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. Author manuscript; available in PMC: 2025 Aug 1.
Published in final edited form as: Curr Opin Pediatr. 2024 May 15;36(4):449–455. doi: 10.1097/MOP.0000000000001365

Semaglutide for Management of Obesity in Adolescents: Efficacy, Safety, and Considerations for Clinical Practice

Megan O Bensignor 1, Silva Arslanian 2, Mary Ellen Vajravelu 2
PMCID: PMC11222026  NIHMSID: NIHMS1992186  PMID: 38774967

Abstract

Purpose of review:

The purpose of this review is to describe the existing limited data related to the use of semaglutide in adolescents with obesity, supplementing with findings from adult studies of semaglutide use.

Recent findings:

Semaglutide, as a once weekly subcutaneous injection for weight management, effectively reduces body mass index (BMI) while improving hyperglycemia, elevated alanine aminotransferase levels, hyperlipidemia, and quality of life in youth with obesity. As of this review, only one large randomized clinical trial of semaglutide in youth has been completed, with a follow-up duration of 68 weeks. Thus, long-term data on the safety in adolescents is limited, particularly regarding the risks of cholelithiasis, pancreatitis, suicidal ideation, and disordered eating. Due to the cost of semaglutide, particularly in the United States, limited cost effectiveness analyses have demonstrated unfavorable incremental cost-effectiveness ratios for semaglutide relative to phentermine-topiramate as an alternative anti-obesity medication in adolescents.

Summary:

Semaglutide represents an important advance in the pediatric obesity management, with clear short-term reductions in BMI and improvement in metabolic parameters. However, its long-term safety and efficacy for youth with obesity remain to be demonstrated. Additional research is needed to assess trends in utilization and adherence to minimize the risk of worsening socioeconomic disparities in pediatric obesity.

Keywords: pediatric obesity, anti-obesity medication, semaglutide, type 2 diabetes, glucagon-like peptide-1 receptor agonists

Introduction

As the prevalence of both obesity and type 2 diabetes (T2D) has increased in youth, the interest in safe and effective pharmacotherapy to treat these diseases has also risen (1–5). Semaglutide 2.4 mg, a once-weekly subcutaneous glucagon-like peptide-1 receptor agonist (GLP-1RA), is the most recent medication approved by the U.S. Food and Drug Administration (FDA) to treat adolescent obesity (6) and represents a growing class of incretin hormone-based therapeutics for obesity (7). Incretin hormones including GLP-1 and glucose-dependent insulinotropic polypeptide are secreted by entero-endocrine cells in response to an oral glucose load and stimulate insulin secretion and regulate appetite (8). Semaglutide and other GLP-1RA reduce gastric emptying, inhibit glucagon secretion, and promote insulin secretion (9). Additionally, GLP-1RA also have effects on appetite modulation by the hypothalamus and brain stem, which can lead to increased satiety and reduced food intake and cravings (10, 11). The use of incretin hormone-based therapies in the treatment of obesity acknowledges the foundational concept that obesity is a biological disease of energy regulation with complex, genetic, societal, and neuro-endocrine pathophysiology (12).

Clinical Trial Outcomes

Body Mass Index (BMI) Reduction

Given the pleiotropic effects on both appetite regulation and glucose homeostasis, GLP-1RA were initially used to treat T2D in adults and subsequently approved to treat adult obesity (7). In 2022, subcutaneous semaglutide, up to a dose of 2.4 mg once weekly, was FDA-approved as an adjunctive agent to lifestyle modifications for chronic weight management in pediatric patients 12 years or older with a BMI ≥ 95th percentile for age and sex. This approval was based on the results of the Semaglutide Treatment Effect in People with obesity [STEP]-Teens trial. This trial was a 68-week, double-blind randomized control trial. Participants ages 12-18 years with a BMI ≥95th percentile or ≥85th percentile with at least one obesity-related comorbidity were randomized 2:1 to subcutaneous semaglutide 2.4 mg or placebo (13). The estimated mean percentage change in BMI from baseline to week 68 was −16.1% with semaglutide 2.4 mg and +0.6% with placebo (Table 1) (13). A greater proportion of participants treated with semaglutide (73%) experienced a reduction in BMI of ≥5% compared to 18% of the placebo group. Additionally, 53% of those treated with semaglutide experienced a ≥15% reduction in BMI compared to 5% in the placebo group. Notably, nearly 45% of participants randomized to semaglutide achieved a BMI in the normal weight or overweight category, versus 12% of participants assigned to placebo (14). Although no direct measures of body fat were obtained, it is likely that this degree of BMI reduction did lead to decreased body fat, which may reduce insulin resistance and other cardiovascular risks (15).

