Cohen 2010: Limitations of Estimated Average Glucose

Background

This review published in Diabetes Care (PMID: 20519377) addresses critical limitations of the estimated average glucose (eAG) concept following the 2008 ADAG study that established the A1C-to-glucose conversion formula.

Study Design

Critical review of the ADAG study methodology and subsequent clinical implementation, examining sources of individual variation in the A1C-glucose relationship.

Key Findings

Sources of individual variation:

Factor	Impact on eAG
Red blood cell lifespan	±15 days normal variation affects A1C
Hemoglobin glycation rate	Genetic polymorphisms alter glycation
Anemia/hemoglobinopathies	Can falsely lower or raise A1C
Pregnancy	Altered RBC turnover
Kidney/liver disease	Affects RBC survival

Key insight: The population-level equation (eAG = 28.7 × A1C − 46.7) has significant individual variation. Two people with identical A1C may have meaningfully different true average glucose levels.

Mechanistic Insights

A1C reflects average glycemia weighted toward recent weeks (due to RBC age distribution). Individuals with shorter RBC lifespan have lower A1C for a given glucose level. Glycation rate polymorphisms further modify the relationship.

Clinical Implications

eAG should not replace direct glucose monitoring. Discordance between A1C-derived eAG and measured glucose average should prompt investigation of interfering factors, not dismissal of patient-reported values.

Metabolic Health Perspective

For metabolic optimization, direct glucose measurement (CGM) provides superior insight into glycemic patterns, variability, and postprandial responses that A1C and eAG cannot capture.