Tirzepatide Tops Semaglutide for Weight Loss: SURMOUNT-5

MALAGA, Spain—In a head-to-head battle between two drugs that reduce body weight, the newer kid on the block, perhaps not unexpectedly, came out on top.

The SURMOUNT-5 trial, published over the weekend in the New England Journal of Medicine and presented at the European Congress on Obesity, showed that treatment with tirzepatide (Zepbound; Eli Lilly) led to greater reductions in body weight and waist circumference over roughly a year-and-a-half compared with semaglutide (Wegovy; Novo Nordisk).

“We have learned over the past 20-odd years that in order to overcome plateau phenomenon in obesity, if you can add mechanisms that are completely different together, you can often get additional weight loss,” said lead investigator Louis Aronne, MD (Weill Cornell Medicine, New York, NY), during a press conference announcing the results.

And that’s exactly what the trial shows.

With subcutaneously-administered tirzepatide, which mimics the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) hormones, patients had a 20.2% reduction in weight by week 72 compared with a 13.7% reduction in those treated with semaglutide, a GLP-1 receptor agonist (P < 0.001). This translated to a loss of 22.8 kg in the tirzepatide-treated patients versus 15.0 kg in those who received semaglutide.

David Horner, MD, PhD (Copenhagen University Hospital, Denmark), who wasn’t involved in the study, said the obesity field is evolving rapidly, adding that the SURMOUNT-5 results make sense given the dual mechanism of action with tirzepatide.

“In the whole field of obesity for 40 years, there was nothing,” he told TCTMD. “Doctors were frustrated in their clinics because they’d [advise] diet and lifestyle [changes], but nobody did it. Nothing changed. Basically, you were just putting on [Band-Aids] or putting out fires.”  

Both tirzepatide and semaglutide are excellent, highly effective medications, he stressed, but he cautioned that the treatments aren’t available to everyone. If tirzepatide can’t be accessed, semaglutide is still a good choice because 15% weight loss, particularly at the population level, is enormous.

“Ten years ago, if someone had told you semaglutide was possible, you wouldn’t believe them,” he said.

SURMOUNT-5

Tirzepatide was approved by the US Food and Drug Administration in 2022 under the trade name Mounjaro as an adjunct to diet and exercise to improve blood sugar control in patients with type 2 diabetes. The following year, it was approved for chronic weight management in adults with obesity or overweight and at least one weight-related condition.

Semaglutide has been around a little longer: in oral form, it was approved under the trade name Rybelsus for patients with type 2 diabetes in 2019 and for chronic weight management in 2021. As a subcutaneous injectable, it gained an indication for reducing major adverse cardiovascular events in 2024.

The SURMOUNT-5 study included 750 patients (mean age 44.7 years; 64.7% women) with a body mass index (BMI) of 30 kg/m² or greater (or 27 kg/m² or greater with at least one obesity-related complication, such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). Mean BMI, body weight, and waist circumference were 39.4 kg/m², 113 kg, and 118.3 cm, respectively. Patients were randomized to the maximum tolerated dose of semaglutide (1.7 or 2.4 mg) or tirzepatide (10 or 15 mg) and followed for 72 weeks.

With respect to weight loss, more participants treated with tirzepatide had reductions in body weight of at least 10%, 15%, 20%, and 25%. More than 80% of those who received tirzepatide lost 10% of their body weight from baseline and nearly 50% lost at least 20% of their body weight (versus 60.5% and 27.3% of patients in the semaglutide arm who lost 10% and 20%, respectively). Roughly one-third of the tirzepatide-treated patients lost 25% of their body weight compared 16.1% in the semaglutide arm.

The mean reduction in waist circumference, an endpoint that served as a surrogate for the location of adipose tissue, was 18.4 cm with tirzepatide and 13.0 cm with semaglutide, a 5.4-cm difference that was statistically significant and “likely clinically meaningful,” said Aronne.

“This is really extraordinary weight loss,” he said. “One of the things we’ve learned now is that there’s a dose response to weight loss and improvement in cardiovascular and other metabolic risk factors that are associated with obesity. In general, the more weight someone loses, the better the metabolic parameters, and we can see that here.”

With both treatments, there was a reduction in systolic and diastolic blood pressure, as well as improvements in glycated hemoglobin, fasting serum glucose, and lipid levels, but the reductions were numerically larger with tirzepatide. Systolic blood pressure, for example, declined 10.2 and 7.7 mm Hg with tirzepatide and semaglutide, respectively. With both drugs, there were larger improvements in cardiovascular and metabolic risk factors with greater reductions in body weight.

Naveed Sattar, MD, PhD (University of Glasgow, Scotland), who was not involved in the study, noted that the amount of weight loss with tirzepatide and semaglutide mirrored that seen in SURMOUNT-1 and STEP-1, respectively. 

“It confirms what everyone expected,” he told TCTMD.