Table 1.

Comparison of Pediatric and Adult Semaglutide Data

Study Name STEP-Young STEP-Teens(13) STEP −1(51)
Clinicaltrials.gov NCT05726227 NCT04102189 NCT03548935
Study Population • Age 6 to 18 years
• Body weight > 45 kg
• BMI ≥ 95th percentile or ≥ 85th percentile with the presence of ≥ 1 weight-related
• For participants with T2D HbA1c ≤ 10.0%		 • Age: 12 to <18 years
• BMI ≥95th percentile or ≥85th percentile with ≥ 1 obesity-related comorbidity
• For participants with T2D, HbA1c ≤10%		 • Age ≥ 18 years
• BMI ≥ 30kg/m2 or ≥ 27 kg/m2 with ≥ 1 treated or untreated weight-related coexisting conditions
• No History of T2D
Weight/BMI related outcomes (vs placebo)
Primary BMI outcome N/A; study currently recruiting Change in BMI%:
−16.1% (vs + 0.6%)		 Change in body weight%:
−14.85% (vs −2.41%)
Weight (kg) −15.3 kg (vs +2.4 kg) −15.3 kg( vs −2.6)
Waist Circumference (cm) −12.7 (vs −0.6) −13.54 (vs −4.13)
Total body fat mass by DEXA (kg) Not measured −8.36 (vs −1.37)
Regional visceral body fat mass by DEXA (kg) −0.36 (vs −0.10)
Total lean body mass by DEXA −5.26 (vs −1.83)
Obesity-related Comorbidities (% change)
HbA1c (%) N/A; study currently recruiting −0.4 (vs −0.1) −0.45 (vs −0.15)
Triglycerides (percent change) −28.4 (vs 2.6) −22.0 (vs −7.0)
Total Cholesterol (percent change) −8.3 (vs −1.3) −3.0 (vs 0.0)
LDL(percent change) −10.2 (vs −3.4) −3.0 (vs. +1.1)
HDL (percent change) 8.0 (vs 3.2) +5.0 (vs +1.0)
ALT (percent change) −18.3 (vs −4.9) Not reported
SBP (mm Hg) −2.7 (vs −0.8) −6.16 (vs −1.06)
DBP (mm Hg) −1.4 (vs −0.8) Not reported
Mental Health Outcomes
Anxiety N/A; study currently recruiting Not reported Not reported
Depression No significant changes between groups
Disordered Eating Not reported Not reported
QOL 5.3 (vs 1.0) 14.67 (vs 5.25)
Safety Outcomes
Any Adverse outcome (%) N/A; study currently recruiting 79 (vs 82) 89.7 (vs 86.4)
Serious GI adverse events (%) 2 (vs 1) 4.5 (vs 0.8)
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BMI, body mass index; HbA1c, hemoglobin A1c; SBP, DBP: systolic, diastolic blood pressure; QOL, quality of life; T2D, type 2 diabetes; GI, gastrointestinal

Glycemic Control

In the STEP-Teens trial, participants treated with semaglutide experienced a significant reduction in hemoglobin A1c of 0.4%, compared to a 0.1% reduction in placebo group (13). As there were only eight participants with T2D in this trial, this data alone cannot be used to draw conclusions regarding semaglutide’s impact on glycemic control in youth-onset T2D (13). For adults with T2D, semaglutide subcutaneous at doses of 2.4 mg or 1.0 mg decreased mean hemoglobin A1c by 1.6% and 1.5%, respectively, versus a reduction of 0.4% among participants assigned placebo (16).

