What this is
- SURMOUNT-4 evaluated tirzepatide's impact on health-related quality of life (HRQoL) in adults with obesity or overweight.
- Participants who continued tirzepatide treatment maintained improvements in HRQoL, while those who switched to placebo experienced declines.
- The study utilized patient-reported outcomes (PROs) to assess changes in quality of life over 88 weeks.
Essence
- Continued tirzepatide treatment significantly improved health-related quality of life in participants with obesity or overweight, compared to those who switched to placebo, who experienced declines.
Key takeaways
- Tirzepatide treatment led to sustained improvements in patient-reported outcomes (PROs) from Weeks 36 to 88, maintaining quality of life benefits.
- Participants who achieved greater weight reductions during treatment reported better HRQoL, indicating a strong association between weight loss and quality of life.
- Switching to placebo resulted in significant declines in HRQoL, highlighting the importance of ongoing treatment to maintain benefits.
Caveats
- The study did not allow for dose adjustments after randomization, which may limit generalizability to broader populations.
- Participants with physical function limitations at baseline were underrepresented, which may affect the applicability of findings to this group.
Simplified
Introduction
Obesity is a chronic, complex, highly prevalent, and relapsing disease associated with numerous complications such as type 2 diabetes (T2D), cardiovascular diseases, obstructive sleep apnea, osteoarthritis, and mental health disorders [1]. According to the National Health and Wellness Survey, high body mass index (BMI) is associated with lower health‐related quality of life (HRQoL) and reduced work productivity [2]. HRQoL encompasses physical and psychosocial health domains, which are important measures for understanding an individual's overall health perception. For people living with obesity, HRQoL, particularly in terms of physical functioning, is a significant concern. Therefore, it is recommended that HRQoL be assessed using patient‐reported outcomes (PROs) as a key measure in clinical trials [3].
American Diabetes Association's Standard of Care treatment guidelines recommend 3%–7% weight reduction for improvement in obesity‐related complications, which is typically associated with enhanced daily functioning and psychosocial well‐being in people with obesity [4, 5]. Long‐term adherence to obesity management programs is often challenging, and weight regain is common [6, 7, 8]. Treatment with obesity pharmacotherapy, as an adjunct to lifestyle interventions, is recommended for sustained weight reduction and improving HRQoL [5]. The impact of pharmacotherapy on HRQoL can be examined using generic or disease‐specific measures, focusing on obesity [9].
Tirzepatide is a once‐weekly glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist that selectively binds to and activates both the GIP and GLP‐1 receptors [10]. Tirzepatide is approved in many countries, including the United States (US), as an adjunct to diet and physical activity for the treatment of adults with T2D, chronic weight management, and obstructive sleep apnea [10, 11].
In the phase 3 SURMOUNT‐4 (NCT04660643↗) trial, participants with obesity or overweight who completed the 36‐week tirzepatide lead‐in period continued treatment with tirzepatide maximum tolerated dose (MTD; 10 or 15 mg) over the next 52 weeks, resulting in an additional mean weight reduction of 5.5%, whereas participants who switched to placebo experienced a mean weight regain of 14.0% (treatment regimen estimand). The mean weight reduction during the entire study (Weeks 0–88) was 25.3% with tirzepatide MTD and 9.9% with placebo [12]. Here, we evaluate the association between continued treatment with tirzepatide MTD and patient‐reported HRQoL among SURMOUNT‐4 participants.
Methods
Study Design and Population
SURMOUNT‐4 was a phase 3, multicenter (conducted at 70 sites in four countries), randomized withdrawal study with a 36‐week open‐label tirzepatide lead‐in period followed by a 52‐week, double‐blind, placebo‐controlled period [12]. Eligible participants were adults (≥ 18 years old) who had obesity (BMI ≥ 30 kg/m2) or overweight (BMI ≥ 25–< 30 kg/m2) with at least one obesity‐related complication (i.e., hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) and a history of at least one self‐reported unsuccessful dietary effort to lose body weight. People with type 1 diabetes, T2D, prior surgical treatment for obesity, or treatment with an obesity medication within 3 months prior to enrollment were excluded. The detailed study design and endpoints have been published previously [12]. The study protocol was approved by the ethical review board and adhered to the principles outlined in the Declaration of Helsinki, the Council of International Organizations of Medical Sciences International Ethical Guidelines, and Good Clinical Practice guidelines. All participants provided written informed consent before study enrollment.
Randomization and Treatments
In SURMOUNT‐4, tirzepatide was subcutaneously administered once weekly with a starting dose of 2.5 mg. Tirzepatide dose escalation was implemented during the 36‐week lead‐in period, with doses increased by 2.5 mg every four weeks until a MTD of 10 mg or 15 mg was achieved. Participants who attained tirzepatide MTD were randomly assigned in a 1:1 ratio to either continue receiving tirzepatide MTD or switch to placebo for an additional 52 weeks (double‐blind treatment period). Throughout the study, all participants received study treatment as an adjunct to lifestyle counseling (500 kcal/day deficit diet and at least 150 min of physical activity/week).
