Impact of Implementing Glycated Hemoglobin Testing for Identification of Dysglycemia in Youth
Perm J 2014 Fall; 18(4):21-27 [Full Citation]
Objectives: To determine the impact of the introduction of the glycated hemoglobin (HbA1C) assay for diabetes mellitus diagnosis among children and adolescents aged 6-17 years and to describe the composition of the population of patients with, and at risk for, diabetes using fasting plasma glucose test and HbA1C assay.
Research Design and Methods: The Kaiser Permanente Hawaii (KPHI) and Kaiser Permanente Northwest (KPNW) sites identified a 2009 and a 2012 cohort of youth who were aged 6-17 years and continuously enrolled in their cohort year and for 1 year prior. We excluded youth with a type 1 or type 2 diabetes diagnosis before their cohort year.
Results: In both sites, fasting plasma glucose testing was significantly more common in 2009 and HbA1C testing was more common in 2012. The proportion with either test increased from 2.56% to 4.02% in KPNW and from 3.18% to 10.48% in KPHI, but the characteristics of the population did not change between 2009 and 2012. In both sites, the characteristics of youth at risk of diabetes changed substantially with a much greater proportion being female (KPNW: 39% vs 55%; KPHI: 35% vs 46%; p < 0.001 for both) and children younger than 10 (KPNW: 7% vs 32%; KPHI: 11% vs 39%; p < 0.001 for both) between 2009 and 2012. The size and composition of the population of youth identified with diabetes was not affected.
Conclusions: Adoption of the HbA1C assay for diabetes diagnosis has increased glycemia testing among youth aged 6-17 years and has altered the composition of the population identified as at risk for diabetes. These findings have important ramifications for targeted screening and diabetes prevention efforts.
Before 2010, the American Diabetes Association (ADA) recommended the use of fasting plasma glucose (FPG) test, casual plasma glucose tests if symptoms of hyperglycemia were present, or 75 g oral glucose tolerance tests to diagnose diabetes.1 Following a consensus report from the International Expert Committee,2 the ADA recommended the inclusion of the glycated hemoglobin (HbA1C) assay as a diagnostic tool in its 2010 Clinical Practice Recommendation.3 Among the advantages of the HbA1C assay is that it does not require the patient to fast, thereby potentially providing increased screening opportunities. However, it is widely recognized that HbA1C assay, FPG, and oral glucose tolerance tests do not perfectly overlap, so the substitution of HbA1C assay for diagnosis would likely change the composition of the diabetes and at-risk population, which in turn would alter the epidemiology of hyperglycemia.4,5 To our knowledge, the population effects of implementing HbA1C assay for diagnosis of diabetes and for identification of individuals at risk for diabetes has not been reported in an outpatient population.
Preventing type 2 diabetes onset in children is becoming increasingly important because of the dramatic rise in the prevalence of at-risk children and adolescents6 and the subsequent risk of developing diabetes in adulthood.7 Furthermore, type 2 diabetes is a growing problem among youth aged 10 to 19 years.8 The ADA9 currently recommends that children with a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) equal to or greater than the 85th percentile for age and sex and with any 2 of these risk factors: family history of type 2 diabetes in first- or second-degree relative, race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander), signs of insulin resistance, and maternal history of diabetes or gestational diabetes mellitus during the child's gestation should be screened for diabetes starting at age 10 years or at the onset of puberty. Given the rise in type 2 diabetes among youth, however, earlier screening may be appropriate, but data on prevalence of diabetes and at-risk children in their first decade of life is scant.
Our primary objective was to determine the impact of the introduction of the HbA1C assay for diabetes diagnosis among children and adolescents aged 6 to 17 years. Secondarily, we describe the composition of the population of patients with, and at risk for, diabetes resulting from the differential use of FPG test and HbA1C assay.