Metabolic Dysfunction Associated Non-Alcoholic Fatty Liver Disease

Semaglutide may also be useful in treating metabolic dysfunction-associated steatotic liver disease (MASLD) by reducing liver fat content and liver enzyme levels in adult populations (17). Within the STEP-Teens trial, adolescents with obesity treated with semaglutide had an 18.3% reduction in alanine aminotransferase (ALT) levels compared to 4.9% reduction with placebo (−14.1, 95% CI [−25.2, −1.4]) (13). Since STEP-Teens was not a trial specifically assessing MASLD, no data on hepatosteatosis, liver stiffness, or visceral body fat was collected to provide more specific evidence regarding the effects on MASLD. Multiple meta-analyses evaluating the role of semaglutide in treatment of adult patients with MASLD or MASH (metabolic-associated steatohepatitis have concluded that semaglutide significantly improves liver enzymes (ALT and aspartate aminotransferase), reduces liver stiffness, improves steatosis and, in some cases, leads to MASH resolution (18–20). However, within an adult population with biopsy-confirmed non-alcoholic steatohepatitis-related cirrhosis, semaglutide 2.4mg weekly did not significantly improve fibrosis or achievement of MASH resolution versus placebo, which may speak to limited efficacy of semaglutide in more advanced liver disease (21). Additional studies evaluating the effects of semaglutide in adolescents with MASLD are needed to evaluate the efficacy in this patient population.

Dyslipidemia and Cardiovascular Risk

In the STEP-Teens trial, semaglutide was found to significantly reduce total cholesterol, low density lipoprotein (LDL) cholesterol, very low density lipoprotein, and triglycerides compared to placebo (13). Although dyslipidemia increases long-term risk of cardiovascular disease, short-term adverse cardiovascular events are uncommon in adolescents, making these outcomes difficult to assess over the timeframe of most clinical trials. However, studies in adults demonstrate the beneficial cardiovascular effects of semaglutide. In adults with cardiovascular disease and obesity without diabetes, semaglutide reduced the risk of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death) (22). The SUSTAIN-6 clinical trial, which randomized 3,297 adults with T2D to semaglutide (0.5 or 1.0 mg once weekly) or placebo for 104 weeks, found that the primary composite outcome of first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly less common in the semaglutide group compared to placebo (6.6% versus 8.9%, hazard ratio 0.74) (23). The SELECT clinical trial randomized 17,604 adults with obesity and cardiovascular disease to 2.4 mg once-weekly semaglutide or placebo, with a mean follow up of approximately 40 months (22). Subcutaneous semaglutide 2.4 mg resulted in lower incidence of cardiovascular-related death, nonfatal myocardial infarction, or nonfatal stroke, with a primary cardiovascular end-point event occurring in 6.5% versus 8.0% of semaglutide versus placebo group (hazard ratio 0.8, 95% CI 0.72-0.90). This may be due to semaglutide’s effects on lowering carotid intima-media thickness, total cholesterol, triglycerides and LDL cholesterol in adults with T2D (24). Additionally, in adults, semaglutide was found to reduce cardiovascular risk by resulting in lower systolic and diastolic blood pressure and C-reactive protein (25).

Safety in Clinical Trials and Post-Marketing Reports

Gastrointestinal Effects

In the STEP-Teens trial, adverse event rates were higher for the semaglutide group than placebo group (435.7 versus 362.9 per 100 person-years), but were reported in the majority of adolescent participants overall (semaglutide group: 103/133, 79%; placebo group: 55/67, 82%) (13). Consistent with adult trials, the most frequent adverse events were gastrointestinal, including nausea, vomiting, and diarrhea, in 62% versus 42% of participants randomized to semaglutide versus placebo. These gastrointestinal effects were most common with increasing doses during the 16-week dose-escalation period. Notably, despite higher prevalence of gastrointestinal adverse events in the semaglutide group, adverse event-related discontinuation rates were 5% in both groups.