Study Outcomes and Assessments
The effect of tirzepatide on HRQoL was assessed using the following PROs during the tirzepatide lead‐in period (Weeks 0–36), the double‐blind treatment period (Weeks 36–88), and the entire study period (Weeks 0–88). With the randomized withdrawal design of SURMOUNT‐4, the primary focus was to demonstrate that tirzepatide MTD was superior to placebo for change in HRQoL from randomization (Week 36) at 88 weeks. A list of prespecified and post hoc endpoints and assessments is provided in Table. S1
Short Form‐36 Version 2 Health Survey (SF‐36v2) Acute Form, 1‐Week Recall Version [] [13]
The SF‐36v2 is a 36‐item validated PRO measure used to assess generic HRQoL and health status. It consists of eight domains: Physical Functioning; Role‐Physical; Bodily Pain; General Health; Vitality; Social Functioning; Role‐Emotional; and Mental Health. Each domain is scored individually, and these scores are combined into two component summary scores: Physical Component Summary (PCS) and Mental Component Summary (MCS). The Physical Functioning domain assesses limitations due to health “now,” while the remaining domains assess functioning “in the last week.” Items are answered on Likert scales of varying lengths (3‐, 5‐, or 6‐point). A 3‐ to 5‐point increase in PCS or MCS score is considered clinically meaningful [14]. The domain and component summary scores are norm‐based to the 2009 US general population, with a mean of 50 and a standard deviation (SD) of 10. Higher scores indicate better HRQoL.
Impact of Weight on Quality of Life‐Lite‐Clinical Trials Version (IWQOL‐Lite‐CT) [] [15]
Weight‐related quality of life was assessed using IWQOL‐Lite‐CT, a 20‐item validated obesity‐specific PRO instrument developed in accordance with US Food and Drug Administration (FDA) guidance for use in clinical trials. This instrument assesses two primary domains of obesity‐related and health‐related quality of life: Physical composite (7 items) and Psychosocial composite (13 items). A 5‐item subset of the Physical composite, the Physical Function composite, is also assessed. Items in the Physical Function composite describe physical impacts related to general and specific physical activities. All items are rated on either a 5‐point frequency (“never” to “always”) or a 5‐point truth (“not at all true” to “completely true”) scale. The overall score range is from 0 to 100 with higher scores indicating better functioning. A change of 13.5–16.6 points in IWQOL‐Lite‐CT scores is considered clinically meaningful [16].
EQ‐5D‐5L [] [17]
The EQ‐5D‐5L is a standardized five‐dimension instrument that yields a simple descriptive profile and a single index value for health status. It comprises five dimensions of health: mobility; self‐care; usual activities; pain/discomfort; and anxiety/depression. Each dimension was scored on five levels (no problems, slight problems, moderate problems, severe problems, or unable to perform/extreme problems). The Health State Index value is derived using a formula that assigns weights to the levels in each dimension. This index value ranges from < 0 to 1, where 0 is a health state equivalent to death; negative values are valued as worse than dead, and 1 is considered perfect health [18]. Additionally, the EQ Visual Analogue Scale (VAS) records the participant's self‐rated health status on a vertical graduated scale of 0–100. A 0.03‐point difference in EQ‐5D index score and 10‐point difference on the EQ‐VAS are considered minimal clinically important difference [19, 20, 21].
Patient Global Impression of Status (PGIS) for Physical Activity
The PGIS for physical activity was specifically developed for the SURMOUNT‐4 study. This is a participant‐rated assessment of current limitations on physical activity due to health and is rated on a 5‐point scale ranging from “not at all limited” to “extremely limited.” Participants with responses of “moderately,” “very much,” or “extremely” limited were classified as having physical function limitations at baseline.
Study endpoints (prespecified from Weeks 36 to 88 and Weeks 0 to 88 and post hoc during Weeks 0 to 36) included changes in 1 SF‐36v2 norm‐based scores, PCS, MCS, and domain (Physical Functioning, Role‐Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role‐Emotional, and Mental Health) scores; 2 IWQOL‐Lite‐CT Total and composite scores (Physical Function, Physical, and Psychosocial); and 3 EQ‐5D‐5L Health State Index (UK) and EQ‐VAS scores. Among participants who had physical function limitations at baseline, changes in SF‐36v2 Physical Functioning domain score and IWQOL‐Lite‐CT Physical Function composite score were assessed. The number and proportion of participants endorsing each PGIS for physical activity response category on a 5‐point scale (“not at all limited” to “extremely limited”) were also reported.
Additionally, post hoc analyses included the proportion of participants achieving meaningful within‐participant change in SF‐36v2 Physical Functioning domain score (improvement of ≥ 5.76). The association of percentage weight reduction categories (≥ 5%, ≥ 10%, ≥ 15%, ≥ 20%, ≥ 25%, and ≥ 30%) and baseline PGIS status (presence or absence of physical function limitations) with PROs (SF‐36v2, IWQOL‐Lite‐CT, and EQ‐5D‐5L) was assessed among tirzepatide‐treated participants. The association between percentage weight regain categories (< 25%, 25%–< 50%, 50%–< 75%, and ≥ 75%) and PROs (SF‐36v2, IWQOL‐Lite‐CT, and EQ‐5D‐5L) was assessed during Weeks 36 to 88 among participants in the placebo group who achieved ≥ 10% weight loss at Week 36.
Statistical Analyses
Statistical analyses were conducted using the SAS version 9.4 software. PROs were analyzed in the efficacy analysis set (all randomly assigned participants who were exposed to at least one dose of the study drug, excluding data after study drug discontinuation).
All participants received tirzepatide during the 36‐week lead‐in period per study design. The results for this period are presented for tirzepatide MTD and placebo groups based on the treatment assignment of participants at randomization (Week 36), for the subsequent 52‐week double‐blind treatment period.
