Why does a patient have a normal fasting plasma glucose but an elevated HbA1c?

Why Normal Fasting Glucose with Elevated HbA1c Occurs

The most common reason for this discordance is that HbA1c reflects average glucose over 2-3 months and captures postprandial (after-meal) glucose elevations that fasting glucose measurements miss entirely. 1

Primary Physiological Explanation

Postprandial hyperglycemia is the predominant contributor to elevated HbA1c when fasting glucose remains normal. This occurs because:

• HbA1c integrates all glucose exposure over the preceding 2-3 months (with 50% weighted to the most recent month, 25% from 30-60 days prior, and 25% from 60-120 days prior), capturing glucose elevations throughout the day that single fasting measurements cannot detect 1, 2

• Postprandial glucose excursions contribute 60-70% of overall glycemic burden in patients with better glycemic control (HbA1c <7.3%), whereas fasting glucose becomes more dominant only when HbA1c exceeds 9.3% 3, 4

• The 2-hour postprandial glucose increases at a rate 4 times greater than fasting glucose as HbA1c rises, meaning postprandial elevations drive HbA1c increases in early diabetes 4

Specific Clinical Scenarios

Early Type 2 Diabetes

• In patients with HbA1c 6.0-7.0%, approximately 80% have normal fasting glucose but abnormal postprandial glucose levels 4
• The pathophysiology involves early loss of first-phase insulin secretion, which specifically impairs postprandial glucose control while hepatic glucose production (determining fasting glucose) remains relatively preserved 4

Steroid-Induced Hyperglycemia

• HbA1c may be disproportionately low relative to observed glucose elevations because steroids cause predictable temporal hyperglycemia (peak at 7-9 hours post-dose) that doesn't persist long enough to substantially elevate HbA1c 2
• However, the reverse pattern (normal fasting with elevated HbA1c) would be unusual with steroids unless there's underlying diabetes 2

Conditions That Falsely Elevate HbA1c

Several non-glycemic factors can elevate HbA1c independent of actual glucose levels:

• Iron deficiency anemia causes falsely elevated HbA1c by prolonging red blood cell survival and increasing glycation time 2
• Occult malignancies affecting bone marrow function and chronic infections causing inflammatory responses artificially raise HbA1c 2
• Hemoglobin variants (such as HbS, HbC, HbE) can produce unpredictably high results depending on the assay method used 1, 2
• African Americans have HbA1c values approximately 0.4% higher than white persons for any given glucose level, unexplained by measured glycemic differences 2
• Age-related increases of approximately 0.1% per decade after age 30 occur even without diabetes 2

Diagnostic Approach

When encountering this discordance, follow this algorithm:

1. Repeat both tests to exclude laboratory error, as preanalytical and analytical variability can cause discordance 1

2. Obtain postprandial glucose measurements (2-hour post-meal or 2-hour oral glucose tolerance test) to capture the likely source of HbA1c elevation 4

3. Screen for conditions affecting HbA1c reliability:

   • Complete blood count to identify anemia (hemolytic, iron deficiency) 2
   • Hemoglobin electrophoresis if hemoglobinopathy suspected (particularly in at-risk ethnic groups) 1, 2
   • Renal function testing, as chronic kidney disease can falsely lower HbA1c 2

4. Consider glycated albumin (GA) testing if HbA1c reliability is questioned, as GA reflects 2-3 week glucose averages and is unaffected by red blood cell disorders 1

5. Use continuous glucose monitoring (CGM) if available, as CGM averages account for the vast proportion of HbA1c variation and definitively establish the glucose-HbA1c relationship 5

Critical Pitfalls to Avoid

• Do not dismiss elevated HbA1c as "false" without investigating postprandial glucose, as this is the most common explanation and represents true diabetes risk 3, 4

• Do not assume normal fasting glucose excludes diabetes—among individuals with HbA1c 6.0-7.0%, 40% meet diabetes criteria on oral glucose tolerance testing despite normal fasting glucose 4

• Ensure the laboratory uses NGSP-certified HbA1c assays traceable to the DCCT reference method, as non-standardized assays produce unreliable results 1

• For patients with hemoglobinopathies but normal red cell turnover (such as sickle cell trait), use HbA1c assays without interference from abnormal hemoglobins (updated list at www.ngsp.org) 1

• For conditions with abnormal red cell turnover (hemolytic anemia, recent blood loss), glucose criteria must be used exclusively for diagnosis 1