The diagnostic threshold for type 2 diabetes (T2D) in pre-menopausal women may need to be "re-evaluated", according to research presented at this year's annual meeting of the European Association for the Study of Diabetes (EASD) in Hamburg, Germany, and published in Diabetes Therapy.
The study found that the distribution of glycated haemoglobin (HbA1c) levels was markedly lower in women under age 50 than in men of the same age, by a mean of 1.6 mmol/mol. The research team suggested that this was due to haemoglobin replacement linked to menstrual blood loss.
Dr Adrian Heald, consultant in diabetes and endocrinology at Salford Royal Hospital, and colleagues, explained that women with T2D were on average older when diagnosed. Diabetes was a stronger risk factor for cardiovascular disease in women, but they were less likely to receive treatment or risk reduction interventions.
Women Have Worse Diabetes Mortality Than Men
Their research, presented at last year's EASD meeting, showed that T2D exacted a greater toll on women's life expectancy than on men's. Men had a 44% increased risk of dying prematurely and 4.5 years lower average life expecancy than the general population, whereas for women the figures were 60% and 5 years, respectively.
However the underlying mechanisms for this sex difference remained unclear. So they analysed all HbA1c requests in two cohorts covering a total of seven clinical biochemistry departments in the Midlands and north of England, representing 6.5% of the total UK population.
The first cohort included 146,907 participants who had a single HbA1c result of ≤ 48 mmol/mol (the cut off for diagnosing diabetes) and covered all tests from one laboratory at University Hospitals of North Midlands NHS Trust between 1 January 2012 and 31 December 2019.
They found an average 1.6 mmol/mol difference (p < 0.0001) between women (mean ± SD 34.4 ± 5.7) and men (mean ± SD 36.0 ± 7.5) for those aged below 50 – a difference of 4.7% of the overall mean. For individuals aged 50 or over, a significant difference was also present, though less marked. At age 50, average HbA1c levels in women lagged by approximately 5 years compared with men.
The researchers replicated the analysis in the second cohort embracing the other six laboratories — comprising 938,678 individuals tested between 1 January 2019 and 31 December 2021 — with consistent findings.
They explained that natural blood loss through menstruation, with shorter erythrocyte survival, could result in shorter exposure of haemoglobin to glucose compared with men.
Lower Threshold Urged for T2D Diagnosis in Women Under 50 years
"Given that the diagnosis of T2D is also based on HbA1c, the use of the same reference range irrespective of age and sex, when a slightly lower point for T2D for premenopausal women may be appropriate, could potentially lead to under-diagnosis of T2D in women, and missed opportunities for intervention," the study authors said.
The possible national impact was estimated by extrapolating findings based on Office for National Statistics (ONS) England population data and National Diabetes Audit published T2D prevalence and related excess mortality.
"While 1.6 mmol/mol may appear only a small difference in terms of laboratory measurement, at a population level this has implications for significant number of pre-menopausal women," they said. If the diagnostic threshold for women under age 50 were lowered by 4.2%, from 48 mmol/mol to 46 mmol/mol HbA1c, an additional 35,345 currently undiagnosed women in England would be reclassified as having T2D – an increase of 17% over the current 208,000 recorded women with T2D aged under 50.
"Timely diagnosis of T2D and initiation of preventative treatment has the potential to improve cardiovascular risk profile over lifetime, and facilitate longer life quality and expectancy in women," they said. "Our findings provide evidence that the HbA1c threshold for this group should be re-evaluated."
Current Clinical Criteria May Miss Thousands of Cases
Asked to comment by Medscape News UK, Dr Lucy Chambers, head of research communications at Diabetes UK, said: "Women tend to be diagnosed with type 2 diabetes later in life than men and this research suggests that this might be because some of the current clinical criteria for a diagnosis do not account for differences between the sexes, potentially contributing to thousands of missed type 2 cases in women."
She noted that accurate and timely diagnosis was needed to ensure that diabetes in women was appropriately managed, and to help to avoid long-term complications, including heart disease, where "sex-based inequalities in care already contribute to poorer outcomes for women".
However, Dr Chambers cautioned that "more research on sex differences in thresholds" was needed to inform any changes to clinical practice. "In the meantime, we encourage clinicians to follow the current guidance of not ruling out T2D based on a one-off HbA1c below the diagnostic threshold," she said.
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