Case Scenario

A 74-year-old man with hypertension, hyperlipidemia, and a body mass index of 35 kg per m² presented for a physical examination. His primary care physician ordered a basic metabolic profile. The laboratory report showed that his blood glucose level was 105 mg per dL (5.83 mmol per L), which is high.

After researching online, the patient's daughter told him that he might have a condition called prediabetes. She arranged an appointment with an endocrinologist, who told the patient to check his glucose level twice per week with a home glucose monitor and ordered an A1C measurement, which was 5.9%. The endocrinologist confirmed the diagnosis of prediabetes and told the patient that he was at high risk of developing diabetes mellitus and its complications unless he gets his glucose levels down.

For the next few months, the patient checked his glucose level three times per day, sometimes graphing the results; ate fewer donuts; and tried to walk more. When his glucose numbers did not improve, his endocrinologist prescribed metformin, which caused diarrhea. Frustrated and stressed, the patient returned to his primary care physician for advice.

Clinical Commentary

ORIGINS AND INCIDENCE

Hyperglycemia below the diabetes threshold was not considered a significant illness until 2004, when the American Diabetes Association (ADA) labeled it as prediabetes to increase awareness and prompt physicians to act. Prediabetes was initially defined as a fasting blood glucose level between 110 and 125 mg per dL (6.11 and 6.94 mmol per L) or an A1C of 6% to 6.4%. In 2010, the ADA lowered these thresholds to between 100 and 125 mg per dL (5.55 to 6.94 mmol per L) or 5.7% to 6.4%. The diagnosis of pre-diabetes has led to increased testing, physician visits, and treatments. In 2012, the cost of treating prediabetes was $44 billion, or 1.6% of all health care costs.¹ In 2017, an estimated 352 million adults had prediabetes, which constitutes 7.3% of the world's adult population.² The prevalence is even higher among older people in the United States.³

PROGRESSION TO DIABETES

The ADA and other organizations have estimated prediabetes to diabetes conversion rates of 5% to 10% within one year, 25% within five years, and 70% any time after a prediabetes diagnosis.⁴ But the reality is more nuanced. Depending on the definition of prediabetes, the conversion rate can be much lower, especially when only people with a fasting blood glucose level between 100 and 110 mg per dL (5.55 and 6.11 mmol per L) are considered.⁵

Older adults also have a much lower rate of progression to diabetes. In a 2019 Swedish study of adults older than 70 years who were followed for 12 years after a diagnosis of prediabetes, 13% progressed to diabetes, and 22% became normoglycemic.² In a 2021 U.S. study of adults 71 to 90 years of age, 73% met at least one diagnostic criterion for prediabetes. After six years, 9% had progressed to diabetes, and 13% were normoglycemic.⁶ In both studies, there was no difference in mortality between those with prediabetes and those with normal blood glucose levels.

PROGNOSIS

An additional concern about prediabetes is the hyperinflammatory ramifications of insulin resistance, which can lead to microvascular and macrovascular complications. There is no evidence of increased cardiovascular incidence or mortality in people with prediabetes when confounding risk factors are considered.⁷ Studies that suggest an increase in microvascular complications use surrogate markers such as albuminuria for kidney disease, retinal fundoscopic changes for ophthalmologic disease, and vagal nerve stimulation markers for neuropathic disease. The only patient-oriented parameter that reaches statistical significance is symptomatic retinopathy, and its incidence is difficult to determine.⁵

It is unclear whether people with prediabetes who progress to diabetes develop complications or severe disease (i.e., an A1C level of greater than 9%). In 1998, the ADA changed the threshold for the diagnosis of diabetes from a fasting blood glucose level of 140 mg per dL (7.77 mmol per L) to 126 mg per dL (6.99 mmol per L). After 10 years, most people with glucose levels of more than 126 mg per dL and less than 140 mg per dL do not progress to higher glucose levels or develop clinical manifestations of diabetes, and treating these patients does not impact vascular complications.⁸ Other studies have shown no clear evidence of micro- and macrovascular disease in the A1C range of 6.5% to 7%.⁷ If people with mild diabetes do not develop complications, it is even less likely that people with prediabetes will.