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Semaglutide (Wegovy): CADTH Reimbursement Review: Therapeutic area: Weight management [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2022 Dec.
An overview of the submission details for the drug under review is provided in Table 1.
Submitted for Review.
The WHO defines overweight and obesity as abnormal or excessive fat accumulation that poses a risk to health. A body mass index (BMI) of 25 kg/m2 or greater is considered to be overweight and a BMI of 30 kg/m2 or greater is considered obese.1 In addition to the increasingly recognized role of various biochemical factors in obesity, there are multiple factors that contribute to the condition, including socioeconomic factors, lack of access to healthy foods and easy access to highly palatable processed foods, and living environment. The Canadian Health Measures Survey (2019) found that 35.5% of adults between the ages of 18 and 79 were in the overweight category and 24.3% were living with obesity2 while the Canadian Task Force on Preventive Health Care has reported that 67% of Canadian males and 54% of Canadian females are living with overweight or obesity.3 There is a wide range of comorbidities associated with obesity, including increased risk of type 2 diabetes, certain cancers, hypertension, cardiovascular disease, and gallstones, as well as psychological and psychiatric issues.
The approach to management of overweight and obesity is multi-pronged, and includes modification of physical activity and behaviour in addition to medical nutrition therapy. According to the Canadian Adult Obesity Clinical Practice Guidelines, drug therapy for overweight or obesity is indicated only for those with a BMI of 30 kg/m2 or more, or for those with a BMI of 27 kg/m2 or more with at least 1 weight-related comorbidity. Semaglutide 2.4 mg joins 3 other weight-loss drugs approved in Canada: orlistat, liraglutide, and the combination of naltrexone and bupropion. The clinical expert consulted by CADTH on this review noted that targeting a “normal” BMI of under 25 kg/m2 is neither realistic nor appropriate for many patients living with obesity; rather, the emphasis should be on improving overall health and well-being as well as these weight-related comorbidities.
Semaglutide, a glucagon-like peptide 1 (GLP-1) agonist, is administered by subcutaneous (SC) injection at a dose of 2.4 mg once weekly. It is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial BMI of 30 kg/m2 or greater (obesity) or 27 kg/m2 or greater (overweight) in the presence of at least 1 weight-related comorbidity such as hypertension, type 2 diabetes dyslipidemia, or obstructive sleep apnea.4 Semaglutide is also indicated for the management of type 2 diabetes, and was previously reviewed by CADTH for that indication.
The objective was to perform a systematic review of the beneficial and harmful effects of semaglutide 2.4 mg for SC injection as an adjunct to a reduced caloric diet and increased physical activity for chronic weight management in adult patients.
The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from clinical expert(s) consulted by CADTH for the purpose of this review.
A total of 5 patient groups provided 4 submissions (Gastrointestinal Society [GI Society]; Obesity Canada and the Canadian Liver Foundation, which provided a joint input; Diabetes Canada; and Obesity Matters). The GI Society is a national charity that focuses on providing Canadians with trusted, commercial-free, medically sound information on gut and liver diseases and disorders, including obesity. Data for its submission came from a variety of sources, including contact with patients and patient caregivers, the results of published studies, and a survey conducted from October 6, 2020, to January 10, 2021, open to individuals who had experienced obesity. The survey was open internationally, but the majority of the 2,050 (96%) respondents were from Canada. Obesity Canada and the Canadian Liver Foundation provided a joint input. Obesity Canada is Canada’s leading obesity registered charity association for health professionals, researchers, trainees, students, policy-makers, and Canadians living with obesity. The Canadian Liver Foundation is dedicated to supporting education and research into all forms of liver disease. Data for the joint submission of Obesity Canada and the Canadian Liver Foundation was based on a survey, conducted from February to March 2022, that was distributed throughout Obesity Canada and Canadian Liver Foundation networks on social media and newsletter mailing lists as well as within Obesity Canada’s online patient support community. There was a total of 109 responses from Canadians living with obesity. More than half of respondents (66%) indicated past or present experience with prescription medications for obesity management, with 57% reporting experience specifically with semaglutide. Diabetes Canada is a national health charity representing the millions of Canadians who are affected by diabetes and leads the fight against diabetes by helping people live healthy lives, preventing the onset and consequences of diabetes, and discovering a cure. Its submission contains patient input from an online survey conducted in March 2022. A total of 29 people in Canada participated in the survey; 3 identified as living with prediabetes and 26 identified as living with type 2 diabetes. Among those who answered the question (n = 21), 19 (90%) respondents said they identify as living with overweight or obesity. Two people said they have experience with the drug under review. Obesity Matters is a group of people with common experiences and concerns. The goal of Obesity Matters is to provide an opportunity for communities across Canada to share personal feelings, experiences, and coping strategies, and to offer support so they can take action and seek the help they deserve. The input from Obesity Matters was based on a survey conducted from March 2 to 15, 2022, with 104 respondents. A video was also provided in Obesity Matters’ input.
