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Zepbound ® (tirzepatide) injection
2.5 mg/ 5 mg/ 7.5 mg/ 10 mg/ 12.5 mg/ 15 mg
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.
How did Zepbound® (tirzepatide) compare with placebo for maintenance of weight reduction in adults with obesity?
Tirzepatide resulted in a statistically significant reduction in body weight compared with placebo in SURMOUNT-4.
See important safety information, including boxed warning, in the attached prescribing information.
Content Overview
Maintenance of Weight Reduction in Adults With Obesity – SURMOUNT-4
Enclosed Prescribing Information
Maintenance of Weight Reduction in Adults With Obesity – SURMOUNT-4
SURMOUNT-4 was a phase 3, double-blind, randomized, 88-week clinical study that investigated the safety and efficacy of tirzepatide maximum tolerated dose (MTD) (10 or 15 mg) once weekly, compared with placebo, on the maintenance of weight reduction after an initial 36-week open-label tirzepatide MTD lead-in treatment period in 670 adults with overweight or obesity without type 2 diabetes (T2D).1
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Key Inclusion and Exclusion Criteria
Inclusion criteria for this study were
age ≥18 years
body mass index (BMI) of
≥30 kg/m² or
≥27 kg/m² with at least 1 weight-related complication (hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease), and
history of at least one unsuccessful dietary effort to lose weight.1
Exclusion criteria for this study were
diabetes
history of pancreatitis
estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2
use of any weight loss medication in the 3 months prior to screening
weight change >5 kg within 3 months prior to screening
prior or planned surgical treatment for obesity, and
obesity induced by other endocrinologic disorders or monogenetic or syndromic forms of obesity.1
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Study Design
In the SURMOUNT-4 study, a total of 670 study participants were randomized in a 1:1 ratio across the United States, Argentina, Brazil, and Taiwan to receive tirzepatide MTD (10 or 15 mg) or placebo.1
The primary outcome of this study was mean percent change in body weight from randomization (week 36) to week 88.1
The study design included an 88-week total treatment period including
36-week open-label lead-in on tirzepatide MTD, and
52-week double-blind treatment period on tirzepatide or placebo (see Figure 1).1
The starting dose of tirzepatide was 2.5 mg once weekly for 4 weeks, escalated in 2.5 mg increments every 4 weeks until the MTD (10 or 15 mg) was achieved. Throughout the study, lifestyle counseling was provided by a qualified health care professional to all participants to encourage adherence to a healthy 500 kcal/d deficit diet and at least 150 minutes of physical activity per week.1
At the end of the lead-in period, participants who attained the MTD of tirzepatide (10 or 15 mg) were randomized in a 1:1 ratio for an additional 52 weeks to either tirzepatide MTD or placebo. Dose adjustments were not permitted during the double-blind treatment period.1
Figure 1. SURMOUNT-4 Study Design1
Figure 1 description: In the SURMOUNT-4 study, the starting dose of tirzepatide was 2.5 mg once weekly for 4 weeks, escalated in 2.5 mg increments every 4 weeks until the MTD (10 or 15 mg) was achieved. Tirzepatide and placebo were used as adjunct to a reduced-calorie diet and increased physical activity. The study design included 88-week total treatment period: 36-week open-label lead-in on tirzepatide, then 52-week double-blind treatment period.
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Baseline Characteristics
Baseline demographics and clinical characteristics of enrolled and randomized patients are presented in Table 1.1
Table 1. SURMOUNT-4 Baseline Demographics and Clinical Characteristics1
Parametera |
Tirzepatide
Lead-in Population |
Randomized
Population |
Randomized
Population |
Age, years |
48±13 |
49±13 |
48±12 |
Female, n (%) |
473 (70.6) |
236 (70.4) |
237 (70.7) |
Race, n (%)b |
|||
Asian |
48 (7.2) |
26 (7.8) |
22 (6.6) |
Black or African American |
75 (11.2) |
39 (11.6) |
36 (10.7) |
Multiple |
8 (1.2) |
5 (1.5) |
3 (0.9) |
Native Hawaiian or Other Pacific Islander |
2 (0.3) |
1 (0.3) |
1 (0.3) |
White |
537 (80.1) |
264 (78.8) |
