Metformin Delivers Unexpected Benefit: Support for Long-Term Weight Loss

Latest findings from the Diabetes Prevention Program Outcomes trial reinforced benefit of taking metformin to maintain long-term weight loss at least among those with prediabetes who achieved modest weight loss during year one.

With Kishore M. Gadde, MD, and Caroline Apovian, MD

Long-term weight loss, as clinicians are only too well aware, remains an elusive goal for most patients. Fortunately, for many at risk for type 2 diabetes, long-term use of metformin may be the key to keeping lost weight off, 1 according to the most recent report from the Diabetes Prevention Program Outcomes Study (DPPOS).

The Diabetes Prevention Program (DPP)—a randomized control trial that enrolled 3,234 patients with excess body weight and a diagnosis of prediabetes from 27 clinics in the United States—was initiated to compare the efficacy of intensive lifestyle intervention or metformin to prevent type 2 diabetes.2 Most of these patients then enrolled in DPPOS and have been followed annually for more than 15 years in their originaly treatment group.

Metformin may help thwart diabetes by keeping lost weight off for up to 15 years.

Indirect Role For Metformin in Lowering Progression to Diabetes

For this latest analysis,1 the investigators identified 1,066 individuals from the initial cohort who had achieved a loss of at least 5% of their baseline body weight at the ned of the first year;1 the results were published in the Annals of Internal Medicine.

“After approximately three years in the DPP, both lifestyle and metformin appeared superior to placebo for the prevention of diabetes in those who had prediabetes," said Kishore M. Gadde, MD, professor and Fairfax Foster Bailey Endowed Chair in Heart Disease Prevention at the Pennington Biomedical Research Center in Baton Rouge, Louisiana, and a senior investigator in the Diabetes Prevention Program Research Group.

"We made an observation that some participants in the Diabetes Prevention Program were maintaining their weight loss," Dr. Gadde told EndocrineWeb, which piqued our interest in wanting to assess what the determinants were that differentiated those who maintained their weight loss from those who regained any lost weight.1

Closer look at the Diabetes Prevention Outcomes of Metformin for Weight Loss Maintenance

The DPPOS investigators reported on findings from post ad hoc analysis of factors related to long-term weight loss in which patients determined to have prediabetes were randomized to one of three groups: metformin, intensive lifestyle intervention, or placebo.

"We followed those patients who achieved at least a 5% weight loss at the end of year one, focusing on following weight changes over the course of the intervening 14 years," Dr. Gadde said. “We wanted to assess whether one group did better or not. It is very rare to find a group of individuals who have successfully kept weight loss off for so long—upward of 15 years," he said.

In assessing the DPPOS participants who achieved weight loss of at least 5% at the end of the first year, Dr. Gadde said, only 28.5% (n=289) of the those taking metformin had achieved a weight loss of 5% or more where as among those in the intensive instruction lifestyle group, 62.6% (640) had met the 5% weight loss cutoff. Even 13.4% (n=137) in the placebo group met this weight loss threshold.1

"In years six to 15, however, there was a noticeable shift in the weight loss trend among the three groups,"Dr. Gadde told EndocrineWeb. After the masked treatment phase ended, the mean weight loss relative to baseline was an average of  6.2% in the metformin group, which was about 2.5% greater than in the average weight loss (3.7%) of the individuals in the lifestyle group.1

During the last decade of follow-up  (years 6-15), an average of 56% of the individuals in the metformin group had maintained at least a 5% weight loss, while 43% in the lifestyle group and nearly the same (42%) in the placebo group, achieved the weight loss cutpoint,1 he said.

Factors Backing Up Benefits of Metformin in Moderating Long-Term Weight Regain

''Year after year, we saw that those on metformin were maintaining their weight loss to a much higher degree," Dr. Gadde said. Regardless of the treatment group, participants who lost 5% or more at the end of year one, had lower incidence of diabetes across the 15-year follow-up. (P < 0.001).1

Given this observed trend, the investigators sought to identify any factors that appeared to predict which patients would be more successful in achieving long-term weight loss. Among both metformin and lifestyle groups, older age at the start greater weight loss in the first year were predictors of whether an individual would maintain the lost weight.1 Additionally, continued use of metformin in the metformin group,  and absence of diabetes onset or a family history of diabetes in the lifestyle group appeared predictive of weight loss maintenance, said Dr. Gadde.

