The cut-off for HbA1c-based diagnosis of diabetes may be too high in women

By Dr. Liji Thomas, MDOct 4 2023Reviewed by Benedette Cuffari, M.Sc.

Women typically develop diabetes mellitus at a later age than men; however, women often have a higher mortality rate than men due to this condition. This has caused researchers to question whether the cut-off values for the diagnosis of diabetes mellitus is correct. If not, the failure to quickly diagnose diabetes in women could be one factor accounting for this disparity.

A recent study published in Diabetes Therapy explores this hypothesis using the distribution of glycated hemoglobin (HbA1c) levels in premenopausal women and men of the same age.

Study: Is the current cut point for glycated haemoglobin (hba1c) correct for 1 diagnosing diabetes mellitus in premenopausal women? Evidence to inform 2 discussion. Image Credit: Image Point Fr / Shutterstock.com

Introduction

Diabetes mellitus causes illness and death due to direct and indirect complications in over 537 million adults throughout the world, mostly with type 2 diabetes. The risk of cardiovascular disease (CVD) in association with diabetes, as well as the risk of diabetes mellitus itself, is higher in women as compared to men of a comparable age.

Women between 35-39 years of age with diabetes are at the highest relative risk for cardiovascular death as compared to any other sex or age group. Women are also much less likely to be treated or receive secondary prevention measures than men, irrespective of the presence of diabetes. Women also use less medication than men with the same level of risk factors.

Women with diabetes between 16-60 years of age have an increased mortality risk by about 27% as compared to diabetic men of the same age when both are compared to the general population. Women lose an average of 5.3 years from their lifespan with diabetes as compared to 4.5 years for men.  

Women with diabetes mellitus are usually diagnosed at a later stage of life than men. However, pre-diabetes, or non-diabetic hyperglycemia (NDH), is more common in women and is associated with a greater rate of CVD; however, both sexes have comparable increases in the risk of death from all causes.

Screening for diabetes is typically achieved through HbA1c levels, which have historically been used as a marker of long-term control of blood glucose and the risk of diabetes. However, the dependence of HbA1c on the lifespan of red blood cells leads to individual- and age-specific differences, such as lower levels in hemolytic conditions or iron deficiency anemia.

The range of normal values for HbA1c has been defined according to a small study that involved only about 200 people with type 1 diabetes mellitus, in which the ratio of females to males was not reported. However, earlier research indicates lower HbA1c levels in premenopausal women as compared to men of the same age. This might be due to the loss of erythrocytes during menstruation, with a shorter resulting red cell lifespan.

Thus, there is a need for a specific cut-off and reference range for HbA1c for premenopausal women to avoid potentially missing a diagnosis of diabetes. The current study examined differences in the distribution of HbA1c in women and men in an effort to establish a new reference range and cut-off for premenopausal women. The researchers also estimated the number of additional new diabetes diagnoses in this category if the resulting new reference range were to be used.

What did the study show?

The study comprised two cohorts. The first included over 146,000 individuals using a single HbA1c reading at or below 50 mmol/mol obtained between 2012 and 2019. The distribution was replicated using readings from a second cohort of about 940,000 people, whose samples were analyzed in six laboratories between 2019 and 2021.

Women 50 years or younger were considered premenopausal in the absence of more specific data. The findings from the first cohort showed HbA1c levels in premenopausal women that were significantly lower than in men of the same age. More specifically, the average HbA1c level in premenopausal women is maintained at 1.6 mmol/mol, lower than in men.

At or after 50 years of age, the difference was lower at 0.9 mmol/mol, with only about 30% of women diagnosed with diabetes. At each HbA1c level, only about 50% of women were diagnosed with diabetes as compared to men below 50 years or younger.

The mean HbA1c level in women at any given age corresponded to that observed in men up to ten years earlier. These findings were corroborated with data obtained from the second cohort.

An undermeasurement of approximately 1.6 mmol/mol HbA1c in women may delay their diabetes mellitus diagnosis by up to 10 years.”

Using a new HbA1c cut-off of 46 mmol/mol, rather than the previous 48 mmol/mol to diagnose diabetes in premenopausal women, 0.26% of women between 16-50 years of age would have been diagnosed with diabetes mellitus.

Extrapolating this to the population in England and Wales, this would indicate that there are about 35,000 missed diagnoses among premenopausal women. This would result in an estimated rise of 17% in the prevalence of diabetes in this age group.

What are the implications?

The findings from the HbA1c analysis of over one million men and women in England showed markedly lower mean HbA1c levels in women as compared to men below the age of 50 years.

This disparity provided the basis for the researchers to estimate that over 17% of women 50 years or younger residing in England or Wales would receive a new diagnosis of diabetes mellitus using an appropriately lower cut-off in women. This large proportion of missed diagnoses could account for almost two-thirds of the difference in mortality rates between men and women with diabetes mellitus in adults 50 years or younger.

The study findings indicate that many women are likely living with diabetes but will be diagnosed later than men, which could adversely affect their CVD profile at the time of eventual diagnosis. The presence of diabetes doubles the prevalence of atherosclerosis and the resulting CVD

The HbA1c cut point for diagnosis of diabetes mellitus may need to be re-evaluated in women under the age of 50 years.” Thus, a new cut-off value for HbA1c values could significantly improve the long-term health outcomes in women by allowing the early identification of diabetes mellitus.