For continuous outcomes, the least squares mean (LSM) difference for pairwise comparison (tirzepatide MTD vs. placebo) was calculated using an analysis of covariance (ANCOVA) model with the last observation carried forward for missing data imputation. The ANCOVA model was used with treatment, stratification factors (country, sex, weight loss at Week 36, and tirzepatide MTD at Week 36), and PRO scores at baseline (Week 0) or randomization (Week 36) as covariates. No multiplicity adjustments were made for the reported PRO measures. The p values reported are unadjusted for multiple testing and should not be interpreted as confirmatory. The counts and percentages of participants endorsing each PGIS response category were summarized by nominal visit and by treatment.
For post hoc analyses, the mean changes in PROs by percentage weight reduction categories and by baseline PGIS status (presence or absence of physical function limitations) were summarized descriptively among tirzepatide‐treated participants. The mean changes in PROs by percentage weight regain categories were summarized descriptively in participants receiving placebo.
Results
Patient Disposition and Baseline Characteristics
A total of 670 participants who attained tirzepatide MTD (15 mg: n = 621 [92.7%]; 10 mg: n = 49 [7.3%]) were randomly assigned at Week 36 to either continue receiving tirzepatide MTD (n = 335) or switch to placebo (n = 335) (Table 1). At baseline (Week 0), participants had a mean body weight of 107.3 kg, BMI of 38.4 kg/m2, and obesity duration of 15.5 years.
At randomization (Week 36), demographics and clinical characteristics were similar between the tirzepatide MTD and placebo groups, with a mean body weight of 85.2 kg and a mean BMI of 30.5 kg/m2 (Table 1).
| Characteristics | Week 0 (start of tirzepatide lead‐in treatment period),= 670N | Week 36 (randomization) | |
|---|---|---|---|
| Tirzepatide MTD,= 335N | Placebo,= 335N | ||
| Age (years) | 47.7 (12.6) | 49.2 (12.8) | 48.1 (12.4) |
| Female,(%)n | 473 (70.6) | 236 (70.4) | 237 (70.7) |
| Duration of obesity(years) 70011 | 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/m)2 | 38.4 (6.6) | 30.3 (6.0) | 30.7 (6.8) |
| BMI category (kg/m),(%)2n | |||
| < 25 | — | 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) |
| Short Form‐36 Version 2 Health Survey Acute Form (SF‐36v2) scores(general quality of life survey) 70011 | |||
| Physical Component Summary (PCS) score | 48.9 (7.6) | 54.7 (5.5) | 54.3 (6.8) |
| Mental Component Summary (MCS) score | 52.5 (8.0) | 54.5 (6.5) | 54.5 (6.9) |
| Physical Functioning domain | 47.6 (8.2) | 53.4 (5.9) | 53.4 (6.4) |
| Role‐Physical domain | 50.1 (7.8) | 54.6 (4.9) | 53.7 (6.8) |
| Bodily Pain domain | 50.4 (9.0) | 54.3 (6.9) | 54.4 (8.2) |
| General Health domain | 50.7 (8.0) | 56.6 (6.3) | 56.2 (7.2) |
| Vitality domain | 52.3 (8.4) | 57.2 (7.3) | 57.1 (7.7) |
| Social Functioning domain | 51.7 (7.5) | 54.5 (5.5) | 53.9 (6.4) |
| Role‐Emotional domain | 49.5 (8.9) | 52.5 (6.9) | 52.2 (7.5) |
| Mental Health domain | 52.6 (7.8) | 54.8 (6.5) | 55.3 (6.7) |
| Impact of Weight on Quality of Life‐Lite‐Clinical Trials Version(IWQOL‐Lite‐CT; weight‐related quality of life questionnaire) 70011 | |||
| Total score | 58.0 (22.4) | 81.5 (15.2) | 82.0 (16.2) |
| Physical Function composite score | 59.1 (24.5) | 81.0 (17.0) | 81.7 (18.2) |
| Physical composite score | 58.8 (23.6) | 79.8 (16.6) | 80.0 (17.8) |
| Psychosocial composite score | 57.5 (24.3) | 82.4 (16.3) | 83.0 (16.8) |
| EQ‐5D‐5L (health status questionnaire) | |||
| Health State Index (UK) | 0.8 (0.2) | 0.9 (0.1) | 0.9 (0.1) |
| EQ Visual Analogue Scale | 73.9 (17.0) | 85.7 (10.5) | 84.8 (12.5) |
Patient‐Reported Outcomes
Short Form‐36 Version 2 Health Survey Acute Form
Improvements in SF‐36v2 PCS, MCS, and domain scores observed during the tirzepatide lead‐in period (Weeks 0–36; Figure 1A) were maintained from Weeks 36 to 88 in participants who continued treatment with tirzepatide MTD, but worsened with placebo, resulting in statistically significant differences between the groups (Figure 1B; PCS: p < 0.001; MCS: p < 0.01; and domain scores: p < 0.001 for Physical Functioning, General Health, and Mental Health, p < 0.01 for Bodily Pain, Vitality, and Role‐Emotional, and p < 0.05 for Role‐Physical and Social Functioning). During the study period (Weeks 0–88), tirzepatide was associated with significant improvements versus placebo in SF‐36v2 PCS (p < 0.001), MCS (p < 0.01), and all the domain scores (p < 0.05) (Figure 1C).
At the end of the 36‐week lead‐in treatment with tirzepatide, the proportion of participants achieving meaningful within‐participant change in the SF‐36v2 Physical Functioning domain scores (improvement of ≥ 5.76; norm‐based) was similar between those subsequently randomized to tirzepatide MTD (46.7%) and placebo (44.6%) at Week 36. More participants achieved meaningful within‐participant change in the SF‐36v2 Physical Functioning domain score with tirzepatide MTD than with placebo during Weeks 36 to 88 (11.6% vs. 4.3%) and Weeks 0 to 88 (53.7% vs. 38.3%) (Figure 2A).
