HbA1c Levels in Non-Diabetic Individuals: Evidence from Observational Studies
In non-diabetic individuals, HbA1c levels show a complex relationship with cardiovascular outcomes, with both low (<5.0%) and elevated (≥6.5%) levels associated with increased cardiovascular risk, while levels in the 5.0-5.9% range appear optimal for cardiovascular health. 1
Key Findings from Population Studies
The ARIC and Related Observational Data
The evidence from large-scale population studies reveals important patterns about HbA1c in non-diabetic populations:
HbA1c levels between 5.0-5.4% serve as the reference range with lowest cardiovascular risk in non-diabetic individuals 1
Elevated HbA1c levels (6.0-6.4%) in non-diabetics are independently associated with increased coronary artery disease presence and severity, with odds ratios of 3.5 for CAD occurrence compared to those with HbA1c <5.5% 2
HbA1c levels ≥6.5% in non-diabetics carry a hazard ratio of 1.77 for cardiovascular disease compared to the 5.0-5.4% reference group 1
The U-Shaped Curve Phenomenon
A critical finding that emerged from Japanese population data demonstrates a non-linear relationship:
Very low HbA1c levels (<5.0%) paradoxically increase cardiovascular risk with a hazard ratio of 1.50 compared to the 5.0-5.4% reference range 1
This U-shaped relationship persisted even after excluding individuals with kidney dysfunction, liver disease, anemia, or low BMI 1
The optimal HbA1c range for cardiovascular protection in non-diabetics appears to be 5.0-5.9% 1
Clinical Implications for Different Populations
Non-Diabetic Patients Undergoing Coronary Interventions
For patients without diabetes undergoing percutaneous coronary intervention:
HbA1c levels of 6.0-7.0% predict significantly worse outcomes, with 33% major adverse cardiac events versus 22% in those with HbA1c <6.0% 3
Cardiovascular mortality at 12 months was nearly 10-fold higher (4.6% vs 0.5%) in non-diabetics with HbA1c 6.0-7.0% compared to those <6.0% 3
Target vessel revascularization rates were 31% versus 19% in the higher HbA1c group 3
Predictive Value for Future Diabetes
The data demonstrates HbA1c's strong predictive capacity for diabetes development:
HbA1c levels are elevated well in advance of clinical diabetes diagnosis, with adjusted relative risks increasing dramatically: 2.9 for HbA1c 5.0-5.4%, 12.1 for 5.5-5.9%, 29.3 for 6.0-6.4%, and 81.2 for ≥7.0% 4
However, HbA1c's association with incident cardiovascular events in non-diabetics is modest and largely explained by traditional risk factors after multivariable adjustment 4
Mechanistic Considerations
Disease Severity Correlations
In non-diabetic populations with coronary disease:
Higher HbA1c levels correlate linearly with number of diseased vessels, presence of left main disease, and triple vessel disease 2
SYNTAX scores (measuring coronary complexity) increase progressively with higher HbA1c quartiles, even in the non-diabetic range 2
Coronary calcium burden and chronic total occlusions are more prevalent with incrementally higher HbA1c levels 2
Important Confounders to Consider
When interpreting HbA1c in non-diabetics, recognize these limitations:
Iron deficiency anemia falsely elevates HbA1c levels independent of glycemic status 5
Anemia should be screened for and corrected before using HbA1c for risk stratification or treatment decisions 5
Hemoglobin variants, hemolysis, and conditions affecting red cell turnover can significantly alter HbA1c measurements 6
Practical Clinical Algorithm
For non-diabetic individuals with measured HbA1c:
If HbA1c <5.0%: Investigate for anemia, hemolysis, or other conditions causing falsely low readings; consider that this range paradoxically increases cardiovascular risk 1
If HbA1c 5.0-5.9%: This represents the optimal range for cardiovascular health in non-diabetics; no intervention needed beyond standard cardiovascular risk factor management 1
If HbA1c 6.0-6.4%: Recognize 3-4 fold increased risk for coronary disease and 29-fold increased risk for future diabetes; intensify cardiovascular risk factor modification 4, 2
If HbA1c ≥6.5%: Consider this diagnostic for diabetes per standard criteria; cardiovascular risk approaches that of known diabetics 1
Critical Caveats
The relationship between HbA1c and cardiovascular outcomes differs fundamentally between diabetic and non-diabetic populations. While intensive glycemic control benefits diabetics through microvascular protection 6, the observational associations in non-diabetics reflect underlying metabolic dysfunction rather than a treatment target 4.
Lowering HbA1c pharmacologically in non-diabetics has not been studied in randomized trials and cannot be recommended based on current evidence. The associations observed are epidemiological markers of risk, not therapeutic targets 4.