Effect of once-weekly subcutaneous semaglutide 2.4 mg on weight- and health-related quality of life in an East Asian population: Patient-reported outcomes from the STEP 6 trial

Summary We assessed the effect of semaglutide 2.4 and 1.7 mg versus placebo on weight-related quality of life (WRQOL) and health-related quality of life (HRQOL) in the STEP 6 trial. Adults from East Asia (body mass index [BMI] ≥ 27.0 kg/m 2 with ≥ 2 weight-related comorbidities, or ≥ 35.0 kg/m 2 with ≥ 1 weight-related comorbidity) were randomized 4:1:2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo, or semaglutide 1.7 mg or placebo, plus lifestyle intervention for 68 weeks. WRQOL and HRQOL were assessed from baseline to Week 68 using the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) and the 36-Item-Short-Form-Survey-version-2.0 acute (SF-36v2), with changes in scores by categories of baseline BMI (</ ≥ 30 and ≥ 35 kg/m 2 ) also assessed. In total, 401 participants (mean body weight 87.5 kg, aged 51 years, BMI 31.9 kg/m 2 , waist circumference 103.2 cm) were included. From baseline to Week 68, the IWQOL-Lite-CT Psychosocial and Total scores were significantly improved with semaglutide 2.4 and 1.7 mg versus placebo. For Physical score, effects were only in favour of semaglutide 2.4 mg versus placebo. In the SF-36v2, Physical Functioning was significantly improved with semaglutide 2.4 mg versus placebo, but no beneficial effects favouring either semaglutide treatment arms versus placebo were seen in the other SF-36v2 domains. Benefits favouring semaglutide 2.4 mg versus placebo were also observed in subgroups with higher BMIs for IWQOL-Lite-CT and SF-36v2 Physical Functioning scores. Treatment with semaglutide 2.4 mg improved aspects of WRQOL and HRQOL in people from East Asia with overweight/obesity.

• Weight loss with pharmacotherapy can improve aspects of WRQOL and HRQOL but little is known regarding the effects of weight management pharmacotherapy on these outcomes in Asian populations.

What this study adds
• As well as substantial reductions in body weight, semaglutide 2.4 mg significantly improved Physical, Psychosocial, and Total scores versus placebo for the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT), and Physical Functioning score for the 36-Item-Short-Form-Survey-version-2.0 acute (SF-36v2).
• Benefits of semaglutide 2.4 mg were observed in subgroups of higher body mass index for IWQOL-Lite-CT Physical Function and SF-36v2 Physical Functioning scores.
• Our analyses demonstrate that in people from East Asia, semaglutide 2.4 mg improved aspects of WRQOL and HRQOL, including the ability to perform daily activities.

| INTRODUCTION
Obesity is a chronic and complex condition associated with the development of weight-related complications such as type 2 diabetes, cardiovascular disease, and osteoarthritis. 1 Beyond the negative effects of obesity on cardiometabolic and physical health, people with overweight or obesity may experience a decline in health-related quality of life (HRQOL). 2,3 Impaired HRQOL can be due to detrimental effects on physical, psychological, psychosocial, social functioning, and wellbeing. 4 Conversely, weight loss can lead to improvements in HRQOL. 2 An individual patient data meta-analysis found that improvements in HRQOL were seen with weight loss in individuals enrolled in five randomized controlled trials of weight loss interventions, with greater improvements in HRQOL seen in those with more severe obesity. 5 Definitions of obesity according to body mass index (BMI) differ between Asian and non-Asian populations due to differences in body composition and characteristics. In Japan and South Korea, obesity is defined as BMI ≥25 kg/m 2 . 6,7 In South Korea, obesity is also categorized into Class 1 (BMI 25-29.9 kg/m 2 ), Class 2 (BMI 30-34.9 kg/m 2 ), and Class 3 (BMI ≥35 kg/m 2 ), 7

