Semaglutide Shows Long-Term Weight Loss Benefits but Raises Concerns About Anxiety and Drug Dependence

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A new long-term analysis from the large SELECT cardiovascular outcomes trial suggests that semaglutide can produce sustained weight loss in people with obesity or overweight without diabetes. However, alongside its metabolic benefits, the study also reports higher treatment discontinuation rates and anxiety-related symptoms, raising concerns about long-term drug dependence and tolerability.

The SELECT trial enrolled more than 17,000 adults with overweight or obesity and established cardiovascular disease who did not have diabetes. Participants were randomly assigned to receive once-weekly semaglutide or placebo and were followed for up to 208 weeks (four years). While the trial was originally designed to assess cardiovascular outcomes, this prespecified analysis focused on long-term changes in body weight and anthropometric measures.

Results showed that participants treated with semaglutide achieved an average weight reduction of more than 10% over four years, compared with only about 1–2% in the placebo group. Significant reductions in waist circumference and waist-to-height ratio were also observed, reflecting improvements in central obesity, a key risk factor for cardiometabolic disease.

These benefits were consistent across sex, baseline body mass index (BMI), and racial and ethnic groups, supporting the broad effectiveness of GLP-1 receptor agonists for weight management beyond diabetes care.

However, the study also highlighted important limitations. Discontinuation rates were higher in the semaglutide group, suggesting challenges in maintaining long-term treatment. In addition to well-known gastrointestinal side effects, anxiety-related symptoms were reported more frequently among individuals receiving semaglutide.

Researchers caution that the need for continuous medication to sustain weight loss raises concerns about potential drug dependence and the long-term sustainability of pharmacological obesity treatment. Previous evidence has shown that stopping GLP-1 therapy often leads to weight regain, reinforcing the idea that semaglutide represents a chronic treatment rather than a permanent solution.

The authors emphasize that clinicians should carefully balance metabolic benefits with psychological well-being. Monitoring mental health outcomes, particularly anxiety, may be just as important as tracking body weight and cardiometabolic markers during prolonged therapy.

“These findings demonstrate both the promise and the complexity of using semaglutide as a long-term obesity treatment in people without diabetes,” the authors note. The results underscore the importance of evaluating obesity medications not only for physical outcomes but also for their impact on mental health and patient adherence.

Overall, the study presents a dual picture: semaglutide can help many individuals achieve sustained weight loss, but its long-term use raises questions about tolerability, psychological effects, and dependence on medication as a primary strategy for obesity management.

Why This Matters for GeneFit Readers

For GeneFit readers, this study highlights that medical weight-loss treatments are not only about reducing numbers on the scale. While semaglutide can offer meaningful and sustained weight reduction, it may also influence mental well-being and create long-term reliance on medication. This reinforces the importance of personalized obesity care that combines genetics, lifestyle interventions, and psychological support rather than depending solely on drugs. Understanding both the benefits and risks empowers individuals to make informed decisions about weight management strategies that are sustainable and safe in the long run.

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Reference

Rubino, D., et al. (2024). Long-term weight loss effects of semaglutide in people with overweight or obesity without diabetes: Results from the SELECT trial. Nature Medicine. https://pubmed.ncbi.nlm.nih.gov/38740993/

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