Among participants who had physical function limitations at baseline (Week 0), the improvements in SF‐36v2 Physical Functioning domain scores during the tirzepatide lead‐in period (Weeks 0–36) were comparable between those randomized to continue tirzepatide MTD (LSM: 10.7; n = 82) and those randomized to placebo (10.0; n = 88) groups at Week 36 (Figure 2B). Continued treatment with tirzepatide MTD (n = 74) versus placebo (n = 69) resulted in sustained improvements in SF‐36v2 Physical Functioning domain scores from Weeks 36 to 88 (LSM difference vs. placebo: 5.4; p < 0.001) and Weeks 0–88 (5.6; p < 0.001) among these participants (Figure 2B).
Effect of tirzepatide versus placebo on general quality of life measured by Short Form‐36 Version 2 Health Survey Acute Form (SF‐36v2). Data are presented as least squares mean change from baseline (Week 0) or randomization (Week 36) using ANCOVA with last observation carried forward for the efficacy analysis set. The SF‐36v2 scores are norm‐based, that is, scores transformed to a scale in which the 2009 US general population has a mean score of 50 and standard deviation of 10. A higher score indicates better health. *< 0.05, **< 0.01, ***< 0.001 versus placebo. MTD, maximum tolerated dose;, number of participants with baseline and post‐baseline value at the specified time point; SE, standard error. [Color figure can be viewed at] p p p n wileyonlinelibrary.com
Effect of tirzepatide versus placebo on the Physical Functioning domain score of the Short Form‐36 Version 2 Health Survey Acute Form (SF‐36v2; general quality of life survey). Data are presented for the efficacy analysis set: (A) proportion of participants achieving within‐treatment change from baseline (Week 0) or randomization (Week 36); (B) least square mean change from baseline (Week 0) or randomization (Week 36) using ANCOVA with the last observation carried forward. The SF‐36v2 scores are norm‐based, that is, scores transformed to a scale in which the 2009 US general population has a mean score of 50 and standard deviation of 10. A higher score indicates better health. *< 0.05, **< 0.01, ***< 0.001 versus placebo.A meaningful within‐participant change from the start of open‐label lead‐in (Week 0) or randomization (Week 36) in SF‐36v2 Physical Functioning domain score was defined as an increase of ≥ 5.76 (range 3.84–9.60) using anchor‐based and distribution‐based methods [].Participants with physical function limitations at baseline were those who rated their physical function as “moderately limited,” or “very much limited,” or “extremely limited” in the Patient Global Impression of Status for physical activity. MTD, maximum tolerated dose;, number of participants with baseline and post‐baseline value at the specified time point;, number of participants with physical function limitations at baseline who had baseline and post‐baseline value at the specified time point; SE, standard error. [Color figure can be viewed at] p p p N n a b [22] wileyonlinelibrary.com
Impact of Weight on Quality of Life‐Lite‐Clinical Trials Version
During the tirzepatide lead‐in period (Weeks 0–36), the tirzepatide MTD and placebo groups showed similar improvements in IWQOL‐Lite‐CT Total (LSM: 23.5 and 23.8) and composite (Psychosocial: 24.9 and 25.3; Physical Function: 21.9 and 22.4; and Physical: 20.8 and 21.2) scores (Figure 3A). During Weeks 36 to 88, continued treatment with tirzepatide showed additional improvements, while switching to placebo showed worsening, with significant differences between groups (IWQOL‐Lite‐CT Total score LSM difference vs. placebo: 11.1, Psychosocial composite score: 12.1, Physical Function composite score: 9.4, and Physical composite score: 9.1; all p < 0.001; Figure 3B). Throughout the study period, tirzepatide treatment was associated with improvements in IWQOL‐Lite‐CT Total score and all the composite scores compared to placebo (all p < 0.001; Figure 3C).
Among participants with physical function limitations at baseline, the improvement in IWQOL‐Lite‐CT Physical Function composite score during the tirzepatide lead‐in period (Weeks 0–36) was the same for the tirzepatide MTD (n = 82) and placebo (n = 88) groups (LSM: 36.3 for both; Figure 4). Continued treatment with tirzepatide MTD (n = 74) versus placebo (n = 70) led to sustained improvements in IWQOL‐Lite‐CT Physical Function composite scores from Weeks 36 to 88 (LSM difference vs. placebo: 14.7; p < 0.001), and Weeks 0 to 88 (13.7; p < 0.001) in these participants (Figure 4).
Effect of tirzepatide versus placebo on weight‐related quality of life measured by Impact of Weight on Quality of Life‐Lite‐Clinical Trials Version (IWQOL‐Lite‐CT). Data are presented as least squares mean change from baseline (Week 0) or randomization (Week 36) using ANCOVA with the last observation carried forward for the efficacy analysis set. ***< 0.001 versus placebo.For tirzepatide MTD and placebo groups, within‐treatment change from Weeks 36 to 88 was significant for total and composite (Psychosocial, Physical Function, and Physical) scores (all< 0.001). MTD, maximum tolerated dose;, number of participants with baseline and post‐baseline value at the specified time point; SE, standard error. [Color figure can be viewed at] p p n a wileyonlinelibrary.com
Effect of tirzepatide versus placebo on the Physical Function composite score of the Impact of Weight on Quality of Life‐Lite‐Clinical Trials Version (IWQOL‐Lite‐CT; weight‐related quality of life questionnaire). Data are presented as least squares mean change from baseline (Week 0) or randomization (Week 36) using ANCOVA with the last observation carried forward for the efficacy analysis set. ***< 0.001 versus placebo. Participants with physical function limitations at baseline were those who rated their physical function as “moderately limited,” or “very much limited,” or “extremely limited” in the Patient Global Impression of Status for physical activity. MTD, maximum tolerated dose;, number of participants with physical function limitations at baseline who had baseline and post‐baseline value at the specified time point; SE, standard error. [Color figure can be viewed at] p n wileyonlinelibrary.com
EQ‐5D‐5L Scores
The improvement from baseline in EQ‐5D‐5L‐Health State Index (UK) scores during tirzepatide lead‐in period (Weeks 0–36) and study period (Weeks 0–88) was comparable between the treatment groups (Figure 5A). From Weeks 36 to 88, improvement in EQ‐5D‐5L‐Health State Index (UK) scores was maintained in the tirzepatide group, whereas worsening was seen in the placebo group (p < 0.05; Figure 5A).
