SCALE KIDS Trial: Evaluating Liraglutide’s Role in Pediatric Obesity Management
Tanmaya Phanda, PharmD
5 min
SCALE KIDS Trial: Evaluating Liraglutide’s Role in Pediatric Obesity Management
By: Tanmaya Phanda, PharmD - The InpharmD Team
This blog will provide an overview of obesity, explore key insights from the SCALE KIDS trial, and discuss the potential impact of liraglutide in chronic weight management of pediatric patients (6 to <12 years old)
Introduction
Obesity, a chronic, multifactorial, progressive disease caused by the accumulation of excessive body fat, is common in the United States, affecting 2 in 5 adults and 1 in 5 children2. People with obesity are at higher risk for many serious comorbidities such as cardiovascular disease, type 2 diabetes, and sleep apnea. Meta-analyses of 53 studies including 8942 participants identified that 75.27% of children with type 2 diabetes also had obesity3. Moreover, obesity, especially in pediatrics, is also associated with psychological problems such as depression and anxiety. In a separate meta-analysis, 21.7% of overweight/obese children were diagnosed with depression and 39.8% with anxiety, but only 18.0% of non-overweight/non-obese children had depression and 14.0% had anxiety, further stressing the importance of prioritizing effective treatment strategies4.
Obesity in adults and pediatric populations is diagnosed differently. In adults, there are fixed body mass index (BMI) cutoffs. However, children have varying growth and development rates, therefore, a simple BMI value is not sufficient for an obesity diagnosis. Childhood obesity is a BMI of at least the 95th percentile of age and gender charts.5
A healthy diet and moderate-intensity physical activity can reduce weight and risks of serious complications in patients with obesity. As adjuncts to these lifestyle changes, there are four FDA-approved medications for chronic weight loss management in pediatric patients ≥12 years old. First-line pharmacotherapy consists of glucagon-like peptide-1 (GLP-1) receptor agonists such as liraglutide (Saxenda®) and semaglutide (Wegovy®) delay gastric emptying, reduce hunger, and increase satiety, resulting in weight loss. In addition, older agents like Orlistat (Xenical®), and phentermine-topiramate (Qsymia®) are other alternatives used for long-term weight loss.—Figure 1. Although, there are no FDA-approved medications for pediatric patients 6 to < 12 years old. The SCALE Kids trial addresses this unmet need to research effective and safe chronic weight loss treatment for this age group6.
Methods
The SCALE Kids (NCT04775082), a phase 3a, double-blind, randomized, placebo-controlled trial, investigated the efficacy and safety of liraglutide, as an adjunct to lifestyle interventions, compared to placebo in children ages six to less than 12 years old. The trial began in March 2021 and concluded in January 2024, comprising a two-week screening period, a 12-week run-in period, and a 56-week treatment period, followed by a 26-week follow-up period. Eligible patients were non-diabetic children (6 to <12 years of age) with obesity (not due to secondary causes). Obesity was defined as an age-adjusted and sex-adjusted BMI in the 95th percentile or higher, according to the Centers for Disease Control and Prevention (CDC) clinical growth charts, and pubertal development of Tanner stage 1 through 5.
A total of 82 children were randomized 2:1, with 56 patients receiving liraglutide (3.0 mg or the maximum tolerated dose) subcutaneously once daily and 26 patients receiving a placebo. Liraglutide was initiated at a dose of 0.6 mg once daily for one week in participants with a baseline weight of ≥45 kg, while 0.3 mg once daily for one week for patients with a baseline weight of <45 kg. The dosing was increased by 0.6 mg weekly, over a maximum of eight weeks for patients ≥45 kg and ten weeks for patients <45 kg, until a 3.0 mg once-daily or maximum tolerated dose was achieved. Alongside their respective treatment arms, patients received individualized counseling at every visit to encourage a healthy diet and a goal of 60 minutes per day of moderate-to-high-intensity physical activity.—Figure 2.
The demographics and baseline characteristics were similar in both treatment groups —Table 1.
Table 1. Patient Baseline Characteristics
|
Baseline Characteristic
|
Liraglutide
|
Placebo
|
Total
|
|
Female (no.)
|
26
|
12
|
38
|
|
Body Weight (kg)
|
69.8±17.7
|
71.0±23.2
|
70.2±19.5
|
|
Mean BMI (kg/m2)
|
30.9±4.7
|
31.3±7.0
|
31.0±5.5
|
|
Class 1 Obesity (no.)
|
10
|
10
|
20
|
|
Class 2 Obesity (no.)
|
26
|
4
|
30
|
|
Class 3 Obesity (no.)
|
20
|
12
|
32
|
Outcomes
The primary endpoint was the percentage change in the BMI from baseline to the end of the treatment period (56 weeks).
