What is the role of A1C testing in diagnosing and managing diabetes in patients with symptoms or risk factors for diabetes?

A1C for Diabetes Diagnosis

A1C ≥6.5% is a valid diagnostic criterion for diabetes when performed using an NGSP-certified laboratory method, offering greater convenience than glucose-based tests, though it identifies fewer cases than fasting glucose and should not be used in conditions affecting red blood cell turnover. 1

Diagnostic Criteria Using A1C

The American Diabetes Association establishes A1C ≥6.5% (48 mmol/mol) as one of four acceptable diagnostic criteria for diabetes mellitus. 1, 2

• The A1C threshold of 6.5% was selected based on epidemiological data showing an inflection point for retinopathy prevalence at this level, similar to the rationale used for glucose-based diagnostic thresholds. 1
• This diagnostic cut point must be confirmed with repeat testing in the absence of unequivocal hyperglycemia or acute metabolic decompensation. 2
• Confirmation can be accomplished by repeating the same A1C test on a different day, using a different diagnostic test (FPG or 2-h PG), or measuring two different tests on the same day. 2

Key Advantages of A1C for Diagnosis

A1C offers significant practical advantages over glucose-based testing, making it more likely to be completed in clinical practice. 1, 3

• No fasting is required, eliminating the need for patients to schedule early morning appointments or abstain from food for 8+ hours. 1, 3
• The test reflects average glycemia over 2-3 months, representing chronic glucose exposure rather than a single point in time. 1
• Greater preanalytical stability means samples don't require immediate processing or ice preservation like plasma glucose samples. 1
• Less day-to-day variability from stress, acute illness, diet changes, or activity level compared to glucose measurements. 1
• Can be drawn at any time of day without regard to meal timing, exercise, or circadian variation. 3

Critical Limitations and When NOT to Use A1C

A1C should NOT be used for diagnosis in conditions that alter red blood cell turnover or hemoglobin glycation, and plasma glucose criteria must be used exclusively in these situations. 1

Absolute Contraindications for A1C Diagnosis:

• Hemoglobinopathies including sickle cell disease (use glucose criteria only). 1
• Pregnancy (second and third trimesters and postpartum period). 1
• Glucose-6-phosphate dehydrogenase deficiency. 1
• HIV infection (particularly those on certain antiretroviral therapy). 1
• Hemodialysis patients. 1
• Recent blood loss or transfusion (within 2-3 months). 1
• Hemolytic conditions or erythropoietin therapy. 1
• Iron deficiency anemia or other conditions with abnormal red cell turnover. 1

Important Caveats:

• A1C at the 6.5% cut point identifies approximately one-third fewer diabetes cases than fasting glucose ≥126 mg/dL, meaning it has lower sensitivity. 1
• Point-of-care A1C devices should NOT be used for diagnosis, even if NGSP-certified, due to insufficient accuracy—only FDA-approved laboratory methods in CLIA-certified facilities are acceptable. 1, 2
• In rapidly evolving type 1 diabetes (particularly in children), A1C may not be significantly elevated despite frank hyperglycemia. 1
• Marked discordance between A1C and plasma glucose should raise suspicion of assay interference and prompt use of an alternative diagnostic method. 1

Technical Requirements for Diagnostic A1C

A1C testing for diagnosis must be performed using a method certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the Diabetes Control and Complications Trial (DCCT) reference assay. 1

• Only laboratory-based testing in CLIA-certified facilities with moderate complexity or higher certification should be used for diagnosis. 1
• Point-of-care devices, even if NGSP-certified for monitoring, lack sufficient accuracy for diagnostic purposes. 1, 2
• Results should be reported as "% HbA1c" or "% HbA1c equivalents." 1

Prediabetes Diagnosis Using A1C

A1C of 5.7-6.4% defines prediabetes (increased risk for diabetes), representing a continuum of risk that increases disproportionately at the higher end of this range. 1, 2

• This range identifies individuals who should receive counseling on weight loss, exercise, and other interventions to prevent progression to diabetes. 2
• The lower threshold of 5.7% was selected to balance sensitivity and specificity for identifying those at meaningful risk. 1
• Risk is continuous below and above these thresholds, not a binary state. 1

Comparative Performance with Glucose Testing

When compared to glucose-based criteria, A1C shows less than 100% concordance, with the 2-hour post-load glucose identifying the most cases of diabetes. 1

• Research demonstrates that A1C ≥6.5% has 47% sensitivity and 98% specificity against a single fasting glucose ≥126 mg/dL, improving to 67% sensitivity against repeated fasting glucose measurements. 4
• The 2-hour plasma glucose during OGTT diagnoses more people with diabetes and prediabetes than either FPG or A1C. 1
• In situations of discordance between A1C and glucose values, FPG and 2-hour PG are considered more accurate. 1

Clinical Algorithm for Using A1C in Diagnosis

When evaluating a patient for diabetes:

1. First, assess for conditions that invalidate A1C use (hemoglobinopathies, pregnancy, anemia, recent transfusion, dialysis, HIV). 1

   • If any are present, use fasting glucose or OGTT exclusively. 1

2. If A1C is appropriate, order laboratory-based testing (not point-of-care) using an NGSP-certified method. 1, 2

3. Interpret results:

   • A1C ≥6.5%: Diabetes (requires confirmation on separate day unless symptomatic). 1, 2
   • A1C 5.7-6.4%: Prediabetes. 1, 2
   • A1C <5.7%: Normal (but doesn't exclude diabetes if symptoms present). 1

4. If marked discordance exists between A1C and clinical picture, verify with fasting glucose or OGTT and investigate for assay interference. 1

5. Consider ethnic/racial factors: Some populations may have different relationships between A1C and average glucose, though current guidelines don't recommend different thresholds. 1

Practical Considerations

The convenience of A1C may offset its lower sensitivity by increasing the number of patients who actually complete testing. 1

• Many patients fail to complete fasting glucose tests due to the inconvenience of fasting and early morning appointments. 1
• The ability to draw A1C at any clinical encounter without preparation may lead to more diagnoses in real-world practice despite lower sensitivity. 1
• Cost is higher for A1C than glucose testing, and availability may be limited in resource-poor settings. 1