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A Hemoglobin A1c of Greater than 5% Can Be a Predictor of Incident Diabetes

The incidence of diabetes progressively and significantly increased among patients with an HbA1c greater than 5.0%….

Several studies have suggested that HbA1c levels may predict incident diabetes. With new recommendations for use of HbA1c in diagnosing diabetes, many patients with HbA1c results below the diagnostic threshold will be identified. Clinicians will need to categorize risk for a subsequent diabetic diagnosis in such patients. The objective of this study was to determine the ability of HbA1c to predict the incidence of a diabetic diagnosis. 

For this study they performed a historical cohort study using electronic medical record data from two Department of Veterans Affairs Medical Centers. Patients (12,589) were identified with a baseline HbA1c <6.5% between January 2000 and December 2001 and without a diagnosis of diabetes. Patients (12,375) had at least one subsequent follow-up visit. These patients were tracked for 8 years for a subsequent diagnosis of diabetes.  

The results showed that during an average follow-up of 4.4 years, 3,329 (26.9%) developed diabetes. HbA1c ≥5.0% carried a significant risk for developing diabetes during follow-up. When compared with the reference group (HbA1c <4.5%), HbA1c increments of 0.5% between 5.0 and 6.4% had adjusted odds ratios of 1.70 (5.0–5.4%), 4.87 (5.5–5.9%), and 16.06 (6.0–6.4%) (P < 0.0001). Estimates of hazard ratios similarly showed significant increases for HbA1c ≥5.0%. A risk model for incident diabetes within 5 years was developed and validated using HbA1c, age, BMI, and systolic blood pressure.  

The results showed that baseline HbA1c was significantly predictive of the subsequent development of a diagnosis of diabetes over an 8-year period. The risk of developing diabetes increased progressively at HbA1c levels 5.0%, with an odds ratio exceeding 16 in those with HbA1c 6.0–6.4%. This latter group had a cumulative incidence of diabetes approaching 80%. Not surprisingly, significant predictors for diabetes incidence included clinical parameters, such as blood pressure, BMI, serum creatinine, prevalent cardiovascular disease, and hypertension. From these data, they also developed risk–calculating equations for determining the probability of developing a diabetic diagnosis within 5 years.   This data will inform clinicians on how to risk–stratify individuals who are screened for diabetes using HbA1c but whose levels do not reach the recommended diagnostic threshold of less than 6.5%.

Several studies have evaluated HbA1c as a predictor of subsequent diabetes or as a tool to diagnose treatment-requiring diabetes. A number of threshold values have been previously proposed for diagnosing diabetes, such as >7.0% (4,7), >6.5% (13), .2 SD above the normal mean (i.e., .6.1%). In addition, a number of HbA1c levels have also been proposed to identify individuals at risk for diabetes (i.e., pre-diabetes), such as 6.1–6.9% [7], 6.0–6.4% [8], or 5.7–6.4% [1]. The implementation of new guidelines for diagnosing diabetes using HbA1c will help standardize the way in which clinicians apply results from this test. However, there remains uncertainty on how to classify and whether to intervene in individuals whose levels fall below this threshold.

There is growing evidence that HbA1c may not only predict diabetes but also cardiovascular disease and death. Among women without diabetes, HbA1c levels were significantly associated with both, although the presence of other cardiovascular risk factors may contribute additionally to this risk. Selvin et al. showed that, in a community based population, HbA1c was significantly associated with risk of developing both diabetes and cardiovascular disease independent of fasting glucose levels. As with the results, they showed that levels at 6.0% carried the greatest risk. Therefore, these results strongly suggest that individuals with HbA1c levels greater than 6.0% should be targeted for prevention strategies to reduce not only incident diabetes but possibly also cardiovascular disease.

Many clinicians have been attracted to using HbA1c as a screening test for diabetes since the test reflects longer-term glucose control, does not require fasting, has less day-to-day biologic variability, and is a well-accepted marker of risk of long-term microvascular complications. Such usage is evidenced by the large cohort of patients in whom HbA1c levels were obtained in patients without a diagnosis of diabetes. However, prior guidelines discouraged use of HbA1c for diagnosing diabetes, largely as a result of standardization and reproducibility issues that precluded its use in such broad settings. Current instrumentation and standardization methods aligned with the Diabetes Control and Complications Trial have abrogated most of these issues. Such evidence was cited by the International Expert Committee and affirmed by the American Diabetes Association in their acceptance of HbA1c for screening and diagnosis.

Significant strengths of this study are its large population drawn from two VA medical centers in different geographic regions, the ability to query a robust electronic medical record for clinical and demographic factors, and patient follow-up for up to 8 years. Important limitations include the largely white men and older population, the reliability of the administrative data set, and the selection and ascertainment bias related to patients for whom HbA1c testing was performed. It is possible that HbA1c tests were performed in patients who were preselected for the presence of other known risk factors for diabetes. Such selective screening might bias the results toward showing a higher risk of developing diabetes for a given HbA1c level. To address this, the analyses controlled for many known risk factors and helped identify those factors that contribute significantly with HbA1c in predicting risk of diabetes.

Limiting factors may include the fact that information on the prevalence of smoking in the study population was not included, which is a known risk factor for diabetes and is higher among veterans than nonveterans. This might tend to inflate the risks of diabetes observed. Another potential bias is that a greater amount of medical care (e.g., increased number of clinic visits) might associate with a higher number of diabetes cases ascertained during the study. The number of medical visits was adjusted for but this did not significantly influence the models. Finally, diagnosed diabetes was identified based on medical record evidence that the patient was actually diagnosed by a clinician and/or treated with a diabetes medication. These criteria would exclude patients who have an unrecorded but true diagnosis of diabetes for whom no medications were prescribed, which could lead to an underestimation of the true risk of developing diabetes. However, the number of such patients should be small because of the use of multiple variables to establish a diagnosis of diabetes and the extended follow-up period.

“In summary, we have characterized the risk of developing diabetes in patients without a diagnosis of diabetes who had a baseline HbA1c levels, 6.5%. These data show a progressive risk for developing diabetes when HbA1c is 5.0%, with nominal risk below that level. We generated a risk calculator using HbA1c and other clinical data that estimate the 5-year risk of developing diabetes. Because clinicians implement HbA1c testing to screen for diabetes, these data may be used to help identify the risk of incident diabetes among individuals with HbA1c levels 6.5%.”

Diabetes Care February 2, 2011 DC_100625