HbA1c as a Continuous Marker of Microvascular Vulnerability: Development of a Non-Linear Risk Framework in a
Mihaela Simona Popoviciu1,2, Alina Manuela Pop1, Timea Claudia Ghitea3
1Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania.
Insights
Glycated hemoglobin (HbA1c) is a continuous marker of metabolic stress. Increased microvascular risk accelerates below traditional diabetes thresholds, particularly in the 5.5-6.4% HbA1c range, aiding early risk stratification.
Area of Science:
- Endocrinology
- Metabolic Health
- Diabetes Research
Background:
- Glycated hemoglobin (HbA1c) is standard for diabetes diagnosis and monitoring.
- Current interpretation relies on fixed thresholds, potentially overlooking risks in sub-diagnostic ranges.
- This study explores HbA1c as a continuous variable for individualized risk assessment.
Purpose of the Study:
- To translate the non-linear relationship between HbA1c and microvascular complications into an individualized risk framework.
- To analyze the glycemic risk continuum beyond fixed diagnostic thresholds.
- To investigate the clinical relevance of the HbA1c sub-diagnostic interval (5.5-6.4%) for risk stratification.
Main Methods:
- Cross-sectional observational study of a real-world clinical cohort.
- HbA1c analyzed as a continuous variable, assessing associations with metabolic parameters and complication burden.
- Restricted cubic spline logistic regression used to model non-linear risks and analyze the HbA1c gray zone.
Main Results:
- HbA1c demonstrated a strong continuous association with fasting plasma glucose.
- A positive association was found between HbA1c and cumulative diabetes-related complication burden.
- Non-linear modeling revealed progressive complication risk increase below diagnostic thresholds, with accelerated risk in the 5.5-6.4% HbA1c range.
Conclusions:
- HbA1c functions as a continuous, non-linear marker of metabolic stress.
- Biologically meaningful increases in complication risk emerge below traditional diagnostic thresholds.
- Findings support a glycemic risk continuum and highlight the utility of the sub-diagnostic HbA1c interval for early preventive strategies.
Background:
Glycated hemoglobin (HbA1c) is widely used for the diagnosis and monitoring of diabetes mellitus; however, its interpretation is largely based on fixed diagnostic thresholds. This study moves beyond describing a glycemic continuum by translating the non-linear HbA1c-microvascular relationship into an individualized risk estimation framework.
Methods:
In this cross-sectional observational study, adult subjects from a real-world clinical cohort were analyzed using HbA1c as a continuous variable. Associations between HbA1c and metabolic parameters were assessed using correlation analysis. Linear regression was applied to evaluate the relationship between HbA1c and cumulative diabetes-related complication burden. Non-linear associations between HbA1c and the risk of presenting at least one complication were explored using restricted cubic spline logistic regression models. Additional risk estimation analyses focused on the HbA1c gray zone (5.5-6.4%).
Results:
HbA1c showed a strong continuous association with fasting plasma glucose (ρ = 0.73, p < 0.001) and was positively associated with cumulative complication burden (β = 0.016 per 1% increase in HbA1c, p = 0.009). Non-linear modeling revealed a progressive increase in complication risk beginning below the diagnostic threshold for diabetes, with an inflection of the risk curve within the HbA1c gray zone. Individuals within this interval exhibited a higher prevalence and increased odds of presenting at least one complication compared with lower HbA1c values, although some estimates did not reach statistical significance.
Conclusions:
HbA1c acts as a continuous and non-linear marker of metabolic stress, with potentially biologically meaningful increases in complication risk emerging below traditional diagnostic thresholds. We demonstrate a non-linear acceleration of microvascular risk within the 5.5-6.4% interval, rather than a simple linear gradient. These findings support the concept of a glycemic risk continuum and highlight the clinical relevance of the HbA1c sub-diagnostic interval for early risk stratification and preventive strategies.
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