Hemoglobin A_1c and Mean Glucose in Patients With Type 1 Diabetes: Analysis of data from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial

The JDRF CGM randomized trial protocol has been described in detail previously (7–9). Major eligibility criteria included age >8 years, type 1 diabetes for at least 1 year, use of either an insulin pump or at least three daily insulin injections, and an HbA_1c value <10.0%. Subjects were randomly assigned to either a CGM group or a control group that used standard home blood glucose monitoring for the first 6 months. After 6 months, both groups used CGM.

Subjects received one of the following CGM devices: the DexCom SEVEN (DexCom, San Diego, CA), the MiniMed Paradigm REAL-Time insulin pump and continuous glucose monitoring system (Medtronic MiniMed, Northridge, CA), or the FreeStyle Navigator (Abbott Diabetes Care, Alameda, CA). Each subject was instructed to wear the sensor on a continuous basis.

HbA_1c values were measured at the University of Minnesota using the Tosoh HbA_1c 2.2 Plus Glycohemoglobin Analyzer (10). The cohort did not contain enough non–white or Hispanic subjects to evaluate race/ethnicity.

We limited our analysis to subjects who averaged ≥4 days per week of CGM use in the 3 months before an HbA_1c measurement. To minimize the impact of changing glycemic control after the introduction of CGM, we only analyzed the 3 months of CGM data collected before the 12-month (end-of-study) HbA_1c measurement. An HbA_1c value was obtained for 436 subjects who completed the 12-month visit. Of these, 252 subjects had worn their CGM device for an average of ≥4 days per week during the prior 3 months and were included in these analyses.

Mean glucose concentrations were calculated over the 91-day period before the HbA_1c measurement, giving equal weight to each of the 24 h of the day. Similar calculations were done for the mean glucose values during the 1-month (30-day) and 2-month (61-day) intervals before the HbA_1c measurement. Least–squares regression analysis was performed using mean glucose concentration as the dependent variable and HbA_1c as the independent variable (linear term). Fitting higher order polynomial terms showed no deviation from linearity. Residual values were examined to verify that they followed an approximate normal distribution. No outliers or overly influential data points were identified. A plot of residuals against predicted values showed no meaningful deviation from the assumption of homoscedasticity.

At the 12-month visit, the 252 subjects in analysis ranged in age from 9 to 74 years (mean ± SD: 32 ± 17), with 21% of subjects <15 years, 24% between 15 and 24 years, and 55% ≥25 years. Median duration of diabetes was 7 years (25th to 75th percentile, 4–9) for children, 8 years (5–10) for adolescents, and 24 years (17–32) for adults; 54% were female and 94% were white. HbA_1c values ranged from 5.1 to 9.6% (7.1 ± 0.8%). Approximately half of subjects had a stable HbA_1c value, with 55% being within ±0.2% of the HbA_1c value measured 3 months prior, 21% improving ≥0.3%, and 24% worsening ≥0.3% over the last 3 months. In total, 346,434 h of CGM glucose values (median 1,433 h per subject) were analyzed.

The slope (95% CI) for mean sensor glucose concentration (area under the curve) versus a centrally measured HbA_1c was 24.4 mg/dL (22.0–26.7) for each 1% change in HbA_1c with an intercept of −16.2 mg/dL (−32.9 to 0.6) (Fig. 1 and Table 1). Using only 1 or 2 months of glucose data before the HbA_1c measurement did not alter the slope (Table 1).

The slope of mean glucose concentration versus HbA_1c value did not vary meaningfully by age, sex, or type of CGM device (Table 1). Although only 42 of the 252 subjects were not insulin pump users, the mode of insulin delivery did not materially alter the slope. Reanalyzing the data using only the 195 subjects whose HbA_1c remained within ±0.4% of the value obtained 3 months earlier or the 138 subjects whose HbA_1c remained within ±0.2% did not materially alter the slopes.

