Weight Loss With Metformin Maintained at 15 Years

Metformin helped maintain long-term weight loss in individuals at risk for type 2 diabetes, a post-hoc analysis of the Diabetes Prevention Program (DPP) trial found.

Among participants who lost 5% of their body weight after a year on trial, mean weight loss from 6 to 15 years was 6.2% less for the metformin group versus 2.8% for the placebo group and 3.7% for the group that received a diet-and-exercise program, reported Kishore M. Gadde, MD, of Louisiana State University’s Pennington Biomedical Research Center in Baton Rouge, and colleagues.

Overall, however, 62.6% of patients undergoing the intensive lifestyle intervention (ILS) lost at least 5% of their body weight after 1 year compared with 13.4% of placebo patients and 28.5% of those on metformin, they wrote in Annals of Internal Medicine.

Although the benefits of metformin on blood glucose and insulin sensitivity are known, the benefits of metformin on weight loss are not quite as well understood, Gadde's group explained.

"Metformin is not known to significantly alter energy expenditure," they wrote, adding that some studies have shown decreases in appetite and food intake with metformin. "It is well recognized that the human body adapts to weight loss with compensatory neuronal, hormonal, and metabolic changes that promote weight regain. Whether metformin counters some of these compensatory changes must be further investigated."

Certain factors were found to be independent predictors of long-term maintenance of weight loss among patients on metformin at 5 years, 10 years, 15 years, and overall, respectively (P<0.001 for all):

• Older age at baseline: OR 1.74, OR 2.25, OR 2.37, OR 1.74
• Greater weight loss after 1 year (per 5% loss): OR 2.08, OR 1.97, OR 1.14, OR 1.70
• Active use of metformin (use vs nonuse): OR 4.83, OR 4.02, OR 2.17, OR 1.91

Original 10-year findings from the DPP trial found that the individuals randomized to metformin therapy or ILS had significantly reduced incidence of overt type 2 diabetes compared with placebo.

Despite the fact that more patients who originally were in the metformin group maintained long-term weight loss, the benefits of ILS shouldn't be overlooked, argued accompanying editorial authors Leslie Katzel, MD, PhD, of the Baltimore VA Medical Center Geriatric Research Education, and John Sorkin, MD, PhD, of the University of Maryland School of Medicine in Baltimore.

"It might make sense to begin with an ILS because this resulted in the greatest weight loss and had the greatest effect on preventing progression to diabetes," they recommended. "For now, clinical judgment should be used to decide whether metformin should be added if ILS does not succeed or if the patient subsequently regains the weight they lost."

Katzel and Sorkin also pointed out some limitations to this study, including the amount of metformin crossover between the original ILS and placebo groups.

"The number of participants in the ILS and placebo groups who received metformin increased over time; by year 15, 37% of those in the placebo group had been treated with metformin," they explained, noting that only 72% of those in the metformin group were actually adherent at 10 years (defined as taking ≥80% of the assigned dose), which decreased to around 49% in the 15-year analysis.

The DPP trial included 3,234 participants with elevated glucose levels who were either overweight or had obesity. Those randomly assigned to ILS received 16 sessions of a behavior modification program over the course of 6 to 8 months -- with the goal of achieving 7% weight loss via changes in diet and 150 minutes of moderate physical activity per week -- followed by reinforcement of the intervention every 2 months.

Those randomly assigned to receive metformin were administered 850 mg twice a day. The masked metformin and placebo patients both received the study drug until their plasma glucose levels increased to 140 mg/dL (7.8 mmol/L), at which point they discontinued the drug or placebo and were transferred to their primary care provider for diabetes management.

Not surprisingly, individuals in each group who lost 5% or more of their weight at 1 year were less likely to develop type 2 diabetes during the 15-year follow-up period compared with those who lost less than 5% of their weight: metformin (41% vs 54%, respectively), ILS (39% vs 61%), placebo (48% vs 57%).