Metformin May Stop Weight Regain After Initial Loss

Metformin may not only lower blood glucose levels, it may also help people who lose weight keep it off, according to the results of a long-term follow-up study.

Specifically, among patients in the Diabetes Prevention Program (DPP) trial who lost at least 5% of their initial weight at 1 year (after being randomized to metformin, intensive lifestyle, or placebo), those in the metformin group who continued on metformin in the follow-up observational Diabetes Prevention Program Outcomes Study (DPPOS) had the greatest weight-loss maintenance 5 to 14 years later.

"Those who lost weight initially after 1 year had remarkable maintenance of the weight loss with metformin, something we had never known before," senior author Kishore M. Gadde, MD, Pennington Biomedical Research Center, Baton Rouge, Louisiana, told Medscape Medical News.

Metformin "doesn't give you the kind of weight loss [or appetite suppression] you would get with a medication approved for treating obesity like Qsymia (phentermine/topiramate), or Saxenda (liraglutide)," Gadde continued.

However, "If you're among those [29%] of people who do well initially, you seem to maintain that weight loss for a really long time," if you continue to take metformin.

The study by John W. Apolzan, PhD, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, and colleagues was published online April 22 in the Annals of Internal Medicine.

Although the DPP was a randomized controlled trial (RCT), the DPPOS was not, so "further studies are needed to confirm the findings of this study in one or more RCTs," Gadde cautioned.

And "because metformin is a generic drug, it is unlikely that any pharmaceutical company would conduct phase three RCTs to file a new drug application (NDA) to seek a new indication," he added, although the National Institutes of Health and nonprofit professional organizations sometimes fund studies of a drug for an unmet clinical need.

"For now, clinical judgment should be used to decide whether metformin should be added if [intensive lifestyle intervention] does not succeed or if the patient subsequently regains the weight they lost," Leslie I. Katzel, MD, PhD, and John D. Sorkin, MD, PhD, Baltimore VA Medical Center, University of Maryland, write in an accompanying editorial.

"Although not all patients were successful, the data show that [long-term weight loss] is achievable...and it makes sense to help patients strive for it," the editorialists add.

"It might make sense," they write, "to begin with an [intensive lifestyle intervention] because this resulted in the greatest weight loss [in the randomized DPP] and had the greatest effect on preventing progression to diabetes."

Invited to comment, Danielle Ostendorf, PhD, a postdoctoral fellow at the University of Colorado Anschutz Medical Campus, Aurora, noted in an email that adhering to an intensive lifestyle intervention poses challenges. "Future work is needed to understand what components of a lifestyle intervention promote sustained behavior change and what we can do to improve the design of our interventions to make them more effective long term," she said

Future research could also look for differences between patients who did or did not have early weight loss success with metformin.

In the meantime, "there are always individual differences in response to treatment," noted Ostendorf, who led a small case-control study that found exercise was important to prevent weight regain, as previously reported. "The best strategy is going to be the one that works for that individual. Exploring different strategies with a [primary care provider] is an important step to achieve successful long-term weight loss maintenance."

Metformin vs Intensive Lifestyle Counseling for Long-Term Weight Loss

When people who are overweight or obese lose weight, glycemia improves, the researchers note. However, it is not clear if this benefit continues only if the weight loss is maintained. In addition, identifying baseline factors associated with better long-term weight loss management may also help in patient management.

To investigate this, the current study looked at long-term weight loss in patients in the DPP who lost at least 5% of their initial weight at 1 year, and they were followed out to 15 years in the DPPOS.

DPP/DPPOS is the largest, longest study to investigate metformin for preventing or delaying type 2 diabetes.

In DPP, 3234 patients with overweight or obesity and elevated glucose levels at risk of diabetes were randomly assigned to an intensive lifestyle intervention (counseling sessions about diet and exercise to promote 7% weight loss), metformin 850 mg twice daily, or placebo, for a mean follow-up of 2.8 years.

After the masked treatment ended, participants could enter the DPPOS, in which all participants were offered less intensive lifestyle counseling.

At baseline, patients were a mean age of about 50 years and about two thirds were women. They had a mean body mass index (BMI) of about 34 kg/m² and approximately two thirds had a family history of diabetes.

At 1 year, 289 of 1014 participants in the metformin group (28.5%), 640 of 1029 participants in the intensive lifestyle intervention group (62.6%), and 137 of 1025 participants in the placebo group (13.4%) had lost at least 5% of their initial weight — a mean weight loss of 8.9%, 11.0%, and 9.2%, respectively.

However, the newly reported data show that patients in the metformin group had greater long-term weight loss maintenance success.

During years 6 to 15 (after the intensive lifestyle counseling was completed and weight stabilized), weight loss relative to baseline was 6.2% (95% CI, 5.2% to 7.2%) in the metformin group, 3.7% (95% CI, 3.1% to 4.4%) in the intensive lifestyle group, and 2.8% (95% CI, 1.3% to 4.4%) in the placebo group — and 56%, 43%, and 42% of patients in these respective groups had kept off at least 5% of their initial weight.

The cumulative incidence of diabetes over the 15 years was lower among patients who lost at least 5% of their weight in the first year.

In all three groups, long-term weight loss (≥ 5% weight loss at 5, 10, and 15 years) was greater among patients who had a greater initial 1-year weight loss.

In the intensive lifestyle group, long-term weight loss was greater among patients who were older and did not develop diabetes or have a family history of diabetes.

And predictors of successful long-term weight loss maintenance included current active use of metformin in the metformin group and higher baseline fasting plasma glucose levels in the placebo group.

Study limitations, the editorialist note, include that 37% of patient in the placebo group received metformin by year 15.

And in the metformin group, only 72% of patients were adherent (took at least 80% of the assigned dose) in the DPP, and only 49% were adherent in the DPPOS.

Moreover, other groups use a different threshold for long-term weight loss; for example, the National Heart, Lung, and Blood Institute use a threshold of 10%.

However, even 5% weight loss confers a health benefit, the researchers write.

DPPOS-3: Effect of Metformin on CVD, Certain Cancers

"Future investigations," the researchers conclude, "should focus on whether metformin could be a useful intervention for [long-term weight loss] after initial weight loss with lifestyle interventions, antiobesity drugs or devices, or bariatric surgery."

They are continuing to follow the participants for another 5 years in DPPOS-3, Gadde said, to investigate, among other things, emerging data suggesting that metformin may reduce the risk of cardiovascular disease or certain cancers.

If DPPOS-3 and the more than 10 clinical trials examining the effect of metformin on various outcomes "show that metformin has the additional salutary effects that have been posited," Katzel and Sorkin conclude, "the magnitude of these effects will have to be part of the decision-making process in choosing the best intervention for promotion of [long-term weight loss]."

The work was funded by the National Institutes of Health. Gadde has reported receiving grants from AstraZeneca and BioKier and other support from AstraZeneca and the American Diabetes Association outside the submitted work. Disclosures of the other authors are listed with the article. Katzel and Sorkin have reported no relevant financial relationships.

Ann Intern Med. Published April 22, 2019. Abstract, Editorial

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