Confirmatory secondary endpoints evaluated the percentage change in body weight and a reduction in BMI of at least 5%. In addition, supportive secondary endpoints included a BMI reduction of at least 10%, a change in BMI as a percentage of the 95th percentile according to age-adjusted and sex-adjusted growth charts; and a change in BMI standard-deviation score, body weight, waist circumference, blood pressure, and glycated hemoglobin level.
Safety was assessed by the number of adverse events and serious adverse events reported during the treatment period. All adverse events were reported from the time of the first dose of liraglutide or placebo to 14 days after the last dose.
Results
The mean percentage change in BMI from baseline was −5.8% with liraglutide and 1.6% with placebo. An estimated treatment difference of −7.4 percentage points (95% confidence interval [CI], −11.6 to −3.2; P<0.001) was reported—Figure 3.
The mean percentage change in body weight was 1.6% with liraglutide and 10.0% with placebo, with an estimated difference of −8.4 percentage points (95% CI, −13.4 to −3.3; P=0.001). A minimum of 5% BMI reduction occurred in 46% of patients in the liraglutide group and 9% in the placebo group (adjusted odds ratio, 6.3 [95% CI, 1.4 to 28.8]; P=0.02). In the liraglutide group, 35% of the children experienced a BMI reduction of at least 10%, while only 4% was observed in children in the placebo group (adjusted odds ratio, 8.2 [95% CI, 1.0 to 65.3]). Compared to the placebo (-4.0), liraglutide resulted in a greater change in BMI as a percentage of the 95th percentile (-14.0), and an estimated treatment difference of −10.0 (95% CI, −15.1 to −4.8) was observed. —Table 2.
Table 2. Select Secondary Outcomes
|
Secondary Outcome
|
Liraglutide
|
Placebo
|
Estimated Treatment Difference (95% CI)
|
|
Change in body weight (%)
|
1.6
|
10.0
|
−8.4 (−13.4 to −3.3); P value = 0.001
|
|
BMI reduction of ≥5% (% of patients)
|
46
|
9
|
6.3 (1.4 to 28.8)*; P value = 0.02
|
|
BMI reduction of ≥10%
(% of patients)
|
35
|
4
|
8.2 (1.0 to 65.3)*
|
|
Change in BMI as a percentage of the 95th percentile
(percentage points)
|
−14.0
|
−4.0
|
−10.0 (−15.1 to −4.8)
|
*Adjusted odds ratio
In the liraglutide group, 50 patients (89%) experienced mild-moderate adverse events, compared to 23 patients (89%) in the placebo group. Gastrointestinal disorders ( mild-to-moderate nausea and vomiting) were the most common adverse events, as it was seen in 45 patients (80%) in the liraglutide group and 14 patients (54%) in the placebo group—Table 3. Antiemetic agents, proton-pump inhibitors, and dose reduction or temporary interruption were used to treat patients who experienced—Figure 4. Serious adverse events were seen in seven liraglutide-treated patients and two patients in the placebo group. There were three serious adverse events (two cases of vomiting and one of colitis) that may have been due to liraglutide. A total of six patients (11%) discontinued liraglutide due to adverse events, three of which were due to gastrointestinal disorders.
Table 4. Safety Outcomes
|
Safety Outcome
|
Liraglutide — no. (%)
|
Placebo — no. (%)
|
|
Adverse event
|
50 (89)
|
23 (89)
|
|
Gastrointestinal event
|
45 (80)
|
14 (54)
|
|
Serious adverse event
|
7 (12)
|
2 (8)
|
|
Discontinuations due to liraglutide
|
6 (11)
|
0
|
Study Conclusions
The SCALE Kids trial concluded that once-daily liraglutide with lifestyle interventions in pediatric patients ages 6 to <12 years was superior in BMI reduction compared to placebo over 56 weeks. Liraglutide also demonstrated a higher proportion of patients experiencing at least a 5% and 10% reduction in BMI from baseline and a change in BMI relative to the 95th percentile.
While both groups had similar rates of adverse events (89% in the liraglutide group and 88% in the placebo group), the liraglutide group reported a higher incidence of gastrointestinal side effects due to dose escalations, however, none resulted in hospitalization.
Despite demonstrating the potential benefits of liraglutide in this pediatric group, the trial presents some key limitations. Although changes in height, height standard deviation score, bone age, and pubertal status from baseline were similar in both groups at week 56, bone mineral density data was not collected. In addition, patients diagnosed with bulimia nervosa disorder were excluded from the study, however, patients were not screened or monitored for eating disorders during the treatment phase. Given liraglutide’s mechanism of action causes increased satiety, there may be an increased risk of young children developing eating disorders. Further studies are needed to investigate liraglutide’s effects on growth and development and eating disorders in this patient population.
