The Rationale Behind Glycemic Worsening in Children and Adults

Are there predictors of glycemic worsening among patients recently diagnosed with type 2 diabetes?  

The prevalence of insulin resistance increases with rising obesity rates, as adipose tissue releases pro-inflammatory cytokines and hormones. As a result, the deteriorated pancreatic beta cells fail to control blood glucose levels. Further loss of beta-cell function is established among patients with prediabetes, as shown in a longitudinal observational study. In the TODAY study, metformin alone led to robust glycemic control in about 50% of children and adolescents with type 2 diabetes. However, the addition of rosiglitazone, a thiazolidinedione, was superior to metformin. The Restoring Insulin Secretion (RISE) studies examined if beta cell function could be preserved using pharmacologic intervention in both youth and adults with impaired glucose interventions or recently diagnosed with type 2 diabetes.  

The RISE Pediatric and Adult Medication studies were two clinical trials in the RISE Consortium, which enrolled patients with a recent diagnosis of type 2 diabetes or impaired glucose tolerance. The RISE Pediatric study was a randomized, open-label clinical trial that compared 12-month interventions with insulin glargine for three months with metformin for nine months vs. metformin alone in patients aged 10-19 years. The Adult Medication study was a randomized, partially blinded trial that compared 12-month interventions with insulin glargine and metformin, metformin alone, liraglutide and metformin, or placebo. In the pediatric study, participants were required to have a fasting blood glucose of ≥90 mg/dL and HbA1c ≤8.0% if they were drug naïve. If they were taking metformin for less than three months, they were required to have an HbA1c of ≤7.5%, and if they were taking metformin for 3-6 months, an HbA1c of ≤7.0% was required. In the adult trial, patients had to be between 20-65 years of age with impaired glucose tolerance or diagnosed with type 2 diabetes for less than 12 months without medications. In addition, they were required to have a fasting blood glucose of 95-125 mg/dl and an HbA1c ≤7%. HbA1c, as well as fasting and postprandial glucose levels, were all measured in these analyses. The goal of the RISE studies was to identify predictors of glycemic intolerance in patients recently diagnosed with type 2 diabetes or who had impaired glucose tolerance. All participants received a 3-hour oral glucose tolerance test at baseline, month 6, month 12, and when off treatment at months 15 and 21. An increase in HbA1c by ≥0.5% from baseline to month 12 and from baseline to month 21 defined glycemic worsening. Baseline factors were identified using Cox proportional hazard models, which were adjusted in the treatment arm.  

During months 12 and 21, youth developed a significantly higher rate of glycemic worsening than adults, defined by an increase in HbA1c by ≥0.5%. (M12: 17.8% vs. 7.5%, P = 0.008; M21 36.7% vs. 20%, respectively, P = 0.002). 14.4% of youth and 3.9% of adults had a significant increase in HbA1c of ≥10% at month 12 (P<0.001), and 31.3% of youth and 14.9% of adults at month 21 (P<0.001). The treatment group did not affect glycemic worsening in the pediatric study, as it was associated with a higher baseline HbA1c at months 12 and 21 (P=0.0241 and P=0.008, respectively). Glycemic worsening at month 21 was also associated with higher baseline fasting glucose levels (P=0.044). In the adult study, the overall treatment group was borderline significant in predicting glycemic worsening with a significant increase in HbA1c of ≥0.5% in only month 12 (P=0.089). Liraglutide and metformin reduced glycemic worsening at month 12 compared with placebo (hazard ratio, 0.21; 95% CI 0.05–0.96, P = 0.044). HbA1c, fasting glucose, and postprandial glucose were not associated with glycemic worsening in adults, while lower basal sensitivity was. 15.9% of youth who had improper glucose tolerance at baseline progressed to diabetes by month 12, while 25% progressed by month 21. In the adult population, 21.2% progressed to diabetes by month 12 and 39.1% by month 21.  

Overall, this study showed that pharmacological interventions did not reduce glycemic worsening or progression of type 2 diabetes in youth, liraglutide and metformin were effective together in adults less than nine months after treatment withdrawal, and glycemic worsening was more significant in youths. In addition, beta-cell dysfunction at baseline was a significant reason for glycemic worsening. In adults, baseline insulin sensitivity was a secondary predictor of glycemic worsening. While previous cross-sectional studies have shown youth gaining a more accelerated progression of type 2 diabetes, this study showed a decline in glycemic control. Although liraglutide and metformin were not effective after treatment withdrawal, they were still effective during treatment, suggesting that this study supports the need for alternative approaches for improving beta-cell function using GLP-1 agonists.   

Practice Pearls:  

• Glycemic worsening is common in adults and children with recently diagnosed diabetes or impaired glucose tolerance.  
• The RISE clinical trials found that glycemic worsening was predicted by lower baseline beta-cell function in adults and children, hyperglycemia in children, and insulin resistance in adults.  
• These trials also suggest GLP-1 agonists have the potential to improve beta-cell function during treatment.  

Kahn, Steven E et al. “Mechanisms linking obesity to insulin resistance and type 2 diabetes.” Nature  

Glauber, Harry et al. “A Simple Model for Predicting Two-Year Risk of Diabetes Development in Individuals with Prediabetes.” The Permanente journal  

TODAY Study Group et al. “A clinical trial to maintain glycemic control in youth with type 2 diabetes.” The New England journal of medicine 

Sam, Susan et al. “Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study.” Diabetes care 

Dalia Elabed, PharmD Candidate 2022, University of South Florida Taneja College of Pharmacy