HbA1c After a Short Period of Monotherapy With Metformin Identifies Durable Glycemic Control Among Adolescents With Type 2 Diabetes

Abstract

Objective: To determine whether clinically accessible parameters early in the course of youth-onset type 2 diabetes predict likelihood of durable control on oral therapy.

Research design and methods: TODAY was a randomized clinical trial of adolescents with type 2 diabetes. Two groups, including participants from all three treatments, were defined for analysis: (1) those who remained in glycemic control for at least 48 months of follow-up and (2) those who lost glycemic control before 48 months. Outcome group was analyzed in univariate and multivariate models as a function of baseline characteristics (age, sex, race/ethnicity, socioeconomic status, BMI, waist circumference, Tanner stage, disease duration, depressive symptoms) and biochemical measures (HbA1c, C-peptide, lean and fat body mass, insulin inverse, insulinogenic index). Receiver operating characteristic curves were used to analyze HbA1c cut points.

Results: In multivariate models including factors significant in univariate analysis, only HbA1c and insulinogenic index at randomization remained significant (P < 0.0001 and P = 0.0002, respectively). An HbA1c cutoff of 6.3% (45 mmol/mol) (positive likelihood ratio [PLR] 3.7) was identified that optimally distinguished the groups; sex-specific cutoffs were 6.3% (45 mmol/mol) for females (PLR 4.4) and 5.6% (38 mmol/mol) for males (PLR 2.1).

Conclusions: Identifying youth with type 2 diabetes at risk for rapid loss of glycemic control would allow more targeted therapy. HbA1c is a clinically accessible measure to identify high risk for loss of glycemic control on oral therapy. Adolescents with type 2 diabetes unable to attain a non-diabetes range HbA1c on metformin are at increased risk for rapid loss of glycemic control.

Trial registration: ClinicalTrials.gov NCT00081328.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1

Flow of participants into the two groups analyzed based on time to study primary outcome (failure to maintain glycemic control on randomized treatment assignment). Group 1 was followed to at least 48 months without having the primary outcome. Group 2 experienced the primary outcome within 48 months of follow-up.

Figure 2

Distribution of baseline HbA1c in each of the analysis groups. Baseline HbA1c was measured after a run-in period in which participants had to maintain HbA1c <8% (<64 mmol/mol) monthly for at least 2 months on metformin alone in order to remain eligible for randomization in the clinical trial. The graphic suggests that HbA1c on metformin monotherapy is a clinically practical indicator of ability to maintain glycemic control on oral agents. mo, months; PO, primary outcome, i.e., failure to maintain glycemic control on randomized treatment assignment.

Figure 3

ROC curves and HbA1c cutoffs, sensitivity, specificity, and PLR based on the Youden index over all participants (A) and by sex (B). PLR >1 indicates that the test result is associated with increased probability of failing oral therapy.

Figure 4

The Youden index HbA1c cutoffs, AUC and its 95% CI, and PLR overall and by sex and racial/ethnic subgroups (“other” race/ethnicity not presented). AUC is a measure of diagnostic accuracy ranging from 0.0 to 1.0, where 0.5 is equivalent to a coin toss (the “curve” looks like a diagonal line); AUC values 0.6–0.7 represent poor ability to predict failure, values 0.7–0.8 represent fair ability, and 0.8–0.9 represent good ability. The TODAY cohort is predominantly female and minority, which affects the overall estimates. The male cutoffs are 0.5–1.0% below the female. The AUC 95% CI includes 0.50 only for NHW males (n = 35) indicating that the cutoff is equivalent to simply guessing. A PLR (sensitivity/1 − specificity) >1 indicates that the test result (HbA1c) is associated with presence of the disease, and the larger the PLR, the greater the likelihood of disease.