Head-to-Head: Comparing the Effectiveness of Weight-Loss Drugs

As the use of modern weight-loss medications increases, researchers are working to determine the most suitable drug for individual patients and the optimal timing for their use during the weight-loss process.

The effectiveness of the drugs and the potential side effects are crucial factors in making these determinations.

A new study, featured in the New England Journal of Medicine and at the European Congress on Obesity, offers insights into these questions. The study presents the results of a direct comparison trial between Novo Nordisk’s Wegovy (semaglutide) and Eli Lilly’s Zepbound (tirzepatide). Initial results were released by Eli Lilly in December, who also provided funding for the study. The current report expands on the initial data, offering further details on the drugs’ effects on waist circumference and other relevant metrics, in addition to side effects.

In the study, 751 participants were randomly assigned to receive weekly injections of either the highest dose of Wegovy or the highest dose of Zepbound for a period of 15 months. Results showed that the Zepbound group experienced a greater reduction in initial body weight (20.2%) compared to the Wegovy group (13.7%). The Zepbound group also saw a larger decrease in waist circumference, with an average reduction of 18.4 cm, while the Wegovy group averaged a 13.0 cm reduction.

Both medications produced similar side effects, primarily gastrointestinal issues such as nausea, constipation, diarrhea, and vomiting. However, the Zepbound group reported a higher incidence of reactions at the injection site, although these tended to decrease over time with continued weekly injections.

“The key takeaway is that we now have more—and better—treatment options than we did before, and these options offer different benefits,” says Dr. Leonard Glass, Senior Vice President of Global Medical Affairs for Lilly’s cardiometabolic health business, and a co-author of the study.

While weight loss is the primary goal of these medications, it should not be the only factor considered when evaluating and prescribing them. Dr. Glass emphasizes that obesity is a complex condition, and individuals with obesity often have co-existing health issues related to the heart, kidneys, and liver. “It’s not just about weight,” he states.

Dr. Jason Brett, Principal U.S. Medical Head for Novo Nordisk, the maker of Wegovy, supports the idea that weight is not the only factor that doctors and patients should consider when evaluating these two medications. He points out that Wegovy has received FDA approval to reduce the risk of heart attack, stroke, and heart disease in overweight or obese individuals with a history of heart problems, which Zepbound has not. “When considering what makes semaglutide and Wegovy unique, it’s the breadth and depth of data supporting it,” he says. “This goes beyond just weight loss and addresses other important health outcomes.”

While Zepbound is not specifically approved for reducing the risk of heart-disease, studies have demonstrated that it, along with Wegovy, can improve cardiovascular health in some patients. Studies also indicate the potential of these drugs to reduce the risk of liver and kidney issues. Further, Zepbound has been approved to mitigate the risk of obstructive sleep apnea in obese individuals.

These findings should help doctors make better decisions about which medication is most appropriate for each patient. Ongoing studies by both companies, including those tracking patients after they have reached their weight-loss goals, will provide additional data on how these drugs can support long-term weight management. Both Lilly and Novo Nordisk are also planning to release oral versions of their injectable medications soon. Novo Nordisk announced that it had requested FDA approval for its oral semaglutide in May, and Lilly anticipates receiving results from its final trials in the coming months. If those results are positive, Lilly plans to seek approval shortly after. Oral versions of these drugs could potentially benefit a wider range of individuals, and the pills could also play a role in maintenance therapy, depending on individual needs. “Currently, these decisions are based on physician experience, and often not on the best available evidence,” says Dr. Glass. “We aim to provide that evidence so that doctors and patients can make more informed decisions.”