n engl j med nejm.org 1 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Author affiliations are listed at the end of the article. Dr. Aronne can be contacted at ljaronne@ med . cornell . edu or at the Comprehensive Weight Control Center, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, 1305 York Ave., New York, NY 10021. *A list of the SURMOUNT-5 trial inves- tigators is provided in the Supplemen- tary Appendix, available at NEJM.org. This article was published on May 11, 2025, at NEJM.org. DOI: 10.1056/NEJMoa2416394 Copyright © 2025 Massachusetts Medical Society. BACKGROUND Tirzepatide and semaglutide are highly effective medications for obesity manage- ment. The efficacy and safety of tirzepatide as compared with semaglutide in adults with obesity but without type 2 diabetes is unknown. METHODS In this phase 3b, open-label, controlled trial, adult participants with obesity but with- out type 2 diabetes were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks. The pri- mary end point was the percent change in weight from baseline to week 72. Key sec- ondary end points included weight reductions of at least 10%, 15%, 20%, and 25% and a change in waist circumference from baseline to week 72. RESULTS A total of 751 participants underwent randomization. The least-squares mean per- cent change in weight at week 72 was −20.2% (95% confidence interval [CI], −21.4 to −19.1) with tirzepatide and −13.7% (95% CI, −14.9 to −12.6) with semaglutide (P<0.001). The least-squares mean change in waist circumference was −18.4 cm (95% CI, −19.6 to −17.2) with tirzepatide and −13.0 cm (95% CI, −14.3 to −11.7) with semaglutide (P<0.001). Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10%, 15%, 20%, and 25%. The most common adverse events in both treatment groups were gastrointestinal, and most were mild to moderate in severity and occurred primarily during dose escalation. CONCLUSIONS Among participants with obesity but without diabetes, treatment with tirzepatide was superior to treatment with semaglutide with respect to reduction in body weight and waist circumference at week 72. (Funded by Eli Lilly; SURMOUNT-5 ClinicalTrials.gov number, NCT05822830.) A BS TR AC T Tirzepatide as Compared with Semaglutide for the Treatment of Obesity Louis J. Aronne, M.D.,1 Deborah Bade Horn, D.O.,2 Carel W. le Roux, M.D., Ph.D.,3,4 Wayne Ho, M.D.,5,6 Beverly L. Falcon, Ph.D.,7 Elisa Gomez Valderas, M.Sc.,7 Sagar Das, M.Sc.,7 Clare J. Lee, M.D., M.H.S.,7 Leonard C. Glass, M.D.,7 Cagri Senyucel, M.D., Ph.D.,7 and Julia P. Dunn, M.D.,7 for the SURMOUNT-5 Trial Investigators* Original Article http://clinicaltrials.gov/show/NCT05822830 n engl j med nejm.org 2 T h e n e w e ngl a nd j o u r na l o f m e dic i n e T irzepatide and semaglutide are part of a new generation of highly effec- tive medications for the management of obesity.1 Tirzepatide is a long-acting glucose- dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist,2 and semaglutide is a long-acting GLP-1 receptor agonist.3 Clinically meaningful weight reductions occur with both medications, with reported mean weight reductions of up to 22.9% after nearly 3.5 years of treatment with tirzepatide4 and of 16.7% after nearly 2 years of treatment with semaglutide.3 Both treatments decrease appetite and regulate food-related behaviors,5,6 presumably through ex- pression of their respective receptor targets in subcortical regions of the brain that regulate food intake. The patterns of central expression of GIP receptors do not fully overlap with those of GLP- 1 receptors,7,8 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 re- ceptor alone in preclinical models.9 In addition, although adipocytes lack functional GLP-1 recep- tors, they do have functional GIP receptors that are hypothesized as being responsible for the di- rect regulation of adipocytes by tirzepatide.10 The additional mechanisms of action provided by the dual agonism of tirzepatide are posited to coun- ter more effectively than monoagonism the com- plex pathways that limit a person’s ability to re- duce body weight and maintain this reduction.11 To address this concept, a head-to-head clinical trial that evaluates the remaining clinical equipoise is warranted. Therefore, we conducted a 72-week, randomized, controlled trial to evaluate the ef- ficacy and safety of the maximum tolerated dose of tirzepatide (10 mg or 15 mg) as compared with the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) in adults with obesity. Me thods Trial Design This phase 3b, multicenter, parallel-arm, open- label, randomized, controlled trial was conducted during 72 weeks at 32 sites in the United States and Puerto Rico (see the Supplementary Appen- dix, available with the full text of this article at NEJM.org). The protocol (available at NEJM.org) was approved by an ethics review board at each site, and the trial was conducted in accordance with the principles of the Declaration of Helsinki and with the Good Clinical Practice guidelines of the International Council for Harmonisation. All the participants provided written informed consent before enrollment. The sponsor (Eli Lilly) and the first two au- thors designed the trial. The trial-site investigators were responsible for data collection, and the sponsor undertook site monitoring, data colla- tion, and