SURPASS-PEDS: clinical promise and priorities for future research on tirzepatide treatment for youth with type 2 diabetes

We read with great interest a recently published article in The Lancet by Hannon et al. 2025 (1), “Efficacy and safety of tirzepatide in children and adolescents with type 2 diabetes (SURPASS-PEDS): a randomised, double-blind, placebo-controlled, phase 3 trial”.

In this study, the investigators demonstrate that receipt of 5 or 10 mg of tirzepatide, a long-acting dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, was effective in lowering hemoglobin A1c (HbA1c) among participants aged 10 to <19 years with type 2 diabetes, following a 30-week treatment period. On average, tirzepatide decreased HbA1c by 2.23% across the two treatment groups, as compared to an increase of 0.05% in the placebo group. Further, 71% and 86% of youth in the 5 and 10 mg treatment groups, respectively, achieved HbA1c levels below the threshold for diabetes (≤6.5%), as compared to 28% in the placebo group; and 47% and 60% (5 and 10 mg treatment groups) had HbA1c levels within the normal range (≤5.7%), vs. 14% in the placebo group. Tirzepatide also improved secondary outcomes of fasting glucose and body mass index (BMI), with larger effects observed for the 10 mg group. The weight loss seen in SURPASS-PEDS (7.4% decrease with 5 mg weekly and 11.2% decrease with 10 mg weekly) was similar to effects of the same doses of tirzepatide in the adult SURPASS study (7.9% with 5 mg weekly and 9.3% with 10 mg weekly) (2). This degree of weight loss differs from prior pediatric studies in youth-onset type 2 diabetes, where GLP-1-receptor agonists including liraglutide, exenatide, and dulaglutide lowered HbA1c by 0.8–1.5%, but did not exhibit the same effect on weight seen in adults with type 2 diabetes (3-5). Importantly, the safety profile of tirzepatide was comparable to what has been observed in adults, with the most common adverse event being mild-to-moderate gastrointestinal upset that improved with time.

Findings of SURPASS-PEDS are clinically relevant as some youth respond poorly to currently available pharmacologic treatments for youth-onset type 2 diabetes—a relatively novel pediatric disease that has an aggressive clinical course (6-8) and carries intergenerational implications as young people start their own families (9). Beyond being the first study to test the effectiveness and safety of tirzepatide in a pediatric population with type 2 diabetes, notable strengths include the gold standard design (phase 3 randomized double-blind, placebo-controlled trial); inclusion of participants from eight countries (Australia, Brazil, India, Israel, Italy, Mexico, UK, and USA); and an open-label extension period after the end of the 30-week trial during which participants in the placebo group received 5 mg tirzepatide for 22 weeks, enabling further assessment of safety, tolerability, and effectiveness of the treatment.

While results of the trial support tirzepatide as a safe and effective treatment for children and adolescents with type 2 diabetes in the short-term, we raise some concerns regarding long-term consequences, generalizability, and equitable access.

First, in addition to the primary endpoint of HbA1c, tirzepatide treatment led to clinically significant reductions in age- and sex-standardized BMI: 0.5 and 0.8 standard deviation for the 5 and 10 mg treatment groups, respectively. As BMI is a crude assessment of body size that comprises both fat and fat-free mass, the decrease in BMI may reflect loss of lean mass, in addition to or instead of, reduced fat mass. Indeed, in SURMOUNT-1, a 73-week phase 3 double-blind randomized controlled trial (RCT) of 2,539 adults with obesity, treatment with tirzepatide resulted in significant and sustained reductions in body weight, but 25% of the reductions were due to loss of muscle mass (10). This occurrence in youth, which has been observed in some studies of GLP-1 receptor agonists (11), is concerning because late childhood and adolescence are critical windows for developing muscle mass and skeletal growth. During puberty, 40–60% of adult bone mass is accumulated, with 25% of peak bone mass acquired during a 2-year window around the time of peak height velocity (12), which occurs around 11.5–12 years for girls and 13.5–14 years for boys (13). By age 18 years, 90% of peak bone mass has been accrued (14). Accrual and maintenance of adequate muscle mass is one of the strongest determinants of bone mass and density, which in turn have implications for lifelong resilience against frailty and frailty-associated multi-comorbidities including cardiovascular (15) and lung diseases (16) as well as neurocognitive deficits (17).