Additional potential gastrointestinal effects include cholelithiasis and pancreatitis, though existing data in youth are limited. In the STEP-Teens trial, cholelithiasis occurred in 5 (4%) participants in the semaglutide group, including one with cholecystitis, versus none in the placebo group. Pancreatitis did not occur in either group, though amylase and lipase levels did increase from baseline in participants in the semaglutide group. In a meta-analysis of randomized clinical trials of adults with T2D comparing GLP-1RA (including semaglutide) use to placebo or other non-GLP-1RA drug, cholelithiasis was significantly more common with GLP-1RA use, with an odds ratio of 1.3 (95% CI 1.01-1.68), while pancreatitis was not associated with GLP-1RA use (26). Cholelithiasis risk was not associated with age, baseline BMI, or variations in BMI during treatment. In direct contrast, in a retrospective claims-based cohort of adults with obesity but without diabetes from 2006—2020 (27), Sodhi and colleagues found that new users of GLP-1RA (n=613 on semaglutide and n=4,144 on liraglutide) versus bupropion-naltrexone (n=654) for weight loss were at increased risk of pancreatitis (hazard ratio [HR] 9.1; incidence per 1000 person-years of 4.6 for semaglutide and 7.9 for liraglutide, versus 1.0 for bupropion-naltrexone), bowel obstruction (HR 4.2; incidence per 1000 person-years 0 for semaglutide and 8.1 for liraglutide, versus 1.7 for bupropion-naltrexone), and gastroparesis (HR 3.7; incidence per 1000 person-years 9.1 for semaglutide and 7.3 for liraglutide, versus 3.1 for bupropion-naltrexone), but not a combined outcome of cholelithiasis, cholecystitis, or choledocholithiasis (incidence per 1000 person-years 11.7 for semaglutide and 18.6 for liraglutide, versus 12.9 for bupropion-naltrexone).

Cardiovascular

The STEP-Teens trial found that heart rate increased by a mean of 1.2 beats per minute in the semaglutide group, while it decreased by 2.3 beats per minute in the placebo group (13). Semaglutide has also been demonstrated to increase heart rate in adults with T2D and obesity, but, importantly, to also reduce cardiovascular risk as discussed above (22, 23).

Mental Health

In STEP-Teens, adolescents were not eligible for enrollment if they had any history of severe psychiatric disorders, bulimia nervosa, or suicide attempt, or if they had major depressive disorders within two years before screening. Thus, the clinical trial should not be used to assess safety of use of semaglutide in these higher-risk populations. However, in the selected trial population, Patient Health Questionnaire 9-item version (PHQ-9) and Columbia-Suicide Severity Rating Scale (C-SSRS) scores were similar between the semaglutide and placebo groups, and psychiatric adverse events were reported more often by the placebo group than the semaglutide group (15% versus 7%) (13). During the trial, 3% of the semaglutide group had follow-up PHQ-9 score of ≥15 (the initial threshold for exclusion due to concern for moderate to severe depression), while this occurred in 6% of the placebo group. Only 1 (0.8%) participant in the semaglutide expressed passive suicidality, while none expressed more severe suicidality. In contrast, 3 (4.5%) participants in the placebo group expressed passive suicidality and 6 (13.5%) expressed more severe suicidality as measured by the C-SSRS.