The improvement in EQ VAS scores was similar between the tirzepatide MTD (LSM: 11.6) and placebo (10.4) groups during the tirzepatide lead‐in period (Weeks 0–36), and these improvements were maintained with tirzepatide treatment from Weeks 36 to 88 (LSM difference vs. placebo: 4.9; p < 0.001) and Weeks 0 to 88 (6.0; p < 0.001) (Figure 5B).
Effect of tirzepatide versus placebo on health status measured by EQ‐5D‐5L. Data are presented as least squares mean change from baseline (Week 0) or randomization (Week 36) using ANCOVA with the last observation carried forward for the efficacy analysis set. *< 0.05, ***< 0.001 versus placebo. Diff, difference; MTD, maximum tolerated dose;, number of participants with baseline and post‐baseline value at the specified time point; SE, standard error. [Color figure can be viewed at] p p n wileyonlinelibrary.com
Patient Global Impression of Status for Physical Activity
Among the participants who had “moderately limited” to “extremely limited” physical activity at baseline (placebo: n = 88; tirzepatide MTD: n = 82), most reported an improvement at Week 36 in both treatment groups (placebo: n = 81, 92.0%; tirzepatide MTD: n = 78, 95.1%; Table 2). At Week 36 (randomization), a majority of the participants in both treatment groups (75.5%; n = 253 for both) reported that their physical activity was “not at all limited.” However, decline in physical activity at Week 88 was higher in participants who switched to placebo than in those who continued to receive tirzepatide MTD (Table 2).
During the entire study period, the proportion of participants who reported that their physical activity was “not at all limited” substantially increased from Weeks 0 to 88 in the tirzepatide MTD group (Week 0: 40.6% to Week 88: 71.6%), while it was similar in the placebo group (41.8%–50.1%) (Table 2).
| Tirzepatide lead‐in period (Weeks 0–36)—Randomized population | ||||||||
|---|---|---|---|---|---|---|---|---|
| Response group at Week 36,(%)n | ||||||||
| Treatment | Response group at Week 0,(%)n | Not at all limited | A little limited | Moderately limited | Very much limited | Extremely limited | Missing | Total |
| Tirzepatide MTD group randomized to placebo at Week 36 (= 335)N | Not at all limited | 124 (37.0) | 13 (3.9) | 1 (0.3) | 0 | 2 (0.6) | 0 | 140 (41.8) |
| A little limited | 76 (22.7) | 26 (7.8) | 4 (1.2) | 1 (0.3) | 0 | 0 | 107 (31.9) | |
| Moderately limited | 46 (13.7) | 17 (5.1) | 4 (1.2) | 1 (0.3) | 0 | 0 | 68 (20.3) | |
| Very much limited | 9 (2.7) | 4 (1.2) | 3 (0.9) | 1 (0.3) | 1 (0.3) | 0 | 18 (5.4) | |
| Extremely limited | 0 | 1 (0.3) | 0 | 1 (0.3) | 0 | 0 | 2 (0.6) | |
| Missing | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Total | 255 (76.1) | 61 (18.2) | 12 (3.6) | 4 (1.2) | 3 (0.9) | 0 | 335 (100.0) | |
| Tirzepatide MTD group continuing treatment at Week 36 (= 335)N | Not at all limited | 120 (35.8) | 12 (3.6) | 3 (0.9) | 1 (0.3) | 0 | 0 | 136 (40.6) |
| A little limited | 85 (25.4) | 28 (8.4) | 3 (0.9) | 0 | 1 (0.3) | 0 | 117 (34.9) | |
| Moderately limited | 36 (10.7) | 19 (5.7) | 3 (0.9) | 0 | 0 | 0 | 58 (17.3) | |
| Very much limited | 11 (3.3) | 8 (2.4) | 2 (0.6) | 0 | 0 | 1 (0.3) | 22 (6.6) | |
| Extremely limited | 2 (0.6) | 0 | 0 | 0 | 0 | 0 | 2 (0.6) | |
| Missing | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
| Total | 254 (75.8) | 67 (20.0) | 11 (3.3) | 1 (0.3) | 1 (0.3) | 1 (0.3) | 335 (100.0) | |
Post Hoc Analyses
Association of Weight Reduction With PROs in the Tirzepatide Group
Tirzepatide‐treated participants who achieved greater weight reduction (≥ 5% to ≥ 30%) at Week 88 showed greater improvements in SF‐36v2 PCS, MCS, and domain (except Mental Health for which improvement was similar across weight reduction categories) scores (Figure); IWQOL‐Lite‐CT Total and composite scores (Figure); and EQ VAS scores during the tirzepatide lead‐in period (Weeks 0–36) (Table). These improvements in PROs were sustained across weight reduction categories from Weeks 36 to 88 (Figures,, and Table). S1A S2A S2 S1B S2B S2
During the study period (Weeks 0 to 88), a greater weight reduction (≥ 5%–≥ 30%) with tirzepatide was associated with increased mean improvements in the SF‐36v2 PCS (range: 6.2 for ≥ 5% to 7.6 for ≥ 30%) and most domain scores (Physical Functioning: 6.6–7.8; Role‐Physical: 4.4–5.2; Bodily Pain: 4.3–5.8; General Health: 6.3–6.7; Vitality: 4.5–5.7; Social Functioning: 2.3–2.9; Mental Health: 2.4–3.0) (Figure). Similarly, a greater weight reduction was associated with greater mean improvements from baseline in IWQOL‐Lite‐CT Total (range: 28.5 for ≥ 5% to 33.1 for ≥ 30%) and composite (Physical Function: 26.6–30.8; Physical: 24.9–29.2; Psychosocial: 30.4–35.3) scores (Figure), and EQ VAS scores (13.8–16.2) (Table). S1C S2C S2
Association of Limitations in Physical Activity at Baseline With PROs in the Tirzepatide Group
For tirzepatide lead‐in period (Weeks 0–36), mean improvements in SF‐36v2 PCS, MCS, and domain scores; IWQOL‐Lite‐CT Total and composite scores; and EQ‐5D‐5L scores were numerically greater in tirzepatide‐treated participants with limitations in physical functioning at baseline than in those without limitations (Table 3). These improvements in PROs were sustained from Weeks 36 to 88 in both groups (Table 3).
