"Metformin provides stable, durable preventive benefits; a 15-year span represents a remarkably robust preventive effect."
Metformin is the most widely prescribed oral hypoglycemic agent for patients with diabetes, valued for its safety, efficacy, and low cost. In recent years, accumulating research and positive findings have continued to emerge regarding metformin's potential in oncology, aging, and metabolic disorders. While these discoveries are striking, they have also earned the drug the playful moniker of a "wonder drug."
Recently, landmark results from the Diabetes Prevention Program (DPP) were unveiled, potentially reaffirming just how remarkable this classic medication truly is. Long-term follow-up data from the DPP study demonstrate that metformin can sustain a reduction in diabetes incidence for up to 15 years among high-risk populations.
Why the DPP Study Was Conducted
Preventive therapy is not currently among metformin's approved indications; however, the American Diabetes Association already recommends its use for diabetes prevention in individuals with prediabetes. The DPP study was initiated to further clarify the long-term benefits and risks of preventive metformin use, as well as to identify which populations stand to benefit most.
Dr. David M. Nathan, Director of the Diabetes Center at Massachusetts General Hospital, stated, "Metformin is very safe, inexpensive, has a long clinical track record, is well understood by clinicians, and is well tolerated by most patients-these are the reasons we chose it first-line for prevention."
In Dr. Nathan's view, the widespread adoption of preventive pharmacotherapy typically encounters resistance. Yet just as statins and antihypertensives help prevent cardiovascular disease, preventing or delaying the onset of diabetes is equally critical. Diabetes carries a host of complications, including vision loss, kidney failure, amputations, and heart disease.
How the DPP Study Was Designed
Conducted between 1996 and 2001, the DPP enrolled a total of 3,234 adults aged 25 years or older at high risk for diabetes. Participants had impaired glucose tolerance, elevated fasting plasma glucose (95–125 mg/dL), and a BMI ≥ 24 (≥ 22 in Asian Americans). Subjects were randomized to one of three arms: placebo (n = 1,082), metformin 850 mg twice daily (n = 1,073), or lifestyle intervention (n = 1,079).
After 2002, all DPP participants received a low-intensity lifestyle intervention curriculum. In addition, 86% (n = 1,861) of participants from the metformin and placebo groups continued follow-up in the Diabetes Prevention Program Outcomes Study (DPPOS). The original metformin group continued treatment until a diagnosis of diabetes was made and the participant was referred onward, while the original placebo group received no further study medication.
15-Year Follow-Up Reveals Significant Diabetes Prevention
Diabetes diagnosis is increasingly based on glycated hemoglobin (HbA1c) levels, whereas fasting plasma glucose and postprandial glucose were the predominant measures during the DPP. After 15 years of follow-up, however, researchers found that metformin significantly prevented diabetes onset regardless of which diagnostic criterion was applied.
Using fasting plasma glucose or 2-hour postload glucose as the diagnostic standard, metformin reduced diabetes incidence by 17% compared with placebo. When HbA1c was used as the confirmatory criterion, the preventive effect of metformin was even more pronounced, reducing diabetes risk by 36%.
Dr. Nathan emphasized, "Metformin provides stable, durable preventive benefits; a 15-year span represents a remarkably robust preventive effect."
Greater Benefit Observed in Selected Subgroups
Researchers also found that metformin's preventive effect was more pronounced in two specific patient subgroups. Dr. Nathan cautioned, however, that this does not mean other individuals with prediabetes derive no benefit.
No significant difference in preventive efficacy was observed between participants with baseline HbA1c below 6% and those between 6% and 6.4%. When considering the absolute number of new cases averted, however, participants with higher baseline glucose levels benefited more substantially.
Among women with a history of gestational diabetes mellitus (GDM), metformin reduced diabetes incidence by a significant 41%. Women without a history of GDM also derived benefit from metformin, with a 6% reduction in diabetes risk, though this did not reach statistical significance.
Furthermore, metformin's preventive effect was independent of body mass index, while older adults appeared to derive less benefit from preventive use.
Will Metformin's Indications Change?
A separate trial currently underway in the United Kingdom is investigating whether metformin can prevent cardiovascular outcomes in high-risk individuals with type 2 diabetes, with results expected in December 2024.
Dr. Nathan believes that repurposing established medications can help more patients reduce treatment costs. If the data demonstrate additional benefits from metformin, applications for new indications will require collaborative efforts between academic institutions and pharmaceutical companies. At the same time, drawing lessons from the aspirin story, the "wonder drug" narrative may be accompanied by considerable debate-and further research will be needed for continued validation.
