We report the longest follow-up to date of metformin on body weight changes and on safety and tolerability. Metformin used in overweight or obese individuals with elevated fasting glucose and impaired glucose tolerance was associated with modest but durable weight loss and was safe and well tolerated over many years.
On an intent-to-treat basis, metformin produced a significant weight loss that persisted during the 2-year double-blind treatment period and for the entire duration of follow-up. Long-term follow-up was excellent at 92%, in contrast with other weight loss drug trials (12
). Effects of metformin on weight have been reported in several trials in diabetes (2
), one in obese adolescents (16
), and in a recent meta-analysis (17
). One report included changes in waist-to-hip circumference ratio, and only three provided data for more than 1 year of follow-up. In a meta-analysis of metformin and weight loss, weight change at 1 year was −1.52 kg (95% CI −2.82 to −0.21) (17
). The mean weight change at 1 year in our study was −2.7 kg in the metformin group and −0.4 kg in the placebo group.
Adherence to metformin improved the magnitude of weight loss—but not waist circumference—during the first 2 years. Adherence to placebo did not affect weight loss, suggesting that metformin, rather than nonspecific adherence to positive health behaviors, was the relevant factor.
Waist circumference increased in all groups after year 2, except for the highly adherent participants where the increase began after 5 years and waist circumference remained lower than baseline. Since body weight did not increase, this suggests that central adiposity increased by redistribution of body fat.
Metformin participants in the low adherence group lost weight but placebo participants with low adherence did not. Many of those in the low adherence metformin group took some metformin but not enough to be labeled “adherent.” In addition, those with low adherence in the placebo group may have personality traits related to accepting advice, ability to change habits, etc., whereas low adherence in the metformin group may also be related to gastro-intestinal side effects. Therefore, one would not expect those with low adherence in the two groups to have the same characteristics.
Metformin lowers glucose and reduces risk for diabetes in part through weight loss (2
). Although basal energy metabolism is highly correlated with body mass, early studies showed that despite appreciable reductions in body weight with metformin treatment, basal energy expenditure remains unchanged (18
). This is because metformin-induced weight loss is almost exclusively confined to reductions in adipose mass (2
) with little change in lean tissue. This pattern is different from that seen with caloric restriction, which tends to induce loss of lean tissue as well as adipose tissue. Metformin has several effects on energy metabolism that parallel physical exercise. Both exercise and metformin stimulate phosphorylation of AMP-activated protein kinase (AMPK) (19
). AMPK is an important regulator of mitochondrial biogenesis (20
), hepatic and muscle fatty acid oxidation, glucose transport, insulin secretion, and lipogenesis (21
). Whether metformin directly affects energy expenditure from physical activity is unknown. Metformin might also influence weight loss through reduced food intake owing to irritation of the gastrointestinal tract, which may motivate a reduction in food intake or change in nutritional preference.
Adherence to metformin was high. In the double-blind phase of the trial, 72% were highly adherent, and throughout the entire trial, 62% of the metformin group was highly adherent.
No significant safety issues were identified. Both hemoglobin and hematocrit declined slightly in the metformin group over the first year after randomization and stabilized after that. Metformin participants reported more gastrointestinal symptoms than placebo participants, however these abated over time and both types of gastrointestinal symptom reports were similar between groups by the latter years of the DPPOS.
One potential bias is that 12% of DPP participants chose not to continue into the DPPOS. It is likely that some of those who discontinued the study or who continued but chose not to take open-label metformin did so because of side effects, which may have influenced the safety and tolerability profile of metformin during the open-label DPPOS period.
In summary, metformin produces a highly significant reduction in body weight and waist circumference with minimal safety issues and limited issues of tolerability (22
). The weight reduction persists for up to 10 years and is related to adherence to metformin. Waist circumference initially declines, then steadily increases after a nadir at 12–36 months in all groups except in the highly adherent group, in which this increase was delayed for 5 years. Metformin was well tolerated with few side effects.