Diabetes Prevention With Metformin Is Safe, Well-Tolerated

Yael Waknine

March 22, 2012

March 22, 2012 — Long-term treatment with metformin is safe for preventing or delaying the development of type 2 diabetes, according to an article published in the April issue of Diabetes Care.

New data from the open-label Diabetes Prevention Program Outcomes Study (DPPOS) demonstrate that metformin is linked to "modest but durable weight loss" of 2% body weight over the course of 10 years, and appears to be safe and well tolerated.

The findings support the conclusions of the original 3-year DPP double-blind study showing that use of metformin (850 mg twice daily) encouraged stable weight loss. In both the metformin and placebo groups, weight loss was a strong predictor of diabetes prevention.

According to the Diabetes Prevention Program Research Group, the pattern of metformin-associated weight loss appears to differ from that observed with caloric restriction, in that adipose tissue is affected more than lean tissue mass. Metformin may also mimic the effects of exercise.

As previously reported by Medscape Medical News, metformin therapy may represent a more cost-effective alternative to lifestyle changes for preventing diabetes.

"We now know how to prevent type 2 diabetes and have the data to show that doing so is not only safe, it is cost-effective," said Vivian Fonseca, MD, president, medicine and science, American Diabetes Association, in a news release. "We should be taking much greater steps on a broad scale to reduce this serious health epidemic in our country.... I would encourage every American to estimate their own risk using simple tools (for example see diabetes.org/risktest) and then, if at risk, take simple measures to prevent the disease."

Metformin Linked to Modest but Durable Weight Loss Over the Course of 10 Years

In the DPP, overweight and obese participants with impaired glucose tolerance were randomly assigned to lifestyle intervention, metformin, or placebo. Results reported in 2002 indicated that metformin therapy resulted in a 31% reduction in the development of diabetes during an average 2.8 years of follow-up.

During the study, participants randomly assigned to receive metformin experienced a decrease in body weight and waist circumference relative to placebo (mean, 2.06% ± 5.65% vs 0.02% ± 5.52%, and 2.13 cm ± 7.06 cm vs 0.79 cm ± 6.54 cm, respectively; P < .001 for both).

Throughout the unblinded follow-up study that covered 10 years from the start, weight loss remained significantly greater in the metformin group relative to placebo (2.0% vs 0.2%; P < .001), and was directly associated with the degree of therapeutic compliance (P < .001).

Participants highly adherent to metformin therapy achieved a weight loss of 3.5% (3.1 kg, 6.8 pounds), whereas those in the low-adherence group experienced an initial weight loss followed by weight changes similar to placebo until 5 years, at which point weight increased.

The authors note that waist circumference increased after 2 years, with the exception of highly adherent participants for whom the increase occurred after the 5-year point. Because body weight did not increase, the authors deduced that central adiposity was increased by a redistribution of body fat.

"[M]etformin-induced weight loss is almost exclusively confined to reductions in adipose mass with little change in lean tissue," the authors write, emphasizing that the pattern is different than that observed with caloric restriction, which tends to induce loss of lean, as well as adipose, tissue.

The authors also note that metformin also has several effects on energy metabolism that parallel physical exercise, such as phosphorylation of AMP-activated protein kinase, which is an important regulator of mitochondrial biogenesis, hepatic and muscle fatty acid oxidation, glucose transport, insulin secretion, and lipogenesis.

"Collectively, the clinical data suggesting 'durable weight loss' combined with the proposed cellular effects on energy metabolism continue to support metformin as a viable strategy for widespread translational efforts in prevention," comments William T. Cefalu, MD, from the Pennington Biomedical Research Center at Louisiana State University in Baton Rouge, in an accompanying editorial.

Long-Term Use of Metformin Is Generally Safe and Well-Tolerated

During the DPP through year 4, metformin-treated participants reported study drug–related gastrointestinal symptoms more frequently than those receiving placebo (9.5% vs 1.1%; P < .001). Reports declined over time, and rates were similar between groups during years 6 through 9 (P > .10).

Nonserious hypoglycemia and anemia were uncommon, and occurred at similar rates in metformin and placebo participants during nearly 18,000 patient-years of follow-up (n = 7 vs 8 and 50 vs 38, respectively). Serious adverse events were rare: there were only 3 reports of anemia (metformin, 2; placebo, 1), and no reports of lactic acidosis or hypoglycemia.

During the DPP, average hemoglobin and hematocrit declined slightly during the first year among metformin-treated participants, but remained stable thereafter (13.6 mg/dL vs 13.8 mg/dL and 40.6% vs 41.1%; P < .001 for both).

Although the proportion of participants with low hemoglobin was similar between groups (11.2% vs 7.6%; P = .17), low hematocrit was more common among metformin-treated participants (12.6% vs 8.4%; P = .035).

The authors note that 12% of DPP participants chose not to continue into the follow-up study, potentially because of adverse events that may have influenced the safety and tolerability profile observed.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Bristol-Myers Squibb and Parke-Davis provided additional funding and material support during the DPP. Lipha (Merck-Sante) provided medication, and LifeScan Inc donated materials, during the DPP and DPPOS. One coauthor reports receiving grants from Novo Nordisk, the Swedish Heart-Lung Foundation, the Swedish Diabetes Association, and the Swedish Research Council. The other authors and Dr. Cefalu have disclosed no relevant financial relationships.

Diabetes Care. 2012;35:663-665, 731-737.


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