The role of hemoglobin A1c in the assessment of diabetes and cardiovascular risk

MONITORING PATIENTS WITH DIABETES

HbA1c should be performed every 3 months in patients with known diabetes and can be spaced to twice yearly in patients meeting treatment goals on stable therapy.

While not recommended for diagnosis, point-of-care testing of HbA1c has been endorsed by the ADA for monitoring patients with diabetes. Studies have shown that a higher percentage of patients achieve HbA1c targets with treatment adjustment based on point-of-care testing of HbA1c at the time of visit vs usual laboratory monitoring.^16,25

Goal HbA1c levels in patients with diabetes should be patient-tailored, as outlined in Figure 2. For example, stricter control with HbA1c (≤ 6.5%) may be desired in a young, otherwise healthy individual, whereas an HbA1c of 8% may be appropriate in a patient with multiple comorbidities.²⁶

HbA1c AND CARDIOVASCULAR RISK

HbA1c has been established as a strong predictor of CV events and mortality in patients with diabetes despite the absence of firm evidence that glycemic control modifies this risk substantially over time.²⁷ Results from the UKPDS and DCCT trials lend strong support to the hypothesis that glycemic control early in the course of disease provides preventive benefit.^3–5 In contrast, three major trials that enrolled older patients at higher baseline risk showed no mortality or CV benefit of tighter glycemic control.^28–30 One of these, the Action to Control Cardiovascular Risk in Diabetes trial,²⁸ found increased mortality risk in the intensive glycemic-control arm among those who did not achieve the HbA1c target, illustrating the complexity of interpreting HbA1c in clinical practice.

While HbA1c may predict the risk of mortality and CV events in diabetes populations, it is unlikely to be a strong predictor in patients without established diabetes. Analysis of data from the Emerging Risk Factors Collaboration indicates that below the HbA1c diagnostic threshold of diabetes (< 6.5%), HbA1c is less predictive than stronger risk factors such as lipids.³¹ In this retrospective analysis, which included a cohort of more than 200,000 individuals without diabetes, the risk model to predict CV events was not enhanced significantly by the addition of HbA1c information.

MISREPRESENTING THE GLYCEMIC ‘BIG PICTURE’

Aside from the previously discussed medical conditions that may affect HbA1c accuracy, other factors may complicate HbA1c interpretation. Recent studies raised concern about the generalizability of HbA1c across racial and ethnic groups. A 2010 study of non-Hispanic black and white participants without diabetes revealed that black participants had higher HbA1c levels across the glycemic continuum.³² In the past, concern was raised that these HbA1c elevations were related simply to poorer glycemic management and healthcare disparities. However, a study using data from the Diabetes Prevention Program compared HbA1c in five racial and ethnic groups and found that racial and ethnic minorities had higher HbA1c levels after adjusting for demographics, socioeconomics, and anthropometrics.³³ This suggests that racial-genetic differences in RBC survival or glycation of hemoglobin may affect HbA1c. These studies did not assess for the presence of hemoglobinopathies despite higher prevalence in certain ethnic groups.

One critique of the HbA1c assay is that HbA1c does not reflect glycemic variability. A 2007 study analyzing DCCT data found that participants with similar HbA1c levels had dissimilar mean plasma glucose (MPG) levels and glucose variability (standard deviation of MPG).³⁴ The authors provided an example of two patients with identical HbA1c and MPG but disparate glucose variability. The patient with higher glucose variability had a 35% to 45% excess risk of hypoglycemia. Failure of HbA1c to clearly define those at risk for frequent hypoglycemic events is problematic, since hypoglycemia is an identified risk factor for CV disease and morbidity.^35,36 Of perhaps greatest concern is that an elevated HbA1c may be a common presentation of variability in the elderly. One study showed that more than 60% of elderly patients taking insulin with an average HbA1c above 8% had several hypoglycemic events per week, and based on elevated HbA1c, they may be advised to increase insulin dosing.³⁷

Glucose variability itself, including wide postprandial excursions, may be a risk factor for CV disease. The recent FLAT-SUGAR trial used HbA1c and continuous glucose monitoring to assess glycemic control and CV risk markers in participants on basal-bolus insulin therapy plus metformin versus subjects on basal insulin, metformin, and a GLP-1 agonist intended to reduce postprandial glucose excursions.³⁸ Although groups achieved similar target HbA1c levels, the intervention group had fewer glycemic excursions as well as reductions in some CV risk markers.

Alternatives to HbA1c are available for monitoring glycemic control. The monosaccharide 1,5-anhydroglucitol, a short-term marker of glycemia, competes with glucose for reabsorption in the kidney. In patients with normal renal function, low serum levels represent short-term hyperglycemia. Fructosamine and glycated albumin, formed by the glycation of proteins, reflect glycemia over the 2- to 4-week protein half-life.³⁹ Fructosamine measurement is confounded by the presence of low molecular weight substances such as bilirubin and uric acid; therefore, it may not be useful in medically complex patients. Glycated albumin is not affected by these substances; it may also be useful in patients in whom variations in RBC survival make HbA1c unreliable.^11,40 Despite the growing body of research about their usefulness, these tests lack the stringent standardization of HbA1c and have not been vetted for use in large clinical trials. Thus, their use in routine clinical practice remains controversial.

CONCLUSION

The focus on HbA1c during the last 40 years has resulted in enhanced test accuracy, availability, and use among patients and providers in the care of diabetes. Because HbA1c has become the standard in how population-based studies evaluate the effects of glycemic control on disease progression and complications, it serves as the basis for guidelines that address diabetes and CV risk definition and management. Although HbA1c may seem familiar, there is much not known about test interpretation and how it may actually miss the mark. As HbA1c use continues, these concerns need to be clarified to optimize the screening, diagnosis, and care of patients with diabetes and CV disease.