Throughout the study (Weeks 0–88) mean improvements in SF‐36v2 scores were greater in participants with versus without limitations in physical functioning at baseline: PCS (11.6 vs. 4.5), MCS (3.8 vs. 0.9), and domain (Physical Functioning: 12.7 vs. 4.6; Role‐Physical: 8.6 vs. 3.0; Bodily Pain: 8.7 vs. 2.8; General Health: 9.7 vs. 5.2; Vitality: 9.5 vs. 2.8; Social Functioning: 5.9 vs. 1.1; Role‐Emotional: 6.0 vs. 2.1; Mental Health 4.8 vs. 1.7) scores. Similarly, mean improvements were numerically greater for IWQOL‐Lite‐CT Total (42.0 vs. 23.9) and composite scores (Physical Function: 40.1 vs. 22.1; Physical: 38.7 vs. 20.3; and Psychosocial: 43.8 vs. 25.8), and EQ VAS scores (23.5 vs. 10.5) (Table 3).
| Patient‐reported outcomes score, mean (SD) | Baseline Patient Global Impression of Status for physical activity response category | |
|---|---|---|
| Participants without physical function limitations 70011 | Participants with physical function limitations 70011 | |
| Tirzepatide lead‐in period (Weeks 0–36)—Randomized population | ||
| Short Form‐36 Version 2 Health Survey Acute Form (SF‐36v2)scores (general quality of life survey) 70011 | = 252n | = 82n |
| Physical Component Summary | 4.3 (5.46) | 11.3 (7.39) |
| Mental Component Summary | 0.6 (5.78) | 3.2 (9.69) |
| Domain scores | ||
| Physical Functioning | 4.3 (6.30) | 10.7 (8.29) |
| Role‐Physical | 3.2 (5.80) | 8.5 (8.75) |
| Bodily Pain | 2.1 (7.68) | 8.7 (8.84) |
| General Health | 4.7 (6.39) | 10.4 (7.27) |
| Vitality | 3.1 (6.55) | 9.1 (9.49) |
| Social Functioning | 1.4 (6.07) | 5.5 (10.27) |
| Role‐Emotional | 1.4 (6.93) | 5.0 (11.95) |
| Mental Health | 1.1 (6.55) | 4.0 (8.16) |
| Impact of Weight on Quality of Life‐Lite‐Clinical Trials Version(IWQOL‐Lite‐CT; weight‐related quality of life questionnaire) 70011 | = 252n | = 82n |
| Total | 19.3 (16.65) | 37.1 (21.59) |
| Physical Function composite | 17.8 (19.76) | 35.5 (23.88) |
| Physical composite | 16.6 (17.76) | 34.4 (22.13) |
| Psychosocial composite | 20.8 (18.96) | 38.6 (24.0) |
| EQ‐5D‐5L (health status questionnaire) | = 241n | = 79n |
| Health State Index (UK) | 0 (0.13) | 0.2 (0.18) |
| EQ Visual Analogue Scale | 9.3 (15.02) | 20.9 (17.79) |
| Double‐blind treatment period (Weeks 36–88)—Efficacy analysis set | ||
| SF‐36v2 70011 | = 229n | = 74n |
| Physical Component Summary | 0.2 (4.82) | 0.8 (4.76) |
| Mental Component Summary | 0 (5.57) | 0.4 (7.94) |
| Domain scores | ||
| Physical Functioning | 0.3 (5.00) | 2.4 (4.24) |
| Role‐Physical | −0.3 (4.38) | 0.5 (5.73) |
| Bodily Pain | 0.6 (6.84) | −0.3 (7.12) |
| General Health | 0.5 (5.59) | −0.3 (6.33) |
| Vitality | −0.5 (6.35) | 0.9 (7.54) |
| Social Functioning | −0.4 (5.86) | 0.5 (7.28) |
| Role‐Emotional | 0.3 (5.34) | 1.0 (10.33) |
| Mental Health | 0.4 (6.36) | 0.4 (6.78) |
| IWQOL‐Lite‐CT 70011 | = 227n | = 74n |
| Total | 4.4 (10.72) | 6.0 (13.82) |
| Physical Function composite | 4.3 (14.15) | 5.2 (16.60) |
| Physical composite | 3.7 (12.52) | 4.9 (15.07) |
| Psychosocial composite | 4.7 (11.95) | 6.6 (15.38) |
| EQ‐5D‐5L | = 227n | = 72n |
| Health State Index (UK) | 0 (0.12) | 0 (0.17) |
| EQ Visual Analogue Scale | 0.9 (10.07) | 2.0 (9.64) |
| Entire study period (Weeks 0–88)—Randomized population—Excluding data after study drug discontinuation | ||
| SF‐36v2 70011 | = 230n | = 74n |
| Physical Component Summary | 4.5 (6.12) | 11.6 (7.44) |
| Mental Component Summary | 0.9 (6.23) | 3.8 (10.38) |
| Domain scores | ||
| Physical Functioning | 4.6 (6.66) | 12.7 (8.40) |
| Role‐Physical | 3.0 (6.20) | 8.6 (9.64) |