Clinical Impact.
As the first GLP-1 clinical study in patients 6 to <12 years, SCALE Kids provides foundational evidence for managing childhood obesity. Approximately 55% of children with obesity continue to have obesity in adolescence, and about 80% of adolescents with obesity remain affected by it in adulthood. Combating the disease early may help prevent its progression and reduce the risks of serious, lifelong complications7. While the American Academy of Pediatrics Clinical Practice Guideline recommends initiating obesity medications for adolescents ≥12 years old with obesity, as adjuncts to lifestyle interventions8, this trial, along with future data evaluating liraglutide’s long-term effectiveness and its potential impact on weight regain upon discontinuation, may change the current standard of care for pediatrics with obesity.
In addition, obesity costs the U.S. healthcare system about $173 billion annually, further underlining the necessity of early weight loss treatment2. In 2019, healthcare costs for childhood obesity are $116 higher per person annually, compared to children with healthy weight. In children with severe obesity, medical costs increase by $310 per person annually9. Timely clinical interventions not only benefit children in weight loss as seen in this trial, but also have the potential to lower patient and healthcare system costs.
Liraglutide, one of the first GLP-1 approved by the FDA, was selected as the investigational therapy in this trial because of its extensive long-term efficacy and safety data in different patient populations. Although 74 (90%) patients completed the trial and 66 (80%) received all doses of liraglutide or placebo, liraglutide’s once-daily dosing creates an injection burden for younger children. In a pediatric vaccination study, the self-reported fear of needles was seen in 68% of children aged 6 to 8 years, and in 65% of children aged 9 to 12 years10. Additional data is needed to measure liraglutide’s effects on the quality of life of these young patients. Semaglutide (Wegovy®) offers a promising solution because of its once-weekly dosing. However, currently, there are no studies with patients 6 to <12 years.
Novo Nordisk intends to use the SCALE Kids trial to expand the Saxenda® (liraglutide) label for children six years or older with obesity. The trial is currently in an open-label extension phase, with expected completion in January 2027, to investigate liraglutide’s long-term efficacy and safety effects.
References:
- Fox CK, Barrientos-Pérez M, Bomberg EM, et al. Liraglutide for Children 6 to <12 Years of Age with Obesity A Randomized Trial. N Engl J Med. DOI: 10.1056/NEJMoa2407379.
- CDC. About Obesity. CDC. Published January 23, 2024. https://www.cdc.gov/obesity/php/about/index.html
- Cioana M, Deng J, Nadarajah A, et al. The Prevalence of Obesity Among Children With Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMA Netw Open. 2022;5(12):e2247186. Published 2022 Dec 1. doi:10.1001/jamanetworkopen.2022.47186
- Kang NR, Kwack YS. An Update on Mental Health Problems and Cognitive Behavioral Therapy in Pediatric Obesity. Pediatr Gastroenterol Hepatol Nutr. 2020;23(1):15-25. doi:10.5223/pghn.2020.23.1.15
- Weir CB, Jan A. BMI Classification Percentile And Cut Off Points. In: StatPearls. Treasure Island (FL): StatPearls Publishing; June 26, 2023.
- Prescription medications to treat overweight & obesity - NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. June 2024. https://www.niddk.nih.gov/health-information/weight-management/prescription-medications-treat-overweight-obesity#:~:text=The%20table%20below%20lists%20prescription,%E2%80%94for%20long%2Dterm%20use.
- Simmonds M, Llewellyn A, Owen CG, Woolacott N. Predicting adult obesity from childhood obesity: a systematic review and meta-analysis. Obes Rev. 2016;17(2):95-107. doi:10.1111/obr.12334
- Dutton WP, Paddu N, Braddock A, Sweeney B. Clinician's Guide for Pediatric Anti-obesity Medications. Pediatr Clin North Am. 2024;71(5):957-980. doi:10.1016/j.pcl.2024.07.006
- CDC. Childhood Obesity. CDC. Published April 2, 2024. https://www.cdc.gov/obesity/childhood-obesity-facts/childhood-obesity-facts.html
- Orenius T, LicPsych, Säilä H, Mikola K, Ristolainen L. Fear of Injections and Needle Phobia Among Children and Adolescents: An Overview of Psychological, Behavioral, and Contextual Factors. SAGE Open Nurs. 2018;4:2377960818759442. Published 2018 Mar 14. doi:10.1177/2377960818759442
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