The study sites were Kaiser Permanente (KP) Hawaii (KPHI) and Kaiser Permanente Northwest (KPNW), 2 group-model health maintenance organizations that provide integrated health care to approximately 220,000 members in Hawaii and 475,000 members in the Portland, OR, area. Both KPHI and KPNW maintain similar electronic medical record databases that contain information on all inpatient admissions, pharmacy dispenses, outpatient visits, and laboratory tests. In each site, we identified 2 cohorts: the first cohort included individuals identified from January 1, 2009, through December 31, 2009, and the second from January 1, 2012, through December 31, 2012. The cohorts consisted of youth who were aged 6-17 years in their cohort year and were continuously enrolled in their cohort year and for 1 year prior. We excluded members with an International Classification of Diseases, Ninth Revision diagnosis of type 1 or type 2 diabetes before their cohort year. We specifically selected 2009 because it was the year before HbA1C assay was endorsed by the ADA for use as a diagnostic test for diabetes, and 2012 because it was the most recent full year available after HbA1C assay was endorsed. The use of 2012 allowed sufficient time to have elapsed for full effect of the use of HbA1C assay to be observed. Age, sex, height, weight, race/ethnicity, FPG, and HbA1C were obtained from the electronic medical record. Self-reported race/ethnicity is routinely collected upon Health Plan enrollment, and patients can report up to 5 races and 5 ethnic groups. For the analysis, we have grouped race/ethnicity into 2 categories. Patients are grouped as non-Hispanic whites if they indicate such with no other race/ethnicity indicated. Patients who indicate a single nonwhite race, Hispanic ethnicity, or multiple races are considered as minority, which includes Asian, Hawaiian Pacific Islander, and other mix. Individual minority race/ethnicity categories were too small to analyze meaningfully, and because they have similar risk factors for developing diabetes, we combined them as "minority race/ethnicity." This study was reviewed and approved by the KPHI and KPNW institutional review boards.
Glucose Testing and Body Mass Index Percentile
Laboratories at KPHI and KPNW use College of American Pathologists proficiency testing as recommended by the ADA, and both sites are certified by the National Glycohemoglobin Standardization Program. In Hawaii, the HbA1C assay is run on two instruments: Bio-Rad Variant II and Bio-Rad Variant II Turbo (Bio-Rad Laboratories, Hercules, CA); KPNW uses Cobas Integra 800 (Roche Diagnostics, USA).
We assessed the proportion of each cohort that received an FPG test or HbA1C test in their cohort year. At-risk for diabetes and diabetes was diagnosed with a single diagnostic laboratory value. We then determined the proportion that met diagnostic criteria for being at risk for diabetes (FPG 100-125 mg/dL or HbA1C 5.7%-6.4% [39-46 mmol/mol]) or for having diabetes (FPG > 126 mg/dL or HbA1C > 6.5% [>48 mmol/mol]). If multiple values of a given test were available, we considered any elevated value above the appropriate diagnostic level as indicative of that form of hyperglycemia. BMI percentile was estimated from the charts provided by the Centers for Disease Control and Prevention.10 We used the mean of all values when multiple BMI percentile measures in a year were available.
Clinicians at both KP Regions have access to the national guidelines, which track very closely to ADA recommendations. The ADA9 currently recommends that children with a BMI equal to or greater than the 85th percentile for age and sex and with any 2 of these risk factors: family history of type 2 diabetes in first- or second-degree relative, race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander), signs of insulin resistance, and maternal history of diabetes or gestational diabetes mellitus during the child's gestation should be screened for diabetes starting at age 10 years or at the onset of puberty. However, there is no mandated policy and KP clinicians are free to practice medicine in the way they believe best suits their patients, but they are encouraged to consult and follow national guidelines.
All analyses were conducted with SAS software, version 9.3 (SAS Institute, Cary, NC). Within each study site, we compared mean values using Fisher exact tests and proportions or categories using c2 tests. We present the results separately for KPHI and KPNW to examine the consistency of the findings across two different geographic locations with a decidedly different mix of race/ethnicity.
The 2009 and 2012 cohorts were of nearly identical size in both KPNW (~58,000) and KPHI (~26,000) (Table 1), and the demographic composition of the cohorts in both sites was similar in each year. Mean age was 11.8 years in both KPNW cohorts, and 11.7 years in both KPHI cohorts. In both sites, the percentage of female participants was identical between cohort years (KPNW 51.1%; KPHI 48.9%). In KPNW, the number with a BMI measurement was substantially lower in 2012, but the distribution of BMI percentile was significantly different with a greater proportion in the upper percentiles. The BMI percentile distribution was not significantly different between cohorts in KPHI. About 17% of each KPNW cohort and 85% of each KPHI cohort were of minority race/ethnicity.