Using real-world data, findings about associations between use of GLP-1RA and suicidal ideation have been mixed. In a post-market pharmacovigilance study (28), Chen and colleagues examined the association between GLP-1RA and suicidal/self-injury reports that were made in the FDA Adverse Event Reporting System (FAERS) database between the second quarters of 2005 and 2023. They analyzed the disproportionality of reports for suicide/self-injury and GLP-1RA, in comparison with other drugs, using a contingency table that categorized reports by presence or absence of suicide/self-injury, in GLP-1RA or other drugs. This study included semaglutide as well as liraglutide, exenatide, albiglutide, dulaglutide, and lixisenatide) and was not restricted by age. Of the 219,376 adverse events related to GLP-1RA, 534 were for suicide/self-injury (106 with semaglutide). These cases occurred most often in the 25-65-year age group, with most (51.5%) reporting symptoms of suicidal ideation, as well as 19% attempted suicide and 19% intentional overdose. The pooled reporting odds ratio (ROR) of 0.16 (95% CI 0.15-0.18) did not suggest over-reporting of suicide/self-injury in GLP-1RA. Notably, the authors did find that the ROR for suicide/self-injury with GLP-1RA was elevated in children (ROR 2.5, 95% CI 1.02-6.13, p=0.05). However, the strength of this signal was considered to be low, and the authors emphasize the need to interpret their results with caution.

Conflicting reports have been published about associations between suicidal ideation and GLP-1RA use in adults. In a study using the TriNetX Analytics Network to evaluate the association between GLP-1RA use and suicidal ideation in over 240,000 adults with overweight or obesity, risk for incident and recurrent suicidal ideation was lower among adults prescribed semaglutide versus non-GLP-1RA anti-obesity medication. The authors found similar lower risk of suicidal ideation among adults with T2D (29). In contrast, using the FAERS database from 2005—2023, McIntyre et al did find elevated ROR for reports of suicidal ideation with semaglutide and liraglutide relative to separate control exposures of insulin and metformin, but no disproportionate reporting of suicidal behavior, attempts, or completion (30). In this study, results were not stratified by age. In early 2024, the FDA released a drug safety communication stating that, based on detailed reviews of reports in FAERS, clinical trials, and analysis of postmarketing data using health insurance claims and patient health records, their preliminary evaluation did not find evidence that GLP-1 RA use causes suicidal thoughts or actions (31).

The potential impact of semaglutide use on disordered eating behaviors remains undetermined, though due to its effect on satiety and decreased food intake, some have postulated that it may be beneficial in binge eating disorder. For example, in an open-label study of adults with binge eating disorder who were prescribed semaglutide (n=19), lisdexamphetamine or topiramate (n=16), or a combination of these medications (n=13), patients prescribed semaglutide alone experienced the greatest reduction in Binge Eating Scale scores (32). In another observational study of adults with obesity (n=69), after 3-month use of semaglutide, the proportion of patients experiencing emotional eating was significantly lower (72.5% to 11.5%, p<0.001) (33). Understanding the impact of semaglutide and other GLP-1RA on disordered eating behaviors is especially important in youth due to the greater frequency among youth with obesity and higher BMI than youth with normal weight (34, 35).

These data it should be interpreted in the context that obesity and type 2 diabetes are associated with both depression and disordered eating in youth (34, 36–39). Further long-term follow-up is needed to determine if anti-obesity therapy increases or decreases the risk of concomitant mental health concerns.

Limitations to Widespread Use

Cost-Effectiveness

A major consideration for widespread use of semaglutide in youth with obesity has been cost effectiveness due to the high cost of approximately $1,000 per month. Mital and Nguyen used a Markov microsimulation model to perform an economic evaluation and determine the incremental cost-effectiveness ratio (ICER) of the four anti-obesity drugs with current FDA approval for pediatric use (semaglutide, phentermine-topiramate, liraglutide, orlistat), with effectiveness measured using quality-adjusted life-years (QALYs) over a 10-year horizon. They found that although semaglutide led to more QALYs than phentermine-topiramate, due to semaglutide’s high cost, phentermine-topiramate was most cost-effective (semaglutide ICER = $1,079,480 per QALY and phentermine-topiramate ICER = $93,620 per QALY, versus no treatment, for 12-17-year-old adolescents with severe obesity) (40). In a similar economic evaluation, Lim and colleagues estimated the cost-effectiveness of semaglutide, mid- and top-dose phentermine-topiramate, and liraglutide, as an adjunct to lifestyle counseling versus lifestyle counseling alone for adolescents with obesity. The ICER for semaglutide was again $1.1 million per QALY gained, but an ICER of $56,876 per QALY gained for top-dose phentermine-topiramate at 5 years (41). As poor cost-effectiveness of semaglutide was driven by its high cost, reductions in this cost would significantly alter these results and subsequent coverage determinations by payers.

