In our battle against the diabetes epidemic, the increasing prevalence of the disease in young people is an important focus. In the SEARCH for Diabetes in Youth (SEARCH), a multicenter observational study conducted in the United States, there was an annual increase of about 7% in the incidence of type 2 diabetes among patients aged 10-19 years old between 2002–03 and 2011–12. This rise was largely found in minority groups compared to non-Hispanic white individuals.¹ Canadian investigators also saw an increase in diabetes among young people less than 20 years of age, with incidence rising from 3.45 per 100,000 in 2003 to 5.16 per 100,000 a decade later.² China also reported a marked increase in the prevalence of type 2 diabetes in young people aged 7-17 years, doubling from 5.2% in 1991 to 13.2% in 2006.³

   The pathophysiology of type 2 diabetes in young people is no different than that of older individuals, however younger patients tend to experience more rapid decline in β-cell function. This finding was seen in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, with β-cell function declining at a rate of 20–35% annually in adolescents with type 2 diabetes, aged 10–19 years, compared to 7-11% annual decline in older individuals with the disease.⁴ Having lower initial β-cell reserve and higher A1C were significant independent predictors of loss of glycemic control. The rising trend of obesity, with its associated increase in inflammatory markers and insulin resistance, is also an important driver for the rise in diabetes in young people.⁵ Complication rates were seen earlier in this younger cohort with evidence of microvascular complications (6.2% had microalbuminuria in the TODAY study) and risk markers for macrovascular complications (11.6% had blood pressure ≥95th percentile, 18.2% had high triglycerides) present at diagnosis. TODAY2, a post-intervention follow-up study of TODAY also revealed high complication rates over a 12-year period. (TODAY2 was discussed in News from the ADA 79 Scientific Sessions.)

   Treatment options for young patients include lifestyle interventions and pharmacotherapy, however, the latter is limited to metformin and insulin therapy. The safety of sulfonylureas in the pediatric population has been demonstrated in clinical studies but has not gained approval for general use.⁶ Agents such as dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT-2) inhibitors have not gained FDA approval for pediatric use (<18 years old) and studies evaluating their safety and efficacy are still underway.

   However, liraglutide, a glucagon-like peptide 1 receptor agonist has recently been approved for use in the treatment of pediatric patients age 10 and above with type 2 diabetes. It is the first injectable non-insulin drug approved for use in the pediatric population after metformin was approved in 2000. This followed the findings of the Evaluation of Liraglutide in Pediatrics with Diabetes (ELLIPSE) trial, which recruited 134 patients aged 10-17 years old. The mean age of the study cohort was 14.6±1.7 years with a higher proportion of female patients (60%). The treatment group had a body mass index (BMI) z-score of 3.03±1.47, which is in the obese range. Patients were randomized to receive subcutaneous liraglutide or placebo for 26 weeks, in combination with metformin, with or without basal insulin. The primary efficacy end point was the change from baseline in glycated hemoglobin (HbA1c) level at week 26; the treatment group saw a fall of 0.64%.⁷ This was comparable to the drop of 0.4% seen in the adult study population in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial.⁸ Among the ELLIPSE patients, there was also a decrease in fasting plasma glucose of 1.08 mmol/L (19.5 mg/dl) that was sustained at week 52. A higher proportion of those in the liraglutide treatment group were able to achieve HbA1c <7% (63.7% vs 36.5%). Moreover, sustained weight loss was seen at week 52 in the liraglutide arm with an average reduction of 1.91kg. Gastrointestinal adverse events occurred more often in patients on liraglutide but were mostly mild. As with other GLP-1 agonists, treatment with liraglutide is inadvisable in patients with a history of medullary thyroid carcinoma (MTC) or family history of MTC, as well as those with multiple endocrine neoplasia 2, due to its potential effect on thyroid C cell proliferation found in animal studies.⁹

   Managing diabetes in youth can be challenging, as these patients not only face longer disease duration, but also a more aggressive phenotype with early onset of complications. There are also psychosocial matters to address, as well as reproductive issues to manage later in adolescence. As additional studies are conducted to evaluate the effectiveness and safety of newer anti-diabetic medication in the younger population, there is good reason to anticipate a future with more treatment options to meet the needs of these patients.

References:

1. Pettitt DJ, Talton J, Dabelea D, et al. Prevalence of diabetes in U.S. youth in 2009: the SEARCH for diabetes in youth study. Diabetes Care. 2014;37(2):402–408.

   2. Amed S, Islam N, Sutherland J, et al. Incidence and prevalence trends of youth-onset type 2 diabetes in a cohort of Canadian youth: 2002-2013. Pediatric Diabetes. 2018;19(4):630–636.

   3. Fu J, Prasad HC. Changing epidemiology of metabolic syndrome and type 2 diabetes in Chinese youth. Curr Diab Rep. 2014; 14(1):447.

   4. TODAY Study Group. Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and β-cell function in TODAY. Diabetes Care 2013; 36(6): 1749–57.

   5. Lumeng CN, Saltiel AR. Inflammatory links between obesity and metabolic disease. J Clin Invest 2011; 121(6): 2111–17.

   6. Gottschalk M, Danne T, Vlajnic A, Cara J. Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes. Diabetes Care. 2007;30(4):790–794.

   7. Tamborlane WV, Barrientos-Pérez M, Fainberg, et al. Liraglutide in Children and Adolescents with Type 2 Diabetes. N Engl J Med. 2019; 381(7):637-646.

   8. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311–322.

   9. Nauck MA, Friedrich N. Do GLP-1-based therapies increase cancer risk?. Diabetes Care. 2013;36: S245–S252.

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