By: Kelly Lavery, PharmD Candidate c/o 2024

              Increasing rates of childhood obesity remain a major risk factor behind a recently increased prevalence of diabetes in the pediatric population. This subject is of particular relevance in light of the ongoing coronavirus disease of 2019 (COVID-19) pandemic, which has limited children to isolation and online learning instead of normal exercise and activities, further exacerbating the childhood obesity crisis. First-line interventions used in children with type 2 diabetes (T2D) included diet and lifestyle modifications to control weight, increase physical activity, and promote healthy eating behaviors.¹ According to a meta-analysis on the effectiveness of education and lifestyle interventions to prevent pediatric diabetes, interventions that involved the patient’s family and schools were most effective, however, adolescents aged 13 to 18 years old received the least benefit in obesity prevention from these interventions.² A need for treatment measures in addition to lifestyle modifications are necessary for this age group to control T2D.

Metformin may be used as a first line agent in addition to lifestyle and diet modifications to achieve optimal glucose control in pediatric patients. If necessary, this regimen can be intensified by adding insulin therapy in patients with reoccurring ketoacidosis or hyperglycemia.¹ In adults with T2D, the American Diabetes Association (ADA) prefers the use of glucagon-like peptide 1 (GLP-1) analogs before insulin therapy due to their efficacy in glucose control, decreased risk of hypoglycemia, less frequent administration rate, and potential benefits in cardiac outcomes and weight loss.³  GLP-1 analogs work by enhancing glucose-dependent insulin secretion via pancreatic beta-cells, suppressing inappropriately elevated glucagon secretion, and slowing gastric emptying.⁴ In 2020, liraglutide, a GLP-1 analog given once daily as a subcutaneous injection, received approval from the Food and Drug Administration (FDA) for use in obese pediatric patients age 12 and older.⁵ This was a major advancement for the management of T2D in pediatrics as it allowed this population to receive the weight loss and cardiac benefits of GLP-1 analogs while delaying the need for initiating insulin therapy. In 2021, Bydureon (exenatide extended release), also a GLP-1 analog, was approved by the FDA for use in pediatric patients age 10 and older with T2D.⁴ Exenatide extended release (ER) is administered as a once weekly subcutaneous injection, creating the opportunity for improved adherence and implementation into the child’s life.

Safety and Efficacy Data Leading to Approval of Bydureon

The FDA based its approval for the use of once weekly exenatide ER on a phase 3, double-blinded, randomized, multicenter, placebo-controlled parallel study that examined the efficacy and safety of exenatide ER vs. placebo for 24 weeks.⁶ The study was funded and designed by AstraZeneca. The average participant age was 15 years old. At baseline, the mean glycated hemoglobin, or hemoglobin A1c (HbA1c), was 8.2%. Regarding prior antihyperglycemic drug use, 12.2% of patients did not receive any prior treatments, 40.2% were treated with Metformin only, 8.5% were treated with insulin only, and 37.8% were treated with metformin and insulin.⁶

Inclusion criteria included having a diagnosis of T2D, being 10 to 18 years of age, having a HbA1c of 6.5 to 12.0%, being treated with diet and exercise for at least 2 months, and having a fasting plasma glucose < 280 mg/dL.⁶ Exclusion criteria included having hepatic disease, renal disease, gastrointestinal disease, previous organ transplant, chronic infection, and previous history using any GLP-1 analog.⁶ The researchers needed at least 77 participants distributed in a 5:2 ratio of either once-weekly exenatide 2 mg or placebo groups to attain significant results. This goal was achieved with a final total of 82 participants distributed as 58 subjects in the exenatide ER group and 24 subjects in the placebo group.⁶

The primary outcome measured the change in HbA1c from baseline to week 24. The results showed an average decrease of 0.36% in HbA1C over the 24-week study period in the group receiving exenatide ER while the placebo group experienced an increase in HbA1c of 0.49% (p = 0.012).⁶ The mean difference in HbA1C values between the two study groups was -0.85% (95% Confidence Interval [CI] -1.51 to -0.19; p = 0.012).⁶

The study also evaluated the incidence of adverse effects over the 24-week period. The exenatide ER group had 25.4% of participants who experienced treatment-related adverse events while the placebo group had 21.7%. 13.6% of patients in the exenatide ER group experienced hypoglycemia.⁶ Neither group experienced any adverse reactions that led to discontinuation of treatments. Adverse effects included abdominal pain, nausea, vomiting, diarrhea, injection site reactions, hyperglycemia, hypoglycemia, headache, pain in extremities, and cough. 3.4% of patients in the exenatide ER group vs. 4.3% in the placebo group experienced serious adverse effects.⁶ In addition to evaluating safety profiles, other secondary outcomes included changes in fasting glucose levels, body weight, systolic blood pressure, and fasting insulin levels. However, for all of these endpoints, the study was unable to produce statistically significant values over the 24-week study period.⁶