273 (81.5) |
Hispanic or Latino, n (%) |
296 (44.2) |
141 (42.1) |
155 (46.3) |
Duration of obesity, yc |
15.5±11.8 |
15.9±12.1 |
15.2±11.4 |
Body weight, kg |
107.3±22.3 |
84.6±19.8 |
85.8±22.3 |
BMI, kg/m2 |
38.4±6.6 |
30.3±6.0 |
30.7±6.8 |
BMI category, n (%) |
|||
<25 |
0 |
59 (17.6) |
63 (18.8) |
≥25 to <30 |
18 (2.7) |
122 (36.4) |
120 (35.8) |
≥30 to <35 |
212 (31.6) |
88 (26.3) |
75 (22.4) |
≥35 to <40 |
215 (32.1) |
41 (12.2) |
43 (12.8) |
≥40 |
225 (33.6) |
25 (7.5) |
34 (10.1) |
Waist circumference, cm |
115.2±14.5 |
96.8±14.1 |
98.2±16.0 |
Blood pressure, mm Hg |
|||
Systolic |
126±13 |
115±13 |
115±12 |
Diastolic |
81±8 |
75±9 |
76±9 |
Pulse rate, beats/min |
72±9 |
77±9 |
78±9 |
Lipid parameters, mg/dL |
|||
Total cholesterol |
192.3±39.6 |
179.9±36.8 |
180.2±37.3 |
HDL-C |
51.5±13.1 |
49.1±11.6 |
48.8±11.5 |
Non-HDL-C |
140.8±37.5 |
130.8±34.5 |
131.7±36.2 |
LDL-C |
113.8±32.9 |
111.0±32.4 |
113.2±33.6 |
VLDL |
60.3±27.7 |
45.3±20.7 |
41.4±16.4 |
Triglycerides |
136.2±80.9 |
99.1±45.1 |
93.0±44.3 |
Free fatty acids, mEq/L |
0.53±0.22 |
0.48±0.20 |
0.51±0.22 |
eGFR, mL/min/1.73 m2d |
97.8±17.2 |
96.4±18.8 |
97.9±17.9 |
HbA1c, % |
5.54±0.36 |
5.07±0.30 |
5.04±0.31 |
Fasting
glucose, |
94.8±10.9 |
85.1±7.4 |
85.0±7.8 |
Fasting insulin, mIU/L |
13.9±10.7 |
7.4±5.2 |
8.0±6.3 |
Comorbidities, n (%) |
|||
Hypertension |
236 (35.2) |
119 (35.5) |
117 (34.9) |
Dyslipidemia |
212 (31.6) |
113 (33.7) |
99 (29.6) |
ASCVD |
41 (6.1) |
18 (5.4) |
23 (6.9) |
PCOSe |
23 (4.9) |
9 (3.8) |
14 (5.9) |
Obstructive sleep apnea |
81 (12.1) |
40 (11.9) |
41 (12.2) |
Osteoarthritis |
133 (19.9) |
70 (20.9) |
63 (18.8) |
Anxiety/depression |
151 (22.5) |
73 (21.8) |
78 (23.3) |
NAFLD |
48 (7.2) |
22 (6.6) |
26 (7.8) |
Asthma or COPD |
69 (10.3) |
34 (10.1) |
35 (10.4) |
Gout |
24 (3.6) |
15 (4.5) |
9 (2.7) |
SF-36 |
47.6±8.2 |
53.4±5.8 |
53.2±6.5 |
Abbreviations: ASCVD = atherosclerotic cardiovascular disease; BMI = body mass index; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; COPD = chronic obstructive pulmonary disease; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MTD = maximum tolerated dose (10 or 15 mg); NAFLD = nonalcoholic fatty liver disease; PCOS = polycystic ovarian syndrome; SF-36 = SF-36v2 short form physical functioning domain score; VLDL = very low-density lipoprotein.
a Data are mean, mean ± SD, or n (%).
b Race and ethnicity was reported by participants.
c Duration of obesity was self-reported by participants.
d The value of the eGFR was calculated according to the serum creatinine–based CKD-EPI equation.
e Percentage is based on total number of female participants in the respective treatment group.
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Efficacy Results from SURMOUNT-4
In the SURMOUNT-4 study, tirzepatide led to statistically significant body weight reductions from randomization (week 36) to week 88 compared with placebo (see Table 2).1
Table 2. Primary and Secondary Endpoints for SURMOUNT-4 (Week 36 to Week 88)1,2
Endpointsa |
Tirzepatide
MTD |
Placebo |
Change in body weight, %b |
-6.7c |
+14.8 |
Placebo-adjusted percent change in body weight, % |
-21.4 |
NA |
Change in body weight, kgb |
-5.7 c |
+11.9 |
Participants maintaining ≥80% of body weight reduction from lead-in, %b |
93.4c |
13.5 |
Change in waist circumference, cmb |
-4.6c |
+8.3 |
Abbreviations: LSM = least squares mean; mITT = modified intention-to-treat; MMRM = mixed-effects model for repeated measures; MTD = maximum tolerated dose (10 or 15 mg); NA = not applicable.
Note: Two statistical estimands, efficacy or treatment-regimen, were used to evaluate efficacy data from the phase 3 clinical trials of tirzepatide. Efficacy estimand evaluates the treatment effect prior to discontinuation of the study drug. Treatment-regimen estimand evaluates the treatment effect irrespective of adherence to the study drug. Differences in reported data may reflect the application of these estimands. This response presents data reflecting the efficacy estimand. For treatment-regimen estimand results, please refer to the manuscript cited and/or the US prescribing information, where applicable.
a Data are LSM from mITT population (efficacy estimand); MMRM or logistic regression analysis.
b Tested for superiority, controlled for Type 1 error.
c p<.001 versus placebo.
