HbA_1c After a Short Period of Monotherapy With Metformin Identifies Durable Glycemic Control Among Adolescents With Type 2 Diabetes

TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) was the first and largest randomized clinical trial to examine approaches to management of youth-onset type 2 diabetes. Among the primary findings of TODAY was that metformin monotherapy was inadequate for maintenance of glycemic control in almost half of participants after median time to failure of ∼11 months (1). Furthermore, there were distinct sex and racial/ethnic differences in the pattern of failure overall and across treatment arms. This degree of failure on monotherapy was higher than expected from studies of adults with type 2 diabetes (2,3) and only partially prevented by the addition of rosiglitazone. Taken together, the findings suggest that type 2 diabetes among adolescents can be more rapidly progressive than in adults (4–7).

On the other hand, ∼50% of TODAY participants maintained durable glycemic control regardless of treatment group. This suggests that type 2 diabetes among adolescents is a heterogeneous disorder grossly divided between those who are and are not able to maintain glycemic control on oral therapy. If so, it would be of substantial clinical importance to properly classify patients early in the course of the disease so that appropriate treatment can be planned.

In this analysis, we address the hypothesis that readily available demographic and metabolic characteristics determined early in the course of type 2 diabetes can distinguish adolescents who will display durable glycemic control from those at risk for loss of glycemic control on oral therapy.

TODAY clinical trial rationale, design, and methods have been reported in detail (8) and are described briefly. Between July 2004 and February 2009, 699 youth aged 10–17 years, diagnosed with type 2 diabetes according to American Diabetes Association (ADA) criteria (9) for <2 years, with BMI ≥85th percentile, and negative for diabetes autoantibodies, were enrolled (10). After screening to determine eligibility, subjects completed a 2- to 6-month prerandomization run-in period in which they demonstrated mastery of standard diabetes education, were weaned from nonstudy diabetes medications, demonstrated tolerance of metformin 500–1,000 mg twice daily, maintained HbA_1c <8% (<64 mmol/mol) monthly for at least 2 months on metformin alone, and demonstrated adherence to study medication and visit attendance (11). Participants were randomized to one of three treatment arms: metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle program. Study baseline data were collected after run-in and before start of randomized treatment assignment. Participants attended clinic visits for medical management every 2 months in the first year and quarterly thereafter. The goal of diabetes medical management was to maintain HbA_1c levels as close to the normal range as possible in order to reduce long-term diabetes complications. During the trial, the investigators and the participants were blinded to specific HbA_1c values but were informed if HbA_1c was 1) ≥8% (≥64 mmol/mol), 2) 6–8% (42–64 mmol/mol) and increased from previous value by ≥0.8% (≥8.7 mmol/mol), or 3) ≤6% (≤42 mmol/mol) (target). The primary objective was to compare the three treatment arms on time to treatment failure, defined as either HbA_1c ≥8% (≥64 mmol/mol) over a 6-month period or inability to wean from temporary insulin therapy within 3 months after acute metabolic decompensation.

The protocol was approved by an External Evaluation Committee convened by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health and by the institutional review boards of each participating institution. All participants provided written informed consent, and minor children confirmed assent according to local guidelines.

Materials developed and used for the TODAY standard diabetes education program and the intensive lifestyle intervention program are available to the public at https://today.bsc.gwu.edu/.

Two outcome groups were defined for analysis. Group designation was assigned irrespective of original treatment arm. Group 1 participants remained in glycemic control (i.e., did not reach the primary outcome, as defined above) for at least 48 months of follow-up, and group 2 reached the primary outcome before 48 months; beyond 48 months, sample size was inadequate for analysis and data are not included.

Demographic and baseline characteristics in the analysis were age, sex, race/ethnicity (classified as non-Hispanic black [NHB], Hispanic [H], non-Hispanic white [NHW], or other), household annual income, highest education level of parents or guardians, first-degree family history of diabetes, Tanner stage (by physician examination), months since diagnosis of type 2 diabetes, and presence of depressive symptoms based on the Children’s Depression Inventory (12) for participants age ≤15 years or the Beck Depression Inventory (13) for participants age ≥16 years.