Additional Evaluation of the Safety and Efficacy of GLP-1 Analogs

Supplementing the data from the AstraZeneca phase 3 trial, a meta-analysis conducted by Ryan et al. was performed to gain a larger insight into the efficacy and toxicity profiles of GLP-1 analogs in children with obesity.⁵ Data was extracted from randomized control trials conducted between 1994 to 2021. A total of 9 studies with 574 participants were included; 3 studies evaluated the use of exenatide while the remaining 6 studies analyzed liraglutide.⁵

Primary outcomes of the meta-analysis evaluated weight and cardiometabolic outcomes, while secondary outcomes evaluated gastrointestinal adverse events.⁵ Regarding change in weight, exenatide was able to exhibit a mean difference (MD) of 2.02 kg (95% CI -4.54 to 0.49; p = 0.03; I² = 72%) whereas liraglutide showed a MD of 1.51 kg (95% CI -2.85 to -0.17; p = 0.03; I² = 67%).⁵ Regarding change in body mass index (BMI), exenatide had a MD of 1.11 kg/m² (95% CI -1.67 to -0.55; p = 0.54; I² = 0%) while liraglutide was found to have a MD of 1.55 kg/m² (95% CI -2.41 to -0.70; p = 0.82; I² = 0%).⁵ When evaluating the incidence of adverse effects in liraglutide, the gastrointestinal, skin, neurologic, endocrine, and hepatobiliary systems experienced the most adverse effects. For exenatide, the gastrointestinal system was predominantly affected. The most common gastrointestinal adverse effects were nausea (36.4 to 62 per 100 participants), vomiting (27.3 to 31 per 100 participants), and abdominal pain (15 to 18.2 per 100 participants).⁵

Limitations of the meta-analysis conducted by Ryan et al. include the fact that almost half of the participants come from 1 trial, and more than half of the trials were conducted for less than 3 months.⁵ Heterogeneity may have been introduced due to the varying strengths in dose between exenatide and liraglutide. However, the authors conveyed that any variance in responses for all primary outcomes in the final statistical analysis were due to the intervention itself and not the introduction of outside sources of heterogeneity, which can provide confidence in the results.⁵ Regardless, continued post-marketing research should be conducted to establish data on long term adverse effects and ensure the safety of patients taking GLP-1 analogs.

Conclusion

AstraZeneca’s phase 3 clinical trial provides statistically significant and clinically significant results that exenatide ER is effective in lowering HbA1c levels without adding a substantially increased risk of adverse effects. Limitations of this study included the fact that it was sponsored by the creator of the drug, performed over a short duration of time, and had a relatively small study sample due to the difficulties that accompany using pediatric patients in clinical research. The meta-analysis on the safety and efficacy of GLP-1 analogs serves to further substantiate the positive aspects of exenatide ER in providing glycemic control and reducing weight and BMI in pediatric patients with minor and manageable gastrointestinal adverse effects. The combined results of these two studies prove that the use of exenatide as a once weekly injection can improve the quality of life of pediatric patients with T2D and should be considered for use before initiating insulin therapy.

References

1. Laffel L, Svoren B. Management of Type 2 Diabetes Mellitus in Children and Adolescents. UptoDate.com. Published 08/01/2022. Last Updated 09/01/2022.
2. Gori, D.,  Guaraldi, F.,  Cinocca, S.,  Moser, G.,  Rucci, P., and  Fantini, M. P. (2017)  Effectiveness of educational and lifestyle interventions to prevent paediatric obesity: systematic review and meta-analyses of randomized and non-randomized controlled trials. Obesity Science & Practice,  3:  235– 248. doi: 10.1002/osp4.111.
3. American Diabetes Association Professional Practice Committee, Draznin B, Aroda VR, et al. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S143. doi:10.2337/dc22-S009
4. Bydureon (Exenatide (Extended Release)) [package insert]. West Chester, OH; Amylin Ohio LLC; Revised 07/01/2021.
5. Ryan P, Seltzer S, Hayward N, Avelar Rodriguez D, Sless R, Hawkes C. Safety and Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Children and Adolescents with Obesity: A Meta-Analysis. Sciencedirect.com. https://www-sciencedirect-com.jerome.stjohns.edu/science/article/pii/S0022347621004327. Published 05/11/2021. Last Updated 08/23/2021.
6. Tamborlane WV, Bishai R, Geller D, et al. Once-Weekly Exenatide in Youth With Type 2 Diabetes. Diabetes Care. 2022;45(8):1833-1840. doi:10.2337/dc21-2275.

Published by Rho Chi Post