Substantial individual variability existed in the relationship between HbA_1c and mean glucose concentration. For HbA_1c values between 6.9 and 7.1% (n = 46), the average sensor mean glucose concentrations ranged from 128 to 187 mg/dL. For HbA_1c values between 7.9 and 8.1% (n = 16), the average sensor mean glucose concentrations ranged from 154 to 223 mg/dL (Fig. 1). The root mean square of the errors between the actual mean sensor glucose concentration versus the value calculated using the regression equation was 14.3 mg/dL, whereas the median absolute difference was 10.1 mg/dL. A total of 91% of subjects had mean glucose concentrations within ±15% of the calculated average glucose concentrations (calculated from HbA_1c).

The estimated slope of the relationship between mean glucose concentration and HbA_1c has varied from study to study (Table 2). In studies that used infrequent discrete blood glucose testing, Hempe et al. (11) found a slope of 18.5 mg/dL for each unit (%) change in HbA_1c, whereas Rohlfing et al. (12) and Makris et al. (13) found slopes of ∼35 mg/dL for each unit (%) change in HbA_1c, a number that was used to describe the relationship for a decade. These investigators also found wide variability between measured mean glucose concentrations and estimated average glucose values calculated using their regression equations.

In our study, the slope of the regression line was 24–25 mg/dL glucose for every 1% change in HbA_1c. This value is lower than values reported earlier using six to seven intermittent sample blood glucose profiles (11,12) but similar to the results of other studies that used CGM (14–16). For example, using CGM, Mazze (14) found a slope of 26.3 with mean glucose concentration as the dependent variable.

Nathan et al. (15) and Borg et al. (17) used a combination of both intermittent discrete and intermittent CGM data from adults with and without diabetes. They found a slope of 28.7 mg/dL glucose for every 1% change in HbA_1c using CGM data (15), which was also similar to the value in the current study, and a correlation of 0.89 between HbA_1c and mean glucose using CGM and self-monitoring blood glucose data combined (17).

It is not surprising that the relationship between measured glucose concentrations and HbA_1c differs with the use of CGM compared with episodic blood glucose monitoring. One might expect that the addition of a more complete 24-h measure of glucose concentrations would provide a tighter and more accurate assessment of the relationship between glucose concentrations and HbA_1c values. There are limitations to the determination of the relationship between glucose and HbA_1c with the current study. However, we did not find any major differences in the relationships between glucose concentrations and HbA_1c values when considering patients whose HbA_1c was stable and patients whose HbA_1c changed over the time interval of observation. Individual biological variation in erythrocyte survival or glycation rates might contribute to the discrepancy between estimated and measured mean glucose concentrations in individual subjects. Future analysis will examine the consistency of the relationship between glucose and HbA_1c in the same patient over time.

Subgroup analyses in our study showed that the slope of mean glucose concentration versus HbA_1c value was not clinically or statistically different by age-group, sex, or sensor type. In our study, we did not have a sufficient number of non-white subjects to evaluate the relationships of mean glucose concentration versus HbA_1c in other ethnic and racial groups.

It is important to note that all studies have reported substantial variability between the measured mean glucose concentrations and the estimated values calculated from regression equations (Table 2). As an example, Nathan et al. (15) reported that only slightly <90% of subjects had measured glucose concentrations within ±15% mean glucose concentrations predicted by HbA_1c. We found a similar value in the current study (91%).

CGM typically has a relative error ranging from 14 to 20% (18–21). Quality control samples conducted during this study for HbA_1c, in contrast, showed that 99% of repeat measurements were within ±0.1% of the original value. This result suggests that the measurement error for HbA_1c is negligible compared with that for CGM used to calculate the mean glucose in this analysis.