Baseline measures were BMI, HbA_1c at screening and randomization, C-peptide, and adiposity. Laboratories were performed by a central laboratory (8). Insulin sensitivity and β-cell function were derived from the 2-h oral glucose tolerance test as follows: insulin inverse = 1/insulin_{min 0}, and insulinogenic index = (insulin_{min 30} − insulin_{min 0})/(glucose_{min 30} − glucose_{min 0}). Measures of adiposity were waist circumference and DXA measures of fat (kg) and lean (kg) body mass; in approximately one-quarter of the subjects, DXA scans were excluded owing to weight limitations (weight >140 kg).

Logistic regression was used to model outcome group as a function of demographic variables, baseline characteristics, and baseline measures in univariate and multivariate analyses. Receiver operating characteristic (ROC) curve analyses were performed to identify optimal baseline HbA_1c cut points predictive of failure (as indicated by outcome group). The standard logistic regression model and the trapezoidal rule method were used to compute the total area under the curve (AUC) and its associated 95% CI in the overall analysis sample by sex, by race/ethnicity (NHB, H, NHW), and for the six sex-by-race/ethnicity combinations. Sensitivity and specificity were computed and the Youden index method was used to select the optimal threshold point from the ROC curve (14). The Youden index [maximum (sensitivity + specificity − 1)] maximizes the vertical distance from the line of equality to identify the point on the curve farthest from chance (15,16) and maximizes the classification rate. The positive likelihood ratio (PLR) (sensitivity/1 − specificity) was used to determine whether a baseline HbA_1c cutoff usefully changed the probability of failing oral therapy; PLR >1 indicates the test result is associated with increased probability (17). P values <0.05 were considered significant. P values were considered exploratory and were not adjusted for multiple testing; the study was powered only for the time-to-failure primary outcome.

The assignment of participants into the two analysis groups is shown in Fig. 1.

Demographic and baseline characteristics in group 1 (n = 172) versus group 2 (n = 305) are shown in Table 1. Group 1 had a significantly higher percentage of NHW and lower of NHB, a lower prevalence of depressive symptoms at the time of entry into the study, and a lower percentage of first-degree relatives with diabetes; total annual household income (≥$50,000) barely missed statistical significance (P = 0.0512). There were no differences by sex, treatment group, age, duration of diabetes, Tanner stage, or highest household education at study entry. There was also no difference in Tanner stage by sex in the analysis sample (90.5% of females and 87.3% of males were Tanner stage 4 or 5). There was no difference at any time between groups 1 and 2 in percentage of participants with study medication adherence ≥80% (data not shown).

In univariate analysis, screening and baseline HbA_1c and baseline insulinogenic index were identified as the only significant metabolic factors distinguishing those with durable glycemic control irrespective of treatment group; participants with durable control had significantly lower HbA_1c and higher insulinogenic index. Baseline measures of insulin sensitivity (fasting C-peptide and insulin inverse), measures of body fatness (BMI, waist circumference, and DXA fat mass), and DXA lean mass were not different between groups. Calculation of oral disposition index did not contribute beyond insulinogenic index alone (data not shown).

In multivariate models including all baseline demographic and metabolic factors significant in univariate analysis, only HbA_1c and insulinogenic index remained significant (P < 0.0001 and P = 0.0002, respectively). This was also true when treatment assignment was included in the model. With all other variable values held as fixed, there was a 16% increase in the odds of failing within 48 months of treatment for each 0.1% (1.1 mmol/mol) increase in HbA_1c from study baseline (after stabilization of HbA_1c <8% [<64 mmol/mol] during run-in but before start of study randomized treatment). Similarly, there was a 16% increase in the odds of failing within 48 months of treatment for each 0.1-unit decrease in insulinogenic index from study baseline.