Equitable Access

Cost-effectiveness analyses do not typically directly consider ethical concerns, including differential considerations for individuals from marginalized backgrounds, such as out-of-pocket costs and access to therapy (42), including at least 26 in-person contact hours for intensive health behavior and lifestyle treatment with a multidisciplinary team (43). Concerns about equitable access to therapy are particularly relevant for pediatric obesity, as it is most common among youth marginalized by race, ethnicity, and socioeconomic status (44, 45). Because insurance coverage for semaglutide and other anti-obesity medications varies widely, with many commercial and most Medicaid policies excluding coverage of anti-obesity medications (42, 46), such medications are cost-prohibitive for many youth, particularly youth of color, who are disproportionately insured by Medicaid. Differential access to highly effective anti-obesity medications such as semaglutide could thus lead to widening of racial and ethnic disparities in pediatric obesity (47). Furthermore, even in the setting of insurance coverage, patients have experienced interruptions in supply due to shortages spurred by high demand for semaglutide (48).

Lack of Durable Effect Once Medication is Discontinued

Although there is limited data, results from the STEP-Teens trial demonstrate rebound weight gain as early as seven weeks following discontinuation of semaglutide (13). Weight regain nearly to baseline BMI was observed after discontinuation of another GLP-1RA, liraglutide, at 26 weeks after discontinuation of study drug (49). Adults treated with semaglutide 2.4 mg and lifestyle intervention regained two-thirds of their weight loss during the STEP-1 study after a year of semaglutide discontinuation (50). Given this data and the fact that obesity is a chronic disease, it is reasonable to surmise that youth may need lifelong therapy with semaglutide to prevent reoccurrence of obesity or weight regain. Interruptions in semaglutide administration due to insurance coverage, drug shortages, or adherence, could lead to significant weight regain.

Conclusion

Semaglutide, a GLP-1RA, has demonstrated efficacy in reducing BMI and weight and improving metabolic parameters in adolescents and adults with obesity. However, long-term data regarding safety and efficacy are currently lacking for adolescents. Clinical trial results and post-marketing reports can be used to guide clinicians when discussing potential risks, though data regarding associations between semaglutide and certain adverse effects, such as suicidal thoughts and behaviors, is particularly inconsistent. Semaglutide’s current high cost limits its cost-effectiveness for use in adolescents with obesity, and varying insurance coverage may contribute to inequities in uptake, exacerbating socioeconomic disparities in pediatric obesity. Ultimately, in order to fully realize semaglutide’s potential to significantly address pediatric obesity, longer-term data and reductions in cost are needed.

Key points:

  • Weekly subcutaneous semaglutide is a glucagon-like peptide-1 receptor agonist that leads to clinically significant reductions in body mass index and weight in youth, with associated improvements in metabolic parameters.

  • Although evidence in youth is currently very limited, findings from large and longer-term studies in adults with obesity, type 2 diabetes, and cardiovascular disease demonstrate positive impacts on metabolic and cardiovascular outcomes.

  • The most common adverse effects of semaglutide are gastrointestinal, with conflicting evidence of impacts on mental health, particularly suicidal ideation.

  • Important considerations for widespread use of semaglutide for management of pediatric obesity include its cost-effectiveness and accessibility in order to minimize the risk of worsening socioeconomic disparities in pediatric obesity as well as probable need for long-term use to avoid weight regain.

Financial support and sponsorship:

Drs. Bensignor and Vajravelu receive support from the National Institute of Health National Institute of Diabetes and Digestive and Kidney Disease: DK129721 (MOB) and DK125719 (MEV). The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.

Conflicts of interest:

MOB receives research support from Novo Nordisk and Vivus Inc.

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