by Matt Toal, Perelman School of Medicine at the University of Pennsylvania

Waterfall plot showing percent change in baseline body weight during the 4-week behavioral treatment run-in (week −4 to week 0) for each of the 131 participants who later enrolled in phase 2. Credit: Nature Medicine (2025). DOI: 10.1038/s41591-025-03556-3

Adding an anti-obesity medication just one month after behavioral therapy begins—rather than waiting the currently recommended six months—can more than double weight loss for patients who struggle initially with lifestyle changes alone, according to new research published in Nature Medicine by a team at the Perelman School of Medicine at the University of Pennsylvania.

Obesity affects more than 40% of American adults and is linked to an increased risk of heart disease, stroke, type 2 diabetes, and certain types of cancer. Both behavioral therapy, also known as lifestyle intervention, and anti-obesity medication can help patients to succeed in meeting their weight and health goals. However, the effectiveness of these treatments varies widely for different individuals. This research addresses a critical gap by providing evidence that people who struggle to lose weight with one treatment method can succeed when a different kind of treatment is added.

Most obesity management guidelines recommend trying behavioral interventions for at least six months as the first-line treatment for individuals who could benefit from weight loss. These lifestyle interventions include a reduced-calorie diet, increased physical activity, and behavioral strategies (like tracking food intake and physical activity).

The sessions are led by trained counselors and focus on helping participants set specific, achievable health and weight goals. They also provide accountability and feedback on goals from the previous week. However, previous research has shown that up to half of patients do not achieve a clinically meaningful loss of at least 5% of their starting weight with these tactics.

“Surprisingly little is known about how to help patients who struggle to lose weight when they are already receiving frequent lifestyle counseling sessions,” said Jena Shaw Tronieri, Ph.D., a Senior Research Investigator at the Center for Weight and Eating Disorders in the Department of Psychiatry. “Some experts have suggested that adding an anti-obesity medication should be the next step, but no studies have tested whether this approach actually improves weight loss.”

Speeding up weight loss

The new study, led by Tronieri, evaluated an early intervention approach for patients who lost less than 2% of their initial body weight after a month of weekly behavioral sessions (less than one pound per week for most patients). These early non-responders to behavioral treatment were randomly assigned to take either the anti-obesity medication phentermine hydrochloride (15.0 mg per day) or a placebo while they completed 24 more weeks of behavioral intervention.

Phentermine, an appetite suppressant, is the oldest weight-loss drug currently on the market and was first approved by the U.S. Food and Drug Administration (FDA) in 1959.

Study participants who took a placebo along with the one-on-one sessions lost only 2.8% of their starting weight after 24 weeks. However, for participants who added phentermine, weight loss more than doubled to 5.9% of their starting weight. For context, a person weighing 250 pounds would lose approximately 15 pounds with the added medication compared to only about 7 pounds with behavioral therapy plus placebo.

Meanwhile, those who responded well from the start of the behavioral sessions—called “early strong responders”—continued without medication and lost an additional 5.1% of their starting weight over the same six-month period.

A new path to better results

“Our results strongly support the addition of anti-obesity medications for patients who do not achieve meaningful weight loss with behavioral methods alone,” said Tronieri. “They also suggest that the medication can be introduced early in treatment, rather than waiting until a patient completes a full 6-month program. Early intervention is crucial because patients who don’t see initial results are more likely to become discouraged and discontinue treatment altogether.”

The researchers hope that the treatment used in this study will provide a road map for health professionals looking to support patients who find it hard to lose weight with diet and exercise alone. However, the efficacy of other FDA-approved weight-loss medications for patients who do not lose significant weight with behavioral methods still needs to be established through formal testing.

“If the people who were early non-responders took one of the newer approved medications, like semaglutide or tirzepatide, it’s likely they could easily double or triple their weight loss compared to phentermine,” said study co-author Thomas A. Wadden, Ph.D., a professor of Psychology in Psychiatry.

“Additional research is needed to confirm this hypothesis,” he added.

More information: Jena S. Tronieri et al, Anti-obesity medication for weight loss in early nonresponders to behavioral treatment: a randomized controlled trial, Nature Medicine (2025). DOI: 10.1038/s41591-025-03556-3

Journal information:Nature Medicine

Provided by Perelman School of Medicine at the University of Pennsylvania

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