Clinical Caveats and Treatment Insights for Patients At Risk for Type 2 Diabetes

Compared to approved weight loss drugs, weight loss associated with metformin was less significant when examined as an average to the entire group.3,4 "The effect of metformin appears to have a subtle effect,'' he said. "I don't view it as an ideal weight loss drug as it has not yielded a rapid and substantial weight loss for most patients."

However, he added, maintaining any weight loss has always been the main struggle for anyone at risk for diabetes. Therefore, perhaps the more significant role for metformin is a delayed benefit—presenting much later on, and only after some initial weight loss has been achieved.1

“For instance, patients may lose weight rapidly with the help of a structured diet program or a weight loss medication over three months to get a jumpstart, then switched to the typically less expensive metformin for long-term use,” Dr. Gadde said. “For clinicians treating anyone with prediabetes or risk factors for type 2 diabetes, in particular, he acknowledged there is generally a comfort with prescribing metformin."  

As enlightening as some aspects of the authors’ findings may be, this new study did not answer a key question regarding whether lifestyle intervention or metformin was superior for long-term weight loss success,5 wrote Leslie I. Katzel, MD, PhD, and John D. Sorkin, MD, PhD, in an editorial accompanying the study.

This lack of a clear determination of weight loss efficacy may be explained by several study limitations, they said. Any interpretation of the percentage of participants who achieved and maintained weight loss of at least 5% from baseline is difficult due to regression to the mean,5 they stated.

A significant problem in parsing the data concerned the fact that metformin was initiated in study participants from the initial lifestyle and placebo groups over time, so by year 15, for example, there were 37% of individuals who began in the placebo group who were being treated with metformin.1 Adherence was another problem in the metformin group, and another confounding element was that individuals in all three groups received lifestyle intervention information at one point in the study.1

Might Patients At High Risk for Diabetes Benefit from Metformin Indefinitely?

"What are the implications of these findings? Given that only 29% lost at least 5% weight after 1 year, metformin is perhaps not an ideal drug for inducing rapid weight loss," Dr. Gadde said. However, the findings of this study strongly suggest that metformin could be an effective drug for weight loss maintenance.1

The editorial authors suggested clinical judgment in assessing which patients, if any, might benefit from metformin when lifestyle intervention does not appear sufficiently effective in reducing risk of diabetes or if the patient begins to regain lost weight.5

Offering an expert perspective as someone not involved in the study: "The bottom line about this is that for [patients with] prediabetes and obesity, metformin should be considered," said Caroline Apovian, MD, FACP, FACN, professor of medicine at Boston University School of Medicine and director of the Center for Nutrition and Weight Management at Boston Medical Center in Massachusetts. She reviewed the findings and agreed to share her insights with EndocrineWeb.

"It is clear that metformin appears to increase the chances of weight loss maintenance over the long-term for many people but like all medications aimed at obesity, some patients will lose weight, while others may even gain weight," Dr. Apovian said.

For those individuals who present with overweight or obesity but do not have prediabetes, more careful judgement concerning initiating metformin may be needed, she said. "If the patient exhibits any adverse side effects or struggles with adherence, there would be no compelling reason to continue."

"In summary, although lifestyle therapy was initially superior for weight loss, metformin appeared to be more effective for weight loss maintenance as years went by," said Dr. Gadde. "We also found that the degree of weight loss in the first year predicted long-term weight loss."

Additional insights are expected in the future as these patients will continue to be followed for at least five more years as part of the DPPO-3 trial. As well, there are more than 10 clinical trials currently examining the effects of metformin on various health conditions so as the study findings unfold,8 the role of metformin for long-term weight loss and diabetes prevention should become better understood.

Neither Dr. Gadde nor Dr. Apovian has any relevant financial disclosures with regard to the reporting of this study.

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