consistent with the World Health
Organization guidelines for the Asia-Pacific region, while Japan has similar classifications to South Korea, but with a fourth classification of ≥40 kg/m 2 . 8 In Asian populations, overweight and obesity have been reported to have a negative impact on HRQOL, particularly in terms of physical HRQOL. [9][10][11][12] In a nationally representative sample (n = 14 221) from the 2001 Taiwan National Health Interview Survey, overweight (BMI 25-29.9 kg/m 2 ) was associated with a negative impact on physical HRQOL, with an even greater impact observed in those with obesity (BMI ≥30 kg/m 2 ). 10 Likewise, in a nationally representative sample of the general Japanese population (n = 2399 adults), overweight and obesity were associated with impaired physical HRQOL relative to normal weight. 11 In a survey of Korean adults with diabetes (n = 1228), the presence of overweight or obesity (BMI ≥25 kg/m 2 ) was a significant negative predictor of overall HRQOL. 12 Due to the impact of overweight and obesity on HRQOL, an important outcome in clinical trial reporting of new weight management medications is to assess patient-reported outcomes pertaining to HRQOL and weight-related quality of life (WRQOL). Onceweekly subcutaneous semaglutide 2.4 mg is a glucagon-like peptide-1 receptor agonist (GLP-1RA) for weight management. In Phase 3 global trials of once-weekly subcutaneous semaglutide 2.4 mg, the observed weight loss was accompanied by improvements in aspects of WRQOL and HRQOL, measured by the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) and the 36-Item-Short-Form-Survey version 2.0 (SF-36v2) acute, respectively. [13][14][15][16] In these trials, the Asian population ranged from 1.8% to 26.2%. [13][14][15][16] Similarly, global trials of other weight management medications have had low Asian representation (12%). 17 As a result, little is known regarding the effects of weight management pharmacotherapy on WRQOL and HRQOL in Asian populations.
Semaglutide Treatment Effect in People with obesity (STEP) 6 was a 68 weeks, randomized, placebo-controlled trial of once-weekly subcutaneous semaglutide 2.4 mg versus placebo, as an adjunct to decreased calorie intake and increased physical activity, in East Asian adults with overweight or obesity (NCT03811574). 18 The trial also included a once-weekly subcutaneous semaglutide 1.7 mg group to explore the effect of a lower dose. We assessed the effect of semaglutide 2.4 and 1.7 mg versus placebo on WRQOL and HRQOL, which were included as supportive secondary endpoints in the STEP 6 trial.

| Trial design and participants
The STEP 6 trial was conducted in accordance with the International

Declaration of Helsinki 2013 and International Conference on
Harmonization Good Clinical Practice guidelines. Informed consent was required before participating in the trial.
The trial design of STEP 6 has been previously reported. 18 In brief, adults from Japan and South Korea with a BMI ≥27.0 kg/m 2 with at least two weight-related comorbidities, or ≥35.0 kg/m 2 with at least one weight-related comorbidity were included. Comorbidities were defined according to the Japanese Society for the Study of Obesity guidelines 6 ; at least one comorbidity had to be hypertension, dyslipidemia, or type 2 diabetes (the latter permitted in Japan only). Participants were randomized 4:1:2:1 to once-weekly subcutaneous semaglutide 2.4 mg or matching placebo, or once-weekly subcutaneous semaglutide 1.7 mg or matching placebo, for 68 weeks, all as an adjunct to lifestyle recommendations (500-kcal deficit diet and ≥150 min of physical activity per week).

| WRQOL and HRQOL measures
WRQOL was assessed using the IWQOL-Lite-CT and HRQOL was assessed using the SF-36v2.
The IWQOL-Lite-CT, an obesity-specific measure designed to assess the impact of body weight changes on quality of life, is comprised of 20 items providing three composite scores (Physical Function, Physical, and Psychosocial) and a Total score. 19 The possible score range for composite scores and Total score is 0-100, with higher values representing improved functioning. The IWQOL-Lite-CT has been validated using multinational clinical trials data of semaglutide for weight management (both subcutaneous and oral) in patients with or without type 2 diabetes. 19,20 The SF-36v2, which measures participants' overall HRQOL, 21 is a 36-item generic measure of health status consisting of eight The SF-36v2 has been validated in East Asian people using crosssectional data from a representative sample of the general population in Japan 22 and South Korea. 23 The IWQOL-Lite-CT and SF-36v2 questionnaires were administered via tablet or similar device.

| Endpoints
The primary endpoints in the STEP 6 trial were change in body weight (%) from baseline to Week 68, and achievement of ≥5%

