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Zepbound ® (tirzepatide) injection
2.5 mg/ 5 mg/ 7.5 mg/ 10 mg/ 12.5 mg/ 15 mg
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How did Zepbound® (tirzepatide) compare with placebo for weight reduction after intensive lifestyle program?
Tirzepatide resulted in a statistically significant reduction in body weight after a 12-week lead-in intensive lifestyle modification program compared with placebo in adults with obesity in SURMOUNT-3.
See important safety information, including boxed warning, in the attached prescribing information.
Content Overview
Weight Reduction in Adults With Obesity or Overweight After Intensive Lifestyle Program – SURMOUNT-3
Enclosed Prescribing Information
Weight Reduction in Adults With Obesity or Overweight After Intensive Lifestyle Program – SURMOUNT-3
SURMOUNT-3 was a 84-week study with a 12-week lead-in intensive lifestyle modification program followed by a 72-week, phase 3, double-blind, randomized study of tirzepatide at the maximum tolerated dose (MTD) (10 or 15 mg) once weekly compared with placebo in 579 adults with obesity or overweight with weight-related comorbidities 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/1.73m2
concomitant use of any weight loss medication in the 3 months prior to screening prior or planned surgical treatment for obesity
weight change >5 kg within 3 months, and
obesity induced by other endocrinologic disorders or monogenetic or syndromic forms of obesity.1
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Study Design
The SURMOUNT-3 study randomized 579 study participants across the United States, Argentina, and Brazil in a 1:1 ratio to receive tirzepatide MTD (10 or 15 mg) or placebo.1
The co-primary outcomes of this study were
percent change in body weight from randomization to week 72, and
percentage of participants who achieve ≥5% body weight reduction from randomization by week 72.2,3
After screening, 806 participants were enrolled in a 12-week intensive lifestyle modification lead-in period that included a low-calorie diet, exercise, and counseling sessions.1
During the 12-week lead-in, participants followed a low-calorie diet (1200 kcal/day for women, 1500 kcal/day for men), which may have included up to two liquid meal replacements per day. Participants were encouraged to perform at least 150 minutes per week of moderate intensity activity. Participants were also counseled on behavior modification strategies to help implement and adhere to the diet and exercise recommendations.1
Participants who had ≥5% weight reduction by the end of the 12-week lead-in period were then randomized 1:1 to tirzepatide MTD (10 or 15 mg) or placebo once weekly for a 72-week treatment period (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. 1
Figure 1. SURMOUNT-3 Study Design1
Figure 1 description: In the SURMOUNT-3 study, participants were enrolled in a 12-week intensive lifestyle modification lead-in period. After randomization 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 maximum tolerated dose (10 or 15 mg) was achieved. Tirzepatide and placebo were used as adjunct to a reduced-calorie diet and increased physical activity.
Abbreviations: MTD = maximum tolerated dose; QW = once week; (T) = telephone visit.
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Baseline Characteristics
Baseline demographics and clinical characteristics of randomized patients are presented in Table 1.1
Table 1. SURMOUNT-3 Baseline Demographics and Clinical Characteristics1
Parametera |
Tirzepatide
MTD |
Placebo |
Total |
Age, years |
45.4±12.6 |
45.7±11.8 |
45.6±12.2 |
Female, n (%) |
