Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management.

Background: Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality, and reduced quality of life. The most common form is polygenic obesity, which results from interactions between multiple gene variants and environmental factors. Highly penetrant monogenic and syndromic obesities result from rare genetic variants with minimal environmental influence and can be differentiated from polygenic obesity depending on key symptoms, including hyperphagia; early-onset, severe obesity; and suboptimal responses to nontargeted therapies. Timely diagnosis of monogenic or syndromic obesity is critical to inform management strategies and reduce disease burden. We outline the physiology of weight regulation, role of genetics in obesity, and differentiating characteristics between polygenic and rare genetic obesity to facilitate diagnosis and transition toward targeted therapies. Methods: In this narrative review, we focused on case reports, case studies, and natural history studies of patients with monogenic and syndromic obesities and clinical trials examining the efficacy, safety, and quality of life impact of nontargeted and targeted therapies in these populations. We also provide comprehensive algorithms for diagnosis of patients with suspected rare genetic causes of obesity. Results: Patients with monogenic and syndromic obesities commonly present with hyperphagia (ie, pathologic, insatiable hunger) and early-onset, severe obesity, and the presence of hallmark characteristics can inform genetic testing and diagnostic approach. Following diagnosis, specialized care teams can address complex symptoms, and hyperphagia is managed behaviorally. Various pharmacotherapies show promise in these patient populations, including setmelanotide and glucagon-like peptide-1 receptor agonists. Conclusion: Understanding the pathophysiology and differentiating characteristics of monogenic and syndromic obesities can facilitate diagnosis and management and has led to development of targeted pharmacotherapies with demonstrated efficacy for reducing body weight and hunger in the affected populations.

Obesity definition, diagnosis, bias, standard operating procedures (SOPs), and telehealth: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022.

Background: The Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) regarding definition, diagnosis, bias, standard operating procedures (SOPs) and telehealth is intended to provide clinicians an overview of obesity medicine and provide basic organizational tools towards establishing, directing, managing, and maintaining an obesity medical practice. Methods: This CPS is based upon published scientific citations, clinical perspectives of OMA authors, and peer review by Obesity Medicine Association leadership. Results: OMA has defined obesity as: "A chronic, progressive, relapsing, and treatable multi-factorial, neurobehavioral disease, wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences." While body mass index may be sufficiently diagnostic for populations and many patients, accurate diagnosis of adiposity in an individual may require anthropometric assessments beyond body weight alone (e.g., waist circumference, percent body fat, and android/visceral fat). Obesity complications can be categorized as "sick fat disease" (adiposopathy) and/or "fat mass disease." Obesity complications predominantly of fat mass origins include sleep apnea and orthopedic conditions. Obesity complications due to adiposopathic endocrinopathies and/or immunopathies include cardiovascular disease, cancer, elevated blood sugar, elevated blood pressure, dyslipidemia, fatty liver, and alterations in sex hormones in both males (i.e., hypogonadism) and females (i.e., polycystic ovary syndrome). Obesity treatment begins with proactive steps to avoid weight bias, including patient-appropriate language, office equipment, and supplies. To help manage obesity and its complications, this CPS provides a practical template for an obesity medicine practice, creation of standard operating procedures, and incorporation of the OMA "ADAPT" method in telehealth (Assessment, Diagnosis, Advice, Prognosis, and Treatment). Conclusions: The OMA CPS regarding "Obesity Definition, Diagnosis, Bias, Standard Operating Procedures (SOPs), and Telehealth" is one in a series of OMA CPSs designed to assist clinicians care for patients with the disease of obesity.

Obesity and Metabolic Care of Children of South Asian Ethnicity in Western Society.

South Asians constitute one-fourth of the world's population and are distributed significantly in western countries. With exponentially growing numbers, childhood obesity is of global concern. Children of South Asian ancestry have a higher likelihood of developing obesity and associated metabolic risks. The validity of commonly used measures for quantifying adiposity and its impact on metabolic outcomes differ by race and ethnicity. In this review we aim to discuss the validity of body mass index (BMI) and other tools in screening for adiposity in South Asian children. We also discuss the prevalence of overweight and obesity amongst South Asian children in western countries and the differences in body fat percentage, adiposity distribution, and metabolic risks specific to these children compared to Caucasian children. South Asian children have a characteristic phenotype: lower lean mass and higher body fat percentage favoring central fat accumulation. Hence, BMI is a less reliable predictor of metabolic status in these children than it is for Caucasian children. Furthermore, the relatively lower birth weight and rapid growth acceleration in early childhood of South Asian children increase the risk of their developing cardiometabolic disorders at a younger age than that of Caucasians. We emphasize the need to use modified tools for assessment of adiposity, which take into consideration the ethnic differences and provide early and appropriate intervention to prevent obesity and its complications.

Pleural Pressure Targeted Positive Airway Pressure Improves Cardiopulmonary Function in Spontaneously Breathing Patients With Obesity.

BACKGROUND: Increased pleural pressure affects the mechanics of breathing of people with class III obesity (BMI > 40 kg/m2). RESEARCH QUESTION: What are the acute effects of CPAP titrated to match pleural pressure on cardiopulmonary function in spontaneously breathing patients with class III obesity? STUDY DESIGN AND METHODS: We enrolled six participants with BMI within normal range (control participants, group I) and 12 patients with class III obesity (group II) divided into subgroups: IIa, BMI of 40 to 50 kg/m2; and IIb, BMI of ≥ 50 kg/m2. The study was performed in two phases: in phase 1, participants were supine and breathing spontaneously at atmospheric pressure, and in phase 2, participants were supine and breathing with CPAP titrated to match their end-expiratory esophageal pressure in the absence of CPAP. Respiratory mechanics, esophageal pressure, and hemodynamic data were collected, and right heart function was evaluated by transthoracic echocardiography. RESULTS: The levels of CPAP titrated to match pleural pressure in group I, subgroup IIa, and subgroup IIb were 6 ± 2 cmH2O, 12 ± 3 cmH2O, and 18 ± 4 cmH2O, respectively. In both subgroups IIa and IIb, CPAP titrated to match pleural pressure decreased minute ventilation (IIa, P = .03; IIb, P = .03), improved peripheral oxygen saturation (IIa, P = .04; IIb, P = .02), improved homogeneity of tidal volume distribution between ventral and dorsal lung regions (IIa, P = .22; IIb, P = .03), and decreased work of breathing (IIa, P < .001; IIb, P = .003) with a reduction in both the work spent to initiate inspiratory flow as well as tidal ventilation. In five hypertensive participants with obesity, BP decreased to normal range, without impairment of right heart function. INTERPRETATION: In ambulatory patients with class III obesity, CPAP titrated to match pleural pressure decreased work of breathing and improved respiratory mechanics while maintaining hemodynamic stability, without impairing right heart function. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02523352; URL: www.clinicaltrials.gov.

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.

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/m(2)) 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/m(2), 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 ß-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.