data analysis. The first draft of the manuscript was written by the first and last au- thors. The investigators worked under confiden- tiality agreements with the sponsor. All the authors participated in the interpretation of the data and the critical review of the manuscript. The authors vouch for the accuracy and complete- ness of the data and for the fidelity of the trial to the protocol. Participants Participants were included if they were 18 years of age or older, had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or a BMI of 27 or higher and at least one prespecified obesity- related complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease), and reported at least one unsuccessful dietary ef- fort for weight reduction. Key exclusion criteria included a diagnosis of diabetes, previous or planned surgical treatment for obesity, treatment with a medication for weight reduction or a GLP-1 receptor agonist within 90 days before screening, or a change in body weight of more than 5 kg within 90 days before screening. A full list of eli- gibility criteria is provided in the Supplementary Appendix. Procedures Participants were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepa- tide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg). Treat- ment was administered subcutaneously by the participants once weekly for 72 weeks. Random- ization was performed with the use of an inter- active Web-response system and was stratified according to baseline BMI (<35 or ≥35), sex, and prediabetes status as determined from laboratory tests performed at screening after the participants had fasted.12 n engl j med nejm.org 3 Tirzepatide vs. Semaglutide for Obesity Tirzepatide was initiated at a dose of 2.5 mg once weekly, and the dose was increased by 2.5 mg every 4 weeks until a maximum tolerated dose of 10 mg or 15 mg was reached (Fig. S1 in the Supplementary Appendix). Semaglutide was ini- tiated at a dose of 0.25 mg once weekly, and the dose was increased every 4 weeks in accordance with recommended dosing (from 0.25 mg to 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg) until the 2.4-mg dose was reached. If unacceptable side effects were associated with the 2.4-mg dose, the partici- pant could continue receiving the 1.7-mg dose as a maintenance dose, an approach consistent with the STEP 1 (Semaglutide Treatment Effect in Peo- ple with Obesity) trial.13 Similar to the protocols for the previous SURMOUNT trials,14 the proto- col for the current trial provided the investigators with guidance on mitigating gastrointestinal symptoms. Participants who had unacceptable side effects while taking tirzepatide at a dose of 10 mg or 15 mg or while taking semaglutide at a dose of 1.7 mg or 2.4 mg, including after no more than two cycles of de-escalation of treat- ment followed by re-escalation, discontinued the trial intervention and were encouraged to remain in the trial for continued follow-up. All the par- ticipants received counseling on nutrition and physical activity. If a participant’s BMI decreased to 22 during the course of trial treatment, efforts were made to maintain body weight at that level; counseling included advice to adjust caloric intake. Further- more, the investigator had the option to reduce the dose (e.g., decreasing the tirzepatide dose from 15 mg to 10 mg or from 10 mg to 5 mg or decreasing the semaglutide dose from 2.4 mg to 1.7 mg). End Points and Assessments The primary end point was the percent change in body weight from baseline to week 72 with tirz- epatide as compared with semaglutide. The key secondary end points were a weight reduction of at least 10%, 15%, 20%, and 25% and a change in waist circumference from baseline to week 72. Additional secondary and tertiary end points are described in the Supplementary Appendix. Safety assessments included adverse events and serious adverse events that occurred during the reporting period, including adverse events that led to the discontinuation of tirzepatide or semaglutide. Major adverse cardiovascular events, pancreatitis, and deaths were reviewed by an independent external adjudication committee. Statistical Analysis We estimated that a sample size of 700 partici- pants (350 per group) would provide approximate- ly 90% power to show that tirzepatide was supe- rior to semaglutide with respect to the mean percent change in body weight from baseline to week 72. We used the following assumptions: a two-sample t-test with a two-sided significance level of 0.05; a trial-drug discontinuation rate of 20%, with a resultant common standard devia- tion of 12%; and a between-group difference in the percent change in body weight of 3 percent- age points. Data from all the participants who received at least one dose of the trial drug were used to analyze the efficacy and safety end points. Two estimands were used to assess the primary and key secondary end points from different perspec- tives. The primary estimand for the trial was the modified treatment-regimen estimand, whereas the secondary estimand was the efficacy esti- mand. Although the primary and key secondary end points were adjusted for multiplicity within each estimand, inferences regarding the treatment effects in this article apply only to the primary estimand. The modified treatment-regimen esti- mand