Which Weight-Loss Drug Works the Best?

As more doctors and patients turn to the latest weight-loss drugs, researchers are trying to figure out which drug is right for which patient—and at what point in their weight-loss journey.

Key to making those decisions is how effective the drugs are and which side effects people might experience while taking them.

A new study published in the New England Journal of Medicine and presented at the European Congress on Obesity provides some of those answers. Researchers report on a head-to-head trial comparing Wegovy (semaglutide), made by Novo Nordisk, to Zepbound (tirzepatide), made by Eil Lilly. The initial findings were released in Dec. by Eli Lilly, who funded the study. The current report includes more details on how the two drugs affected waist circumference and other measures, as well as their side effects.

Among the 751 people randomly assigned to receive weekly injections of either the maximum dose of Wegovy or the maximum dose of Zepbound for a year and three months, those taking Zepbound lost more of their initial body weight—20.2%—than those taking Wegovy, who lost 13.7%. The Zepbound group lost about 18.4 cm in their waist circumference, compared to 13.0 cm among those taking Wegovy.

The medications had similar side effects, mainly relating to gastrointestinal symptoms including nausea, constipation, diarrhea, and vomiting. However, those taking Zepbound reported more injection-site reactions than people getting Wegovy. These tended to become less frequent with additional weekly injections.

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“The idea here is that we didn’t have options before—or we had very bad options—and now we have better and better therapies, and they are different,” says Dr. Leonard Glass, senior vice president of global medical affairs for Lilly’s cardiometabolic health business, and one of the co-authors of the study.

While the primary target for these medication is weight loss, it’s not the only metric by which the drugs should be evaluated and prescribed. Glass points out that obesity is a complex condition, and people with obesity often have other health issues as well, related to the heart, kidney, and liver. “It’s not just about weight,” he says.

Dr. Jason Brett, principal U.S. medical head for Novo Nordisk, which makes Wegovy, agrees that weight is not the only outcome that doctors and patients should consider when evaluating the two medications. He notes that Wegovy—unlike its competitor—is approved by the U.S. Food and Drug Administration to reduce the risk of heart attack, stroke, and heart disease in people with a history of heart problems who are overweight or obese. “When I think about what makes semaglutide and Wegovy unique, it’s the breadth and depth of data behind it,” he says. “We’re talking about going beyond weight loss alone to some of these other health outcomes.”

Zepbound does not include a heart-disease indication, but studies have shown that Zepbound, as well as Wegovy, can reduce the risk of heart failure in some patients with the condition. Studies are also showing that the drugs can reduce the risk of liver and kidney symptoms as well. And Zepbound is approved to reduce the risk of obstructive sleep apnea in people with obesity.

The current findings should help doctors better understand which drug might be right for which patient. Additional studies that both companies are conducting—including those following people once they have reached their weight-loss goals—should also provide more data on how these drugs could help people maintain a healthy weight. Both Lilly and Novo Nordisk also plan to have oral versions of their injectable drugs available soon. Novo Nordisk announced it had requested FDA approval for its oral semaglutide in May, and Lilly expects to have results from its final trials in a few months; if those are positive, it plans to apply for approval soon after. Oral versions of these drugs could reach more people who might benefit from them, and the pills could also be considered part of maintenance therapy depending on their individual needs. “Right now, [those decisions] are based on physician experience, and sometimes not necessarily on the best evidence,” says Glass. “We are trying to provide that evidence so doctors and patients can better make those decisions.”