What is the workup for a patient with a normal Hemoglobin A1c (HbA1c) and elevated fasting glucose?

Workup for Normal A1c with Elevated Fasting Glucose

For patients with normal HbA1c but elevated fasting glucose, a comprehensive evaluation for prediabetes should be performed, including a 75g oral glucose tolerance test (OGTT) to assess postprandial glucose metabolism, which is often abnormal despite normal A1c values. 1

Understanding the Discordance

The discrepancy between normal A1c and elevated fasting glucose represents an important clinical scenario that requires careful evaluation:

• Physiological explanation: This pattern often indicates early glucose metabolism abnormalities where postprandial glucose excursions may be contributing more significantly than fasting hyperglycemia 2
• Test characteristics: A1c reflects average glucose over 2-3 months, while fasting glucose represents a single point measurement 1
• Diagnostic criteria reminder:
  • Normal fasting glucose: <100 mg/dL (5.6 mmol/L)
  • Impaired fasting glucose: 100-125 mg/dL (5.6-6.9 mmol/L)
  • Normal A1c: <5.7%
  • Prediabetes A1c: 5.7-6.4% 1

Recommended Diagnostic Workup

1. Confirm the abnormal fasting glucose

   • Repeat fasting plasma glucose test to rule out laboratory error or transient elevation 1
   • Ensure proper fasting conditions (at least 8 hours) 1

2. Perform 75g OGTT

   • Essential test when A1c and fasting glucose are discordant 1
   • Measures 2-hour post-challenge glucose
   • Identifies impaired glucose tolerance (2-h glucose 140-199 mg/dL) or diabetes (≥200 mg/dL) 1
   • Studies show that many patients with normal A1c may have abnormal 2-hour glucose values 3

3. Evaluate for factors affecting A1c accuracy

   • Hemoglobinopathies or anemias
   • Recent blood loss or transfusion
   • Erythropoietin therapy
   • Increased red blood cell turnover 1

4. Assess cardiovascular risk factors

   • Lipid profile
   • Blood pressure
   • BMI/waist circumference
   • Family history of diabetes
   • Physical activity level 1

Clinical Implications and Management

The presence of elevated fasting glucose with normal A1c has important clinical implications:

• Prediabetes risk: These patients often have early glucose metabolism abnormalities that may progress to diabetes 3
• Cardiovascular risk: Even with normal A1c, elevated fasting glucose increases cardiovascular disease risk 1
• Management approach:

  1. Lifestyle modifications (first-line)

     • Dietary changes focusing on reduced carbohydrate intake
     • Regular physical activity
     • Weight loss if overweight/obese 1

  2. Consider metformin if:

     • BMI ≥35 kg/m²
     • Age <60 years
     • Prior gestational diabetes
     • Rising A1c despite lifestyle intervention 1

Follow-up Recommendations

• Repeat both fasting glucose and A1c in 3-6 months 1
• Annual OGTT if initial results show impaired glucose tolerance 1
• Regular monitoring of cardiovascular risk factors 1

Common Pitfalls to Avoid

1. Relying solely on A1c for diagnosis - A1c may miss early glucose abnormalities, particularly in the postprandial period 3

2. Ignoring elevated fasting glucose when A1c is normal - This pattern often represents early dysglycemia and increased cardiovascular risk 4

3. Failing to consider factors affecting A1c accuracy - Conditions affecting red blood cell turnover can result in falsely normal A1c values 1

4. Delaying intervention - Early lifestyle intervention can prevent progression to diabetes even when only fasting glucose is elevated 1

Remember that the discordance between fasting glucose and A1c is relatively common and represents an opportunity for early intervention to prevent diabetes and reduce cardiovascular risk.