The alternative criterion proposed by the joint IEC to use HbA1c
≥6.5% to diagnose T1D is premature given contradictory reports on its utility in pediatric and adolescent populations (16
). DPT-1, TrialNet, TEDDY, and TRIGR are among the largest high-risk T1D studies worldwide. Assessment of the value of HbA1c
as a diagnostic tool in subjects <21 years of age in these four studies demonstrated that the current HbA1c
threshold of 6.5% is not a sensitive indicator of T1D diagnosis in high-risk asymptomatic hyperglycemic individuals and in those diagnosed with T1D by OGTT. This study demonstrated that many subjects diagnosed with T1D by OGTT have an HbA1c
<6.5%, which suggests that this HbA1c
cutoff is too high as an early indicator of T1D. All four studies provided evidence that HbA1c
≥6.5% does not always mean that a subject has T1D, as shown by varying PPVs. Additionally, HbA1c
≥5.7% was not a sensitive indicator of IGT. These findings provide evidence that HbA1c
≥6.5% is not an adequate alternative criterion for diagnosing T1D in high-risk subjects <21 years of age.
Studies of HbA1c
and diabetes in pediatric populations have been sparse, and their findings have been contradictory. A recent study from the Diabetes Incidence Registry (DIARY) Group Baden Wuerttemberg concluded that HbA1c
is a reliable measure for diagnosing T1D in youth (17
); however, these findings were based on cross-sectional data, which only included youth with blood glucose >200 mg/dL (11.1 mmol/L). Those with blood glucose <200 mg/dL were not assessed. They noted that HbA1c
≥6.35% was optimal in their sample. A larger study using National Health and Nutrition Examination Survey data (16
) evaluated the utility of HbA1c
as a diagnostic tool for diabetes (predominantly T2D) in an adolescent population and concluded that HbA1c
, compared with FPG, is not a sensitive indicator of diabetes in adolescence (75% [95% CI 30–95]). This finding was consistent with the current study. HbA1c
may be a promising alternative criterion for diagnosing T2D, which develops more slowly over time and is characterized by a more stable increase in hyperglycemia because of insulin resistance. T1D arises more rapidly, and children tend to have more bouts of transient hyperglycemia that may not be identified by HbA1c
while still meeting the IEC definition for diabetes as measured by OGTT or FPG.
measures over time may show promise as an early indicator in individuals at high risk. In the Diabetes Autoimmunity Study in the Young (DAISY) (4
), an increase in HbA1c
over time was predictive of progression to T1D. Stene et al. (4
) reported that a 0.4% point increase in HbA1c
corresponded to a fivefold increase in T1D risk with modest increases starting as early as 5 years prior to diagnosis, followed by a sharp increase 6 months prior to diagnosis.
This analysis is not without limitations. Our primary limitation is that our population was all high risk, which accounts for 15–20% of all cases of T1D. Secondly, both the TEDDY and TRIGR studies did not conduct routine OGTTs; TRIGR only performed OGTTs on subjects ≥6 years of age, so it is possible that these subjects were further along in T1D progression and may have had higher HbA1c levels as a result. The TRIGR study did not use a reference laboratory for processing HbA1c and OGTT samples, and TEDDY used local laboratories for OGTT sample evaluations. Although these two studies used methods that adhere to a more practical manner of monitoring high-risk subjects, the TEDDY results were very similar to those found in both DPT-1 and TrialNet. The current study used the diagnostic HbA1c in asymptomatic hyperglycemic subjects because two measures of HbA1c were not uniformly collected in TEDDY at or postdiagnosis. A second HbA1c is primarily used as a confirmation test, with the implication that it would reduce the number of false positives. However, our false-positive rate was very low (). Given this, if a second HbA1c failed to confirm diabetes then the sensitivity would actually be less than we have shown. Lastly, a 90-day window for the HbA1c-OGTT pair was used to determine eligibility; however, the vast majority of the HbA1c measures were conducted within 30 days of the OGTT. Although the HbA1c is a 90-day moving average, it has been shown to be more heavily weighted toward the last 30 days; thus, we extended our analysis to assess the effect those few subjects who had an HbA1c-OGTT pairing outside of the 30-day window had on our findings by only including those with a 30-day window and found there were no differences in sensitivity, specificity, or PPV.
The diagnostic performance of various diabetes indicators is in need of careful evaluation. Redefining a lower threshold for HbA1c
will be more optimal for diagnosing diabetes. Further understanding of the relationship between known markers of clinical disease (HbA1c
, FPG, random glucose, and OGTT) and T1D symptoms and complications with a focus on when to initiate treatment is needed. Until then, the OGTT, a sensitive indicator of diabetes and an early marker of impaired glucose homeostasis (18
), is the better diagnostic option for T1D.