The larger reduction in blood pressure with tirzepatide is related to the larger reduction in body weight, Sattar added, noting that mediation analyses from SURMOUNT-1 have suggested weight loss explains most of the reduction in blood pressure. A low-calorie, low-salt diet will also induce weight loss and reductions in blood pressure, said Sattar. 

To TCTMD, Horner said that as treatments become so effective, there is now growing attention paid to potentially detrimental weight loss. For example, when patients are losing 25% or more of their body weight, there are worries about lean muscle loss. “It’s an evolving field,” he said, noting there is ongoing research looking into muscle quality after medically induced weight loss.

Safety Profile

While the SURMOUNT-5 results might not have been a surprise to many—the top-line results were announced in December 2024—there was an interesting twist in that women had larger on-treatment weight loss with tirzepatide than men. Overall, women had a 23.8% reduction in body weight with tirzepatide compared with an 18.0% reduction on semaglutide. For men, there was a 17.8% and 11.0% reduction in body weight on tirzepatide and semaglutide, respectively.

“In the old days when you put people on a diet, men would lose much more weight than women,” said Aronne. “With this new category of super-effective drugs, we see that women lose more weight than men.”

Researchers don’t yet understand why women and men respond differently. Women weighed less at baseline than men—106 versus 127 kg, respectively—so you’d expect the men to lose more weight as they have more to lose, Aronne said. “But that’s not how it is.”

In terms of adverse events, gastrointestinal side effects were the most frequently reported. Serious adverse events occurred in 4.8% of those treated with tirzepatide compared with 3.5% in the semaglutide group. There were no adverse events leading to death, but 6.1% and 8.0% of the tirzepatide- and semaglutide-treated patients, respectively, stopped treatment because of adverse events (2.7% and 5.6% stopped treatment because of GI events, respectively). 

The adverse events, particularly GI events, mostly occurred during the dose-escalation phase of the trial, said Aronne. In clinical practice where doctors aren’t aiming to push patients onto higher and higher doses if they are losing weight, the side effect profile likely will be better, he said.

Sattar pointed out that injection-site reactions were less frequent with semaglutide (0.3% vs 8.6% with tirzepatide) whereas vomiting occurred less often with the newer drug (15.0% vs 21.3% with semaglutide). With vomiting, it may have occurred because the patient struggled to adapt to the higher dose of semaglutide or it may be that activation of GIP with tirzepatide attenuates this particular side effect. These possible reasons, said Sattar, are speculative at this point.

Major Endpoint Trials Coming

Aronne stressed that this study is not an indictment of semaglutide, stating the drug still has a major role.  

“Semaglutide is a great medication,” he said. “It is extremely effective. With this trial, we’re not trying to minimize the effect of semaglutide.” The study included patients who weighed more than people in past trials, but the majority of people with obesity in the US have class 1 obesity, which is defined as a BMI of 30 to 35 kg/m².  “There are plenty of people who will do just fine with semaglutide,” Aronne told TCTMD. For those with class 2 or 3 obesity, tirzepatide may ultimately be more effective, he said.

Semaglutide is also backstopped by randomized, controlled trial evidence showing that its use reduces the risk of major adverse cardiovascular events, as demonstrated in the SELECT trial. “That’s a very powerful study,” said Aronne, noting that there are no outcomes data with tirzepatide yet. SURMOUNT-MMO is underway and will include approximately 15,000 participants with obesity, but the trial isn’t expected to be completed until 2027.

“I believe we’re going to see a positive outcome,” said Aronne. Meta-analyses, including studies of patients with and without diabetes, have hinted at the potential benefit in hard outcomes, “but that’s not the same as doing a prospective trial,” he said. “But we’re very optimistic.”

Also asked to predict the future, Sattar hedged, saying tirzepatide has the “potential” to reduce cardiovascular events. All evidence to date shows that more weight loss equals a greater improvement in cardiovascular and metabolic risk factors. But, he said, it’s possible that the direct effects of the two drugs—one a GLP-1 receptor agonist and one an agonist of both the GLP-1 and GIP receptors—on atherosclerosis could be different.

The SURPASS-CVOT trial will help researchers learn more, Sattar said. The cardiovascular outcomes trial is testing tirzepatide against the incretin mimetic dulaglutide (Trulicity; Eli Lilly), a drug that results in 1 to 2 kg of weight loss, in patients with type 2 diabetes and the results are expected later this year. The primary outcome is the time to first occurrence of cardiovascular death, MI, or stroke. 

Right now, Aronne said there are roughly 150 medicines in development to manage chronic overweight and/or obesity. Retatrutide (Eli Lilly), for example, is an agonist of GIP, GLP-1, and glucagon receptors while others are also targeting amylin in addition to these receptors. Aronne called it a “golden age” of pharmacotherapies for managing weight, adding that he’s been doing trials in the field since 1989 and “it’s only in the last couple [of years] that we’ve been successful.”