New Study Finds Zepbound Outperforms Wegovy in Direct Comparison for Effective Weight Loss

As the demand for effective weight-loss medications continues to rise, a new study has provided further insights into how leading options compare. This month, researchers published the results of a large clinical trial in The New England Journal of Medicine, examining the efficacy and safety of two prominent anti-obesity drugs: tirzepatide (Zepbound) and semaglutide (Wegovy).

The clinical trial, known as SURMOUNT-5, enrolled 751 individuals with obesity but without type 2 diabetes across the United States and Puerto Rico. The participants were randomly assigned to receive either tirzepatide or semaglutide for 72 weeks. All participants were also provided counseling on nutrition and physical activity throughout the trial.

"Doctors, insurance companies and patients are always asking, ‘Which drug is more effective?’" said Dr. Louis Aronne, director of the Comprehensive Weight Control Center at Weill Cornell Medicine and principal investigator in the trial. “This study allowed us to do a direct comparison.”

Key findings from the trial include:

• Tirzepatide led to an average weight loss of about 50 pounds, or 20.2% of participants' body weight.
• Semaglutide recipients lost an average of 33 pounds, equating to 13.7% of their baseline weight.
• 32% of those taking tirzepatide lost at least 25% of their body weight, compared to 16% in the semaglutide group.
• Tirzepatide users showed a greater reduction in waist circumference than those on semaglutide.

According to Dr. Aronne, tirzepatide’s superior performance may be due to its "dual mechanism of action." While semaglutide acts on receptors for glucagon-like peptide 1 (GLP-1), tirzepatide mimics both GLP-1 and an additional hormone called glucose-dependent insulinotropic peptide (GIP). Together, these mechanisms help reduce hunger, lower blood-sugar levels, and influence fat metabolism.

The study noted that side effects were similar for both drugs:

• 44% of participants reported nausea
• 25% experienced abdominal pain

While most symptoms were mild, some patients had more severe reactions, such as pancreatitis. Medical experts emphasized the importance of discussing personal medical history and concerns with healthcare providers before starting these treatments.

Dr. Ada Londono, a primary care physician specializing in obesity medicine, commented that the study’s results align with earlier research, confirming tirzepatide’s advantage over semaglutide’s single-hormone mechanism. Beyond weight loss, semaglutide has demonstrated potential benefits for cardiovascular health, sleep apnea, and kidney disease, highlighting the need for further studies into the overall effects of these drugs.

“Weight loss is biological, but it’s also emotional,” stressed Dr. Rekha Kumar, an endocrinologist and chief medical officer at a weight care program. She underscored the importance of tailored, whole-person support and working closely with a physician to choose the best medication for an individual’s health needs, especially when coexisting conditions like fatty liver disease are present.

Researchers acknowledged certain limitations of the study. It was conducted as an open-label trial, meaning participants knew which medication they were receiving, which can introduce bias. Additionally, the study was funded by Eli Lilly, the manufacturer of Zepbound (tirzepatide), raising the possibility of conflicts of interest. The 72-week duration also leaves questions about long-term safety and efficacy unanswered.

Looking ahead, the investigative team plans to study new medications such as retatrutide, which mimics multiple hormones, in hopes of achieving even greater weight-loss outcomes for those who do not respond optimally to existing treatments.

A spokesperson for Novo Nordisk, maker of Wegovy (semaglutide), highlighted that both medications have shown significant weight reduction in trials. They noted that comprehensive management of obesity should extend beyond weight loss alone, and referenced previous research showing sustained results for Wegovy users over two years.

As weight-loss medications grow in popularity and their benefits expand to additional health conditions, experts agree that the choice of therapy should be guided by individual health profiles, ongoing medical supervision, and the understanding that lifestyle factors remain a cornerstone of effective, sustainable weight control.