evaluated the treatment effect regardless of premature discontinuation of the trial drug or initiation of other medications for obesity man- agement (unless a participant who had been as- signed to tirzepatide initiated semaglutide outside the trial or a participant assigned to semaglutide initiated tirzepatide outside the trial). This esti- mand also assumed that participants who under- went any surgical weight-reduction procedures had not benefited from their randomly assigned trial treatment or possibly had an increase in body weight; therefore, the highest trial weight recorded before the participants underwent the surgical procedure would be applied as the end point. The efficacy estimand is described in the Supplementary Appendix. All results are report- ed for the modified treatment-regimen estimand unless otherwise specified. For the primary and key secondary end points, the type I error rate was controlled at a two-sided alpha level of 0.05 within each estimand by means of a graphical testing procedure.15 Statistical analyses of continuous end points n engl j med nejm.org 4 T h e n e w e ngl a nd j o u r na l o f m e dic i n e for the modified treatment-regimen estimand were conducted with the use of an analysis-of-covari- ance model. Model terms included treatment, stratification factors (prediabetes status at ran- domization, sex, and BMI category at random- ization [<35 vs. ≥35]), and baseline values as covariates. Continuous end points for the effi- cacy estimand were conducted with the use of a mixed model for repeated measures. Categorical variables were evaluated with the use of a logis- tic-regression analysis with treatment, stratifica- tion factors, and baseline values as covariates. Full details on each estimand, handling of missing data, and statistical analysis methods are provid- ed in the Supplementary Appendix. R esult s Participants The trial was conducted between April 21, 2023, and November 13, 2024. Of 948 participants as- sessed for trial eligibility, 751 underwent ran- domization, and 750 received at least one dose of tirzepatide or semaglutide (Fig. S3). Overall, 85.0% of the participants completed the trial (85.1% in the tirzepatide group and 84.8% in the semaglutide group) and 80.2% completed the 72 weeks of trial treatment (81.6% in the tirzepatide group and 78.7% in the semaglutide group). The trial treatment was discontinued because of adverse events by 6.1% of the partici- pants in the tirzepatide group and 8.0% of those in the semaglutide group. In the tirzepatide group, 89.3% of the participants received at least one 15-mg dose, and in the semaglutide group, 92.8% received at least one 2.4-mg dose. In general, demographic and clinical charac- teristics of the participants were similar in the two groups (Table 1 and Table S1). The mean age of the participants was 44.7 years; the majority were women (64.7%) and White (76.1%). The mean body weight was 113.0 kg, the mean BMI 39.4, and the mean waist circumference 118.3 cm. The average reported duration of obesity was 16 years; 50.1% of the participants had at least two obesity-related complications (Table 1). Change in Body Weight The least-squares mean percent change in body weight from baseline to week 72 was −20.2% with tirzepatide (95% confidence interval [CI], −21.4 to −19.1) and −13.7% with semaglutide (95% CI, −14.9 to −12.6) (Fig. 1A and Table 2). Tirzepatide was superior to semaglutide with respect to weight reduction (estimated treatment difference, −6.5 percentage points; 95% CI, −8.1 to −4.9; P<0.001). Results for the efficacy esti- mand are provided in Figure 2A and Table S2. The least-squares mean change in body weight from baseline to week 72 was −22.8 kg with tirz- epatide (95% CI, −24.1 to −21.5) and −15.0 kg with semaglutide (95% CI, −16.3 to −13.7) (Ta- ble 2). The results for the efficacy estimand are provided in Figure S5. More participants treated with tirzepatide than those treated with semaglutide had reductions in body weight of at least 10%, 15%, 20%, and 25% from baseline (P<0.001) (Fig. 1B, Fig. S4, and Table 2). Participants treated with tirzepatide were 1.3, 1.6, 1.8, and 2.0 times more likely than participants treated with semaglutide to have weight reductions of at least 10%, 15%, 20%, and 25%, respectively. A total of 19.7% of the participants in the tirzepatide group had a reduc- tion in body weight of at least 30% (an explor- atory end point) as compared with 6.9% of those in the semaglutide group, which indicated that the likelihood of meeting this weight-reduction target with tirzepatide was 2.8 times as high as that with semaglutide (Table 2). In both trial- treatment groups, the weight reduction was ap- proximately 6% greater among women than among men (Table S12). Change in Waist Circumference and Cardiometabolic Risk Factors The least-squares mean change in waist circum- ference from baseline to week 72 was −18.4 cm with tirzepatide (95% CI, −19.6 to −17.2) and −13.0 cm with semaglutide (95% CI, −14.3 to −11.7) (Fig. 1C and Table 2). Tirzepatide was su- perior to semaglutide with respect to reduction in waist circumference (estimated treatment dif- ference, −5.4 cm; 95% CI, −7.1 to −3.6; P<0.001). The results for the efficacy estimand are provided in Figure 2B. Systolic blood pressure showed improvements