Tirzepatide Linked to More Weight Loss Than Semaglutide 7.2 mg

Tirzepatide (Zepbound; Eli Lilly) 10 mg and 15 mg was associated with greater weight loss than high-dose semaglutide 7.2 mg (Wegovy HD; Novo Nordisk) in adults with obesity, according to an indirect treatment comparison (ITC) presented at the 62nd Annual Meeting of the European Association for the Study of Diabetes (EASD) in Milan, Italy. The advantage was statistically significant under one analytic approach but not another, and no randomized trial has yet compared the 2 drugs at these doses.¹

The findings are best read as hypothesis-generating for pharmacists fielding questions about the newest semaglutide strength.¹

Inside the Analysis

The Lilly-funded ITC drew on 2 separate 72-week trials. SURMOUNT-1 (NCT05556512) randomly assigned 2539 adults without diabetes who had obesity or overweight with at least 1 weight-related complication to tirzepatide 5 mg, 10 mg, or 15 mg or placebo. STEP UP (NCT05646706), funded by Novo Nordisk, randomly assigned 1407 adults with a body mass index of 30 kg/m² or greater and without diabetes to semaglutide 7.2 mg, semaglutide 2.4 mg, or placebo.^1-3

After adjustment for gender, age, baseline weight, and baseline hemoglobin A1c, participants taking tirzepatide 15 mg lost 4.5% more body weight on average than those taking semaglutide 7.2 mg (95% credible interval [CrI], -6.3 to -2.8). Those taking tirzepatide 10 mg lost 3.2% more (95% CrI, -5.0 to -1.4). These results used the treatment-regimen estimand, which estimates the average effect regardless of whether participants stopped treatment.¹

Under the efficacy estimand, which reflects effects before discontinuation of the study drug, the differences narrowed to 1.8% for tirzepatide 15 mg (95% CrI, -3.8 to 0.1) and 0.7% for tirzepatide 10 mg (95% CrI, -2.6 to 1.3). Neither reached statistical significance. The release did not address the difference between the 2 estimands.¹

For the proportion of participants reaching at least 20% weight loss, tirzepatide 15 mg was associated with higher odds than semaglutide 7.2 mg under both the efficacy estimand (odds ratio [OR], 4.15; 95% CrI, 1.02-15.64) and the treatment-regimen estimand (OR, 3.54; 95% CrI, 1.05-11.05). The wide intervals reflect considerable uncertainty. Results for tirzepatide 10 mg on this end point were not statistically significant. Lilly reported comparable rates of discontinuation due to adverse events between tirzepatide and semaglutide 7.2 mg but did not provide figures.¹

Where the Direct Evidence Stands

The randomized head-to-head evidence Lilly cited comes from SURMOUNT-5 (NCT05822830), a Lilly-funded trial. It tested maximum tolerated doses of tirzepatide (10 mg or 15 mg) against semaglutide (1.7 mg or 2.4 mg) in 751 adults with obesity but without type 2 diabetes. At 72 weeks, weight fell 20.2% with tirzepatide versus 13.7% with semaglutide (P < .001).^1,4

"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," John Wilding, DM, FRCP, professor of medicine and honorary consultant physician in the Department of Cardiovascular and Metabolic Medicine at the University of Liverpool's Institute of Life Course and Medical Sciences and first author of the analysis, said in the release. Wilding also spoke with Pharmacy Times in an interview about the results.¹

In STEP UP itself, semaglutide 7.2 mg produced a mean weight change of -18.7% vs -15.6% with 2.4 mg and -3.9% with placebo under the treatment policy estimand.³

Counseling Considerations

The FDA approved semaglutide 7.2 mg in March 2026 for adults with obesity who have tolerated the 2.4-mg dose for at least 4 weeks and need additional weight reduction. It functions as an escalation step rather than a starting dose.⁵

"I think in this case, there would have to be very strong reasons for switching; the differences in weight outcomes for an individual person are likely to be small and likely outweighed by the complexities involved in changing treatment rather than simply increasing the dose," Wilding told Pharmacy Times in an exclusive interview. "Ultimately, this would require a discussion between the treating clinician and the patient—i.e., shared decision-making."

The higher dose carries a distinct adverse effect to discuss. In STEP UP, dysesthesia occurred in 22.9% of participants taking semaglutide 7.2 mg vs 6.0% taking 2.4 mg and 0.5% taking placebo. Gastrointestinal adverse events were also more common with 7.2 mg (70.8%) than with 2.4 mg (61.2%).³

"It is important to highlight the possibility of this adverse event," Wilding said of dysesthesia. "It has been reported with high doses of injectable incretin treatments, so people need to be made aware. They can also be reassured that in many cases it will resolve over time, even with continued treatment."

For patients considering tirzepatide, pharmacists should note that it should not be combined with other glucagon-like peptide-1 receptor agonists. Patients taking oral contraceptives may need a backup method for 4 weeks after starting treatment and after each dose increase.¹

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. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038

3. Wharton S, Freitas P, Hjelmesæth J, et al. Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. 2025;13(11):949-963. doi:10.1016/S2213-8587(25)00226-8

4. Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. N Engl J Med. 2025;393(1):26-36. doi:10.1056/NEJMoa2416394

5. FDA approves Novo Nordisk's new Wegovy HD injection, delivering the highest weight loss to date for a Wegovy injection, adding to its already expansive clinical profile. News release. Novo Nordisk. March 19, 2026. Accessed September 29, 2026. https://www.prnewswire.com/news-releases/fda-approves-novo-nordisks-new-wegovy-hd-injection-delivering-the-highest-weight-loss-to-date-for-a-wegovy-injection-adding-to-its-already-expansive-clinical-profile-302718982.html