Why is hemoglobin A1c used to diagnose diabetes despite its susceptibility to interference?

Why A1C Is Used to Diagnose Diabetes Despite Known Interferences

A1C is used to diagnose diabetes because it reflects chronic glycemia over 2-3 months, correlates directly with microvascular complications (particularly retinopathy at the 6.5% threshold), and has been rigorously standardized through the National Glycohemoglobin Standardization Program, making it a reliable diagnostic tool when properly applied. 1

The Evidence-Based Rationale

Direct Correlation with Diabetic Complications

The 6.5% diagnostic threshold was not arbitrarily chosen—it represents an inflection point for retinopathy prevalence, the same way fasting glucose ≥126 mg/dL and 2-hour glucose ≥200 mg/dL do. 1 This means the A1C cutoff identifies patients at the glycemic level where microvascular damage begins, making it a biologically meaningful diagnostic marker rather than just a convenient test. 1

Practical Advantages Over Glucose Testing

A1C offers several critical advantages in real-world clinical practice:

• No fasting required, eliminating the logistical barrier that prevents many patients from completing glucose testing 1
• Greater preanalytical stability, meaning specimens are less likely to degrade before analysis 1
• Less day-to-day variability during stress, illness, or other acute conditions that can falsely elevate glucose measurements 1
• Reflects chronic glycemia rather than a single point in time, providing a more comprehensive picture of metabolic status 1

The American Diabetes Association acknowledges that while A1C at the 6.5% cutoff identifies one-third fewer cases than fasting glucose ≥126 mg/dL in universal screening scenarios, the greater convenience may actually increase the total number of diagnoses made because more people will complete the test. 1

Assay Standardization Solved the Historical Problem

Prior expert committees avoided recommending A1C for diagnosis specifically because of lack of standardization. 1 This problem has been definitively resolved—A1C assays are now highly standardized through the National Glycohemoglobin Standardization Program (NGSP) and traceable to the Diabetes Control and Complications Trial reference assay, allowing results to be uniformly applied across populations and over time. 1

When A1C Should NOT Be Used

The guidelines are explicit about situations where A1C is unreliable and glucose criteria must be used exclusively:

Conditions with Abnormal Red Cell Turnover

• Hemolytic anemias shorten red blood cell lifespan, causing A1C to underestimate glycemia 1, 2
• Iron deficiency anemia affects A1C accuracy 1
• Sickle cell disease makes A1C unreliable (though sickle cell trait can use interference-free assays) 1, 2
• G6PD deficiency can decrease A1C by 0.7-0.8% in homozygous individuals 2
• Recent blood loss, hemorrhage, or transfusion within 2-3 months 2
• Hemodialysis and end-stage kidney disease 2
• Erythropoietin therapy 2
• Pregnancy requires glucose-based diagnosis exclusively 1, 3

Rapidly Evolving Type 1 Diabetes

In children or adults with acute-onset type 1 diabetes, A1C may not be significantly elevated despite frank diabetes because the disease progresses too quickly for A1C to reflect the severity. 1, 3 Random plasma glucose ≥200 mg/dL with symptoms confirms the diagnosis immediately. 3

The Algorithmic Approach to Diagnosis

When to Use A1C

1. Screening asymptomatic adults for type 2 diabetes—A1C ≥6.5% is diagnostic 1, 4
2. Must use NGSP-certified laboratory method, not point-of-care assays 1
3. Confirm with repeat testing unless clinical hyperglycemia is unequivocal 1

When to Use Glucose Criteria Instead

1. Any condition affecting red cell turnover—use fasting glucose ≥126 mg/dL or 2-hour OGTT ≥200 mg/dL 1, 2
2. Pregnancy—glucose criteria only 1
3. Acute hyperglycemic symptoms—random glucose ≥200 mg/dL confirms diagnosis immediately 1, 3
4. Suspected type 1 diabetes—do not delay treatment waiting for A1C 3

When Results Are Discordant

If A1C and glucose tests disagree, the test above the diagnostic threshold should be repeated for confirmation. 1 If both tests are above their respective thresholds on initial testing, diabetes is confirmed even if they don't perfectly agree. 1

Critical Pitfalls to Avoid

The most dangerous error is accepting a normal A1C at face value in a patient with clinical suspicion for diabetes without first ruling out conditions that falsely lower A1C. 2 Always obtain direct glucose measurements (fasting glucose or OGTT) when clinical suspicion is high despite normal A1C. 2

For patients with hemoglobinopathies but normal red cell turnover (like sickle cell trait), use an A1C assay specifically designed to avoid interference from abnormal hemoglobins. 1

Never use point-of-care A1C assays for diagnostic purposes—they lack sufficient accuracy. 1, 3

The Bottom Line

A1C is used diagnostically because it works—it identifies patients at the glycemic threshold where complications begin, it's been rigorously standardized, and its practical advantages mean more patients actually get diagnosed. 1 The known interferences are specific, identifiable conditions where clinicians should use glucose criteria instead. 1, 2 This is not a flaw in A1C as a diagnostic tool; it's a well-characterized limitation that guidelines explicitly address with clear alternative pathways. 1, 2