with tirzepatide (least-squares mean change, −10.2 mm Hg; 95% CI, −11.4 to −8.9) and with semaglu- tide (least-squares mean change, −7.7 mm Hg; 95% CI, −8.9 to −6.4) (Table S4). Diastolic blood pressure also showed improvements with both treatments. Glycated hemoglobin, fasting serum glucose, and lipid levels improved with both trial n engl j med nejm.org 5 Tirzepatide vs. Semaglutide for Obesity treatments, which is consistent with previous trials.13,14 For both trial treatments, a comparison of weight-reduction categories (<10%, 10 to <20%, 20 to <30%, and ≥30%) showed that higher cat- egorical weight reductions were associated with greater improvements in each cardiometabolic risk factor (Table S5). Safety Overall, 76.7% of the participants treated with tirzepatide and 79.0% of those treated with semaglutide reported at least one adverse event that occurred or worsened during the treatment period (Table 3). The most frequently reported adverse events were gastrointestinal (e.g., nausea, constipation, diarrhea, and vomiting). Most gastro- intestinal adverse events were mild to moderate in severity and occurred primarily during dose escalation, with some variation in pattern between the two trial-treatment groups with respect to inci- dence and prevalence (Figs. S8 and S9). Gastroin- testinal events were the most common adverse events leading to treatment discontinuation and were observed more often in the semaglu- tide group (21 participants [5.6%]) than in the tirzepatide group (10 participants [2.7%]). Injec- tion-site reactions were more common in the tirzepatide group than in the semaglutide group (8.6% vs. 0.3%). Serious adverse events were reported by 31 participants (4.1%) overall, with a similar occur- rence in the tirzepatide group (4.8%) and the semaglutide group (3.5%) (Table 3). One adjudi- cation-confirmed case of pancreatitis was re- Table 1. Demographic and Clinical Characteristics of the Participants at Baseline.* Characteristic Tirzepatide (N = 374) Semaglutide (N = 376) Total (N = 750) Age — yr 45.0±12.9 44.4±12.7 44.7±12.8 Age categories — no. (%) <65 yr 342 (91.4) 349 (92.8) 691 (92.1) ≥65 yr 32 (8.6) 27 (7.2) 59 (7.9) Female sex — no. (%) 242 (64.7) 243 (64.6) 485 (64.7) Race or ethnic group — no. (%)† American Indian or Alaska Native 6 (1.6) 0 6 (0.8) Asian 11 (2.9) 7 (1.9) 18 (2.4) Black 77 (20.6) 67 (17.8) 144 (19.2) White 276 (73.8) 295 (78.5) 571 (76.1) Multiple 4 (1.1) 7 (1.9) 11 (1.5) Hispanic or Latino 93 (24.9) 103 (27.4) 196 (26.1) Prediabetes at randomization — no. (%) 215 (57.5) 210 (55.9) 425 (56.7) Duration of obesity — yr 16.4±11.6 14.7±11.0 15.6±11.3 Body weight — kg 112.7±24.8 113.4±26.3 113.0±25.6 Body-mass index‡ 39.4±7.4 39.4±7.7 39.4±7.6 Waist circumference — cm 117.7±16.1 118.8±17.6 118.3±16.9 Body-mass index category — no. (%)‡ <35 115 (30.7) 118 (31.4) 233 (31.1) ≥35 259 (69.3) 258 (68.6) 517 (68.9) Participants with multiple obesity-related compli- cations — no. (%)§ 187 (50.0) 189 (50.3) 376 (50.1) * Plus–minus values are means ±SD. † Race or ethnic group was reported by the participants. ‡ The body-mass index is the weight in kilograms divided by the square of the height in meters. § Participants were considered to have multiple obesity-related complications if they had two or more complications re- lated to obesity, including a history of conditions reported at screening. n engl j med nejm.org 6 T h e n e w e ngl a nd j o u r na l o f m e dic i n e ported in the semaglutide group. No adjudication- confirmed major cardiovascular events, deaths, cases of medullary thyroid cancer, or cases of pancreatic cancer were reported. Additional mea- sures of safety are reported in Table S9. The results with respect to adverse events of special interest were consistent with those of previous trials.3,13,14 Discussion In our trial, adults with obesity but without dia- betes had a 20.2% reduction in weight at 72 weeks when receiving tirzepatide, as compared with a 13.7% reduction when receiving semaglutide. Weight reduction was approximately 6% lower among men than among women in both treat- ment groups, a finding that is believed to ex- plain the slightly lower weight reduction in the current trial than in previous trials. The current trial included a higher percentage of men (35%) than previous trials, especially when compared with the STEP trials involving persons without diabetes, in which 19 to 26% of the participants were men.3,17 The current findings align with re- sults reported in the SURMOUNT14,18-20 and STEP trials21 as well as in a recent cohort study that showed greater weight reduction with tirzepatide than with semaglutide.22 The complexity of energy-balance regulation has been a major impetus for the development of therapeutic agents with multiple mechanisms of action. The combination of pharmacotherapies that have different mechanisms results in greater weight reduction than the use of a single compo- nent, as seen with phentermine combined with extended-release topiramate23 and with bupropion combined with naltrexone.24 Although it is a sin- gle molecule, tirzepatide pharmacologically acti- vates two metabolic receptors, GIP and GLP-1, Figure 1. Effect of Tirzepatide as Compared with Semaglutide on Body Weight and Waist Circumfer- ence. Shown is the effect of once-weekly tirzepatide (maxi- mum tolerated dose, 10 mg or 15 mg) as compared with once-weekly semaglutide (maximum tolerated dose, 1.7 mg or 2.4 mg) on body weight and waist cir- cumference. Panel A shows the least-squares mean percent change from baseline to week 72 in body weight, which was derived with the use of an analysis- of-covariance model for the modified treatment-regi- men estimand (which evaluated the treatment effect regardless of premature discontinuation of the trial drug or initiation of other medications for obesity management). Panel B shows the percentages of par- ticipants who had weight reductions of at least 10%, 15%, 20%, and 25% from baseline to week 72, as cal- culated for the modified treatment-regimen estimand. The percentages were calculated with the use of Ru- bin’s rules by combining the percentages of partici- pants who met each target in imputed data sets. Pan- el C shows the least-squares mean change from baseline to week 72 in waist circumference (in centi- meters), which was derived with the use of an analy- sis-of-covariance model for the modified treatment- regimen estimand. I bars indicate 95% confidence intervals. B Weight Reductions A Change in Body Weight C Change in Waist Circumference Pe rc en ta ge o f P ar tic ip an ts 100 40 20 80 60 0 Tirzepatide Semaglutide Pe rc en t C ha ng e 0 −10 −5 −15 −25 −20 Tirzepatide Target Reduction in Body Weight Semaglutide −20.2 81.6 64.6 40.1 48.4 27.3 31.6 16.1 60.5 −13.7 C ha ng e (c m ) 0 −10 −5 −15 −25 −20 Tirzepatide Semaglutide −18.4 −13.0 10% 15% 20% 25% n engl j med nejm.org 7 Tirzepatide vs. Semaglutide for Obesity which have both overlapping and nonoverlapping expression and function.2 This dual-agonism ac- tivity of tirzepatide may contribute to the greater weight reduction observed with tirzepatide than with semaglutide, a monoagonist used in the cur- rent trial. Currently recommended magnitudes of weight reduction often lead to a threshold effect with respect to abatement in specific obesity-related complications,25 because the magnitude that may contribute to remission or partial remission of many obesity-related complications is difficult to achieve or has not been defined. In persons with type 2 diabetes, a linear relationship between the incidence of early disease remission and a weight reduction of up to approximately 10 to 15% has been established,26 yet recommendations support- ing weight-reduction targets of this magnitude are limited.27 In two recent clinical trials, 42 to 50% of participants with moderate-to-severe obstructive sleep apnea and obesity who received tirzepatide had a decrease in disease activity to mild disease without sleepiness or had remission with mean weight reductions of 18 to 20%.28 A weight reduction of this magnitude is substan- tially greater than the approximate 7 to 11% reduc- tion recommended in guidance for patients with obesity-related obstructive sleep apnea.25 With a new generation of medications for obesity man- agement, higher magnitudes of weight reduction become more readily achievable and sustainable, which provides the opportunity to modify rec- ommendations to a treat-to-target approach.1 With both treatments in our trial, as weight reduction increased, greater improvements oc- curred in cardiometabolic risk factors, including blood pressure, glycemia, and lipid levels, which is consistent with the findings in previous re- ports.17 The mean differences between tirzepa- tide 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.29 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. For example, among the participants who had a weight reduc- tion of at least 20% while receiving treatment and had available data at week 72 (46.5% of par- ticipants in the tirzepatide group and 26.1% in Table 2. Primary and Secondary End Points for the Modified Treatment-Regimen Estimand. End Point Tirzepatide (N = 374) Semaglutide (N = 376) Treatment Difference or Relative Risk (95% CI)* Primary end point Least-squares mean percent change in body weight (95% CI) −20.2 (−21.4 to −19.1) −13.7 (−14.9 to −12.6) −6.5 (−8.1 to −4.9) Key secondary end points Least-squares mean change in waist circumference — cm −18.4 (−19.6 to −17.2) −13.0 (−14.3 to −11.7) −5.4 (−7.1 to −3.6) Weight reduction of ≥10% — no. (%)† 304 (81.6) 227 (60.5) 1.3 (1.2 to 1.5) Weight reduction of ≥15% — no. (%)† 241 (64.6) 151 (40.1) 1.6 (1.4 to 1.9) Weight reduction of ≥20% — no. (%)† 181 (48.4) 103 (27.3) 1.8 (1.5 to 2.2) Weight reduction of ≥25% — no. (%)† 118 (31.6) 60 (16.1) 2.0 (1.5 to 2.6) Additional secondary end points‡ Weight reduction of ≥30% — no. (%)† 74 (19.7) 26 (6.9) 2.8 (1.9 to 4.3) Least-squares mean change in body weight — kg −22.8 (−24.1 to −21.5) −15.0 (−16.3 to −13.7) −7.9 (−9.7 to −6.0) Least-squares mean change in body-mass index −8.0 (−8.5 to −7.5) −5.3 (−5.8 to −4.8) −2.7 (−3.3 to −2.0) * Values are shown as the estimated percentage-point treatment difference between groups with the exception of the weight-reduction categories of at least 10%, 15%, 20%, 25%, and 30%, which are shown as the relative risk. Relative risk was calculated with the use of G-computation methods16 on the basis of logistic regression. P<0.001 for all primary and key secondary end points. † The number and percentage were calculated according to imputed data. The number