| Statistical analysis
Baseline data were summarized using descriptive statistics and data for the two placebo groups were pooled in all analyses.
The IWQOL-Lite-CT and SF-36v2 were assessed for the full analysis set (all randomized participants according to the intentionto-treat principle) using the in-trial observation period (while in trial, regardless of treatment discontinuation or rescue intervention). All results are based on the treatment policy estimand (assesses treatment effect regardless of treatment discontinuation or rescue intervention). 24 Differences in IWQOL-Lite-CT and SF-36v2 scores from baseline to Week 68 were analysed using an analysis of covariance with randomized treatment and type 2 diabetes status at screening as fixed factors and baseline assessment as covariate. Estimated treatment differences (ETDs) were presented with two-sided 95% confidence intervals (CIs). A multiple imputation method from retrieved participants, regardless of randomized treatment arm, was used for missing data. 25 Anchor-based methods, using patient global impression of change and patient global impression of status ratings, were used to derive responder thresholds for clinically meaningful within-patient score changes for the Physical Function, Physical, Psychosocial, and Total scores for the IWQOL-Lite-CT. 20 These thresholds were defined as increases of ≥14.6 (Physical Function), ≥13.5 (Physical), ≥16.2 (Psychosocial), and ≥16.6 (Total) points in IWQOL-Lite-CT scores. 20 An increase of ≥3.7 points was defined as the responder threshold for clinically meaningful within-patient improvement in SF-36v2 Physical Functioning score. [13][14][15] The odds of achieving a clinically meaningful improvement in score were analysed using a logistic regression model with randomized treatment and type 2 diabetes status at screening as fixed factors and baseline assessment as covariate. Statistical analyses of IWQOL-Lite-CT and SF-36v2 endpoints were not controlled for multiplicity; therefore, inferences of statistical significance should be interpreted with caution.

| Participant characteristics
A total of 401 participants from Japan and South Korea randomized in the STEP 6 trial were included in the IWQOL-Lite-CT and SF-36v2 analyses (semaglutide 2.4 mg, n = 199; semaglutide 1.7 mg, n = 101; placebo, n = 101). Mean body weight was 87.5 kg, aged 51 years, BMI 31.9 kg/m 2 , and waist circumference 103.2 cm. In total, 25% of participants had type 2 diabetes. 18
For the IWQOL-Lite-CT, greater proportions of females achieved clinically meaningful within-person improvements in each domain than males in both semaglutide treatment arms. The opposite was seen with placebo ( Figure S2a).

| SF-36v2
At baseline, the mean SF-36v2 scores for all eight individual health domains were comparable across all treatment groups and were close to the maximum possible scores ( Figure 1B).  Figure 3B). There did not appear to be any clear patterns across BMI subgroups for other SF-36v2 scores.
Greater proportions of females than males in all treatment arms achieved clinically meaningful within-person improvements in Physical Functioning for the SF-36v2 ( Figure S2b).  13,14 In addition, the highest score that could be achieved using the norm-based scoring system was 57.6. The higher baseline score in the STEP 6 trial, indicating better baseline functioning, may have made it more difficult to achieve a clinically meaningful increase in score, as per the defined threshold (a ≥3.7-point increase).  34 The greater improvements in WRQOL observed with semaglutide 2.4 mg for those with more severe obesity, as well as the significant overall reduction in body weight seen in the STEP 6 trial, 18 could represent a more suitable alternative to bariatric surgery in this population.

| DISCUSSION
While the patient population of the present analysis is smaller than in the global trials, this is the first report of the effects of a GLP-1RA for weight management in people from East Asia. However, the STEP 6 trial was not powered to show treatment differences in patient-reported outcomes, and although treatment effects tended to favour semaglutide compared with placebo, there were too few patients in the trial to obtain statistically significant results. In the BMI subgroup analysis, there is the potential for false statistical positives, and results should be interpreted with caution due to the multiple comparisons being made. 35 In addition, the BMI eligibility criteria in the STEP 6 trial (≥27.0 kg/m 2 with two or more weight-related comorbidities, or a BMI of ≥35.0 kg/m 2 with one or more weightrelated comorbidity), 18 did not reflect the diagnostic criteria for obesity in Japan and South Korea (BMI ≥25.0 kg/m 2 ). 6,7 It would therefore be beneficial to understand the effect of semaglutide in people from East Asia with a BMI of ≥25.0 kg/m 2 . One of the main strengths of this trial is the high retention rate of participants. 18 In conclusion, overweight and obesity can have a negative impact on WRQOL and HRQOL. Our results demonstrate that in people from East Asia with overweight or obesity, treatment with once-weekly subcutaneous semaglutide 2.4 mg, in addition to a reduced caloric diet and increased physical activity, improved aspects of WRQOL and HRQOL, including the ability to perform daily activities.

AUTHOR CONTRIBUTIONS
Ronette L. Kolotkin contributed to conceptualization, and writingreview and editing. Ole Kleist Jeppesen contributed to formal analysis, and writingreview and editing. James Baker-Knight contributed to writingreview and editing. Sang Yeoup Lee contributed to conceptualization, investigation, resources, and writingreview and editing.
Asako Tokita contributed to conceptualization, and writingreview and editing. Takashi Kadowaki contributed to conceptualization, investigation, resources, and writingreview and editing.