LISBON, Portugal — Efforts are underway to better identify which individuals with so-called “prediabetes” are at greatest risk for developing type 2 diabetes and subsequent complications, and therefore merit more intensive intervention.
“Prediabetes” is the term coined to refer to either “impaired fasting glucose (IFG)” or “impaired glucose tolerance (IGT),” both denoting levels of elevated glycemia that don’t meet the thresholds for diabetes. It’s a heterogeneous group overall, and despite its name, not everyone with prediabetes will progress to develop type 2 diabetes.
There have been major increases in prediabetes in the United States and globally over the past two decades, epidemiologist Elizabeth Selvin, PhD, MPH, told the recent International Diabetes Federation 2022 meeting.
She noted that the concept of “prediabetes” has been controversial, previously dubbed a “dubious diagnosis” and a “boon for Pharma” in a 2019 Science article.
Others have said it’s “not a medical condition” and that it’s “an artificial category with virtually zero clinical relevance” in a press statement issued for a 2014 BMJ article.
“I don’t agree with these statements entirely but I think they speak to the confusion and tremendous controversy around the concept of prediabetes…I think instead of calling prediabetes a ‘dubious diagnosis’ we should think of it as an opportunity,” said Selvin, of Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
She proposes trying to home in on those with highest risk of developing type 2 diabetes, which she suggests could be achieved by using a combination of elevated fasting glucose and an elevated A1c, although she stresses that this isn’t in any official guidance.
With the appropriate definition, people who are truly at risk for progression to type 2 diabetes can be identified so that lifestyle factors and cardiovascular risk can be addressed, and weight loss efforts implemented.
“Prevention of weight gain is…important. That message often gets lost. Even if we can’t get people to lose weight, preventing [further] weight gain is important,” she noted.
Asked to comment, Sue Kirkman, MD, told Medscape, “The term prediabetes — or IFG or IGT or any of the ‘intermediate’ terms — is pragmatic in a way. It helps clinicians and patients understand that they are in a higher-risk category and might need intervention and likely need ongoing monitoring. But like many other risk factors [such as] blood pressure, [high] BMI, etc., the risk is not dichotomous but a continuum.
“People at the low end of the ‘intermediate’ range are not going to have much more risk compared to people who are ‘normal,’ while those at the high end of the range have very high risk,” said Kirkman, of the University of North Carolina, Chapel Hill, and a co-author of the American Diabetes Association’s diabetes and prediabetes classifications.
“So we lose information if we just lump everyone into a single category. For individual patients, we definitely need better ways to estimate and communicate their potential risk.”
Currently Five Definitions for Prediabetes: Home in on Risk
The problem, Selvin explained, is that currently there are five official definitions for “prediabetes” using cutoffs for hemoglobin A1c, fasting glucose, or an oral glucose tolerance test.
Each one identifies different numbers of people with differing risk levels, ranging from a prevalence of 4.3% of the middle-aged adult population with the International Expert Committee’s definition of A1c 6.0 – 6.4% to 43.5% with the American Diabetes Association’s 100-125 mg/dL fasting glucose.
“That’s an enormous difference. No wonder people are confused about who has prediabetes and what we should do about it,” Selvin said, adding that the concern about overdiagnosing “prediabetes” is even greater for older populations, in whom “it’s incredibly common to have mildly elevated glucose.”
Hence her proposal of what she sees as an evidence-based, “really easy solution” that clinicians can use now to better identify which patients with “intermediate hyperglycemia” to be most concerned about: Use a combination of fasting glucose above 100 mg/dL and an A1c greater than 5.7%.
“If you have both fasting glucose and hemoglobin A1c, you can use them together…This is not codified in any guidelines. You won’t see this mentioned anywhere. The guidelines are silent on what to do when some people have an elevated fasting glucose but not an elevated A1c…but I think a simple message is that if people have both an elevated fasting glucose and an elevated A1c, that’s a very high-risk group,” she said.
On the other hand, Kirkman pointed out, “most discrepancies are near the margins, as in one test is slightly elevated and one isn’t, so those people probably are at low risk.”
“It may be that both being elevated means higher risk because they have more hyperglycemia…so it seems reasonable, but only if it changes what you tell people.”
For example, Kirkman said, “I’d tell someone with A1c of 5.8% and fasting glucose of 99 mg/dL the same thing I’d tell someone with that A1c and a glucose of 104 mg/dL — that their risk is still pretty low — and I’d recommend healthy lifestyle and weight loss if overweight either way.”
However, she also said “Certainly people with higher glucose or A1c are at much higher risk, and same for those with both.”
Tie “Prediabetes” Definition to Risk, as Cardiology Scores do?
Selvin also believes that risk-based definitions of prediabetes are needed. Ideally, these would incorporate demographics and clinical factors such as age and body mass index (BMI). Other biomarkers could potentially be developed and validated for inclusion in the definition, such as C-reactive protein (CRP), lipids, or even genetic/proteomic information.
Moreover, she thinks that the definition should be tied to clinical decision-making, as is the pooled cohort equation in cardiology.
“I think we could do something very similar in prediabetes,” she suggested, adding that even simply incorporating age and BMI into the definition could help further stratify the risk level until other predictors are validated.
Kirkman commented, “The concept of risk scores a la cardiology is interesting, although we’d have to make them simple and also validate them against some outcome.”
Regarding the age issue, Kirkman noted that although age wasn’t a predictor of progression to type 2 diabetes in the placebo arm of the landmark Diabetes Prevention Program (DPP) trial, “I do agree that it’s a problem that many older folks have the label of prediabetes because of a mildly elevated A1c and we know that most will never get diabetes.”
And, she noted, in the DPP people with prediabetes who had a BMI over 35 kg/m2 did have significantly higher progression rates than those with lower BMI, while women with a history of gestational diabetes mellitus are also known to be at particularly high risk.
Who Should We Throw the Kitchen Sink at?
Some of this discussion, Kirkman said, “is really a philosophical one, especially when you consider that lifestyle intervention has benefits for almost everyone on many short- and long-term outcomes.”
“The question is probably who we should ‘throw the kitchen sink at,’ who should get more scalable advice that might apply to everyone regardless of glycemic levels, and whether there’s some more intermediate group that needs more of a [National Diabetes Prevention Program] approach.”
Selvin’s group is now working on gathering data to inform development of a risk-based prediabetes definition. “We have a whole research effort in this area. I hope that with some really strong data on risk in prediabetes, that can help to solve the heterogeneity issue. I’m focused on bringing evidence to bear to change the guidelines.”
In the meantime, she told Medscape, “I think there are things we can do now to provide more guidance. I get a lot of feedback from people saying things like ‘my physician told me I have prediabetes but now I don’t.’ or ‘I saw in my labs that my blood sugar is elevated but my doctor never said anything.’ That’s a communications issue where we can do a better job.”
Selvin is deputy editor of Diabetes Care and on the editorial board of Diabetologia. She receives funding from the NIH and the Foundation for the NIH, and royalties from UpToDate for sections related to screening, diagnosis, and laboratory testing for diabetes. Kirkman reports no relevant financial relationships.
Selvin’s comments were presented December 7, 2022 during the International Diabetes Federation 2022 meeting.
Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.
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