was calculated by averaging the number of partici- pants who achieved the target weight reduction across imputed data sets and then rounding to the integer; the percentage was calculated by combining the percentage of participants who achieved the target weight reduction in imputed data sets with the use of Rubin’s rule. ‡ The confidence intervals for the additional secondary end points have not been adjusted for multiplicity and should not be used to make inferences. n engl j med nejm.org 8 T h e n e w e ngl a nd j o u r na l o f m e dic i n e the semaglutide group), the mean reduction in systolic blood pressure ranged from 9.1 to 17.5 mm Hg, as compared with 3.4 to 6.7 mm Hg among those who had a weight reduction of less than 10%. Whereas semaglutide has shown a benefit with respect to cardiovascular outcomes in persons with obesity and a history of cardio- vascular disease in the SELECT (Semaglutide Ef- fects on Cardiovascular Outcomes in People with Overweight or Obesity) trial,30 the ongoing SURMOUNT-MMO trial (ClinicalTrials.gov num- ber, NCT05556512) with tirzepatide may provide data regarding prevention of cardiovascular dis- ease in persons with obesity with a history of cardiovascular disease and those at high risk for cardiovascular disease. Greater weight reduction, including during treatment with semaglutide31 and tirzepatide,32 generally improves quality of life, mostly through an improvement in physical functioning.33 Although some patients will not require the higher magnitudes of weight reduc- tion, the findings of improved health with greater magnitudes of weight reduction lend support to the clinical relevance of the current trial because the majority of the participants who received tirzepatide had a weight reduction of at least 15%, and nearly a third had a reduction of at least 25%, as compared with 16.1% of the par- ticipants who received semaglutide. The addi- tional 5.4-cm reduction in waist circumference with tirzepatide as compared with semaglutide is also clinically relevant. In a large pooled analy- sis of waist circumference and mortality, each 5-cm increase in waist circumference predicted a 7% increase in mortality among men and a 9% increase among women.34 In alignment with these data, published guidance has emphasized the im- portance of treating patients with abdominal obe- sity25 and aiming for a reduction of at least 4 cm.35 Patient preferences are an essential compo- nent of shared decision making;36 however, older guidelines detailed patients’ weight-reduction goals as often not realistic37 and were from an era when available interventions led to weight reductions of only 5 to 10%.38 Recently, the OBSERVE study reported that adults with obesity may have weight-reduction goals of greater than 10%, especially those with class II and III obe- sity who have preferred weight-reduction goals of 20% or higher.39 In the study, the preferred weight reductions were not clinically excessive, given that approximately 85% of respondents were projected to continue to have obesity or overweight according to BMI after reaching their goal weight.39 Treatment that aligns with patient preferences may lead to increased adherence with better treatment outcomes.39 Both tirzepatide and semaglutide had safety profiles consistent with those in previous tri- als.13,14,18-20 As typically observed with incretin- based therapies, gastrointestinal adverse events were predominantly mild to moderate in severity, occurred mostly during dose escalation, and led to treatment discontinuation more often with semaglutide than with tirzepatide. The tirzepa- Figure 2. Change in Body Weight and Waist Circumference from Baseline to Week 72 (Efficacy Estimand). Shown are the least-squares mean percent changes in body weight (Panel A) and the least-squares mean changes in waist circumference (Panel B) ac- cording to weeks since randomization. Values were derived with the use of a mixed-model-for-repeated-measures analysis for the efficacy estimand (described in the Supplementary Appendix). I bars indicate 95% confi- dence intervals. Pe rc en t C ha ng e −24 −20 −16 −12 −8 −4 0 0 4 8 12 16 20 24 36 48 52 60 72 Weeks since Randomization Overall mean baseline weight=113.2 kg −15.4 −21.6 B Change in Waist Circumference A Change in Body Weight C ha ng e (c m ) −24 −20 −16 −12 −8 −4 0 0 4 8 12 16 20 24 36 48 52 60 72 Weeks since Randomization Overall mean baseline waist circumference=118.4 cm −14.7 −20.0 Tirzepatide Semaglutide Tirzepatide Semaglutide http://clinicaltrials.gov/show/NCT05556512 n engl j med nejm.org 9 Tirzepatide vs. Semaglutide for Obesity Table 3. Adverse Events and Safety.