Indirect Comparison Links Tirzepatide to Greater Weight Loss Than Semaglutide

Eli Lilly and Company (Lilly) announced results from an indirect treatment comparison in which tirzepatide (Zepbound) 10 mg and 15 mg was associated with greater weight loss than semaglutide 7.2 mg (Wegovy HD) in adults with obesity. The analysis, presented at the 62nd Annual Meeting of the European Association for the Study of Diabetes in Milan, Italy, drew on data from the SURMOUNT-1 (NCT04184622) and STEP UP (NCT05646706) trials.¹

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist. SURMOUNT-1 randomized 2539 adults without type 2 diabetes who had obesity or overweight with at least 1 weight-related comorbidity to tirzepatide 5 mg, 10 mg, or 15 mg or placebo.¹

Weight Loss Gap Depends on the Estimand

The analysis was covariate-adjusted for gender, age, baseline weight, and baseline A_1C. Using the treatment-regimen estimand, which represents the estimated average treatment effect regardless of treatment discontinuation, participants taking tirzepatide 15 mg lost 4.5% more of their body weight on average than those taking semaglutide 7.2 mg at 72 weeks (95% credible interval [CrI], –6.3 to –2.8). Participants taking the 10 mg dose lost 3.2% more (95% CrI, –5.0 to –1.4).¹

The efficacy estimand, which represents efficacy before discontinuation of the study drug, told a less definitive story. Tirzepatide 15 mg and 10 mg were associated with 1.8% (95% CrI, –3.8 to 0.1) and 0.7% (95% CrI, –2.6 to 1.3) greater mean weight reduction, respectively, and neither difference reached statistical significance.¹

Odds of reaching at least 20% body weight reduction favored the 15 mg dose under both estimands with an odds ratio (OR) of 4.15 (95% CrI, 1.02-15.64) for the efficacy estimand and 3.54 (95% CrI, 1.05-11.05) for the treatment-regimen estimand. For the 10 mg dose, the ORs were 2.8 (95% CrI, 0.7-10.8) and 2.46 (95% CrI, 0.7-7.8), respectively, and were not statistically significant. Rates of treatment discontinuation due to adverse events were comparable between both tirzepatide doses and semaglutide 7.2 mg across both estimands.¹

Thomas Seck, MD, senior vice president of product development at Lilly Cardiometabolic Health, said the comparison "suggests the same doses of Zepbound may outperform Wegovy HD, as well," in the news release.¹

SURMOUNT-5 Supplies the Direct Comparison

Lilly framed the analysis alongside SURMOUNT-5 (NCT05822830), a randomized, open-label phase 3b trial in which tirzepatide 10 mg and 15 mg outperformed semaglutide 1.7 mg and 2.4 mg. John Wilding, DM, professor of medicine at the University of Liverpool, said the indirect approach addresses a gap in the evidence.¹

"In the absence of a head-to-head trial comparing tirzepatide 15 mg against semaglutide 7.2 mg, this indirect comparison offers useful evidence for physicians as they make treatment decisions," Wilding said in the news release.¹

In SURMOUNT-5, which randomized 751 adults without diabetes, participants taking tirzepatide lost an average of 20.2% of body weight at 72 weeks versus 13.7% with semaglutide using the treatment-regimen estimand, a 47% greater relative weight loss. That equated to 50.3 lb (22.8 kg) and 33.1 lb (15.0 kg), respectively.¹

Full results published in the New England Journal of Medicine showed tirzepatide superior across the primary end point and 5 key secondary end points, including waist circumference, which fell 18.4 cm with tirzepatide and 13 cm with semaglutide.²

Topline results showed that 31.6% of participants in the tirzepatide group achieved at least 25% body weight loss, compared with 16.1% in the semaglutide group.³ Approximately 76.7% of patients taking tirzepatide and 79% taking semaglutide experienced at least 1 adverse event. Gastrointestinal events were the most frequently reported and the most likely to lead to treatment discontinuation, at 5.6% in the tirzepatide group and 2.7% in the semaglutide group.²

Shared Decision-Making Remains Central

Weight loss magnitude is one input among several for patients and pharmacists. Jennifer Clements, PharmD, BCACP, BC-ADM, BCPS, CDCES, FADCES, FCCP, a clinical professor and director of pharmacy education at the University of South Carolina College of Pharmacy, discussed the tirzepatide-semaglutide comparison in a Drug Topics interview after her presentation at the American Society of Health-System Pharmacists 2024 Midyear Clinical Meeting.⁴

"Decisions will vary from person to person based on individual needs and preferences," Clements said.⁴ She added that "there should be shared decision-making on the best agent for an individual when considering lifestyle habits, budget/financial restraints, and insurance coverage."

In that interview, she also noted that "semaglutide has an indication for cardiovascular risk reduction whether used for people living with [type 2 diabetes] or obesity."⁴

Weight Regain After Stopping Therapy

A separate Bayesian hierarchical longitudinal meta-analysis published in Endocrinology, Diabetes, & Metabolism reconstructed data from 6 randomized trials, comprising 10 intervention arms and 1776 participants, to model what happens after patients stop semaglutide or tirzepatide. The model estimated that patients regain half of their treatment-associated weight loss within 7.5 months (95% CrI, 5.05-10.57).⁵

A projected return to baseline weight at approximately 15 months relied on a constant linear regain rate, and the authors cautioned that the estimate extends beyond observed follow-up and is a model-based extrapolation rather than an observed outcome. After adjustment, the researchers found no clear independent drug-specific difference in regain between the 2 medications.⁵

A retrospective Cleveland Clinic cohort of 7938 adults who discontinued semaglutide or tirzepatide after 3 to 12 months found smaller regain. Patients treated for obesity, who lost an average of 8.4% of body weight before stopping, regained an average of 0.5% 1 year later, and approximately 45% maintained their weight loss or continued losing weight. Researchers pointed to treatment-switching patterns as a likely explanation where 27% of patients switched to an alternative obesity medication and 20% restarted their original medication.⁵

REFERENCES

1. Lilly's Zepbound (tirzepatide 10 mg and 15 mg) was associated with more weight loss than Wegovy HD (semaglutide injection 7.2 mg) in a new indirect treatment comparison. News release. Eli Lilly and Company. September 29, 2026. Accessed September 29, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-zepbound-tirzepatide-10-mg-and-15-mg-was-associated-more

2. Gallagher A. Tirzepatide shows superior weight loss over semaglutide in phase 3 trial. Drug Topics. May 12, 2025. Accessed September 29, 2026. https://www.drugtopics.com/view/tirzepatide-shows-superior-weight-loss-over-semaglutide-in-phase-3-trial

3. Biscaldi L. Tirzepatide bests semaglutide in relative, average weight loss in obesity, overweight. Drug Topics. December 4, 2024. Accessed September 29, 2026. https://www.drugtopics.com/view/tirzepatide-bests-semaglutide-in-relative-average-weight-loss-in-obesity-overweight

4. Nowosielski B, Clements J, Gallagher A. Q&A: factors showing tirzepatide is more beneficial than semaglutide | ASHP Midyear. Drug Topics. January 7, 2025. Accessed September 29, 2026. https://www.drugtopics.com/view/factors-showing-tirzepatide-is-more-beneficial-than-semaglutide

5. Gallagher A. Model finds weight regain after stopping semaglutide or tirzepatide. Drug Topics. September 10, 2026. Accessed September 29, 2026. https://www.drugtopics.com/view/model-finds-weight-regain-after-stopping-semaglutide-or-tirzepatide