181 (63.1) |
183 (62.7) |
364 (62.9) |
Race, n (%)b |
|
|
|
White |
246 (85.7) |
252 (86.3) |
498 (86.0) |
Black or African American |
31 (10.8) |
32 (11.0) |
63 (10.9) |
Multiple |
6 (2.1) |
2 (0.7) |
8 (1.4) |
American Indian or Alaskan |
2 (0.7) |
4 (1.4) |
6 (1.0) |
Asian |
2 (0.7) |
2 (0.7) |
4 (0.7) |
Duration of obesity, years |
15.4±11.6 |
14.8±10.8 |
15.1±11.2 |
Body weight, kg |
102.5±22.1 |
101.3±20.7 |
101.9±21.4 |
BMI, kg/m2 |
36.1±6.1 |
35.7±6.4 |
35.9±6.3 |
BMI category, n (%) |
|||
<27 |
5 (1.7) |
12 (4.1) |
17 (2.9) |
≥27 to <30 |
32 (11.1) |
38 (13.0) |
70 (12.1) |
≥30 to <35 |
100 (34.8) |
107 (36.6) |
207 (35.8) |
≥35 to <40 |
95 (33.1) |
79 (27.1) |
174 (30.1) |
≥40 |
55 (19.2) |
56 (19.2) |
111 (19.2) |
Waist circumference, cm |
109.3±15.2 |
109.6±15.1 |
109.4±15.0 |
Blood pressure, mm Hg |
|||
Systolic |
121.4±12.7 |
120.5±12.4 |
121.0±12.6 |
Diastolic |
79.1±8.9 |
78.1±9.2 |
78.6±9.1 |
Lipid parameters, geometric mean mg/dL |
|||
Total cholesterol |
185.2±37.2 |
185.3±38.2 |
185.3±37.6 |
HDL |
48.4±12.7 |
49.3±12.9 |
48.9±12.8 |
Non-HDL |
136.7±35.6 |
135.90±35.7 |
136.3±35.6 |
LDL |
112.5±32.5 |
112.3±32.3 |
112.4±32.4 |
VLDL |
54.4±21.7 |
54.2±24.4 |
54.3±23.1 |
Triglycerides |
121.4±55.7 |
118.6±53.3 |
120.0±54.5 |
Free fatty acids |
0.6±0.3 |
0.6±0.2 |
0.6±0.2 |
eGFR, mL/min/1.73 m2 |
95.6±17.1 |
97.1±16.7 |
96.4±16.9 |
Obesity-related complications, n (%) |
|||
Hypertension |
95 (33.1) |
104 (35.6) |
199 (34.4) |
Dyslipidemia |
71 (24.7) |
81 (27.7) |
152 (26.3) |
ASCVD |
5 (1.7) |
6 (2.1) |
11 (1.9) |
PCOS |
8 (4.4) |
8 (4.4) |
16 (4.4) |
Obstructive sleep apnea |
25 (8.7) |
34 (11.6) |
59 (10.2) |
Osteoarthritis |
43 (15.0) |
48 (16.4) |
91 (15.7) |
Anxiety/depression |
61 (21.3) |
55 (18.8) |
116 (20.0) |
NAFLD |
9 (3.1) |
16 (5.5) |
25 (4.3) |
Asthma or COPD |
21 (7.3) |
31 (10.6) |
52 (9.0) |
Gout |
6 (2.1) |
9 (3.1) |
15 (2.6) |
Number of weight-related complications, n (%) |
|||
None |
96 (33.4) |
100 (34.2) |
196 (33.9) |
1 |
102 (35.5) |
81 (27.7) |
183 (31.6) |
2 |
48 (16.7) |
54 (18.5) |
102 (17.6) |
3 |
22 (7.7) |
36 (12.3) |
58 (10.0) |
4 |
14 (4.9) |
14 (4.8) |
28 (4.8) |
≥5 |
5 (1.7) |
7 (2.4) |
12 (2.1) |
Abbreviations: ASCVD = atherosclerotic cardiovascular disease; BMI = body mass index; COPD = chronic obstructive pulmonary disease; eGFR = estimated glomerular filtration rate; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MTD = maximum tolerated dose; NAFLD = nonalcoholic fatty liver disease; PCOS = polycystic ovarian syndrome; VLDL = very low-density lipoprotein.
a Data were presented as mean ± SD unless otherwise specified.
b Race was determined by the participant according to fixed selection categories.
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Efficacy Results from SURMOUNT-3
Tirzepatide met both co-primary endpoints during the 72-week double-blind treatment period (Table 2).1
Table 2. Primary and Secondary Endpoints for SURMOUNT-3 from Randomization to Week 721,4
Endpoints |
Tirzepatide
MTD (10 or 15 mg) |
Placebo |
Change in body weight, %a |
-21.1 |
+3.3 |
Participants with body weight reduction ≥5%, %a |
94.4 |
10.7 |
Participants with body weight reduction ≥10%, %a |
88.0 |
4.8 |
Participants with body weight reduction ≥15%, %a |
73.9 |
2.1 |
Participants with body weight reduction ≥20%, %a |
54.9 |
1.0 |
Participants with body weight reduction ≥25%, % |
36.3 |
0.3 |
Participants maintaining ≥80% of lead-in body weight reduction, %a |
98.6 |
37.8 |
Change in waist circumference, cma |
-16.8 |
1.1 |
Abbreviations: MTD = maximum tolerated dose; 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 Controlled for type 1 error.