In both settings, FPG testing was significantly more common in 2009 compared with 2012, but HbA1C testing was more common in 2012 (Table 2). The proportion with either test increased from 2.56% to 4.02% in KPNW and from 3.18% to 10.48% in KPHI (p < 0.001 for both sites). The proportion identified as at-risk for diabetes by either test increased significantly in both sites from 2009 to 2012 (KPNW: 0.19% vs 1.34%; KPHI: 0.56% vs 1.77%, p < 0.001 for both sites), but the proportion identified with diabetes was not significantly different in either site.
Table 3 displays the characteristics of youth identified as at-risk for diabetes by cohort year and study site. In both KPNW and KPHI, mean age for youth at risk for diabetes declined significantly between 2009 and 2012, owing to a much larger proportion aged 6 to 9 years in 2012 (KPNW: 7% vs 32%; KPHI: 11% vs 39%; p < 0.001 for both sites). In addition, a significantly larger proportion of females were identified in 2012 in both sites (KPNW: 39% vs 55%; KPHI: 35% vs 46%; p < 0.001 for both sites). Following the pattern of the total cohorts, the distribution of BMI percentile shifted significantly at KPNW but not at KPHI among at-risk youth. The proportion at risk for diabetes that was of minority race/ethnicity was not significantly different between cohorts at either site. At KPHI, mean age among those identified with diabetes was higher in 2009 compared with 2012 (13.8 vs 11.5, p = 0.044), but there were no other differences between cohorts in the characteristics of youth identified with diabetes at either site (Table 4).
Table 5 displays the percentage tested with either FPG test or HbA1C assay, the percentage at risk for diabetes, and the percentage with diabetes for key age, sex, BMI, and racial/ethnic strata. Testing was more common at KPHI, but overall the results were consistent across all strata; similar percentages were found in each cohort year, and similar changes were observed from 2009 to 2012 regardless of the age, sex, BMI, or race/ethnicity strata.
Following the addition of the HbA1C assay for diagnosing diabetes, our comparison of 2009 and 2012 cohorts from KPHI and KPNW found that the proportion of youth aged 6-17 that are tested and subsequently identified as at risk for diabetes has risen dramatically. Despite differential uptake of HbA1C testing and the substantially different racial composition of the two sites, we found similar patterns of testing. Moreover, we observed important differences in the size and composition of the resulting populations identified as at risk for developing diabetes.
In KPHI, a best practice alert was put in place in 2010, which probably increased screening, and KPNW changed their established best practice alert from FPG test to HbA1C assay after departmental grand rounds and lectures. At both sites the best practice alert triggers for all 6- to 18-year-olds with BMI equal to or greater than the 85th percentile. So the results at least partially reflect the power of the electronic medical record to enhance clinical care.
Current ADA guidelines recommend screening for diabetes among youth beginning at age 10 years when other risk factors such as overweight/obesity are present.9 The increased use of the HbA1C assay resulted in 32% to 39% of youth at risk for diabetes being younger than age 10 years in 2012, compared with 7% to 11% in 2009. A recent study of primarily Hispanic obese adolescents concluded that the use of HbA1C assay was associated with increased diabetes screening in primary care. The percentage of obese teens (> 95th percentile) screened for diabetes increased from 40% in period 1 (April 19, 2008, to October 19, 2009) to 47% in period 2 (May 3, 2010, to November 3, 2011).11 Our study was not limited to obese youth and included a wider age range, thus providing a more comprehensive analysis of the adoption and effectiveness of the HbA1C assay in overweight and normal weight youth.
There are no specific recommendations for the use of HbA1C assay in the pediatric population, and we hope this article highlights the need for them. The increase in use we observed is probably based on recommendations for adults. If so, our study shows the effect of moving to HbA1C assay in youth if a universal recommendation were made.
It appears that the ease of using HbA1C assay increased the number of youth being tested. Despite the increase, however, we did not observe a change in the number of cases identified with diabetes, but we did see a substantial increase in those identified as at risk for diabetes. Whether this means that HbA1C assay inappropriately identifies individuals or that FPG testing misses patients who should be identified as at risk cannot be determined from these data. In any case, it appears that targeted screening has increased as a result of the use of HbA1C assay, allowing for greater opportunity to intervene. This is important because targeted intervention is essential for the efficient use of diabetes prevention resources. There is no doubt that lifestyle changes or medication can reduce or delay diabetes onset in adults,12-15 but evidence of whether such preventive success applies to youth is scant. One recent study in adolescents (aged 10 to 17 years) at high risk of developing type 2 diabetes showed that a 6-month lifestyle intervention combined with metformin showed a modest weight loss and increased insulin sensitivity,16 but it was not of sufficient duration to assess risk of diabetes onset. Research is needed to determine effective risk reduction strategies for youth.
