Zepbound beat Wegovy on average weight loss in first head-to-head trial, Lilly says

Eli Lilly said on Dec. 4, 2024 that its obesity drug Zepbound (tirzepatide) produced greater average weight loss than Novo Nordisk's Wegovy (semaglutide) in the first large randomized trial to compare the two medicines directly. Over 72 weeks, adults taking Zepbound lost an average of 20.2% of their body weight, compared with 13.7% for those taking Wegovy — a 47% greater relative weight loss ^[1][2].

The trial, called SURMOUNT-5, enrolled 751 adults across the United States and Puerto Rico and assigned them in a 1-to-1 ratio to one drug or the other ^[1][3]. Participants had obesity, or were overweight with at least one related condition such as high blood pressure, high cholesterol, obstructive sleep apnea or cardiovascular disease. None had diabetes ^[1][3].

Zepbound and Wegovy work differently. Tirzepatide, sold as Zepbound for obesity and Mounjaro for type 2 diabetes, activates two gut-hormone receptors, GIP and GLP-1. Semaglutide, sold as Wegovy for obesity, Ozempic for diabetes and Rybelsus as a pill, activates only GLP-1 ^[1][3].

Participants received the highest dose they could tolerate: 10 mg or 15 mg of Zepbound, or 1.7 mg or 2.4 mg of Wegovy ^[1][3]. In pounds, the average loss was 50.3 lbs (22.8 kg) on Zepbound and 33.1 lbs (15.0 kg) on Wegovy ^[1][3].

On the secondary measures reported at the time, 31.6% of people taking Zepbound lost at least 25% of their body weight, compared with 16.1% on Wegovy ^[1]. The complete results, published in May 2025 in The New England Journal of Medicine and presented at the European Congress on Obesity, showed that 81.6% of Zepbound participants lost at least 10% of body weight versus 60.5% on Wegovy; 64.6% versus 40.1% lost at least 15%; and 48.4% versus 27.3% lost at least 20%. Waist circumference fell by an average of 7.2 inches (18.4 cm) on Zepbound and 5.1 inches (13.0 cm) on Wegovy ^[3].

Side effects in the trial were mostly gastrointestinal and generally mild to moderate, similar to earlier tirzepatide trials ^[1]. In the published results, 6.1% of participants on Zepbound stopped treatment because of side effects, compared with 8.0% on Wegovy. Lilly noted the trial was not designed, or "powered," to compare safety and tolerability between the two drugs ^[3].

On the day the top-line numbers were released, Lilly's shares rose 2.5%, adding about $19 billion to its market value and pushing it above $790 billion. Novo Nordisk's Copenhagen-listed shares fell as much as 1.8% and were down 0.5% in afternoon trading ^[2].

Novo Nordisk said it would wait for the complete data, including how doses were distributed between the two groups, once the results were peer-reviewed and published. The company also said Wegovy is the only obesity drug shown to reduce the risk of heart attack or stroke ^[2]. The U.S. approved Wegovy as a treatment for heart disease in March 2024, and Zepbound has since been approved to treat moderate-to-severe obstructive sleep apnea with obesity ^[2][3].

Why it matters for patients

Both drugs are prescribed for long-term weight management and are meant to be used with a reduced-calorie diet and increased physical activity ^[1][3]. Until now, doctors and patients choosing between them had no single trial comparing them under the same conditions. Much of the prescribing had instead been driven by which drug happened to be in stock during intermittent supply shortages ^[2].

A clear difference in average weight loss could change how insurers and health authorities decide which drug to cover. Reuters reported that the results may persuade U.S. insurers and cost-conscious European health authorities to favor Zepbound over Wegovy ^[2].

The figures are group averages, and the trial did not report how any one person responded. BMO Capital Markets analyst Evan Seigerman said before the data was released that a confirmed efficacy difference "could be a differentiator when the market matures in the long-term and physicians are not capacity constrained" — that is, when doctors can pick a drug on effectiveness rather than on what is available ^[2].

What happens next

Novo Nordisk is counting on a dual-action drug candidate, CagriSema, to regain an edge on weight loss. Late-stage trial results, which the company said could show about 25% weight loss, were expected in December 2024 ^[2]. Lilly is also testing an oral drug, orforglipron, in Phase 3 trials, with data expected in the first half of 2025, according to fund manager Lukas Leu of Bellevue Asset Management ^[2]. Whether insurers change coverage based on SURMOUNT-5 has not been disclosed.