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Safety Results from SURMOUNT-3
Treatment discontinuation rates due to adverse events were
10.5% in the tirzepatide MTD arm
2.1% in the placebo arm.1
The safety profile of tirzepatide in SURMOUNT-3 was similar to that observed in the pooled SURMOUNT-1 and -2 trials.1,5
The most commonly reported adverse events of tirzepatide were gastrointestinal-related and were mostly mild to moderate, usually occurring during the dose escalation period.1
There were no reported cases of medullary thyroid carcinoma.1
Table 3. Overview of Adverse Events Through 72 Weeks in SURMOUNT-31
Parameter, n (%) |
Tirzepatide
MTD |
Placebo |
Participants with ≥1 TEAE |
250 (87.1) |
224 (76.7) |
Serious TEAE |
17 (5.9) |
14 (4.8) |
Deatha |
1 (0.3) |
1 (0.3) |
Abbreviations: AE = adverse events; MTD = maximum tolerated dose; TEAE = treatment-emergent adverse event.
a Deaths are also included as serious adverse events.
Table 4. Treatment-Emergent Adverse Events With ≥5% Frequency Through 72 Weeks in SURMOUNT-31
Parameter, n (%) |
Tirzepatide
MTD |
Placebo |
Nausea |
114 (39.7) |
41 (14.0) |
Diarrhoea |
89 (31.0) |
27 (9.2) |
Constipation |
66 (23.0) |
20 (6.8) |
COVID-19 |
66 (23.0) |
74 (25.3) |
Vomiting |
52 (18.1) |
4 (1.4) |
Injection site reaction |
32 (11.1) |
3 (1.0) |
Abdominal pain |
30 (10.5) |
7 (2.4) |
Decreased appetite |
27 (9.4) |
12 (4.1) |
Dyspepsia |
27 (9.4) |
9 (3.1) |
Headache |
27 (9.4) |
22 (7.5) |
Upper respiratory tract infection |
25 (8.7) |
21 (7.2) |
Alopecia |
20 (7.0) |
4 (1.4) |
Dizziness |
20 (7.0) |
6 (2.1) |
Fatigue |
20 (7.0) |
9 (3.1) |
Flatulence |
19 (6.6) |
8 (2.7) |
Gastrooesophageal reflux disease |
19 (6.6) |
7 (2.4) |
Back pain |
17 (5.9) |
15 (5.1) |
Eructation |
16 (5.6) |
3 (1.0) |
Influenza |
12 (4.2) |
25 (8.6) |
Urinary tract infection |
11 (3.8) |
15 (5.1) |
Anxiety |
9 (3.1) |
19 (6.5) |
Arthralgia |
7 (2.4) |
15 (5.1) |
Sinusitis |
6 (2.1) |
16 (5.5) |
Abbreviations: MTD = maximum tolerated dose.
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Discontinuation
The overall treatment discontinuation rates were
21.3% in the tirzepatide MTD arm, and
30.5% in the placebo arm.1
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Enclosed Prescribing Information
ZEPBOUND® (tirzepatide) injection, for subcutaneous use, Lilly
References
The published reference below is available by contacting 1-800-LillyRx (1-800-545-5979).
1. 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(11):2909-2918. https://doi.org/10.1038/s41591-023-02597-w
2. le Roux CW, Zhang S, Aronne LJ, et al. Tirzepatide for the treatment of obesity: rationale and design of the SURMOUNT clinical development program. Obesity (Silver Spring). 2023;31(1):96-110. https://doi.org/10.1002/oby.23612
3. A study of tirzepatide (LY3298176) in participants after a lifestyle weight loss program (SURMOUNT-3). ClinicalTrials.gov identifier: NCT04657016. Updated May 24, 2023. Accessed July 27, 2023. https://clinicaltrials.gov/ct2/show/NCT04657016
4. Tirzepatide demonstrated significant and superior weight loss compared to placebo in two pivotal studies. Press release. Eli Lilly and Company; July 27, 2023. Accessed July 27, 2023. https://investor.lilly.com/news-releases/news-release-details/tirzepatide-demonstrated-significant-and-superior-weight-loss
5. Mounjaro [package insert]. Indianapolis, IN: Eli Lilly and Company; 2026.
Date of Last Review: July 22, 2026