Second, beyond the above concerns related to loss of muscle mass, little is known of the long-term consequences of GIP and GLP-1 receptor agonist treatment in youth. Important endpoints to consider include treatment effects on tempo of maturation and linear growth, fertility, neurocognition, eating behaviors, and mental health/affect. A recent retrospective cohort study (18) of ~150,000 singleton pregnancies with deliveries between 2016 and 2025 observed higher risk of excessive gestational weight gain, gestational diabetes, hypertensive disorders, and preterm delivery among pregnant women who used GLP-1 receptor agonists prior to conception or in early pregnancy and then discontinued it, per current recommendations (19), as compared to matched controls. All the above pregnancy complications are risk factors for unfavorable long-term outcomes, including excess adiposity and cardiometabolic disease in both the offspring (9) and the mother (20,21). Additional research assessing the safety and ideal duration of tirzepatide treatment and cessation—both within and outside the context of pregnancy—is crucial.

Third, the small sample size of the trial (n=99) precluded subgroup analysis. With mounting evidence of heterogeneity in the etiology and pathophysiology of type 2 diabetes (22), understanding response to tirzepatide across subtypes in youth is important. This endeavor will require larger sample sizes with more racial and ethnic diversity than in SURPASS-PEDS.

Fourth, generalizability of findings may be somewhat limited due to the trial’s eligibility criteria of current treatment with metformin ≥1,000 mg/day and/or basal insulin, which capture youth with more severe type 2 diabetes and longer disease duration. Additionally, the full 15 mg dose was not tested in SURPASS-PEDS, so adverse events and safety across the full dosage spectrum remain unknown.

Finally, equitable access to novel pharmaceuticals like tirzepatide for vulnerable populations (i.e., low-income, rural, racial and ethnic minorities) is a challenge owing to high costs, limited insurance coverage, and other structural factors that lead to disparities in prescriptions, despite evidence of effectiveness. Long-term treatment with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists will likely be required because, unlike bariatric surgery, which appears to have more durable effects in youth with type 2 diabetes (23-27), the benefits of these pharmaceuticals diminish after treatment is discontinued. Overcoming such barriers will require expanded insurance coverage, price reductions, appropriate training of providers, and targeted support for under-resourced communities.

