Prediabetes is essentially an intermediate condition between normal blood sugar levels and diabetes. Because it’s considered a significant risk factor for type 2 diabetes, as well as other cardiometabolic conditions, identification of prediabetes can be a good opportunity for intervention before it progresses to diabetes.

But what about pre-prediabetes? If your initial reaction is “is that really a thing?” consider what Ralph DeFronzo, MD, has to say about it.

DeFronzo, who recently co-authored a paper in The Journal of Clinical Endocrinology & Metabolism and helped coin the term, suggests that it’s important for clinicians to watch out for signs of a risk category that precedes prediabetes.

People in this stage may have a normal glucose tolerance, but they’re already severely insulin resistant and have early beta cell dysfunction, even without having obesity. Diabetes, as well as cardiovascular disease, could be on their horizon. Earlier identification of their risk opens more possibilities for intervention.

How to Identify Pre-Prediabetes

A number of reports suggest that the global prevalence of prediabetes is on the rise. In the US, an estimated 98 million people, or 38% of the adult population, have prediabetes.

With prediabetes, blood glucose levels are elevated but not high enough to qualify for a diabetes diagnosis. The American Diabetes Association (ADA) offers the following criteria for a prediabetes diagnosis: 

• an A1c that ranges from 5.7 to 6.4
• a fasting plasma glucose in the 120-125 mg/dL range
• oral glucose tolerance test result in the 140-199 mg/dL range

However, there’s not a standard criteria or specific way to identify people who are at risk for prediabetes. Some experts fear that they may fall through the cracks, losing an opportunity for earlier intervention that could prevent the eventual progression to diabetes.

Enter the oral glucose tolerance test. According to DeFronzo, this test was once used more frequently but has fallen out of use to some degree, in favor of the A1c and fasting glucose tests, which take less time to administer. However, he said, the 1-hour glucose levels detected during this test can provide a much more sensitive measure of prediabetes — and also of pre-prediabetes.

“If you have a 1-hour glucose (concentration) > 155, you already have a significant beta cell defect, and this defect in insulin secretion is associated with that 1-hour glucose of 155 and, of course, explain from a pathophysiological standpoint why these people are at risk for developing future diabetes,” said DeFronzo, professor of medicine and chief of the Diabetes Division at The University of Texas at San Antonio Health Science Center and deputy director of University Health Texas Diabetes Institute, San Antonio.

How Useful Is a Pre-Prediabetes Diagnosis?

One question to consider is whether clinicians would be on board with the effort needed to screen patients for pre-prediabetes.

Some research already suggests that a prediabetes diagnosis could lead to extra testing, overtreatment, and unnecessary costs, and a prediabetes diagnosis is not as useful in older adults as it may be in younger ones.

However, others see the value in diagnosing a patient with prediabetes.

“If you can identify them earlier, then you can probably help those people avoid the development of diabetes and its complications,” said Fernando Ovalle, MD, professor of medicine and director of the Division of Endocrinology, Diabetes & Metabolism at The University of Alabama at Birmingham School of Medicine.

The most likely management strategy for patients identified as pre-prediabetic will be the same as recommendations for patients diagnosed with prediabetes: lifestyle modifications involving diet and exercise.

“For people at the highest risk, the early treatments are going to be the same, focusing on lifestyle, which is what I preach day in and day out here,” said Richard Siegel, MD, an endocrinologist and co-director of the Diabetes and Lipid Center at Tufts Medical Center in Boston.

Siegel expressed some skepticism that clinicians would embrace using the oral glucose tolerance test on a widespread basis, especially given the time that the test would take to administer.

“I think it won’t replace the 6-minute A1C or the fasting glucose test anytime soon,” he said.

Clinicians may also be able to potentially identify people at risk for prediabetes (and type 2 diabetes) by looking at other criteria, such as waist circumference and family history, he added.

As for the feasibility question, DeFronzo said he recognizes that physicians are busy, but they could still send high-risk patients to a lab to undergo the oral glucose tolerance test. And they could be selective about choosing whom to test.

“We’re not recommending that you do this in every single person in the world,” he said. “We’re recommending that you do this in high-risk individuals.”

Ovalle noted that an abnormal 1-hour blood glucose reading could be useful information to have. “We’ve known that for a long time, but we didn’t know what to do with that information,” he said. “So maybe we should be paying attention to that.” 

How much benefit is there to employing a test to identify pre-prediabetes in patients, if the most likely management strategy is the same as for prediabetes? According to DeFronzo, not only could it be helpful to identify high-risk patients but also it could offer an opportunity to keep an eye on them. Then, it would be possible to put them on medication earlier to stave off or even prevent the conversion from prediabetes to diabetes and reduce their risk for cardiovascular events.

Newer medications, notably semaglutide and tirzepatide, have already shown promise in slowing the progression toward diabetes. According to the results of a post hoc analysis of the 3-year SURMOUNT-1 trial that were recently published in Diabetes, Obesity, and Metabolism, tirzepatide is associated with a reduction in the predicted 10-year risk for type 2 diabetes and cardiovascular outcomes in people with prediabetes and obesity.

However, doctors wouldn’t even have to prescribe GLP-1s if the cost is a barrier, which it often is. Metformin is one possible option. According to ADA guidelines, metformin is a recommended preventive treatment for patients with prediabetes who are in the high-risk category (for example, they have an A1C of 6.1-6.4 or a fasting plasma glucose ≥ 110 mg/dL).

But DeFronzo noted that studies have shown that diet, exercise, and weight loss decrease the conversion from prediabetes to diabetes at a higher rate than metformin.

His recommendation: consider a low dose of pioglitazone, a thiazolidinedione that increases insulin sensitivity, although it would be an off-label use if not used to treat type 2 diabetes. DeFronzo acknowledged that pioglitazone tends to cause fluid retention and weight gain but lowers insulin resistance by improving beta cell function. It could also be combined with metformin, which has some weight-loss effect albeit not as strong as that of the GLP-1 receptor agonists.

Another benefit, he added, is that this combination would be very inexpensive. However, if cost isn’t a barrier, the pioglitazone could be combined with a GLP-1 to address weight gain concerns.

“Screen high risk people,” DeFronzo said. “You can identify a group of high-risk people that, in my opinion, should be treated. You can argue about what should be the treatment.”