Figure 2 shows a shift in the distributions of baseline HbA_1c for groups 1 and 2. Because HbA_1c is easily obtained in the clinical setting, this shift suggested a clinically practical basis for distinguishing between the groups. Overall, the Youden index identified an HbA_1c cutoff of 6.3% (45 mmol/mol) that maximized correct classification of participants (Fig. 3A), with sensitivity 54%, specificity 86%, and PLR 3.7. Figure 3B shows a sex difference in HbA_1c operator characteristics. Although both sexes had the same AUC (0.77), the ROC curves crossed, indicating that HbA_1c had higher specificity in females and higher sensitivity in males. The Youden index identified HbA_1c of 6.3% (45 mmol/mol) for females (sensitivity 59%, specificity 87%, and PLR 4.4) and 5.6% (38 mmol/mol) for males (sensitivity 88%, specificity 59%, and PLR 2.1) as the optimal cutoffs for classifying the risk of loss of durable control. This sex difference in optimal cutoff was true across race/ethnicity; the Youden index identified optimal HbA_1c cutoffs of 6.3, 6.4, and 6.6% (45, 46, and 49 mmol/mol) for NHB, H, and NHW females, respectively, but 5.8% (40 mmol/mol) for NHB and 5.6% (38 mmol/mol) for H and NHW males. Figure 4 summarizes HbA_1c cutoffs, AUC, and PLR overall and by sex and race/ethnicity in the sample of groups 1 and 2 combined. (Supplementary Table 1 gives sensitivity, specificity, and PLR overall by sex, by race/ethnicity, and by the interaction of sex with race/ethnicity.)

Since the ADA recommends a treatment target of 6.5% (48 mmol/mol), this value is often used by diabetes health care providers as a cutoff for determining whether to alter therapy. We compared the cutoff of 6.3 vs .6.5% (45 vs. 48 mmol/mol) in our analysis sample. Sensitivity for identification of participants who will lose glycemic control was 54 vs. 43%, while specificity rose from 86 to 91%. The PLR for an HbA_1c of 6.3% (45 mmol/mol) was 3.7 vs. 5.0 for 6.5% (48 mmol/mol). At an HbA_1c of 5.9% (41 mmol/mol), the PLR for loss of glycemic control was still >2. As expected from the sex-specific differences in Youden index, a cutoff of 6.5% (48 mmol/mol) had even lower sensitivity for identifying those likely to fail among males (35%, PLR 3.0) than females (48%, PLR 6.7). At an HbA_1c of 6.0% (42 mmol/mol), the PLR for both males and females was >2.

The TODAY primary outcome analysis demonstrated that type 2 diabetes presenting during adolescence was characterized by high rates of loss of glycemic control over a relatively brief period of time compared with adults (1). Although addition of rosiglitazone to metformin reduced the rate of loss of glycemic control by 23% over the course of the study, the median time to glycemic failure was the same regardless of treatment assignment. Furthermore, the incidence of loss of glycemic control plateaued over time regardless of treatment assignment. Taken together, these observations suggest that there may be subsets of adolescents with type 2 diabetes characterized as those at risk of losing glycemic control rapidly, those who will maintain glycemic control for a prolonged period of time, and those who may respond to addition of a second oral agent with improved maintenance of glycemic control. In particular, the early ability to distinguish patients who maintain glycemic control from those who are going to rapidly lose glycemic control would allow clinicians to identify high-risk patients who would benefit from closer monitoring and earlier intensification of therapy while supporting a less aggressive approach for those who are likely to maintain good glycemic control on metformin alone.

To examine this question, we analyzed the effect of demographic, anthropometric, and biochemical characteristics of the participants at the time of their randomization into TODAY on the likelihood of loss of glycemic control during follow-up. In univariate analysis, NHB race/ethnicity, depressive symptoms, first-degree family history of diabetes, and lower family income were all associated with rapid loss of glycemic control, as might be expected from previous literature in adults (18–21). Surprisingly, age, duration of diabetes, BMI, waist circumference, fat mass, and lean body mass at randomization had no effect on outcome, though this may be due, in part, to the relatively narrow range of each of these measures in the TODAY cohort (22). Among metabolic measures, only screening and baseline HbA_1c and insulinogenic index were associated with maintenance of glycemic control; insulin sensitivity did not differ between the groups. We did not explore screening HbA_1c further because the heterogeneous nature of the screened cohort in terms of treatment modalities made generalization of findings to a clinical population difficult.