The 4 patient group inputs reported that overweight and obesity affect many areas of life and patients usually present with various comorbid conditions, such as arthritis, hypertension, sleep apnea, gastroesophageal reflux disease, irritable bowel syndrome, high cholesterol, diabetes, fatty liver disease, asthma, osteoarthritis, infertility, cancers, and mental health issues. Overweight and obesity lead to a multitude of negative impacts, including pain and impacts on mobility, regular activities, self image, and patients’ families and relationships. A common theme in the submissions was the stigma associated with the disease, with patients experiencing discrimination from physicians and employers. Regarding current management options, there are very few medication options, and those that are available do not have public or full private coverage. In addition, patients indicated that these drugs have side effects that include nausea, diarrhea, constipation, and headaches. Patients considered it important for them to have a medication for weight management with long-term effectiveness and fewer side effects, and that the medication also be affordable and easy to administer. Key outcomes identified by the patient advocacy groups as important to patients with overweight or obesity were weight loss, reducing weight-related comorbidity, and improving health-related quality of life (HRQoL).
In the input by the GI Society, those who had tried semaglutide found it easier to adhere to lifestyle modifications while taking that medication. In the input by Diabetes Canada, both patients said their ability to maintain or lose weight and meet target blood sugar levels was “much better” on semaglutide injection 2.4 mg than before, though 1 patient indicated improved gastrointestinal (GI) side effects on semaglutide injection while the other patient indicated “much worse” GI side effects. One patient from the Obesity Canada and the Canadian Liver Foundation input stated that semaglutide had been very effective and described increased energy and reduction in medication needed to control blood pressure and cholesterol.
According to the clinical expert consulted by CADTH on this review, current therapies do not fully address the multifaceted nature of obesity, as they only target a few of the known pathways involved in managing weight. The clinical expert believed that the majority of patients who were able to tolerate semaglutide would likely benefit to some extent from treatment; however, patients who have difficulty reducing portion sizes and have significant hunger are likely the ones to benefit most from the drug. Patients who do not report issues with significant hunger and overeating may therefore be least likely to benefit.
Patients most in need of pharmacological intervention are those who are experiencing weight-related comorbidities, according to the clinical expert. To assess response to treatment, markers that are used to monitor improvement in weight-related comorbidities should be measured, such as hemoglobin A1C. With respect to discontinuing treatment, 1 of the key indications for stopping therapy would be the development of gallstones, or treatment failure (gaining weight or failure to lose weight).
The clinical expert also noted that the issue of whether to continue semaglutide immediately after bariatric surgery if a patient happened to be on it before surgery has not been well studied, and there is likely a difference in practice between different surgical centres.
Four groups provided input. These groups were the Calgary Weight Management Centre, Centre de Médecine Métabolique de Lanaudière, Obesity Canada, and the Canadian Association of Bariatric Physicians and Surgeons — the latter 2 of which provided a joint input. The input from the clinician groups was consistent with that provided by the clinical expert consulted by CADTH on this review. The clinician groups believed that semaglutide is likely to replace liraglutide and naltrexone-bupropion for many patients.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for semaglutide: considerations for initiation, continuation or renewal, and discontinuation of therapy, generalizability, care provision issues, and system and economic issues. The clinical expert consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Four placebo-controlled, double-blind (DB) randomized controlled trials (RCTs) — STEP 1 (N = 1,950), STEP 2 (N = 1,210), STEP 3 (N = 611), and STEP 4 (N = 803) — compared semaglutide 2.4 mg to placebo, and 1 open-label RCT compared semaglutide to liraglutide and placebo (STEP 8, N = 338), all over 68 weeks of treatment. All patients in the included studies had overweight (BMI of 27 kg/m2 or greater with at least 1 weight-related comorbidity) or obesity (BMI of 30 kg/m2 or greater), and patients enrolled in STEP 2 also had type 2 diabetes. All studies were funded by the sponsor and all were multi-centre. Two studies (STEP 1 and STEP 2) had Canadian sites. STEP 4 included a 20-week run-in period where all patients were titrated to the target dosage of semaglutide 2.4 mg once weekly before randomization at week 20. All patients in the STEP trials received counselling regarding diet and physical activity. In STEP 3, the first 8 weeks of the study consisted of a 1,000 kcal per day to 1,200 kcal per day liquid calorie diet, after which patients were gradually transitioned to a less strict hypocaloric diet consisting of conventional foods. The primary outcome of all studies was the percentage reduction in body weight from baseline to week 68, and the co-primary outcome of the STEP 1 to STEP 3 studies was patients achieving at least a 5% reduction in body weight by week 68. Other confirmatory secondary outcomes controlled for multiplicity included patients achieving at least a 10% reduction (in 3 studies), a 15% reduction (in 3 studies), and a 20% reduction (in 1 study) in body weight by week 68, and change from baseline to week 68 in the physical function component of the Short Form (36) Health Survey (SF-36) version 2 acute (in 4 studies).