| Bodily Pain | 2.8 (8.72) | 8.7 (9.15) |
| General Health | 5.2 (6.39) | 9.7 (8.61) |
| Vitality | 2.8 (7.32) | 9.5 (9.38) |
| Social Functioning | 1.1 (7.15) | 5.9 (10.11) |
| Role‐Emotional | 2.1 (6.83) | 6.0 (12.33) |
| Mental Health | 1.7 (6.90) | 4.8 (9.17) |
| IWQOL‐Lite‐CT 70011 | = 228n | = 74n |
| Total score | 23.9 (17.63) | 42.0 (21.38) |
| Physical Function composite | 22.1 (20.59) | 40.1 (23.96) |
| Physical composite | 20.3 (18.55) | 38.7 (23.27) |
| Psychosocial composite | 25.8 (19.89) | 43.8 (23.33) |
| EQ‐5D‐5L | = 221n | = 71n |
| Health State Index (UK) | 0.0 (0.15) | 0.2 (0.19) |
| EQ Visual Analogue Scale | 10.5 (15.63) | 23.5 (17.23) |
Association of Weight Regain With PROs Among Participants in the Placebo Group
During Weeks 36 to 88, greater weight regain among participants who switched to placebo was associated with worsening of SF‐36v2 PCS (mean range: −0.9 for < 25% to −3.4 for ≥ 75% weight regain), MCS (−0.7 to −3.6), and domain scores (Physical Functioning: −2.1 to −3.7; Role‐Physical: −0.4 to −2.7; Bodily Pain: 0.1 to −3.9; General Health: −0.3 to −4.5; Vitality: −1.6 to −4.4; Social Functioning: −0.9 to −2.1; Role‐Emotional: −0.2 to −2.4; and Mental Health: −1.1 to −5.3). Similarly, worsening was also seen in IWQOL‐Lite‐CT Total (mean range: −0.8 for < 25% to −12.8 for ≥ 75% weight regain) and composite (Physical Function: −0.9 to −11.8; Physical: −0.9 to −3.4; and Psychosocial: −0.3 to −13.5) scores, and EQ VAS scores (−2.0 to −6.6) (Table). S3
Discussion
Participants in the SURMOUNT‐4 trial who continued to receive tirzepatide MTD experienced a significant and sustained improvement from baseline in all domains of general health‐related (SF‐36v2 and EQ‐5D‐5L) and weight‐related (IWQOL‐Lite‐CT) quality of life when compared to participants who switched to placebo. The number of participants who achieved clinically meaningful improvements in physical functioning was also higher in the tirzepatide MTD than in the placebo group. Consistent with other phase 3 studies [23, 24, 25, 26], greater weight reduction among tirzepatide‐treated participants was associated with greater improvements in quality of life. Tirzepatide‐treated participants who reported limitations in physical functioning at baseline showed greater improvement in PROs than those who did not report these limitations. Participants who regained weight after switching to placebo showed worsening of PROs; greater weight regain was associated with greater worsening of PROs.
In addition to the SURMOUNT‐4 trial [12], several other withdrawal studies evaluating the efficacy of obesity medications have shown that participants regain substantial weight after withdrawal of pharmacotherapy [27, 28, 29, 30]. In STEP 4, HRQoL worsened in participants who switched to placebo after receiving semaglutide 2.4 mg during the run‐in period compared to those who continued treatment with semaglutide [23]. Consistent with these findings, improvements in PROs observed during the tirzepatide lead‐in period (Weeks 0 to 36) in the current study were sustained during the double‐blind period (Weeks 36 to 88) in participants who were maintained on tirzepatide. However, improvements in PROs were lost in participants who switched to placebo, suggesting that the benefits observed with tirzepatide MTD may be reversible after its withdrawal. Given the chronic and relapsing nature of obesity, the study findings underscore the importance of continuing pharmacotherapy to maintain the weight reduction and HRQoL benefits in people with obesity.
