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Findings from head-to-head Phase IIIb SURMOUNT-5 trial (NCT05822830) show that tirzepatide (Zepbound) outperformed semaglutide (Wegovy) in sustained weight reduction over 72 weeks in adults with obesity or overweight with comorbidities.^1,2 The trial results, published by The New England Journal of Medicine (NEJM), mark the first direct clinical comparison between the dual glucose-dependent insulinotropic polypeptide (GIP)/ glucagon-like peptide-1 (GLP-1) agonist and the leading GLP-1 monotherapy.³

"Thanks to the latest advancements in obesity management medications, more physicians and patients are witnessing significant weight reduction beyond what they have seen before," SURMOUNT-5 principal investigator Louis J. Aronne, MD, FACP, DABOM, director of the Comprehensive Weight Control Center and the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine, said in a press release. "The SURMOUNT-5 head-to-head results demonstrated tirzepatide led to greater weight reduction compared to semaglutide, providing further evidence to support tirzepatide as an effective option for obesity management."¹

Semaglutide, a GLP-1 receptor agonist, was initially approved in June 2021 for chronic weight management in those with obesity or overweight and at least one weight-related condition, including high blood pressure, type 2 diabetes, or high cholesterol, in addition to diet and increased exercise.⁴ Semaglutide has also been approved by the FDA in both long-acting injectable (Wegovy and Ozempic) and daily oral tablet (Rybelsus) formulations. Wegovy is indicated for weight loss and weight maintenance in patients aged 12 years and older with obesity; and for reducing major cardiovascular event risks in adults with type 2 diabetes with known heart disease.⁵

Tirzepatide was approved in November 2023 as the first and only medication indicated for obesity that activates both GIP and GLP-1 hormone receptors.5 It is indicated for adults with obesity and a BMI of 30 kg/m² or greater, or overweight individuals with a BMI of 27 kg/m² or greater who also have weight-related medical problems, including hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease. Preclinical and clinical trials have shown that dual GIP/GLP-1 agonist therapy produces superior glucose control and weight loss compared to selective GLP-1 receptor agonists.⁶

GLP-1 and GIP are classified as incretins, which are expressed throughout the body, in areas such as pancreatic beta cells and the gastrointestinal tract. GLP-1 and GIP have been found to increase insulin from beta cells and glucose uptake by muscles while lowering blood glucose. GLP-1 stimulates glucose-dependent reduction of glucagon from alpha cells, lowering glucose production from the liver, and reducing blood glucose.⁵

“Both treatments decrease appetite and regulate food-related behaviors, presumably through expression of their respective receptor targets in subcortical regions of the brain that regulate food intake,” the authors of the current NEJM study wrote. “The patterns of central expression of GIP receptors do not fully overlap with those of GLP-1 receptors, and this variation is hypothesized to contribute to the higher weight reduction that has been noted with the dual agonism of GIP and GLP-1 receptors than with agonism of either receptor alone in preclinical models.”³

Trial Design

The open-label, controlled SURMOUNT-5 trial enrolled adults with obesity but without type 2 diabetes. A total of 751 patients were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide at 10 mg or 15 mg or the maximum tolerated dose of semaglutide at 1.7 mg or 2.4 mg administered subcutaneously once weekly for 72 weeks. The trial’s primary endpoint was percent change in weight from baseline to week 72, with key secondary endpoints that included weight decrease of at least 10%, 15%, 20%, and 25% and change in waist circumference from baseline to week 72.

Results show the least-squares mean percent change in weight at week 72 was −20.2% (95% confidence interval [CI], −21.4 to −19.1) among those administered tirzepatide compared to −13.7% (95% CI, −14.9 to −12.6) among those administered semaglutide (P<0.001). The least-squares mean change in waist circumference was −18.4 cm (95% CI, −19.6 to −17.2) in the tirzepatide cohort compared to −13.0 cm (95% CI, −14.3 to −11.7) in the semaglutide cohort (P<0.001). Further, patients in the tirzepatide cohort were found more likely than the semaglutide cohort to achieve weight decreases of at least 10%, 15%, 20%, and 25%.

“With both treatments in our trial, as weight reduction increased, greater improvements occurred in cardiometabolic risk factors, including blood pressure, glycemia, and lipid levels, which is consistent with the findings in previous reports,” the study authors wrote. “The mean differences between tirzepatide and semaglutide in the cardiometabolic risk factors may be clinically relevant considering that reductions in systolic blood pressure of 2 to 5 mm Hg have been shown to reduce the risk of cardiovascular events. The evaluation of the effect of greater weight reduction on decreases in cardiometabolic risk factors may translate to improved shared decision making by assisting with the selection of treatment goals.”³

In terms of safety, the most frequently reported adverse events (AEs) in both cohorts were gastrointestinal in nature and mostly mild to moderate in severity. These AEs primarily were reported during the dose escalation phase, causing treatment discontinuation more frequently in the semaglutide cohort compared to tirzepatide.

“Although it is a single molecule, tirzepatide pharmacologically activates two metabolic receptors, GIP and GLP-1, which have both overlapping and nonoverlapping expression and function,” the study authors concluded. “This dual-agonism activity of tirzepatide may contribute to the greater weight reduction observed with tirzepatide than with semaglutide, a monoagonist used in the current trial.”³

References

1. Zepbound (tirzepatide) showed superior weight loss over Wegovy (semaglutide) in complete SURMOUNT-5 results published in The New England Journal of Medicine. News release. Eli Lilly and Company. May 11, 2025. Accessed May 12, 2025. https://investor.lilly.com/news-releases/news-release-details/zepbound-tirzepatide-showed-superior-weight-loss-over-wegovy

2. A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight With Weight Related Comorbidities (SURMOUNT-5). ClinicalTrials.gov. Updated December 11, 2024. Accessed May 12, 2025. https://clinicaltrials.gov/study/NCT05822830

3. Aronne L., et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med 2025; DOI/full/10.1056/NEJMoa2416394.

4. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA. News release. June 4, 2021. Accessed May 12, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014

5. FDA Approves Lilly's Zepbound™ (tirzepatide) for Chronic Weight Management, a Powerful New Option for the Treatment of Obesity or Overweight with Weight-Related Medical Problems. Eli Lilly and Company. News release. November 8, 2023. Accessed May 12, 2025 https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-zepboundtm-tirzepatide-chronic-weight

6. Rosenstock, J, et. al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. doi: 10.1016/S0140-6736(21)01324-6. Accessed August 20, 2024.