Youth-onset type 2 diabetes mellitus: lessons learned from the TODAY study

Abstract

Type 2 diabetes mellitus is increasingly diagnosed in obese children and adolescents. Evidence suggests that this disease commonly progresses more rapidly in youth compared with adults and is associated with high rates of early microalbuminuria, hypertension, and dyslipidemia. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study was the first multiethnic, multicenter randomized trial in the United States to compare 3 treatment approaches in obese youth with new-onset type 2 diabetes (n=699; ages 10-17 years): monotherapy with metformin, metformin with rosiglitazone, and metformin with an intensive lifestyle intervention. The primary outcome was glycemic control. Diabetes-related complications and cardiovascular risk factors were also examined. Approximately half of the participants could not maintain glycemic control by using metformin alone. Combination therapy with metformin and rosiglitazone resulted in better durability of glycemic control, and metformin plus intensive lifestyle intervention was intermediate but not superior to metformin alone. Deterioration in glycemic control was associated with rapid loss of beta cell function, not worsened insulin sensitivity, and could not be explained by differences in adherence or body mass index. After 3.9 years, 236 (33.8%) of participants had hypertension and 116 participants (16.6%) had microalbuminuria. Only 55.9% of participants had a low-density lipoprotein cholesterol level less than 100 mg/dL (to convert to mmol/L, multiply by 0.0259) after 3 years, and 71 of 517 participants (13.7%) had retinopathy. The significance of the findings from this important trial for the management of youth and young adults with youth-onset type 2 diabetes and its complications is discussed. An aggressive multifaceted approach is needed to prevent or forestall premature microvascular and macrovascular complications in youth-onset type 2 diabetes.

Figure 1. Design of the TODAY Study

ACE-I=angiotensin converting enzyme inhibitor; BMI=body mass index; GAD=glutamic acid decarboxylase; HbA1C: hemoglobin A1C; IA-2= insulinoma-associated protein 2 Adapted from Pediatr Diabetes¹⁵, with permission. Data also from N Engl J Med¹⁸

Figure 2. The TODAY Study: Overall Primary Outcome Results

Survival curves for freedom from glycemic failure are shown. Data are for up to 60 months of follow-up (accounting for 98.4% of cases of glycemic failure), although the rates and analysis are based on the complete data set. From N Engl J Med¹⁸, with permission.