Metformin for Prediabetes: Treating the Label, Not the Patient

I’ve tried unsuccessfully to publish a version of this post as a letter to the editor to JAMA twice, once in 2017 in response to a Medical Letter, and again in 2023 in response to a review article. Both times it was rejected, which is par for the course from my experience when you challenge the raison d'être of an article, rather than some minor methodological critique. I’ve also circulated a version on Twitter a few times, presented similar critiques about diabetes more broadly in academic presentations, and published my thesis in Circulation as a narrative review. It ruffles many feathers. I’ve even been scolded in anonymous feedback for one of my talks that I should have my materials vetted by my supervisors because it was “dangerous.” Yet, I have still not heard a compelling scientific argument supporting the logic of treating prediabetes with metformin. If you have one, please reply in the comments.

A 2023 JAMA review on the diagnosis and management of prediabetes repeats a familiar claim: metformin is an effective therapy for prediabetes.

On the surface, the logic is compelling. The use of metformin lowers the chance that people with prediabetes cross the diagnostic threshold into diabetes. Therefore, metformin should prevent diabetes complications. Open-and-shut case, right?

The problem is that prediabetes is not a distinct clinical syndrome.

It is not a disease with a recognizable constellation of symptoms, signs, pathology, and prognosis. It is a category created by a lab threshold. The difference between prediabetes and diabetes is not a biologic cliff. It is a glycemic cutpoint.

That does not make the cutpoint entirely meaningless. Risk rises as glucose rises. Labels can crudely help identify people at higher future risk. But a risk label is not the same thing as an illness, and lowering the chance of acquiring a more serious label is not the same thing as making people live better or longer. This is the central problem with prescribing metformin for prediabetes.

The strongest argument for metformin comes from the Diabetes Prevention Program and its long-term follow-up. In the 15-year outcomes study, metformin reduced the absolute incidence of diabetes by about 6 percentage points. That is real. But the key question is not whether metformin delays crossing a hemoglobin A1c or glucose threshold. The key question is whether delaying that threshold prevents the outcomes patients actually care about: kidney failure, blindness, neuropathy, amputations, heart attacks, strokes, death, or even meaningful symptoms.

On that question, the evidence is disappointing. In the same long-term follow-up, metformin did not reduce the composite microvascular outcome (which also were largely surrogate outcomes). If anything, the point estimate went in the wrong direction: 13.0% in the metformin group versus 12.4% in the placebo group, not statistically significant. That certainly does not mean it was harmful, and is more than likely just noise. But it does undercut the causal story that preventing the diabetes label necessarily prevents diabetes complications.

The second problem is treatment burden.

One possible benefit of preventing diabetes is that patients may avoid pharmacologic treatment later. But if the prevention strategy is to give metformin now, then the prevention strategy simply moves the treatment burden earlier.

This is an odd bargain. To prevent some fraction of people from eventually needing metformin, we prescribe metformin to everyone now.

That may still be reasonable if metformin clearly improves patient-important outcomes. But per above, that is wishful thinking. Without that, we are not preventing treatment burden. We are frontloading it.

This is also why the argument resembles a longstanding but debunked proposal to lower the treatment threshold for diabetes. Committing patients with prediabetes to metformin is akin to further intensify glycemic targets for initiation of metformin at an Hgb A1c of 6%, despite no improvement in outcomes even with a higher HbA1c target of 7%.

In other words, if metformin should be prescribed at an A1c of 6.0% to prevent progression to diabetes at 6.5%, then why not intensify therapy in diabetes to lower thresholds? Why is first-line therapy for diabetes with an A1c of 7.0% lifestyle change, and not metformin initiation?

As Oanh Kieu Nguyen and I argued in our review in Circulation on antihyperglycemic therapy and overtreatment, the point of diabetes treatment is not to normalize laboratory values. It is to reduce complications while minimizing treatment burden and harm. The same principle should apply before diabetes is diagnosed.

To be clear, this is not an anti-metformin argument. I prescribe it regularly for type 2 diabetes. Metformin is inexpensive, familiar, and generally safe.

It is also not an argument against identifying patients at high risk and supporting intensive lifestyle interventions. Diet, physical activity, weight loss, sleep, and cardiometabolic risk reduction matter.

But the standard for medicating a risk state should not be “does the drug move the arbitrary glycemic surrogate?” It should be “does the drug improve outcomes enough to justify treating people who do not yet have the disease?”

Metformin is usually well tolerated, but “usually” is not always.

Gastrointestinal side effects like nausea, upset stomach, and diarrhea are common. Vitamin B12 deficiency is more infrequent but real. There is also the daily burden of taking a pill, the downstream monitoring, the medicalization of risk, and the subtle behavioral tradeoff that can occur when pharmacologic prevention creates false reassurance. A similar phenomenon has been described with statins, where users appeared to increase caloric and fat intake over time in a study memorably titled “Gluttony in the Time of Statins?”

None of these harms are catastrophic for most patients. But when there is no apparent benefit whatsoever, small harms matter.

That is the asymmetry of preventive medicine. When we treat symptomatic disease, patients may accept substantial downsides for a chance at relief. But when we treat people who feel well, the evidentiary bar should be higher. We should be especially cautious when the main demonstrated benefit is delaying a diagnostic label.

Summary

Prediabetes is useful as a risk marker for cardiovascular disease. It is a signal to take metabolic health seriously. It is a reason to discuss weight, diet, physical activity, blood pressure, lipids, smoking, sleep, and the other conditions that make healthy living harder.

But metformin for prediabetes is a different claim. It says that changing the timing of a diagnosis is itself enough to justify medication. That is where the logic breaks.

The clearest effect of metformin is not to help people with prediabetes live better or longer, but to alter when the label “pre” is affixed and when it is dropped, an arbitrary cutoff that lacks inherent value.