When metformin therapy fails in youth / children with type 2 diabetes (T2D), alternatives are limited to human insulin and liraglutide.
Researchers of a previously conducted TODAY study found high rates of oral treatment failure in young patients with T2D. The failure rate of Metformin with Rosiglitazone was 38.6%, Metformin with lifestyle was 46.6%, and Metformin alone was 51.7%. The median time to failure was approximately 11 months. Decreased beta-cell function was found to be associated with the loss of medication effectiveness. The RISE Consortium study was developed to find ways to preserve beta-cell function in youth and adults with T2D. Inclusion criteria encompassed: pediatric individuals aged 10-19 years, Tanner stage >2, BMI >85th percentile, BMI <50, fasting plasma glucose >90, and oral glucose tolerance test >140. A1C was <8% for drug naïve, <7.5% with Metformin use less than three months, and <7% with Metformin use three to six months. Patients had a diabetes diagnosis for less than six months. Metformin use was less than six months, and insulin use was less than two weeks. Patient autoantibodies were negative for IA-2 and GAD. Most participants were female (71%), approximately 14 years old, Tanner Stage V (63%), and had a BMI of 36.7. The largest portion of the youth were Hispanic (37%), with the remainder being white (27%) and African American (25%). The majority also had pre-diabetes (59%), with the rest having the diagnosis of diabetes (41%).
Researchers used a two-step hyperglycemic clamp protocol to measure insulin sensitivity and beta-cell response post a 20% dextrose infusion. The study also assessed if beta-cell function might be preserved in youth with impaired glucose tolerance or recent T2D diagnosis. Patients were treated with diabetes medications for one year, then evaluated post-withdrawal to determine if positive outcomes were sustained. In this proof-of-principle trial, two unblinded interventions were randomized. Regimen 1 included three months of insulin glargine alone, followed by nine months of Metformin alone. Patients on regimen 2 took twelve months of Metformin only. Steady C-peptide response was categorized as hyperglycemia of approximately 200 mg/dL. Beta-cell secretory capacity was classified as hyperglycemia of >450 mg/dL plus arginine.
Using either clamp insulin sensitivity or the oral glucose tolerance test (OGTT) insulin sensitivity, researchers found that youth were more insulin resistant than adults (P<0.001). Younger participants were also found to have more responsive beta-cells. There was no difference in glucagon suppression between age groups. With Metformin alone, individuals had a stable C-peptide steady-state response that declined once treatment was removed. In those taking Insulin glargine followed by Metformin, there was a decreased C-peptide steady-state response, which further fell after medication withdrawal. Beta-cell secretory capacity decreased dramatically during and post-treatment with both medication regimens. Over 15 months, beta-cell secretory capacity declined in youth and remained steady in adults. In young individuals, BMI, fasting glucose, OGTT 2-hours, and A1C did not change during treatment but were significantly higher after withdrawal in both treatment groups (P<0.05).
Dr. Isganaitis and her team examined using GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors for treating youth with T2D. Approved treatment options for children are regrettably limited to human insulin, Metformin, and Liraglutide. Most guidelines recommend Metformin as first-line treatment with pediatrics, yet there is a 60% failure rate within two years in this population. The TODAY study found an insufficient Metformin response due to non-adherence (11%), uncontrolled blood glucose (6%), need for multiple medications (2.5%), intolerance (2%), and being of non-Hispanic black ethnicity. Therefore, more diabetes medication options are required to counteract these issues. Liraglutide has been FDA approved for treating pediatric patients with T2D. A multicenter, randomized trial found that it improved glycemic control when added to Metformin with/without insulin in children and adolescents. In addition, a randomized, double-blind study found that Liraglutide coupled with lifestyle changes reduced BMI in youth compared to lifestyle changes alone. Dapagliflozin, Exenatide ER, Alogliptin, and Empagliflozin/linagliptin are currently ongoing clinical trials.
- With Metformin alone, individuals had a stable C-peptide steady-state response that declined once treatment was removed. However, in those taking Insulin glargine followed by Metformin, there was a decreased C-peptide steady-state response, further falling after medication withdrawal.
- Over 15 months, beta-cell secretory capacity declined in youth and remained steady in adults.
- Dapagliflozin, Exenatide ER, Alogliptin, and Empagliflozin/linagliptin are currently ongoing clinical trials to treat youth-onset diabetes.
Gandica, Rachelle, and Phil Zeitler. “Update on Youth-Onset Type 2 Diabetes: Lessons Learned from the Treatment Options for Type 2 Diabetes in Adolescents and Youth Clinical Trial.” Advances in pediatrics vol. 63,1 (2016): 195-209. doi:10.1016/j.yapd.2016.04.013
Hannon, Tamara S et al. “Review of methods for measuring β-cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium.” Diabetes, obesity & metabolism vol. 20,1 (2018): 14-24. doi:10.1111/dom.13005
Liese, D.A. et al. (2021, June). Children with Type 2 Diabetes Are Not Just Little Adults. Copenhagen; Denmark. (Requires ADA Symposium login.)
Kornelia Ilias, Pharm.D. Candidate, Creighton University School of Pharmacy and Health Professions