Plasma metabolites mediate the effect of HbA1c on incident cardiovascular disease

Area of Science:

• Metabolomics
• Cardiovascular Research
• Endocrinology

Background:

• Elevated glycated hemoglobin (HbA1c) is a known risk factor for cardiovascular disease (CVD).
• The precise mechanisms by which HbA1c contributes to CVD remain incompletely understood, particularly the role of endogenous metabolites.

Purpose of the Study:

• To investigate whether endogenous metabolites mediate the association between HbA1c and incident cardiovascular disease (CVD).
• To identify specific metabolic pathways involved in HbA1c-related CVD pathogenesis.

Main Methods:

• Analysis of 2019 plasma samples using liquid chromatography-quadrupole time-of-flight mass spectrometry.
• Application of logistic and linear regression to identify metabolites associated with both HbA1c and CVD.
• Utilized VanderWeele's mediation approach to quantify direct and indirect effects.

Main Results:

• Identified 48 metabolites associated with both HbA1c and CVD risk.
• Forty-four of these metabolites acted as significant mediators (indirect effect odds ratio [OR]_IE 0.997–6.098), explaining 0.4%–85.4% of HbA1c's effect on CVD.
• Pathway analysis revealed significant mediation by butanoate, alanine/aspartate/glutamate, TCA cycle, phenylalanine, and glycerophospholipid metabolism.

Conclusions:

• Endogenous metabolites significantly mediate the relationship between HbA1c and incident CVD.
• These findings offer novel insights into the pathophysiological mechanisms linking glycemic control to cardiovascular risk.