In summary, SURPASS-PEDS is a rigorous, high-quality RCT with impactful findings that hold potential to impact clinical care of youth-onset type 2 diabetes. However, additional research is needed to understand the short- and long-term effects of treatment on muscle mass and bone density in youth, understand long-term consequences of treatment and treatment cessation on a range of health endpoints including those of future generations, assess heterogeneity in treatment response and safety, and ensure generalizability of findings. Additionally, should tirzepatide be a safe and effective treatment for youth with type 2 diabetes, ensuring access for those in under-resourced settings will be crucial to closing, as opposed to widening, disparities in type 2 diabetes and its comorbidities/complications.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0017/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0017/coif). K.N. reports receipt of semaglutide donated by Novo Nordisk for the NHLBI investigator-initiated R01 investigating the effects on CVD, renal, and insulin sensitivity in type 1 diabetes. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Hannon TS, Chao LC, Barrientos-Pérez M, et al. Efficacy and safety of tirzepatide in children and adolescents with type 2 diabetes (SURPASS-PEDS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2025;406:1484-96. [Crossref] [PubMed]
2. Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet 2021;398:143-55. [Crossref] [PubMed]
3. Arslanian SA, Hannon T, Zeitler P, et al. Once-Weekly Dulaglutide for the Treatment of Youths with Type 2 Diabetes. N Engl J Med 2022;387:433-43. [Crossref] [PubMed]
4. Tamborlane WV, Barrientos-Pérez M, Fainberg U, et al. Liraglutide in Children and Adolescents with Type 2 Diabetes. N Engl J Med 2019;381:637-46. [Crossref] [PubMed]
5. Tamborlane WV, Bishai R, Geller D, et al. Once-Weekly Exenatide in Youth With Type 2 Diabetes. Diabetes Care 2022;45:1833-40. [Crossref] [PubMed]
6. Perng W, Conway R, Mayer-Davis E, et al. Youth-Onset Type 2 Diabetes: The Epidemiology of an Awakening Epidemic. Diabetes Care 2023;46:490-9. [Crossref] [PubMed]
7. Impact of Insulin and Metformin Versus Metformin Alone on β-Cell Function in Youth With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes. Diabetes Care 2018;41:1717-25.
8. TODAY Study Group. Long-Term Complications in Youth-Onset Type 2 Diabetes. N Engl J Med 2021;385:416-26.
9. Perng W, Oken E, Dabelea D. Developmental overnutrition and obesity and type 2 diabetes in offspring. Diabetologia 2019;62:1779-88. [Crossref] [PubMed]
10. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med 2022;387:205-16. [Crossref] [PubMed]
11. Zaitoon H, Wauters AD, Rodriguez LM, et al. Beyond Weight Loss: Optimizing GLP-1 Receptor Agonist Use in Children. Children (Basel) 2025;12:1427. [Crossref] [PubMed]
12. Golden NH, Abrams SACommittee on Nutrition. Optimizing bone health in children and adolescents. Pediatrics 2014;134:e1229-43. [Crossref] [PubMed]
13. Tsutsui T, Iizuka S, Sakamaki W, et al. Growth until Peak Height Velocity Occurs Rapidly in Early Maturing Adolescent Boys. Children (Basel) 2022;9:1570. [Crossref] [PubMed]
14. Bachrach LK. Acquisition of optimal bone mass in childhood and adolescence. Trends Endocrinol Metab 2001;12:22-8. [Crossref] [PubMed]
15. Newman AB, Gottdiener JS, Mcburnie MA, et al. Associations of subclinical cardiovascular disease with frailty. J Gerontol A Biol Sci Med Sci 2001;56:M158-66. [Crossref] [PubMed]
16. Wang L, Zhang X, Liu X. Prevalence and clinical impact of frailty in COPD: a systematic review and meta-analysis. BMC Pulm Med 2023;23:164. [Crossref] [PubMed]
17. Guo CY, Sun Z, Tan CC, et al. Multi-Concept Frailty Predicts the Late-Life Occurrence of Cognitive Decline or Dementia: An Updated Systematic Review and Meta-Analysis of Longitudinal Studies. Front Aging Neurosci 2022;14:855553. [Crossref] [PubMed]
18. Maya J, Pant D, Fu Y, et al. Gestational Weight Gain and Pregnancy Outcomes After GLP-1 Receptor Agonist Discontinuation. JAMA 2025;334:2186-96. [Crossref] [PubMed]
19. Drummond RF, Seif KE, Reece EA. Glucagon-like peptide-1 receptor agonist use in pregnancy: a review. Am J Obstet Gynecol 2025;232:17-25. [Crossref] [PubMed]
20. Walter JR, Perng W, Kleinman KP, et al. Associations of trimester-specific gestational weight gain with maternal adiposity and systolic blood pressure at 3 and 7 years postpartum. Am J Obstet Gynecol 2015;212:499.e1-12. [Crossref] [PubMed]
21. Perng W, Stuart J, Rifas-Shiman SL, et al. Preterm birth and long-term maternal cardiovascular health. Ann Epidemiol 2015;25:40-5. [Crossref] [PubMed]
22. Kreienkamp RJ, Smith K, Wangden TY, et al. Novel Phenotypic Clusters of Youth-Onset Type 2 Diabetes Offer No Added Prognostic Value to Simple Clinical Measures. Diabetes Care 2026;49:137-46. [Crossref] [PubMed]
23. Bjornstad P, Hughan K, Kelsey MM, et al. Effect of Surgical Versus Medical Therapy on Diabetic Kidney Disease Over 5 Years in Severely Obese Adolescents With Type 2 Diabetes. Diabetes Care 2020;43:187-95. [Crossref] [PubMed]
24. Dobbs TJ, Cree MG, Bailey AJ, et al. Glycemia, Insulin Sensitivity, and Secretion Improve 3 Months Post-sleeve Gastrectomy in Youth With Type 2 Diabetes. J Endocr Soc 2025;9:bvaf020. [Crossref] [PubMed]
25. Dobbs TJ, Gutierrez L, Hu HH, et al. MRI Analysis of Cardiac Fat, Abdominal Adiposity and Cardiac Function After Vertical Sleeve Gastrectomy in Youth With Type 2 Diabetes. Pediatr Obes 2026;21:e70068. [Crossref] [PubMed]
26. Inge TH, Courcoulas AP, Jenkins TM, et al. Five-Year Outcomes of Gastric Bypass in Adolescents as Compared with Adults. N Engl J Med 2019;380:2136-45. [Crossref] [PubMed]
27. Ryder JR, Xu P, Nadeau KJ, et al. Effect of surgical versus medical therapy on estimated cardiovascular event risk among adolescents with type 2 diabetes and severe obesity. Surg Obes Relat Dis 2021;17:23-33. [Crossref] [PubMed]