In multivariate analysis, only baseline HbA_1c and insulinogenic index remained significant irrespective of treatment assignment. Studies in adults (2,3) and previous studies in the TODAY cohort (23,24) have shown that β-cell function is a strong determinant of HbA_1c. Therefore, HbA_1c already reflects information about β-cell function. Although both measures were significant predictors of durable control, HbA_1c is clinically more accessible than determination of insulinogenic index. Similarly, although demographic factors were shown to contribute to diabetes outcome in univariate analysis, it may be that the HbA_1c value already reflects these contributions, and these factors, therefore, disappeared as significant contributors to prediction of glycemic control in multivariate analysis in this cohort. Given the limitations of our data, we can only speculate on how these factors affect HbA_1c, perhaps through genetic, hormonal, nutritional, or behavioral influences on β-cell function. This analysis suggests that HbA_1c obtained after a short course of metformin monotherapy in adolescents with type 2 diabetes can function as a simple clinical measure to predict outcome and allow more effective targeting of therapy to those at highest risk for loss of glycemic control.

The next question is whether there is a specific HbA_1c cutoff value that is useful as a predictor of likely outcome. ROC analysis identified an HbA_1c of 6.3% (45 mmol/mol) as the optimal Youden cutoff for correctly categorizing an individual’s risk for loss of glycemic control on oral therapy, with an AUC of 0.77. The optimal cutoff was similar for females, reflecting the >60% representation of females in the cohort, but was substantially lower for males. This cutoff is lower than the ADA-recommended treatment target of 6.5% (48 mmol/mol) and probably lower than the level at which most clinicians would consider addition of a second agent. At a minimum, the analysis suggests that an HbA_1c cutoff of 6.5% (48 mmol/mol) has low sensitivity for identifying those adolescents; a youth with HbA_1c >6.5% (>48 mmol/mol) after a few months on metformin had a >70% chance of experiencing loss of glycemic control in a relatively short time on oral therapy alone. Indeed, both boys and girls with an HbA_1c >6.0% (>42 mmol/mol) had approximately double the risk for failure as individuals with an HbA_1c <6.0% (<42 mmol/mol). Together these data indicate that adolescents with type 2 diabetes who do not attain a non–diabetes range HbA_1c after a few months on metformin are at increased risk for losing glycemic control, and the clinicians caring for these youth should not be reassured that HbA_1c is “in target.” These individuals may benefit from closer monitoring or earlier initiation of supplemental therapy, despite an HbA_1c that meets current targets. For example, females with baseline HbA_1c higher than their optimal cutoff of 6.3% (45 mmol/mol) treated with rosiglitazone and metformin had a failure rate of 52% compared with 83% for metformin alone (Supplementary Data). Although the future role of rosiglitazone in the treatment of youth with type 2 diabetes remains unclear, these results point out the potential benefits of initiating combination therapy in selected patients who do not reach the optimal cutoff after a short course of metformin. Conversely, a youth with HbA_1c <6.0% (<42 mmol/mol) after a few months on metformin had a better than 70% chance of remaining in control on monotherapy for at least 4 years.

These findings do not suggest that there is benefit to treating patients to a lower HbA_1c than the ADA target; we did not perform an intervention trial with different targets to address this question. Rather, the analysis suggests that HbA_1c at the end of a relatively short course of metformin in these adolescents may reflect the severity of the underlying disorder and may be a marker of risk. Given the association of durable control with insulinogenic index and our previous demonstration that HbA_1c is strongly determined by insulin secretion in these youth (23,24), those who are not able to get their HbA_1c into the non–diabetes range within a few months are likely to have substantial deterioration in β-cell function already.

This analysis has a number of important strengths. First, although the analysis sample is composed of participants in a randomized clinical trial with rigorous eligibility criteria who remained in follow-up for at least 4 years, the demographics of the analyzed sample are comparable with demographics of the general population of youth-onset type 2 diabetes in the U.S. (25). Second, the participants in TODAY have been extensively characterized, allowing analysis of a broad set of demographic, anthropometric, and biochemical measures. Third, the cohort was followed longitudinally and all diabetes care was provided to the participants, allowing for analysis of causal relationships not possible in small and/or cross-sectional studies. On the other hand, despite the relatively large size of the TODAY cohort, the sample size is too small for more than exploratory analysis of sex-by-racial/ethnic subgroups. In addition, the ROC analysis yields AUC values in the range indicating fair predictive ability for HbA_1c, suggesting that there are other factors involved in determining likelihood of failure that are not fully reflected in HbA_1c. However, despite this limitation, HbA_1c remains the strongest predictor of likelihood of success or failure on metformin monotherapy in youth with type 2 diabetes and is an easily obtained clinical measure that may provide important clinical insight.