Although there are challenges in measuring mean glucose concentrations with CGMS as well, the errors with these devices are generally unbiased, with mean errors typically centered around zero. Moreover, CGMS can provide an unprecedented view across time. In the current study, we had nearly complete glycemic data, day and night, for the entire 3 months of glucose concentrations before an HbA_1c measurement. Consequently, our findings of considerable discrepancies between actual and estimated mean glucose concentrations lead us to disagree with the conclusions of Nathan et al. (15) that a calculated mean glucose is clinically equivalent to a measured mean glucose. HbA_1c measures are extremely precise, and there are substantial individually persistent variations in the ratio between HbA_1c and mean glucose. Thus, estimated mean glucose values calculated from measured HbA_1c values should be used with caution.

Co-authors: Darrell M. Wilson, MD¹; Dongyuan Xing, MPH²; Roy W. Beck, MD, PHD²; Jennifer Block, RN, CDE¹; Bruce Bode, MD³; Larry A. Fox, MD⁴; Irl Hirsch, MD⁵; Craig Kollman, PHD²; Lori Laffel, MD, MPH⁶; Katrina J. Ruedy, MSPH²; Michael Steffes, MD, PHD⁷; William V. Tamborlane, MD⁸, of the JDRF Continuous Glucose Monitoring Study Group.

¹Stanford University, Stanford, California; the ²Jaeb Center for Health Research, Tampa, Florida; ³Atlanta Diabetes Associates, Atlanta, Georgia; the ⁴Nemours Children’s Clinic, Jacksonville, Florida; the ⁵University of Washington, Seattle, Washington; the ⁶Joslin Diabetes Center, Boston, Massachusetts; the ⁷University of Minnesota, Minneapolis, Minnesota; ⁸Yale University, New Haven, Connecticut.

This study was supported by JDRF (Grants 22-2006-1107, 22-2006-1117, 22-2006-1112, 22-2006-1123, and 01-2006-8031).

J.B. has received consulting fees from Abbott Medtronic MiniMed. B.B. has received consulting fees, honoraria, travel reimbursement, and research funds from Medtronic MiniMed and grant support from DexCom. I.H. has received consulting fees and travel reimbursement from Abbott Diabetes Care. C.K. has received consulting fees from Medtronic MiniMed. L.L. has received consulting fees and a speaker honorarium from Abbott Diabetes Care and consulting fees and research funding from Medtronic MiniMed. W.V.T. has received consulting fees from Medtronic MiniMed. No other potential conflicts of interest relevant to this article were reported.

D.M.W. researched data, contributed to discussion, wrote the manuscript, and reviewed and edited the manuscript. D.X. contributed to discussion, wrote the manuscript, and reviewed and edited the manuscript. R.W.B. contributed to discussion and reviewed and edited the manuscript. J.B. contributed to discussion. B.B. researched data, contributed to discussion, and reviewed and edited the manuscript. L.A.F. researched data, contributed to discussion, and reviewed and edited the manuscript. I.H. researched data, contributed to discussion, and reviewed and edited the manuscript. C.K. contributed to discussion and reviewed and edited the manuscript. L.L. researched data, contributed to discussion, and reviewed and edited the manuscript. K.J.R. researched data, contributed to discussion, and reviewed and edited the manuscript. M.S. researched data and reviewed and edited manuscript. W.V.T. researched data, contributed to discussion, and reviewed and edited the manuscript.

The study was designed and conducted by the investigators. The writing group collectively wrote the manuscript and vouch for the data. The investigators had complete autonomy to analyze and report the trial results. There were no agreements concerning confidentiality of the data between the JDRF, the authors, or their institutions. The Jaeb Center for Health Research had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Continuous glucose monitors and sensors were purchased at a bulk discount price from DexCom (San Diego, CA), Medtronic MiniMed (Northridge, CA), and Abbott Diabetes Care (Alameda, CA). Home glucose meters and test strips were provided to the study by LifeScan and Abbott Diabetes Care. The companies had no involvement in the design, conduct, or analysis of the trial or the manuscript preparation.

The JDRF CGM study group would like to recognize the efforts of the subjects and their families and thank them for their participation.