Safe and Cheap Metformin Prevents Type 2 Diabetes Over 15 Years

Metformin continues to reduce the likelihood of developing type 2 diabetes among those at high risk for it over 15 years, particularly among those with higher baseline glycemia and women with a history of gestational diabetes mellitus (GDM).

Findings from the long-term follow-up of participants in the landmark Diabetes Prevention Program (DPP) were recently published online in Diabetes Care by the DPP Research Group.

The diabetes prevention benefit of metformin was seen in both relative and absolute risk reduction and regardless of whether the diagnosis was made by oral glucose tolerance testing, fasting blood glucose, or HbA_1c (which was analyzed post-hoc as HbA_1c wasn't recommended for diagnosing diabetes when DPP started). 

"Whichever method you use, you get this persistent and durable benefit with metformin. To me, that's the most important message," lead author David M. Nathan, MD, director of the Diabetes Center at Massachusetts General Hospital, Boston, told Medscape Medical News in an interview.

He added, "It's not just 3 or 10 years, as we reported before, but goes on for 15 years. That's a pretty powerful effect."

Cheap, Well-Tolerated With Powerful Effects, Especially in Subgroups

"Metformin remains this incredibly safe, inexpensive [agent], that's well-tolerated by most patients and it's really one of the few drugs in the world that makes sense for [diabetes] prevention, just because we know so much about it and have been using it for so long. That's why we selected it in the first place," Nathan explained.

Moreover, the current analysis identified two groups of high-risk patients who experienced even greater risk reduction with metformin: those with blood glucose measures on the higher glycemic end of the "prediabetes" ranges and women with a history of GDM.

"That doesn't mean that others with prediabetes criteria don't benefit, but that some subgroups have even more benefit," Nathan noted.

However, he emphasized that use of metformin for diabetes prevention is off-label and because it's been off-patent for more than a decade it's unlikely that any pharmaceutical company would seek the indication. On the other hand, its low cost and safety record make it a desirable option as an adjunct to lifestyle approaches.

"There's certainly an overall resistance to taking medicine for disease prevention. But on the other hand, how is this different from taking statins or blood pressure medications to prevent heart disease?" he wonders.

"It really isn't different at all. This prevents diabetes, which is important because it leads to vision loss, renal failure, amputations, and heart disease.

I think we would argue that preventing or delaying or reducing the risk for diabetes is, in and of itself, important."

Diabetes Prevention Seen at 15 Years, Regardless of Analytic Method

In the original DPP trial, 3234 participants aged 25 years or older at high risk for type 2 diabetes were randomized to intensive lifestyle modification, metformin, or placebo. Of those, 1073 participants received metformin 850 mg twice daily and 1082 received masked placebo.

After DPP ended in 2001, all participants were offered a lower-intensity group version of the lifestyle intervention and those who had been randomized to metformin continued to take it during the observational follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS).

All participants who develop diabetes during the DPPOS were referred back to their personal physicians, and many of those patients were again prescribed metformin.

Over the 15-year follow-up, the incidence of diabetes development was 17% lower among those in the original metformin group compared with the placebo group (hazard ratio, 0.83), with a rate difference of 21.25 cases/100 person-years, and diagnosis was based on a fasting and/or 2-hour glucose tolerance test.

When HbA_1c was used for diagnosis, metformin was associated with a 36% relative risk reduction (hazard ratio, 0.64) and an absolute rate difference of 21.67 cases/100 person-years (all statistically significant.)

The effect of metformin versus placebo didn't differ among those with baseline HbA_1c below 6% (hazard ratio, 0.61 vs 0.63).

But among those with HbA_1c 6.0% to 6.4%, metformin prevented significantly more cases of diabetes compared with those with an HbA_1c below 6% (rate difference, –3.88 vs –1.03 cases/100 person-years; P = .001).

And for women with a history of GDM, there was a significant 41% reduction in diabetes development with metformin versus placebo (hazard ratio, 0.59; P = .03). This relationship was even stronger by absolute rate difference (–4.57 vs –0.38/100 person-years, respectively; P = .01).

However, for parous women without a history of GDM the 6% difference between metformin and placebo wasn't significant (HR, 0.94).

No major differences in metformin's effect were seen by body mass index (BMI), and the benefit of metformin was lower in older age groups.

Will Metformin's Label Be Changed?

Nathan noted that another trial taking place in the United Kingdom, the Glucose Lowering in Non-diabetic Hyperglycaemia Trial (GLINT), is examining whether metformin prevents cardiovascular outcomes in people at high risk for type 2 diabetes. Results are expected in December 2024.

But even if that trial combined with other data show further benefit for using metformin in people at high risk for developing type 2 diabetes, there's no financial incentive for any pharmaceutical company to seek a label change by the US Food and Drug Administration or any other regulatory body worldwide.

However, there is another avenue in the United States: a "citizen's petition" to the FDA.

This was used by three academic institutions and, in April 2016, the agency loosened the chronic kidney disease (CKD) restrictions for metformin, allowing it to be used in patients with moderate CKD (30-60 mL/minute/1.73m²).

"There is a movement underfoot to do the same for metformin as a preventative for diabetes," Nathan said. "The cost of medicines is in the headlines every day. Here's a drug that's generic and incredibly inexpensive that may be appropriate for repurposing. If more data come out, it may be just what the drug companies hate — a drug that costs 10 cents a pill, less than 0.1 US dollar a day - fantastic!"

During the DPP and DPPOS, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and coordinating center for the design and conduct of the study and collection, management, analysis, and interpretation of the data. 

Diabetes Care. Published online March 15, 2019. Full text

http://care.diabetesjournals.org/content/42/4/601

From www.medscape.com

ABSTRACT

Long-term Effects of Metformin on Diabetes Prevention: Identification of Subgroups That Benefited Most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study

Diabetes Prevention Program Research Group

Abstract

OBJECTIVE We examined the effects of metformin on diabetes prevention and the subgroups that benefited most over 15 years in the Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS).

RESEARCH DESIGN AND METHODS During the DPP (1996–2001), adults at high risk of developing diabetes were randomly assigned to masked placebo (n = 1,082) or metformin 850 mg twice daily (n = 1,073). Participants originally assigned to metformin continued to receive metformin, unmasked, in the DPPOS (2002–present). Ascertainment of diabetes development was based on fasting or 2-h glucose levels after an oral glucose tolerance test or on HbA_1c. Reduction in diabetes incidence with metformin was compared with placebo in subgroups by hazard ratio (HR) and rate differences (RDs).

RESULTS During 15 years of postrandomization follow-up, metformin reduced the incidence (by HR) of diabetes compared to placebo by 17% or 36% based on glucose or HbA_1c levels, respectively. Metformin’s effect on the development of glucose-defined diabetes was greater for women with a history of prior gestational diabetes mellitus (GDM) (HR 0.59, RD −4.57 cases/100 person-years) compared with parous women without GDM (HR 0.94, RD −0.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for RD]). Metformin also had greater effects, by HR and RD, at higher baseline fasting glucose levels. With diabetes development based on HbA_1c, metformin was more effective in subjects with higher baseline HbA_1c by RD, with metformin RD −1.03 cases/100 person-years with baseline HbA_1c <6.0% (42 mmol/mol) and −3.88 cases/100 person-years with 6.0–6.4% (P = 0.0001).

CONCLUSIONS Metformin reduces the development of diabetes over 15 years. The subsets that benefitted the most include subjects with higher baseline fasting glucose or HbA_1c and women with a history of GDM.

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