Currently, more than half of US children and adolescents are either overweight or obese.¹ This high prevalence of childhood obesity is largely due to a combination of physical inactivity and poor eating habits. Less than 1% of US children aged 12-19 meet the recommended ideal diet endorsed by the American Heart Association.² Consequently, 18% of adolescents have pre-diabetes,³ a risk factor which increases the incidence of cardiovascular disease and mortality by 37%.⁴

Childhood and adolescent obesity are associated with premature atherosclerosis in postmortem studies⁵ and expected to increase the prevalence of coronary artery disease in young adults by up to 16%.⁶ Half of all US adults currently have some form of cardiovascular disease, and the decline in cardiovascular mortality seen over the past decades has stalled, which has been attributed to the rise in obesity and metabolic disease.⁷

Because the vast majority of children with obesity will remain obese as adults, early intervention is imperative.⁸ Current guidelines for the treatment of pediatric obesity focus on early recognition, preventive efforts, lifestyle education, formal programs of intensive lifestyle modification, and consideration of medication only if these attempts fail to reduce obesity.⁹ The only two medications currently approved by the US Food and Drug Administration (FDA) for the treatment of adolescent obesity are orlistat and phentermine. Orlistat is approved for obesity treatment of ages 12-16 while phentermine is approved above age 16. In the largest trial in adolescents, orlisatat resulted in a body mass index (BMI) reduction of 0.55 kg/m² after 52 weeks, and the drop-out rate was 35%.¹⁰ Randomized placebo-controlled trials with phentermine in adolescents have not been conducted. Therefore, pharmacological therapy for obesity in adolescents is not only limited by low efficacy but also by lack of supporting trial data and concern about long-term safety.

Liraglutide is a glucagon-like peptide (GLP-1) analogue, which elicits its efficacy by increasing glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and decreasing food intake. Liraglutide is approved by the FDA for weight loss in adults, improvement in glycemic control in type 2 diabetes, and cardiovascular event reduction in patients with type 2 diabetes. In the landmark LEADER trial,¹¹ liraglutide reduced death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes, a cardiovascular benefit only afforded to only one other class of anti-hyperglycemic agents, the SGLT2 inhibitors. Therefore, liraglutide may represent a rational and ideal treatment for obesity, type 2 diabetes, and associated cardiovascular disease.

In adolescents, liraglutide is currently indicated for use in type 2 diabetes as an adjunct to diet and exercise. In a randomized, placebo-controlled trial, Kelly and colleagues now investigated the effects of liraglutide on weight loss in an adolescent patient population.¹² Among the subjects, 251 adolescents age 12 to less than 18 with obesity defined as BMI that correspond to an adult of more than 30 were randomized to receive either liraglutide or placebo. All participants enrolled in a lifestyle modification, which consisted of nutritional and exercise counseling. The study design consisted of 56 weeks of treatment with liraglutide titrated to 3 mg versus placebo, followed by 26 weeks follow-up without treatment. After 56 weeks, liraglutide treatment resulted in a 0.22 reduction in the BMI standard-deviation score, which is above the recommended BMI standard deviation goal of 0.2. The mean change for BMI at week 56 for liraglutide was 1.6 kg/m² versus 0.1 kg/m² for placebo. Notably, a reduction in BMI of at least 5% occurred in over half the adolescents treated with liraglutide. However, 26 weeks after treatment discontinuation, weight regain to almost baseline was seen in the liraglutide group while the placebo group gained weight above the baseline (BMI at week 82 for liraglutide (n=112) was –0.2 kg/m² from baseline vs. placebo 0.8 kg/m²).

This trial provides encouraging results and establishes that safe, pharmacological weight loss can be achieved. Although speculative at this point, liraglutide may ultimately prove as an effective and ideal long-term weight loss medication to treat early adolescent obesity and its ensuing complications, including type 2 diabetes and associated cardiovascular disease. However, the trial also highlights the limitations of anti-obesity medications and illustrates that pharmacological weight loss is currently not sustained. The cornerstone of management remains the prevention of excess weight gain and early recognition of obesity. However, counseling for weight loss and treatment of obesity occurs infrequently,¹³ which suggests the presence of important barriers. Physicians must overcome the inertia to discuss weight problems and develop sensitive and self-empowering strategies to lead this discussion. The approach to dietary, physical activity, and behavioral modification must focus on family-centered intervention rather than on the individual patient. It is imperative to extend simple nutritional and exercise counseling to a more comprehensive approach that includes a multidisciplinary health care team, including pediatrician, endocrinologist, nutritionist, exercise physiologist, behavioral therapist, and support coaches. Frequent patient visits, long-term care, education, and models of individual accountability are required for success. However, probably the most important step in the management of obesity involves change in the current permissive environment. Success in the managing of obesity will require access to healthy and affordable food, change to healthy food choices in schools, limitation to food marketing, and routine engagement in physical activity. Until such policy change is in place, a simple rule prevails: "go out to play; if it's not fresh, don't eat it".

References

1. Skinner AC, Ravanbakht SN, Skelton JA, Perrin EM, Armstrong SC. Prevalence of obesity and severe obesity in US children, 1999-2016. Pediatrics 2018;141:e20173459.
2. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation 2019;139:e56-e528.
3. Andes LJ, Cheng YJ, Rolka DB, Gregg EW, Imperatore G. Prevalence of prediabetes among adolescents and young adults in the United States, 2005-2016. JAMA Pediatr 2019;174:e194498.
4. Vistisen D, Witte DR, Brunner EJ, et al. Risk of cardiovascular disease and death in individuals with prediabetes defined by different criteria: the Whitehall II study. Diabetes Care 2018;41:899-906.
5. Strong JP, Malcom GT, McMahan CA, et al. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. JAMA 1999;281:727-35.
6. Bibbins-Domingo K, Coxson P, Pletcher MJ, Lightwood J, Goldman L. Adolescent overweight and future adult coronary heart disease. N Engl J Med 2007;357:2371-9.
7. Shah NS, Lloyd-Jones DM, O'Flaherty M, et al. Trends in cardiometabolic mortality in the United States, 1999-2017. JAMA 2019;322:780-2.
8. Ward ZJ, Long MW, Resch SC, Giles CM, Cradock AL, Gortmaker SL. Simulation of growth trajectories of childhood obesity into adulthood. N Engl J Med 2017;377:2145-53.
9. Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity-assessment, treatment, and prevention: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2017;102:709-57.
10. Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J. Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial. JAMA 2005;293:2873-83.
11. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
12. Kelly AS, Auerbach P, Barrientos-Perez M, et al. A randomized, controlled trial of liraglutide for adolescents with obesity. N Engl J Med 2020;382:2117-28.
13. Newman JD, Berger JS, Ladapo JA. Underuse of medications and lifestyle counseling to prevent cardiovascular disease in patients with diabetes. Diabetes Care 2019;42:e75-e76.

Clinical Topics: Cardiovascular Care Team, Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Prevention, Atherosclerotic Disease (CAD/PAD), CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Prevention

Keywords: Diabetes Mellitus, Metabolic Syndrome, Primary Prevention, Secondary Prevention, Adolescent, Pediatric Obesity, Pediatrics, Body Mass Index, Phentermine, Weight Loss, Glucagon-Like Peptide 1, Prediabetic State, Glucagon, Diabetes Mellitus, Type 2, Sedentary Behavior, Coronary Artery Disease, Gastric Emptying, Obesity

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