As type 2 diabetes becomes increasingly common among younger individuals, the lifetime risk of developing complications will likely rise. However, there is evidence that effective glycemic control early in the course of both type 1 and type 2 diabetes can reduce the risk of microvascular and macrovascular disease.17,18 HbA1C assay is clearly an effective method for identifying future diabetes risk,19,20 and being at risk for diabetes is associated with increased prevalence of retinopathy and nephropathy,21 chronic kidney disease,22 and cardiovascular disease.23,24 Furthermore, these complications are all associated with duration of diabetes.25-27 Therefore, in terms of prevention of type 2 diabetes and its complications, early recognition with targeted screening is essential.
We also observed a shift in the sex distribution of those identified as at risk for diabetes following implementation of HbA1C assay, with substantially more females recognized in 2012 than in 2009. This is not surprising given that FPG identifies more men than women with hyperglycemia,28 although whether this metabolic difference between sexes applies to youth is unclear. In any case, our results suggest that the risk of diabetes among young females, the likelihood of future gestational diabetes, and the number of pregnancies complicated by existing diabetes may be considerably greater than previously believed.
Our study has several limitations. It is likely that those receiving glucose tests are ordered for youth believed to be more at risk for diabetes, so our results should not be viewed as an outcome of general screening efforts. Whether the proportions we identified as at risk for diabetes or with diabetes represent true prevalence cannot be determined from these observational data. However, our objective was not to estimate prevalence but to assess the impact of introducing the HbA1C assay as a diagnostic tool. The finding that glucose testing rates are increasing should result in a more representative analysis sample in the future. We did not differentiate between type 1 and type 2 diabetes, a very difficult task when limited to observational data. This might have resulted in disproportionately identifying children with type 1 diabetes. Nonetheless, increased use of HbA1C assay did not affect diabetes identification but had a marked effect on the size and composition of the at-risk population. Therefore, the inability to distinguish between type 1 and type 2 diabetes is probably negligible. We determined those at risk and those with diabetes with a single diagnostic laboratory value. A one-year period may be too short to capture those with confirmatory tests or to determine whether the test we did capture was itself confirmatory. In any case, we acknowledge that our results may overstate the number with diabetes. Large proportions of our samples did not have race/ethnicity recorded, but racial differences among those with available data did not affect the results. Furthermore, findings were remarkably similar between the two sites, suggesting that our results are robust and unaffected by race/ethnicity. FPG may be skewed because we were unable to reliably differentiate between routine values captured during "well child" visits and those captured during acute events that could affect the values. Approximately half of the enrolled children did not have BMI data available. It is possible that results for those with and without BMI data were different. However, the testing data, which is the main emphasis of this article, are based on whole samples regardless of availability of BMI. Although use of the HbA1C assay to diagnose diabetes appears to have increased the proportion of youth receiving glycemia tests, other unmeasured factors such as education (of both provider and parent) cannot be ruled out. Last, our data came from two Regions of a comprehensive integrated health system that has excellent information technology support. Whether the testing rates and the resulting proportions we report could be generalized to other settings is unknown.
The purpose of this research was to address whether the endorsement of HbA1C assay for diagnosing diabetes affected the screening, detection, and composition of populations of youth with dysglycemia. Although our data answered that question, whether screening is adequate or not is unknown. Unfortunately, because this was an observational study we cannot determine clinician rationale for testing in either cohort year, nor can we assess whether all who should be screened are being screened. This is a vitally important question that we hope to answer with future research.
In conclusion, the 2010 introduction of the HbA1C assay to diagnose diabetes appears to have increased the proportion of youth receiving glycemia tests. As a result, many more youth are now being recognized as at risk for developing diabetes, and a greater proportion of them are younger (< age 10 years) and female. This change in the number and composition of at-risk youth has important implications for the delivery of diabetes prevention efforts.
Gregory A Nichols, PhD, receives funding for unrelated research support from GlaxoSmithKline, AstraZeneca, Bristol-Myers Squibb, Novartis, and Merck. The author(s) have no other conflicts of interest to disclose.
We would like to thank Valentyna Pishchalenko (Kaiser Permanente Hawaii) for her support with data acquisition.
Mary Corrado, ELS, provided editorial assistance.
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