Effect of Early Glycemic Control in Youth-Onset Type 2 Diabetes on Longer-Term Glycemic Control and β-Cell Function: Results From the TODAY Study

Abstract

Objective: Little is known about the impact of early attainment of tight glycemic control on long-term β-cell function and glycemic control in youth-onset type 2 diabetes. We examined the effect of the initial 6 months of glycemic control on β-cell function and glycemic control longitudinally over 9 years and the impact of sex, race/ethnicity, and BMI on these relationships in adolescents with youth-onset type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.

Research design and methods: Oral glucose tolerance tests were performed longitudinally through year 9 to derive estimates of insulin sensitivity and secretion. Early glycemia was defined by mean HbA1c during the first 6 months postrandomization, categorized into five HbA1c groups (<5.7%, 5.7 to <6.4%, 6.4 to <7.0%, 7.0 to <8.0%, and ≥8.0%). The long-term period was defined as the period between years 2 and 9.

Results: A total of 656 participants (64.8% female, baseline mean age 14 years, diabetes duration <2 years) had longitudinal data available over an average of 6.4 ± 3.2 years of follow-up. HbA1c significantly increased in all early glycemic groups during years 2-9, with a steeper increase (+0.40%/year) among participants with the tightest initial control (mean early HbA1c <5.7%), in parallel to a decline in the C-peptide-derived disposition index. Nevertheless, the lower HbA1c categories continued to have relatively lower HbA1c over time.

Conclusions: Early tight glycemic control in the TODAY study was related to β-cell reserve and translated to better long-term glycemic control. However, tight early glycemic control on the randomized treatment in the TODAY study did not prevent deterioration of β-cell function.

Graphical abstract

Figure 1

Longer-term (study years 2–9) rates of change of HbA_1c, insulin sensitivity, C-peptide index, C-oDI, and AUC_0–30 C-peptide/glucose (AUC Cpep/Glu) index by the five early-glycemia groups (defined as change in HbA_1c in 0–6 months). Linear mixed-effects models (unadjusted) were used for assessment of the effect of early glycemia categorized into five groups (<5.7%, 5.7–6.3%, 6.4–6.9%, 7.0–7.9%, and ≥8.0%) on longer-term outcomes means for HbA_1c (A), insulin sensitivity (B), C-peptide index (C), C-oDI (D), and AUC_0–30 C-peptide/glucose index (E) during study years 2–9. Log-transformed values of the outcomes were used for insulin sensitivity, C-peptide index, and C-oDI. Predicted means of the outcomes (arithmetic means for A and E; geometric means for B, C, and D) over time in each of the five groups are plotted, and the slope (β ± SE) representing the estimated change in the outcome per year is provided in each panel. Asterisks indicate if the slope is significantly increasing or decreasing (i.e., different from 0 or a flat line): *P < 0.05; **P < 0.01. Mean baseline BMI in each of the five groups is given in the legend for panel A. Significant differences (P < 0.05) in slopes between the five groups were evaluated in each linear mixed-effects model and are reported in each panel. Sample sizes at years 2, 3, 4, 5, 6, and 9 in the longer-term period were 495, 411, 392, 374, 349, and 300, respectively.