* Variable Tirzepatide (N = 374) Semaglutide (N = 376) Total (N = 750) number of participants (percent) Adverse events that occurred or worsened during the treatment period 287 (76.7) 297 (79.0) 584 (77.9) Serious adverse events 18 (4.8) 13 (3.5) 31 (4.1) Adverse events leading to death 0 0 0 Discontinuation from the trial because of adverse events 6 (1.6) 6 (1.6) 12 (1.6) Discontinuation of the trial treatment because of adverse events 23 (6.1) 30 (8.0) 53 (7.1) Discontinuation of the trial treatment because of gastrointestinal adverse events 10 (2.7) 21 (5.6) 31 (4.1) Adverse events occurring in ≥5% of participants in either group† Nausea 163 (43.6) 167 (44.4) 330 (44.0) Constipation 101 (27.0) 107 (28.5) 208 (27.7) Diarrhea 88 (23.5) 88 (23.4) 176 (23.5) Vomiting 56 (15.0) 80 (21.3) 136 (18.1) Coronavirus disease 2019 51 (13.6) 47 (12.5) 98 (13.1) Fatigue 39 (10.4) 46 (12.2) 85 (11.3) Eructation 37 (9.9) 29 (7.7) 66 (8.8) Injection-site reaction 32 (8.6) 1 (0.3) 33 (4.4) Upper respiratory tract infection 32 (8.6) 43 (11.4) 75 (10.0) Alopecia 31 (8.3) 23 (6.1) 54 (7.2) Abdominal distention 27 (7.2) 24 (6.4) 51 (6.8) Headache 27 (7.2) 27 (7.2) 54 (7.2) Abdominal pain 24 (6.4) 26 (6.9) 50 (6.7) Dizziness 24 (6.4) 18 (4.8) 42 (5.6) Gastroesophageal reflux disease 23 (6.1) 40 (10.6) 63 (8.4) Dyspepsia 22 (5.9) 28 (7.4) 50 (6.7) Decreased appetite 17 (4.5) 19 (5.1) 36 (4.8) Nasopharyngitis 17 (4.5) 23 (6.1) 40 (5.3) Sinusitis 11 (2.9) 21 (5.6) 32 (4.3) Adverse events leading to discontinuation of the trial treatment‡ Nausea 5 (1.3) 7 (1.9) 12 (1.6) Vomiting 3 (0.8) 4 (1.1) 7 (0.9) Constipation 1 (0.3) 2 (0.5) 3 (0.4) Diarrhea 1 (0.3) 2 (0.5) 3 (0.4) Fatigue 1 (0.3) 1 (0.3) 2 (0.3) Cholelithiasis 0 2 (0.5) 2 (0.3) * Safety end points were analyzed with the use of data from participants regardless of whether participants adhered to treatment, initiated other antiobesity medication, or underwent bariatric surgery. † Adverse events are listed according to preferred terms in the Medical Dictionary for Regulatory Activities, version 24.1. ‡ Shown are adverse events that were reported more than once. n engl j med nejm.org 10 T h e n e w e ngl a nd j o u r na l o f m e dic i n e tide group had more injection-site reactions than the semaglutide group, which is consistent with other SURMOUNT trials.14,20 In the current trial, no participants were reported to have had severe or serious injection-site reactions nor to have discon- tinued trial treatment because of such reactions. This trial has certain strengths and limita- tions. One strength is the diversity of the par- ticipants, with 19% reporting their race as Black and 26% reporting their ethnic group as Hispanic or Latino, which is representative of the popula- tions living with obesity (Table S6). By evaluating the maximum tolerated dose for both treatments, the trial addressed a potentially more meaningful real-world question than would have been ad- dressed with a fixed-dose approach. A limitation is that the trial was not blinded; however, the consistency of the current findings with those from previous blinded trials supports their gen- eralizability. In this trial, treatment with tirzepatide, a dual GIP and GLP-1 receptor agonist, was superior to treatment with semaglutide, a selective GLP-1 re- ceptor agonist, with respect to reduction in body weight and waist circumference. Supported by Eli Lilly. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. We thank Rhea Lewis, Ph.D., of Eli Lilly for editorial assis- tance with an earlier version of the manuscript and preparation of the figures, tables, and references before submission of the manuscript; the trial participants and the trial site coordinators and investigators who cared for them; and all the Eli Lilly col- leagues who supported the trial, including the trial lead, Rachel Barosh, M.Sc. Author Information 1 Comprehensive Weight Control Center, Division of Endocri- nology, Diabetes and Metabolism, Weill Cornell Medicine, New York; 2 University of Texas Center for Obesity Medicine and Metabolic Performance, Department of Surgery, University of Texas McGovern Medical School, Houston; 3 Diabetes Compli- cations Research Centre, Conway Institute, University College Dublin, Dublin; 4 Diabetes Research Centre, Ulster University, Coleraine, United Kingdom; 5 Veterans Affairs Greater Los An- geles Healthcare System, Los Angeles; 6 David Geffen School of Medicine at the University of California, Los Angeles, Los Ange- les; 7 Eli Lilly, Indianapolis. References 1. Garvey WT. New horizons: a new paradigm for treating to target with sec- ond-generation obesity medications. J Clin Endocrinol Metab 2022; 107(4): e1339-e1347. 2. Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab 2018; 18: 3-14. 3. Garvey WT, Batterham RL, Bhatta M, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med 2022; 28: 2083-91. 4. Jastreboff AM, le Roux CW, Stefanski A, et al. Tirzepatide for obesity treatment and diabetes prevention. N Engl J Med 2025; 392: 958-71. 5. Friedrichsen M, Breitschaft A, Taday- on S, Wizert A, Skovgaard D. The effect of semaglutide 2.4 mg once weekly on ener- gy intake, appetite, control of eating, and gastric emptying in adults with obesity. Diabetes Obes Metab 2021; 23: 754-62. 6. Heise T, DeVries JH, Urva S, et al. Tirzepatide reduces appetite, energy in- take, and fat mass in people with type 2 diabetes. Diabetes Care 2023; 46: 998-1004. 7. Adriaenssens AE, Biggs EK, Darwish T, et al. Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. Cell Metab 2019; 30(5): 987-996.e6. 8. Samms RJ, Christe ME, Collins KA, et al. GIPR agonism mediates weight-inde- pendent insulin sensitization by tirzepa- tide in obese mice. J Clin Invest 2021; 131(12): e146353. 9. Zhang Q, Delessa CT, Augustin R, et al. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab 2021; 33(4): 833-844.e5. 10. Regmi A, Aihara E, Christe ME, et al. Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor. Cell Metab 2024; 36(7): 1534-1549.e7. 