The IWQOL‐Lite‐CT has been developed in accordance with the FDA's PRO guidance to specifically assess weight‐related functioning in clinical trials [15]. The baseline IWQOL‐Lite‐CT scores (58.1–59.6) were low in the current study. In a confirmatory psychometric analysis, a within‐participant mean change of 16.6 points for IWQOL‐Lite‐CT Total score and 13.5–16.2 points for IWQOL‐Lite‐CT composite scores was considered meaningful in people with obesity or overweight [16]. During the study period, these clinically meaningful thresholds were not only achieved in both treatment groups, but also were significantly greater with tirzepatide MTD versus placebo for the IWQOL‐Lite‐CT Total (27.8 vs. 16.7) and composite scores (24.4–29.6 vs. 15.3–17.5). At Week 88, treatment with tirzepatide was associated with significant improvements in SF‐36v2 PCS, MCS, and domain scores and in EQ‐VAS scores, compared with placebo (p < 0.05, for all). These findings are in congruence with the available literature, where treatment with tirzepatide was associated with significant improvements in SF36 v2 scores and EQ‐VAS scores (p < 0.05, for all) compared with placebo [31, 32].
In a qualitative study examining meaningful change in physical function associated with weight reduction, nearly two‐thirds of people with overweight or obesity considered a 5% weight reduction sufficient to yield some benefit in physical functioning. However, all participants considered ≥ 10% body weight reduction necessary for a meaningful and noticeable improvement in their physical functioning [33]. At Week 88, tirzepatide‐treated participants with ≥ 5% body weight reduction showed meaningful improvements in SF‐36v2 Physical Functioning domain score (mean: 6.6) and IWQOL‐Lite‐CT Physical Function composite score (mean: 26.6). These results suggest that improvements in HRQoL and physical functioning could be due to weight reduction.
A patient‐centric approach and partnership between the patient and clinician is needed to manage obesity [34]. While weight and BMI are widely used to assess the efficacy of obesity medications, it is important to integrate outcomes meaningful to patients in treatment decisions and to provide a holistic view of patients' health [35]. This study evaluated the effect of continuing treatment with tirzepatide MTD versus switching to placebo on various PROs assessing health‐related and weight‐related quality of life across physical and mental health domains. Our study findings are consistent with those of other phase 3 SURMOUNT studies that have shown improvement in quality of life with tirzepatide versus placebo [25, 26, 36, 37, 38, 39, 40].
This study assessed PROs in a large patient population with obesity or overweight. The randomized withdrawal design and the duration of the open‐label lead‐in period allowed the study to assess the maintenance of HRQoL. The dose escalation strategies implemented during the open‐label lead‐in period helped to maximize tolerability and may assist prescribers in optimizing treatment plans for obesity management.
The study design did not allow for dose adjustments after randomization and did not evaluate the effects of intensive behavioral therapy on maintaining body weight reduction. Participants who tolerated initial treatment with tirzepatide MTD (10 or 15 mg) may represent a subgroup of the general population. The proportion of participants with physical function limitations at baseline was relatively low. Future studies should focus on people with severe baseline physical function limitations to understand the effectiveness of tirzepatide in real‐world clinical settings. The post hoc analyses were descriptive among tirzepatide‐treated participants; no comparison between tirzepatide and placebo groups was performed due to the lack of corresponding data for the placebo group.
Conclusion
In the SURMOUNT‐4 trial in participants with obesity or overweight, continued treatment with tirzepatide was associated with maintaining improvements in HRQoL, while treatment withdrawal was associated with worsening of HRQoL. Limitations in physical function at baseline and greater weight reduction among tirzepatide‐treated participants were associated with numerically greater improvements in HRQoL. Greater weight regain after switching to placebo was associated with worsening of HRQoL.
Author Contributions
Theresa Hunter Gibble: conception and design of the work, interpretation of data for the work, and critical review of the work for important intellectual content. Dachuang Cao: conception and design of the work, acquisition of data for the work, analysis of data for the work, interpretation of data for the work, and critical review of the work for important intellectual content. Madhumita Murphy: analysis of data for the work, interpretation of data for the work, drafting of the work, and critical review of the work for important intellectual content. Irina Jouravskaya, Birong Liao, and Harold Edward Bays: interpretation of data for the work and critical review of the work for important intellectual content.
Conflicts of Interest
Theresa Hunter Gibble, Dachuang Cao, Madhumita Murphy, Irina Jouravskaya, and Birong Liao are employees and stockholders of Eli Lilly and Company, Indianapolis, United States. Harold Edward Bays (H.E.B.)'s research site institution has received research grants from 89Bio, Allergan, Alon Medtech/Epitomee, Aligos, Altimmune, Amgen, Anji Pharma, AbbVie, AstraZeneca, Bioage, Bionime, Boehringer Ingelheim, Carmot, Chorus/Bioage, Eli Lilly, Esperion, Evidera, Fractyl, GlaxoSmithKline, HighTide, Home Access, Horizon, Ionis, Kallyope, LG‐Chem, Madrigal, Merck, Mineralys, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Satsuma, Selecta, Shionogi, Skye/Birdrock, TIMI, Veru, Viking, and Vivus. H.E.B. has served as a consultant/advisor for 89Bio, Altimmune, Amgen, Boehringer Ingelheim, Kiniksa, HighTide, Lilly, Novo Nordisk, Regeneron, Veru, Zomagen, and ZyVersa.
Supporting information
Acknowledgments
Moksha Shah and Era Seth of Eli Lilly Services India Pvt. Ltd. provided medical writing support. The authors thank Cathy Xie for providing statistical peer review support.
Gibble T. H., Cao D., Murphy M., Jouravskaya I., Liao B., and Bays H. E., “Tirzepatide Associated With Improved Health‐Related Quality of Life in Adults With Obesity or Overweight in SURMOUNT‐4,” Obesity 33, no. 11 (2025): 2076–2092, 10.1002/oby.70011.
Data Availability Statement
Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at https://www.vivli.org↗.
References
Associated Data
Supplementary Materials
Data Availability Statement
Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at https://www.vivli.org↗.