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HbA1c as an Independent Predictor of Peripheral Artery Disease: Nonlinear Threshold and Causal Evidence from NHANES

Xixi Guo1, Jianke Wang2, Qiang Guo3

  • 1Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.

Clinical and Applied Thrombosis/Hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis
|April 13, 2026
PubMed

Insights

Elevated glycated hemoglobin (HbA1c) is independently and causally linked to peripheral artery disease (PAD) risk. This suggests HbA1c can help identify individuals at higher risk for PAD.

Area of Science:

  • Cardiovascular Medicine
  • Endocrinology
  • Epidemiology

Background:

  • Peripheral artery disease (PAD) significantly contributes to cardiovascular disease burden, yet early detection biomarkers are limited.
  • Glycated hemoglobin (HbA1c), a marker of long-term blood sugar control, has an incompletely understood association with PAD in the general population.

Purpose of the Study:

  • To investigate the association between HbA1c levels and PAD in a large adult population.
  • To explore the causal relationship between HbA1c and PAD risk using Mendelian randomization.

Main Methods:

  • Analysis of 6284 adults from the National Health and Nutrition Examination Survey (NHANES) (1999-2004).
  • PAD defined by ankle-brachial index ≤0.90; statistical models included logistic regression and restricted cubic splines.
  • Two-sample Mendelian randomization (MR) using genome-wide association data for HbA1c and PAD.

Main Results:

  • Each 1% increase in HbA1c correlated with increased PAD likelihood (fully adjusted OR 1.18).
  • Highest HbA1c tertile showed over twofold PAD risk (OR 2.30) compared to the lowest.
  • MR analysis confirmed a positive causal association between genetically predicted HbA1c and PAD risk (IVW OR 1.23, p=0.0002).

Conclusions:

  • Elevated HbA1c is independently and causally associated with peripheral artery disease risk.
  • A nonlinear dose-response pattern exists, with a steep rise in PAD risk below an HbA1c threshold of 6.11%.
  • HbA1c shows potential as a biomarker for identifying individuals at elevated risk for PAD.

Keywords:
HbA1cNational Health and Nutrition Examination Surveymendelian randomizationperipheral artery disease

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