11. Magkos F, Sørensen TIA, Rauben- heimer D, et al. On the pathogenesis of obesity: causal models and missing pieces of the puzzle. Nat Metab 2024; 6: 1856-65. 12. American Diabetes Association. Stan- dards of medical care in diabetes — 2022 abridged for primary care providers. Clin Diabetes 2022; 40: 10-38. 13. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384: 989-1002. 14. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022; 387: 205-16. 15. Vansteelandt S, Linder M, Vandenber- ghe S, Steen J, Madsen J. Mediation analy- sis of time-to-event endpoints accounting for repeatedly measured mediators subject to time-varying confounding. Stat Med 2019; 38: 4828-40. 16. Ye T, Bannick M, Yi Y, Shao J. Robust variance estimation for covariate-adjusted unconditional treatment effect in random- ized clinical trials with binary outcomes. Stat Theory Relat Fields 2023; 7: 159-63. 17. Kosiborod MN, Bhatta M, Davies M, et al. Semaglutide improves cardiometa- bolic risk factors in adults with overweight or obesity: STEP 1 and 4 exploratory analy- ses. Diabetes Obes Metab 2023; 25: 468-78. 18. Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA 2024; 331: 38-48. 19. Garvey WT, Frias JP, Jastreboff AM, et al. Tirzepatide once weekly for the treat- ment of obesity in people with type 2 dia- betes (SURMOUNT-2): a double-blind, ran- domised, multicentre, placebo-controlled, phase 3 trial. Lancet 2023; 402: 613-26. 20. Wadden TA, Chao AM, Machineni S, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med 2023; 29: 2909-18. 21. Kushner RF, Calanna S, Davies M, et al. Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP trials 1 to 5. Obesity (Silver Spring) 2020; 28: 1050-61. 22. Rodriguez PJ, Goodwin Cartwright BM, Gratzl S, et al. Semaglutide vs tirz- epatide for weight loss in adults with n engl j med nejm.org 11 Tirzepatide vs. Semaglutide for Obesity overweight or obesity. JAMA Intern Med 2024; 184: 1056-64. 23. Aronne LJ, Wadden TA, Peterson C, Winslow D, Odeh S, Gadde KM. Evalua- tion of phentermine and topiramate ver- sus phentermine/topiramate extended-re- lease in obese adults. Obesity (Silver Spring) 2013; 21: 2163-71. 24. Greenway FL, Dunayevich E, Tollefson G, et al. Comparison of combined bupro- pion and naltrexone therapy for obesity with monotherapy and placebo. J Clin En- docrinol Metab 2009; 94: 4898-906. 25. Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of pa- tients with obesity. Endocr Pract 2016; 22: Suppl 3: 1-203. 26. Sattar N, Welsh P, Leslie WS, et al. Di- etary weight-management for type 2 dia- betes remissions in South Asians: the South Asian diabetes remission ran- domised trial for proof-of-concept and feasibility (STANDby). Lancet Reg Health Southeast Asia 2023; 9: 100111. 27. American Diabetes Association Pro- fessional Practice Committee. Obesity and weight management for the prevention and treatment of type 2 diabetes: standards of care in diabetes — 2024. Diabetes Care 2024; 47: Suppl 1: S145-S157. 28. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the treatment of ob- structive sleep apnea and obesity. N Engl J Med 2024; 391: 1193-205. 29. Whelton PK, He J, Appel LJ, et al. Pri- mary prevention of hypertension: clinical and public health advisory from the Na- tional High Blood Pressure Education Program. JAMA 2002; 288: 1882-8. 30. Lincoff AM, Brown-Frandsen K, Col- houn HM, et al. Semaglutide and cardio- vascular outcomes in obesity without dia- betes. N Engl J Med 2023; 389: 2221-32. 31. Rubino D, Bjorner JB, Rathor N, et al. Effect of semaglutide 2.4 mg on physical functioning and weight- and health-relat- ed quality of life in adults with overweight or obesity: patient-reported outcomes from the STEP 1-4 trials. Diabetes Obes Metab 2024; 26: 2945-55. 32. Gudzune KA, Stefanski A, Cao D, et al. Association between weight reduction achieved with tirzepatide and quality of life in adults with obesity: results from the SURMOUNT-1 study. Diabetes Obes Metab 2025; 27: 539-50. 33. Kolotkin RL, Andersen JR. A system- atic review of reviews: exploring the rela- tionship between obesity, weight loss and health-related quality of life. Clin Obes 2017; 7: 273-89. 34. Cerhan JR, Moore SC, Jacobs EJ, et al. A pooled analysis of waist circumference and mortality in 650,000 adults. Mayo Clin Proc 2014; 89: 335-45. 35. National Institutes of Health. Clinical guidelines on the identification, evalua- tion, and treatment of overweight and obesity in adults — the evidence report. Obes Res 1998; 6: Suppl 2: 51S-209S. 36. Raja S, Hasnain M, Vadakumchery T, Hamad J, Shah R, Hoersch M. Identifying elements of patient-centered care in un- derserved populations: a qualitative study of patient perspectives. PLoS One 2015; 10(5): e0126708. 37. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Obesity Society. Circulation 2014; 129: Sup- pl 2: S102-S138. 38. Foster GD, Wadden TA, Vogt RA, Brew- er G. What is a reasonable weight loss? Patients’ expectations and evaluations of obesity treatment outcomes. J Consult Clin Psychol 1997; 65: 79-85. 39. Gudzune KA, Kaplan LM, Kahan S, et al. Weight-reduction preferences among OBSERVE study participants with obesity or overweight: opportunities for shared decision-making. Endocr Pract 2024; 30: 917-26. Copyright © 2025 Massachusetts Medical Society.