Table 3. Secondary Endpoints for SURMOUNT-4 (Week 0 to Week 88)1,2
Endpointsa |
Tirzepatide
MTD |
Placebo |
Change in body weight, %b |
-26.0 |
-9.5 |
Placebo-adjusted percent change in body weight, %b |
-16.4 |
NA |
Change in body weight, kgb |
-27.6 |
-10.0 |
Participants with body weight reduction ≥5%, %c |
98.5d |
69.0 |
Participants with body weight reduction ≥10%, %c |
94.0d |
44.4 |
Participants with body weight reduction ≥15%, %c |
87.1d |
24.0 |
Participants with body weight reduction ≥20%, %c |
72.6d |
11.6 |
Participants with body weight reduction ≥25%, %b |
56.6d |
4.0 |
Abbreviations: LSM = least squares mean; mITT = modified intention-to-treat; MMRM = mixed-effects model for repeated measures; MTD = maximum tolerated dose (10 or 15 mg); NA = not applicable.
a Data are LSM from mITT population (efficacy estimand); MMRM or logistic regression analysis.
b Tested for significant difference, not controlled for Type 1 error.
c Tested for superiority, controlled for Type 1 error.
d p<.001 versus placebo.
In a time-to-event analysis of participants who had lost ≥5% body weight from week 0, the hazard ratio for returning to >95% baseline body weight during the double-blind period was 0.013 (95% CI, 0.004-0.046; p<.001) for participants who continued tirzepatide compared with participants who switched to placebo.1
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Safety Results from SURMOUNT-4
The overall treatment discontinuation rates were
10% participants from the tirzepatide MTD (10 or 15 mg) arm, and
18% participants from the placebo arm.1
During the double-blind period, treatment discontinuation rates due to adverse events were
1.8% in the tirzepatide MTD arm
0.9% in the placebo arm.1
The safety profile of tirzepatide in SURMOUNT-4 was similar to that observed in the pooled SURMOUNT-1 and -2 trials.1,3
There were no reported cases of medullary thyroid carcinoma or pancreatic cancer.1
Table 4. Overview of Adverse Event From Randomization (Week 36) Through Safety Follow-Up in SURMOUNT-41
Parametersa |
Tirzepatide
MTD |
Placebo |
Patients with ≥1 TEAE |
202 (60.3) |
187 (55.8) |
Serious AE |
10 (3.0) |
10 (3.0) |
Deaths |
1 (0.3) |
1 (0.3) |
Abbreviations: AE = adverse event; MTD = maximum tolerated dose (10 or 15 mg); TEAE = treatment-emergent adverse event.
a Data are number of patients (%).
The most commonly reported adverse events were gastrointestinal-related and generally mild to moderate in severity.1
Table 5. Treatment-Emergent Adverse Eventsa with ≥5% Frequency During Open-Label Tirzepatide Lead-in Period1
Parameterb |
Tirzepatide
Lead-In |
Nausea |
278 (35.5) |
Diarrhea |
165 (21.1) |
Constipation |
162 (20.7) |
Vomiting |
128 (16.3) |
COVID-19 |
83 (10.6) |
Decreased appetite |
74 (9.5) |
Gastroesophageal reflux disease |
69 (8.8) |
Injection site reaction |
64 (8.2) |
Dyspepsia |
63 (8.0) |
Headache |
56 (7.2) |
Fatigue |
53 (6.8) |
Abdominal pain |
48 (6.1) |
Alopecia |
40 (5.1) |
Abbreviation: COVID-19 = coronavirus disease 2019.
a Adverse events are listed according to Medical Dictionary for Regulatory Activities, version 26.0, preferred terms.
b Data are number of patients (%).
Table 6. Treatment-Emergent Adverse Events With ≥5% Frequency From Randomization (Week 36) Through Safety Follow-up in SURMOUNT-41
Parametera |
Tirzepatide
MTD |
Placebo |
COVID-19 |
47 (14) |
50 (14.9) |
Diarrhea |
36 (10.7) |
16 (4.8) |
Nausea |
27 (8.1) |
9 (2.7) |
Vomiting |
19 (5.7) |
4 (1.2) |
Upper respiratory tract infection |
8 (2.4) |
18 (5.4) |
Abbreviations: COVID-19 = coronavirus disease 2019; MTD = maximum tolerated dose (10 or 15 mg).
a Data are number of patients (%).
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Enclosed Prescribing Information
ZEPBOUND® (tirzepatide) injection, for subcutaneous use, Lilly
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1. Aronne LJ, Sattar N, Horn DB, et al; SURMOUNT-4 Investigators. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38-48. https://doi.org/10.1001/jama.2023.24945
2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.
3. Mounjaro [package insert]. Indianapolis, IN: Eli Lilly and Company; 2026.
Date of Last Review: July 22, 2026