesity/week and 19% prescribed weight-loss medications. POWER participants were more likely to prescribe weight-loss medications than PES participants (46% vs. 18%, p = 0.02). Metformin was the most commonly prescribed medication. Response to medication was poor. Use of dietary non-pharmacological treatment options was uncommon. Over half of the respondents (56%) referred patients for bariatric surgery and 53% had local access to pediatric bariatric surgery. Conclusions Metformin was the most common drug prescribed among respondents, but successful weight-loss responses were uncommon. Among practitioners who are using pharmacological interventions, therapeutic strategies vary widely. Targeted research in pharmacologic and surgical treatment for pediatric obesity is urgently needed.