Is there a need to re-evaluate HbA1c cutoff in premenopausal women?

In an analysis of over a million individuals in England, women aged <50 years had a markedly lower HbA_1c distribution than men, suggesting that the application of the current HbA_1c reference range may lead to underdiagnosis of type 2 diabetes (T2D) in premenopausal women.

Among participants aged <50 years in cohort 1, HbA_1c was lower in women than in men by 1.6-mmol/mol (mean 34.4 vs 36.0 mmol/mol; p<0.0001). For those aged ≥50 years, the difference was less pronounced (mean 39.1 vs 40.0 mmol/mol; p<0.0001). [EASD 2023, abstract 815]

Moreover, HbA_1c in women lagged by up to 10 years vs men. To illustrate, a median HbA_1c of 36 mmol/mol was seen in men aged 34–36 years and in women aged 46–47 years. “Taken together, an HbA_1c undermeasurement of ~1.6 mmol/mol in women may delay their T2D diagnosis by up to 10 years,” the researchers explained.

The findings were replicated in cohort 2.

“We estimated that an additional 17 percent of undiagnosed women aged <50 years in England and Wales could be reclassified to have T2D, which may contribute to up to 64 percent of the difference in mortality rates between men and women with T2D aged 16–50 years,” said the researchers. “[Therefore,] moving the threshold for T2D diagnosis from 48 to 46 mmol/mol would reclassify ~35,000 women as having T2D.”

Misdiagnosis, missed chances for intervention

HbA_1c is considered an overall measure of average blood glucose levels over the previous 120 days. [Diabetes Care 2002;25:275-278] However, the current HbA_1c reference range was based on a small trial conducted on individuals with type 1 diabetes, with no reports based on sex differences. [Diabetes 1986;35:530-545]

The lower HbA_1c in premenopausal women could be attributed to menstruation and shorter erythrocyte survival, resulting in shorter exposure of haemoglobin to glucose, as opposed to individuals who do not menstruate.

“Given that the diagnosis of T2D is based on HbA_1c, the use of a nonspecific reference range and cut point for T2D that does not account for gender differences could potentially lead to misdiagnosis of T2D in women and missed opportunities for intervention,” the researchers pointed out.

The investigators thus sought to evaluate whether sex difference in HbA_1c levels due to haemoglobin replacement linked to menstrual blood loss is a contributing factor to this late diagnosis. To establish an HbA_1c reference range specific for premenopausal women, they compared HbA_1c values in individuals from multiple sites in the UK, who underwent single testing and had HbA_1c ≤50 mmol/mol.

Cohort 1 (n=146,907) comprised data from HbA_1c requests from the University Hospitals of North Midlands NHS Trust Clinical Biochemistry Department (CBD) between 2012 and 2019. Cohort 2 (n=938,678) comprised requests from six other CBDs between 2019 and 2021.

Clinical relevance

T2D is typically diagnosed at a later age in women than in men, and by the time they are diagnosed, women are already burdened with other risk factors such as hypertension and obesity. [Diabetologia 2011;54:3003-3006; Diabetes Care 2020;43:3061-3069]

“In addition, women with T2D have worse health outcomes as manifested by poorer glycaemic control, higher risk of cardiovascular complications, and death, as well as higher standardized mortality ratio compared with men,” the investigators noted.

“Our findings provide evidence that the HbA_1c cut point for diagnosis of T2D needs to be re-evaluated in women under 50 years of age. Timely diagnosis of T2D and initiation of preventive treatment in women has the potential to improve their cardiovascular risk profile over their lifetime and facilitate a longer life expectancy,” they concluded.

“More work is ongoing to explore the long-term implications of our findings. Further research is needed regarding the most effective implementation strategy to change the diagnostic cutoff,” they added.