Researcher: A1C May Be Inaccurate for Women Under 50

A new study has suggested that A1C measurements may be inaccurate in younger women, due to increased red blood cell turnover triggered by blood loss during menstruation. If true, it could mean that many women with diabetes have been diagnosed late and systematically undertreated. The lead researcher believes that this may explain why women with diabetes, especially younger women, appear to have higher relative macrovascular risks than men.

The study, which has been published in the medical journal Diabetes Therapy, is the work of a team led by Adrian Heald, MD, an endocrinologist at the United Kingdom’s Salford Royal Hospital. Dr. Heald believes that diabetes authorities should consider changing the A1C cutoffs used to help diagnose diabetes to account for this factor.

Though Heald’s study only considers type 2 diabetes, it is possible that women with type 1 diabetes are similarly affected.

The Problem: Women with Diabetes Have Higher Relative Rates of Mortality and Complications

Heald’s theory begins with the observation that women with type 2 diabetes are more likely to suffer severe negative outcomes attributable to diabetes. In a paper published earlier this year (PDF), Heald and collaborators found that women in the Salford area, especially younger women, had a higher relative mortality rate, due mostly to an enhanced risk of cardiovascular disease.

This is a global pattern. A 2007 meta-analysis considered 37 studies from across the world, and concluded that “the relative risk for fatal coronary heart disease associated with diabetes is 50 percent higher in women than it is in men.” And a 2017 editorial in The Lancet noted that women with type 2 diabetes “have up to 27 percent higher excess risk of stroke and 44 percent higher excess risk of coronary heart disease.” There is, the editorial states, “ever-increasing evidence that diabetes adversely affects women more than men.”

Despite the differences in outcomes, women in the Salford area had better glycemic control, as measured by A1C, and were diagnosed with diabetes at later ages. Their risk factors seemed superficially lower, and they were less frequently prescribed cardioprotective drugs such as beta-blockers, SGLT2 inhibitors, or statins.

This outcome disparity could have multiple possible causes. Women could have a biological tendency to experience worse outcomes from diabetes than men. But it is arguably more probable that the gap is related to the quality of care that women receive. The Lancet editorial concludes that “sex differences in psychosocial factors, health-seeking behavior, and provision of health care are probably more important.”

The Possible Cause: Menstruation and A1C

The relative risks to women with type 2 diabetes appear to peak before the end of the menopausal transition. Heald writes that “women with diabetes aged 35–59 years have the highest relative cardiovascular death risk across all age and sex groups.”

A 2021 study found that women under the age of 50 have much lower A1C measurements than men of the same age — but that after the age of 50, the women’s A1Cs escalate rapidly. All adults tend to have rising A1Cs as they age, but after the age of 50, women in the sample experienced a much more dramatic rise.

In his new paper, Heald offers a potential explanation. It is possible that premenopausal women may be receiving lesser care because their A1Cs have been systematically misinterpreted, a consequence of blood loss during the menstrual cycle:

“This may be due to menstruation and hence shorter erythrocyte [red blood cell] survival which results in shorter exposure of haemoglobin to glucose compared with individuals who do not menstruate.”

Here’s how it works: The A1C test is an indirect way to measure average blood sugar levels over the last few months. Sugar in the bloodstream binds to hemoglobin molecules in red blood cells when they’re created. Red blood cells tend to live for about three or four months, and so measuring the sugar bound to hemoglobin gives an estimate of recent blood sugar history. However, any loss of blood requires the body to create more new red blood cells. The more red blood cell turnover, the less time new cells are exposed to sugar, which results in misleadingly low A1C measurements.

For now, this is only a hypothesis. Speaking to Diabetes Daily, Heald stated that the phenomenon has “not been looked at in detail before.” He’s hopeful that his speculation will spur more research: “It definitely needs to be looked at!”

There is also some corroborating evidence: we know that donating blood can result in a falsely lowered A1C. A 2017 study found that slightly more than half of adults, both with and without diabetes, had a significant reduction in A1C following blood donation. Among participants with type 2 diabetes, the largest A1C drop was about -12.0 percent. On the American A1C scale, that could represent a fall from an A1C of 8.0 percent all the way down to 7.0 percent. That’s a striking result, though it’s important to note that blood donation usually removes far more liquid (500 mL) all at once than a typical menstrual cycle does (60 mL) over a period of days.

The Negative Impact of Misleading A1C Results

If menstruation truly does have this misleading effect, it means that the medical system is systematically underestimating the scale of hyperglycemia in a huge percentage of people.

A1C is not the only measurement used to diagnose diabetes, and some experts believe that A1C results should always be confirmed with alternative criteria. Women with polycystic ovary syndrome (PCOS), which is extremely common in type 2 diabetes, are recommended to use an oral glucose tolerance test (OGTT) rather than A1C. But A1C remains popular among clinicians, partially because it can be administered quickly and without any special preparations.

When the diagnosis of diabetes is delayed, it means that patients are slower to receive medication and lifestyle counseling. It means they’re slower to be prescribed statins, anti-hypertensive drugs, or other therapies commonly recommended to people with diabetes. And as a result, it could explain some of the outcome gap between women and men.

To put it simply, men under the age of 50 might be receiving appropriate medical care more quickly than women of the same age.

Imprecise A1C results, of course, may only be one piece of the puzzle. Heald believes that diabetes authorities should consider lowering the diagnostic threshold for type 2 diabetes for premenopausal women in order to accelerate their treatment:

“Timely diagnosis of type 2 diabetes and initiation of preventative treatment has the potential to improve cardiovascular risk profile over the lifetime and facilitate longer life quality and expectancy in women. Our findings provide evidence that the A1C threshold for this group should be re-evaluated.”

A1C isn’t only used for the diagnosis of diabetes, but also for its management. If Heald is correct, it could eventually lead to different glycemic targets for younger women with established diabetes:

“Should there be a true difference in A1C between men and women up to the age of fifty … that would mean slightly lower A1C targets for monitoring as well as diagnosis.”

Could A1C Be Misleading for Women with Type 1 Diabetes, Too?

Heald’s article focuses on type 2 diabetes, but he speculates that “the same principle applies” to women with type 1 diabetes.

There is also a similar pattern of outcome inequities in type 1 diabetes. Diagnosis usually occurs later for women and girls, and the disease is more dangerous, too:

Women with type 1 have a 40 percent greater risk of early death
Girls and young women with type 1 have poorer metabolic control and experience more diabetic complications, both at diagnosis and after

This gap cannot be entirely the result of menstruation, because some of these differences exist before puberty. And we know that hormonal changes bring their own serious management challenges which continue through the menopausal transition.

More Study Needed

Heald stressed that his work is only preliminary — “there needs to be validation of our findings in other population samples, ideally with detailed phenotype data as well as biochemistry data.” At the moment, he doesn’t advise women with diabetes to change anything about their management. He is hopeful that his work will spur other researchers and diabetes authorities to consider these issues seriously.

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