Pediatric Research Update: Efficacy and Safety of GLP1RAs in Children and Adolescents With Obesity or Type 2 Diabetes

Each month, the OMA Pediatric Committee reviews a pediatric-focused obesity research update to help keep you up to date about the latest findings. This month’s article reviews GLP-1 receptor agonists in children with obesity and/or Type 2 Diabetes, showing they can safely reduce weight and blood sugar while helping prevent long-term complications.

Article Summary

The authors provide us with a meta-analysis and systematic review of 18 trials including those published in the last 2 years to review primary efficacy outcomes, exploratory efficacy outcomes and safety outcomes. GLP-1 RAs significantly improve outcomes for children and adolescents with Type 2 Diabetes or obesity.

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Article Review

Childhood obesity affects one in five children and adolescents under the age of 18 years and has reached epidemic levels. Obesity has been associated with the rising levels of Type 2 Diabetes (T2D) among this young population. T2D and obesity increase risk of other comorbidities such as hyperlipidemia leading to increased cardiovascular risk, liver disease, and hypertension. Children and adolescents are faced with a longer period with disease leading to complications sooner than later. Timely intervention and effective treatment are critical to improving outcomes for children and adolescents with T2D and/ or obesity.

The authors analyzed 18 randomized placebo-controlled trials with 1402 participants. Trials were focused on 3 subgroups: 11 obesity, 6 T2D and 1 prediabetes and the use of GLP-1 RAs. Examples of primary efficacy outcomes include hemoglobin A1c (HbA1c), fasting glucose, and body mass index.Exploratory outcomes focused on metabolic dysfunction-associated steatohepatitis (MASH/MASLD) and obstructive sleep apnea (OSA). A few safety outcomes explored included gastrointestinal adverse effects, infections, suicidal ideation and depression.

Efficacy Outcomes

• Glycemic Outcomes

Significant reductions in hemoglobin A1c were demonstrated compared to placebo in all trials evaluated. Across the 18 trials, there was an absolute reduction of 0.44% in HgbA1c. The trials for T2D and GLP-1 RA use showed a greater absolute reduction of HbgA1c: -0.94%. Compared to the obesity trials, the absolute reduction of -0.10% was comparatively smaller, but significant. Fasting plasma glucose (FPG) was significantly improved across all trials (-9.92 mg/dl) and T2D subgroup (-22.56 mg/dl). However, the obesity subgroup did not have significant reduction in FPG (-1.39 mg/dl).

• Weight-Related Outcomes

GLP-1 RA treatment resulted in significant decrease in BMI. Overall, BMI decreased by -1.45. Obesity trials had larger effects (-1.71) compared to the T2D trials (0.42). BMI percentile reductions were significant overall (-7.24%) and obesity subgroup (-8.78%); T2D subgroup had a non-significant reduction of -0.23%. Waist circumference measurements were obtained in the obesity subgroup trials with significant reduction. No data presented in T2D trials.

• Lipid Outcomes

The GLP-1 RAs demonstrated modest effects on lipid profile. There were minimal differences in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL): estimated treatment ratio of 1.0 each.

• Blood Pressure Outcomes

Nine of the 11 obesity trials showed a slightly more pronounced effect of systolic blood pressure (SBP) reduction (-2.85 mmHg) compared to T2D trials (-2.29 mmHg). Across all studies analyzed, the SBP reduction was significant at -2.73 mm/Hg. There was no significant reduction in diastolic blood pressure (DBP).

• Exploratory Efficacy Outcomes

A nonsignificant reduction trend for OSA was demonstrated in obesity trials. The data for MASH/MASLD was only available from 1 T2D trial and showed no significant difference in liver disease between GLP-1 RA and placebo.

Safety Outcomes

• Gastrointestinal Adverse Events, Hepatobiliary Disorders, and Infections

Gastrointestinal adverse events were significantly increased with GLP-1 RA treatment versus placebo with a notable increase in the obesity trials. A nonsignificant trend for hepatobiliary outcomes was identified. A possible increased rate of infections was identified but was not significant.

• Psychological Outcomes

No significant difference in depression was identified in the GLP-1 RA group compared to placebo, nor in the obesity and T2D subgroups. Only 5 of the 18 trials mentioned the use of the Columbia-Suicide Severity Rating Scale (C-SSRS) for evaluation of mental health with medication use. In the data available, GLP-1 RAs were associated with decreasing trend of suicidal ideation or behaviors (although not statistically significant); same for the obesity and T2D subgroups.

• Hypoglycemia

There was a trend toward more hypoglycemia in 7 of the trials, again not statistically significant. Two studies reported serious hypoglycemia adverse events, one in a treatment group and one in the placebo group.

• Treatment Discontinuation Due to Adverse Events

An increasing trend was observed overall, although not statistically significant. Obesity subgroups had a higher toward discontinuation, not statistically significant. The T2D trials demonstrated no notable effect.

Conclusion

The authors have provided us with clinically relevant data indicating the effectiveness of GLP-1 RAs in the treatment of children and adolescents with T2D and/or obesity. Reductions in weight, BMI, HgbA1c, and FBG are crucial in the treatment and prevention of complications for those with T2D and/or obesity. Early and effective treatment reduces duration and risk of complications as well as healthcare costs in the future. Results of these trials are congruent with many of the studies available in the adult population.

Knowing the most common side effects of GLP-1 RAs, it is not surprising the most significant risk or safety outcome was the degree of gastrointestinal adverse events. However, discontinuation due to gastrointestinal adverse events was not statistically significant. More study is needed, as the data available for suicidal ideation and behaviors, depression and MASH/MASLD may be underreported or not clearly classified in these trials. There is also a lack of long-term data and effects of GLP-1 RAs on children and adolescents. The current data from this meta-analysis indicates GLP-1 RAs are efficacious and safe in the treatment of T2D and obesity among children and adolescents.