Sex differences in the association of fasting glucose with HbA1c, and their consequences for mortality: A Mendelian randomization study

BACKGROUND: Hemoglobin A1c (HbA1c) is used for diabetes diagnosis and management. HbA1c also represents iron-related erythrocyte properties which differ by sex. We investigated erythrocyte properties on HbA1c and glucose, and whether corresponding consequences for mortality differed by sex. METHODS: In this two-sample Mendelian randomization study using the largest publicly available European descent summary statistics, we assessed sex-specific associations of iron (n=163,511) and hemoglobin (188,076 women/162,398 men) with HbA1c (185,022 women/159,160 men) and fasting glucose (73,089 women/67,506 men), of fasting glucose with HbA1c and diabetes (cases=6,589 women/10,686 men, controls=187,137 women/155,780 men), and of fasting glucose (n=140,595), HbA1c (n=146,806) and liability to diabetes (74,124 cases/824,006 controls) with parental attained age (412,937 mothers/415,311 fathers). FINDINGS: Iron and hemoglobin were inversely associated with HbA1c but not fasting glucose. Fasting glucose was more strongly associated with HbA1c and diabetes in women (1.65 standard deviation (SD) per mmol/L [95% confidence interval 1.58, 1.72]; odds ratio (OR) 7.36 per mmol/L [4.12, 10.98]) than men (0.89 [0.81, 0.98]; OR 2.79 [1.96, 4.98]). The inverse associations of HbA1c and liability to diabetes with lifespan were possibly stronger in men (-1.80 years per percentage [-2.77, -0.42]; -0.93 years per logOR [-1.23, -0.59]) than women (-0.80 [-2.69, 0.66]; -0.44 [-0.62, -0.26]). INTERPRETATION: HbA1c underestimates fasting glucose in men compared with women, possibly due to erythrocyte properties. Whether HbA1c and liability to diabetes reduce lifespan more in men than women because diagnostic and management criteria involving HbA1c mean that glycemia in men is under-treated compared to women needs urgent investigation. FUNDING: None.