How to monitor HbA1c (Hemoglobin A1c) in patients with G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency?

Monitoring Glycemic Control in G6PD Deficiency

In patients with G6PD deficiency, HbA1c significantly underestimates true glycemic control and should not be used as the sole monitoring tool; instead, use continuous glucose monitoring (CGM) or fructosamine as primary measures, with self-monitoring of blood glucose (SMBG) as an adjunct.

Why HbA1c is Unreliable in G6PD Deficiency

G6PD deficiency causes shortened red blood cell lifespan, which reduces the time hemoglobin is exposed to glucose, resulting in falsely low HbA1c readings that underestimate actual glycemic control 1, 2, 3. The American Diabetes Association explicitly identifies G6PD deficiency as a condition that interferes with HbA1c accuracy 1, 2, 3.

• In homozygous G6PD deficiency, HbA1c can be falsely decreased by 0.7-0.8%, making glycemic control appear better than reality 2
• The X-linked G6PD G202A variant (common in African Americans with 11% T-allele frequency) causes an absolute HbA1c decrease of 0.81%-units in hemizygous men and 0.68%-units in homozygous women 4
• This discrepancy can cause approximately 2% of African American adults with type 2 diabetes to remain undiagnosed when screened with HbA1c alone 4

Recommended Monitoring Strategy

Primary Monitoring Tools

Use continuous glucose monitoring (CGM) as the preferred method for assessing glycemic control in G6PD deficiency 1. CGM provides:

• Real-time glucose data without reliance on red blood cell turnover 1
• Time in range (TIR), time below range (TBR), and time above range (TAR) metrics that correlate with microvascular complications 1
• Glucose management indicator (GMI), calculated as: GMI (%) = 3.31 + 0.02392 × [mean glucose in mg/dL] 1

Factory-calibrated CGM systems are preferred because they don't require fingerstick calibrations that could be affected by G6PD-related hemolysis 1:

• Abbott FreeStyle Libre uses glucose oxidase-based technology with minimal interference from common medications 1
• Dexcom G6 is factory-calibrated and has been studied in populations with kidney disease where HbA1c is also unreliable 1

Alternative Glycemic Marker: Fructosamine

Fructosamine is a reliable alternative that reflects glycemia over 2-4 weeks and is not affected by red blood cell turnover 1:

• Fructosamine ≥250 µmol/L predicts incident retinopathy, even in patients with HbA1c <7.0% 5
• Fructosamine ≥300 µmol/L predicts incident microalbuminuria 5
• Target fructosamine <250 µmol/L to prevent microvascular complications 5
• Fructosamine shows significant association with mean sensor glucose from CGM with no difference between G6PD-deficient and normal populations 6

Important caveat: Fructosamine assays are biased high by hypoalbuminemia, so check serum albumin and use albumin-adjusted fructosamine if albumin is low 1.

Adjunctive Monitoring: Self-Monitoring of Blood Glucose

Use SMBG with glucose oxidase-based or hexokinase-based meters (not glucose dehydrogenase-pyrroloquinoline-quinone [GDH-PQQ] based, which can have interferences) 1:

• Frequency should match treatment intensity: multiple daily injections or insulin pump therapy requires 6-10 checks daily 1
• Check fasting, pre-meal, 2-hour post-meal, bedtime, and during illness 1

Practical Algorithm for G6PD Deficiency

1. Screen for G6PD deficiency in newly diagnosed diabetes patients from high-prevalence populations (African, Mediterranean, Asian descent) 7, 4

2. If G6PD deficiency confirmed:

   • Do not rely on HbA1c alone for diagnosis or monitoring 1, 2, 3
   • Obtain fasting plasma glucose (≥126 mg/dL confirms diabetes) or 2-hour oral glucose tolerance test (≥200 mg/dL confirms diabetes) for diagnosis 2, 3
   • Initiate CGM as primary monitoring tool 1
   • Measure fructosamine every 2-4 weeks initially, then monthly once stable, targeting <250 µmol/L 5

3. If HbA1c is measured (e.g., by another provider):

   • Calculate the fasting glucose-to-HbA1c ratio: ratio >26 suggests G6PD deficiency 8
   • If ratio is elevated, confirm with direct glucose measurements 8
   • Use GMI from CGM data instead of HbA1c for treatment decisions 1

4. Monitor for hemolysis risk: G6PD-deficient patients with diabetic ketoacidosis are prone to hemolytic anemia, which typically occurs 2-7 days after admission when hyperglycemia is corrected 7

Critical Pitfalls to Avoid

• Never accept a normal HbA1c at face value in G6PD deficiency without confirming with direct glucose measurements 2, 3
• Do not use GDH-PQQ-based glucose meters, as they can have serious interferences; use glucose oxidase or hexokinase-based methods 1
• Avoid methylene blue (used for methemoglobinemia treatment) in G6PD deficiency, as it is ineffective and can worsen hemolysis 1
• Do not assume fructosamine is accurate if albumin is low; use albumin-adjusted values 1
• In populations with high G6PD prevalence, screen for G6PD genotype when using HbA1c for diabetes diagnosis to avoid missed diagnoses 4