Should Metformin Be Used to Treat Prediabetes?


About one third of all American adults have prediabetes, an astonishing 88 million Americans, according to the criteria developed by the American Diabetes Association (ADA). The CDC further estimates that 84% of them, some 74 million, don’t even know that they have it.

There’s no doubt that tens of millions of these adults will progress to full-blown Type 2 diabetes, itself a health crisis of almost incomprehensible scale. If this progression could be halted, that would represent a massive victory for public health. At the same time, however, a majority of these 88 million will never develop diabetes, and have only the slightest risk of the complications and outcomes that make diabetes such a damaging illness. Many of them will even naturally return to a state of normal, healthy glucose regulation. Medicating these folks unnecessarily could be a costly mistake.

Is prediabetes a big deal? Opinions differ. A 2019 exposé in Science magazine alleged that the very term “prediabetes” was essentially a marketing creation, a new medical condition invented by the ADA and its pharmaceutical industry allies in order to create tens of millions of new potential customers. While that explanation might sound too cynical for some, the category definitely remains controversial—the World Health Organization, for example, does not use the word “prediabetes” in its official literature. That organization does have a rough equivalent of prediabetes, termed “intermediate hyperglycemia,” but the diagnostic criteria are narrower, an intentional effort to focus on the patients that are truly most likely to progress to full Type 2 diabetes.

Metformin, the first drug prescribed to most patients with Type 2 diabetes, reduces the amount of glucose that is both produced and absorbed by the body, and increases insulin sensitivity. It is an inexpensive drug, and considered safe. Should metformin be prescribed more aggressively to people with prediabetes?

While medical custom draws a bright line between diabetes and prediabetes, the hyperglycemia and insulin resistance that define both conditions are continuous risk factors, and the border between the two is somewhat arbitrary. A patient with an HbA1c 6.4% (prediabetes) is likely to benefit from improved glycemic control for the same reasons that a patient with an HbA1c of 6.5% (diabetes) would. If metformin could improve a patient’s chronic hyperglycemia, it stands to reason that it could prevent some patients from ever crossing the diabetes threshold.

Our best evidence for the effectiveness of metformin as a prophylactic comes from the Diabetes Prevention Program Outcomes Study (DPPOS), a major effort to evaluate the effectiveness of diabetes prevention measures. That study did show that metformin could delay or even prevent the development of Type 2 diabetes in high-risk patients. But the results were modest: patients taking metformin were only 18% less likely to develop diabetes than patients taking a placebo, and they did not exhibit a significantly reduced risk of diabetic complications. Metformin was also less effective than lifestyle interventions in preventing the progression of diabetes.

Only 1-4% of adults with prediabetes currently take metformin, indicating that to date there is relatively little interest among doctors in using metformin to prevent the progression of diabetes. Should that change?

That question is the subject of a debate published in the most recent issue of Diabetes Care, a highly-respected medical journal published by the American Diabetes Association (ADA).

Arguing in favor of the use of metformin to treat prediabetes were Doctors William Herman and Robert Ratner, of the University of Michigan and Georgetown University respectively.

Herman and Ratner contend that prediabetes ought to be treated more aggressively than it is currently. The damage that hyperglycemia causes is long-term and cumulative, they say, and aggressive early glycemic management confers lifelong health benefits. Conversely, delays in providing the proper care can create lifelong health problems. Type 2 diabetes is typically diagnosed as much as 3-8 years after its onset, a delay so long that a significant minority of the newly diagnosed already display notable microvascular complications, such as retinopathy and neuropathy.

The authors agree that not every patient with prediabetes is likely to benefit from metformin. Rather, the treatment should be restricted to the patients that are at the highest risk of developing full-blown diabetes. Unfortunately, the biomarkers most frequently used to diagnose prediabetes are not necessarily our best measure of that risk. Broadly speaking, the prediabetic patients most at risk of disease progression are the “younger, more obese, more hyperglycemic, or [those] who have histories of gestational diabetes.”

Writing against the use of metformin in prediabetic patients is Doctor Mayer Davidson of Charles R. Drew University. Dr. Davidson argues that prediabetes is not, in and of itself, a damaging enough condition to warrant medical intervention: “people who meet the glycemic criteria for prediabetes are not at risk for the microvascular complications of diabetes.” Dr. Davidson contends that even those at the highest risk of developing diabetes—including patients whose HbA1c or fasting glucose is just barely below the diagnostic threshold—should receive nothing but extra attention from their doctors. He would have doctors begin interventions only if and when diabetes onset finally occurs.

Dr. Davidson further argues “that metformin does not fundamentally change the pathophysiology of prediabetes” – its benefits are temporary and last only as long as the drug is used. Some patients with prediabetes, then, could be looking at an entire lifetime of prophylactic metformin use. That’s quite a lot to prescribe to a patient that may not actually benefit from the drug in the first place.

Writers on both sides of the debate agree that only a fraction of people that have prediabetes are truly at risk of developing Type 2 diabetes. Whether those patients require immediate pharmaceutical intervention or merely extra observation, the standards of care should do a better job of distinguishing who they are. Adults with a fasting blood glucose level of 110-125 mg/dL or an HbA1c of 6.0%-6.4% should be cognizant that they are at an elevated risk of progressing to diabetes, especially if they are younger, more overweight, or have a history of gestational diabetes. It is also worth reiterating that the DPPOS found that lifestyle interventions—weight loss and increased physical activity—were more effective than metformin at delaying and preventing the onset of diabetes.

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