Use of A1c levels for the diagnosis of type 2 diabetes in women younger than 50 years may lead to underdiagnosis, owing to the effects of menstrual blood loss on A1c readings, shows the first study of its kind.

The analysis estimates that an additional 17% of undiagnosed women younger than 50 years could be reclassified as having type 2 diabetes, and that women under 50 had an A1c distribution that was markedly lower than that of men under 50, by a mean of 1.6 mmol/mol.

In a study that was presented at this year's annual meeting of the European Association for the Study of Diabetes (EASD), the researchers wanted to investigate whether a contributing factor to late diagnosis of type 2 diabetes in women under 50 may be the difference in A1c levels due to hemoglobin replacement linked to menstrual blood loss.

The study was published online in Diabetes Therapy, where the researchers note that "If the threshold for diagnosis of diabete was lowered by 2 mmol/mol in women under the age of 50, an additional 17% of these women (approximately equivalent to 35,000 women in England and Wales) would be diagnosed with diabetes…, which may contribute to up to 64% of the difference in mortality rates between men/women with diabetes mellitus aged 16-50 years."

They add that A1c levels in women under 50 years were found to be consistently lower than those in men, and with A1c levels in women reaching the equivalent of those in men up to 10 years later, this "may result in delayed diagnosis of diabetes mellitus in premenopausal women."

Noting that the study was observational, senior author Adrian Heald, MD, consultant endocrinologist, Salford Royal NHS Foundation Trust, Salford, United Kingdom, said that "It may be the case that prediabetes and type 2 diabetes in women are not being spotted because the set point needs to be slightly lower, but a systematic study sampling from the population of at risk individuals is needed further to our findings.

"We also need to refer back to use of the glucose tolerance test, because A1c has been used for the past 15 years but it is not the gold standard," added Heald. "Clinicians have often wondered if patients might be missed with A1c measurement, or even overdiagnosed."

Lucy Chambers, PhD, from Diabetes UK, acknowledged that the research was valuable but added that "More research on sex differences in thresholds for a type 2 diagnosis is needed to inform any changes to clinical practice. In the meantime, we encourage clinicians to follow the current guidance of not ruling out type 2 diabetes based on a one-off A1c below the diagnostic threshold."

But in support of greater understanding around the sex differences in A1c diagnostic thresholds, Chambers added, "Receiving an accurate and timely diagnosis ensures that women get the treatment and support needed to manage their type 2 diabetes and avoid long-term complications, including heart disease, where sex-based inequalities in care already contribute to poorer outcomes for women." 

Effect of A1c Reference Range on T2D Diagnosis and Associated CVD

Compared with men, women with type 2 diabetes have poorer glycemic control; a higher risk for cardiovascular (CV) complications; reduced life expectancy (5.3 years shorter vs 4.5 years shorter); and a higher risk factor burden, such as obesity and hypertension at diagnosis.

In addition, type 2 diabetes is a stronger risk factor for CV disease (CVD) in women than in men, and those aged 35-59 years who receive a diagnosis have the highest relative CV death risk across all age and sex groups.

The researchers point out that previous studies have observed differences in A1c relative to menopause, and they too found that "A1c levels rose after the age of 50 in women."

However, they highlight that the implication of differing A1c reference ranges on delayed diabetes diagnosis with worsening CV risk profile had not been previously recognized and that their study "[h]ighlights for the first time that, while 1.6 mmol/mol may appear only a small difference in terms of laboratory measurement, at population level this has implications for significant number of premenopausal women."

The researchers initially observed the trend in local data in Salford, in the northwest of England. "These…data highlighted that women seemed to be diagnosed with type 2 diabetes at an older age, so we wanted to examine what the source of that might be," study author Mike Stedman, BSc, director, Res Consortium, Andover, United Kingdom, told Medscape Medical News.

Stedman and his colleagues assessed the sex and age differences of A1c in individuals who had not been diagnosed with diabetes (A1c ≤ 48 mmol/mol [≤ 6.5%]).

- "We looked at data from other labs [in addition to those in Salford, totaling 938,678 people] to see if this was a local phenomenon. They could only provide more recent data, but these also showed a similar pattern," he added.

Finally, Stedman, Heald, and their colleagues estimated the possible national impact by extrapolating findings based on population data from the UK Office of National Statistics and on National Diabetes Audit data for type 2 diabetes prevalence and related excess mortality. This brought them to the conclusion that type 2 diabetes would be diagnosed in an additional 17% of women if the threshold were lowered by 2 mmol/mol, to 46 mmol/mol, in women under 50 years.

Lower A1c in Women Under 50 May Delay T2D Diagnosis by Up to 10 Years 

The analysis found that the median A1c increased with age, with values in women younger than 50 years consistently being 1 mmol/mol lower than values in men. In contrast, A1c values in women over 50 years were equivalent to those in men.

However, at age 50 years, compared with men, A1c in women was found to lag by approximately 5 years. Women under 50 had an A1c distribution that was lower than that of men by an average of 1.6 mmol/mol (4.7% of mean; < .0001), whereas this difference in individuals aged 50 years or older was less pronounced (< .0001).

The authors write that "an undermeasurement of approximately 1.6 mmol/mol A1c in women may delay their diabetes diagnosis by up to 10 years."

Further analysis showed that, at an A1c of 48 mmol/mol, 50% fewer women than men under the age of 50 could be diagnosed with type 2 diabetes, whereas only 20% fewer women than men aged 50 years or older could be diagnosed with type 2 diabetes.

Lowering the A1c threshold for diagnosis of type 2 diabetes from 48 mmol/mol to 46 mmol/mol in women under 50 led to an estimate that an additional 35,345 undiagnosed women in England could be reclassified as having a type 2 diabetes diagnosis.

The authors point out that "gender difference in adverse cardiovascular risk factors are known to be present prior to the development of [type 2] diabetes" and that "once diagnosed, atherosclerotic CVD prevalence is twice as high in patients with diabetes…compared to those without a diagnosis."

Heald added that there is always the possibility that other factors might be at play and that the work posed questions rather than presented answers.

Taking a pragmatic view, the researchers suggest that "one alternative approach may be to offer further assessment using fasting plasma glucose or oral glucose tolerance testing in those with A1c values of 46 or 47 mmol/mol."

"In anyone with an early diagnosis of type 2 diabetes, in addition to dietary modification and especially if there is cardiovascular risk, then one might start them on metformin due to the cardiovascular benefits as well as the sugar-lowering effects," said Heald, adding that "we certainly don't want women missing out on metformin that could have huge benefits in the longer term."

Annual Meeting of the European Association for the Study of Diabetes (EASD). Abstract 815. To be presented October 3, 2023.

Diabetes Ther. Published online September 30, 2023. Full text

Press release EASD



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