In summary, the population of youth with type 2 diabetes is heterogeneous and consists of subsets of individuals who are more or less likely to have durable glycemic control on oral therapy. Furthermore, the analysis demonstrates that HbA_1c after a few months of metformin monotherapy was the strongest predictor of response, likely reflecting underlying insulin secretion. Finally, these analyses indicate that adolescents with type 2 diabetes who do not attain a non–diabetes range HbA_1c after a few months on metformin are at increased risk of losing glycemic control, and the clinician caring for these youth should not be reassured with an HbA_1c “in target.” These findings suggest that HbA_1c obtained after a short course of metformin monotherapy in adolescents with type 2 diabetes may be a simple clinical measure to predict short- and medium-term outcome and allow better targeting of therapy to those adolescents at highest risk for loss of glycemic control. In the future, long-term follow-up of the TODAY cohort will be used to confirm and readjust our analysis and understanding of early markers for both diabetes control and diabetes-related complications and comorbidities.

Acknowledgments. The authors gratefully acknowledge the participation and guidance of the American Indian partners associated with the clinical center located at the University of Oklahoma Health Sciences Center, including members of the Absentee Shawnee Tribe, Cherokee Nation, Chickasaw Nation, Choctaw Nation of Oklahoma, and Oklahoma City Area Indian Health Service.

The opinions expressed in this article are those of the authors and do not necessarily reflect the views of the respective Tribal and Indian Health Service institutional review boards or their members.

Funding. This work was completed with funding from NIDDK and the National Institutes of Health Office of the Director through grants U01-DK-61212, U01-DK-61230, U01-DK-61239, U01-DK-61242, and U01-DK-61254; from the National Center for Research Resources (NCRR) General Clinical Research Centers Program through grants M01-RR00036 (Washington University School of Medicine), M01-RR00043-45 (Children’s Hospital Los Angeles), M01-RR00069 (University of Colorado Denver), M01-RR00084 (Children’s Hospital of Pittsburgh), M01-RR01066 (Massachusetts General Hospital), M01-RR00125 (Yale University), and M01-RR14467 (University of Oklahoma Health Sciences Center); and from the NCRR Clinical and Translational Science Awards through grants UL1-RR024134 (Children’s Hospital of Philadelphia), UL1-RR024139 (Yale University), UL1-RR024153 (Children’s Hospital of Pittsburgh), UL1-RR024989 (Case Western Reserve University), UL1-RR024992 (Washington University in St. Louis), UL1-RR025758 (Massachusetts General Hospital), and UL1-RR025780 (University of Colorado Denver). The NIDDK project office was involved in all aspects of the study, including design and conduct; collection, management, analysis, and interpretation of data; review and approval of the manuscript; and decision to submit the manuscript for publication.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Duality of Interest. The TODAY Study Group thanks the following companies for donations in support of the study’s efforts: Becton, Dickinson and Company; Bristol-Myers Squibb (BMS); Eli Lilly and Company; GlaxoSmithKline; LifeScan, Inc.; Pfizer; and Sanofi. P.Z. is a consultant for Daiichi-Sankyo, Merck, Takeda, Lilly, and BMS. L.L.K. is a consultant for Takeda Pharmaceuticals. N.H.W. serves on data-monitoring committees for Novo Nordisk and Daiichi-Sankyo. D.W. is a consultant for Shire Pharmaceuticals. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. P.Z. and K.H. researched data, contributed to the discussion, wrote the manuscript, and reviewed and edited the manuscript. K.C.C., L.L.K., and N.H.W. researched data, contributed to the discussion, and reviewed and edited the manuscript. L.E.g. researched data and reviewed and edited the manuscript. L.L.L., B.L., and D.W. contributed to the discussion and reviewed and edited the manuscript. P.M. contributed to the discussion and reviewed the manuscript. K.H. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.