Across studies, the mean age of patients was 46 years to 49 years, with the exception of STEP 2, where the mean age was 55 years. The majority of patients (75% to 80%) was female, with the exception of STEP 2 where there was a roughly equal percentage of females and males in the study. The vast majority of patients across the studies was White (75% to 93%), with the exception of STEP 2, where about 60% of patients were White and 27% were Asian. Baseline body weight in STEP 1, STEP 3, and STEP 8 was approximately 105 kg, and slightly lower (approximately 100 kg) in STEP 2, which focused on patients with type 2 diabetes, and even lower in STEP 4 (approximately 96 kg). Baseline hemoglobin A1C was approximately 5.7% in STEP 1 and STEP 3, 5.5% in STEP 8, and 5.4% in STEP 4, which featured the run-in, and much higher in STEP 2 (8.1%), which enrolled patients with type 2 diabetes.
Key efficacy results are presented in Table 2. The percentage change from baseline to week 68 in body weight was a primary outcome in all studies. There was a statistically significant difference in percentage reduction in body weight for semaglutide versus placebo in each of STEP 1 (difference between groups of –12.44% [95% confidence interval, or CI, –13.37% to –11.51%; P < 0.0001]), STEP 2 (difference between groups of –6.21% [95% CI, –7.28% to –5.15%; P < 0.0001]), STEP 3 (difference between groups of –10.27% [95% CI, –11.97% to –8.57%; P < 0.0001]), and STEP 4 (difference between groups of –14.75% [95% CI, – 16.00% to – 13.50%; P < 0.0001]), and a statistically significant difference in percentage reduction in body weight for semaglutide versus liraglutide in STEP 8 (difference between groups of –9.38% [95% CI, –11.97% to –6.80%; P < 0.0001]).
Patients achieving a 5% reduction from baseline in body weight was a co-primary outcome in the STEP 1 to STEP 3 studies, and there were greater percentages of patients in the semaglutide group than in the placebo group who achieved a 5% weight loss by week 68 in each of STEP 1 (odds ratio [OR] = 11.22 [95% CI, 8.88 to 14.19; P < 0.0001]), STEP 2 (OR = 4.88 [95% CI, 3.58 to 6.64; P < 0.0001]), and STEP 3 (OR = 6.11 [95% CI, 4.04 to 9.26; P < 0.0001]). In STEP 4, where it was a supportive secondary outcome, the OR was 8.52 (95% CI, 5.93 to 12.24) for semaglutide versus placebo.
Patients achieving a weight reduction from baseline of at least 10%, 15%, and 20% were confirmatory secondary outcomes in STEP 8, and greater percentages of patients in the semaglutide group than the liraglutide group achieved at least a 10% reduction (OR = ||||| |||| || |||||| | | |||||), at least a 15% reduction (OR = ||||| ||| ||| |||| || |||||| | | ||||||), and at least a 20% reduction (OR = ||||| ||| ||| |||| || |||||| | | ||||||). Similarly, there were statistically significant differences in favour of semaglutide for percentages of patients with at least a 10%, 15%, and 20% reduction in the STEP 1 to STEP 3 studies.
Change from baseline to week 68 in waist circumference was also a confirmatory secondary outcome in the STEP 1 to STEP 4 studies. The mean waist circumference was reduced for semaglutide versus placebo in each of STEP 1 (treatment difference of – 9.42 cm [95% CI, –10.30 to –8.53; P < 0.0001]), STEP 2 (treatment difference of –4.88 cm [95% CI, –5.97 to –3.79; P < 0.0001]), STEP 3 (treatment difference of –8.34 cm [95% CI, –10.08 to –6.59; P < 0.0001]), and STEP 4 (treatment difference of –9.74 cm [95% CI, –10.94 to –8.54; P < 0.0001]). The change from baseline to week 68 was a supportive secondary outcome in STEP 8, and the difference between semaglutide and liraglutide was ||||| || |||| ||| ||||| || |||||||
The mean change from baseline to week 68 in BMI was reported as a supportive secondary outcome in the STEP 1 to STEP 4 studies, and thus was not part of the statistical testing hierarchy. The difference between groups with respect to mean change in BMI in STEP 1 was –4.61 kg/m2 (95% CI, –4.96 to –4.27), in STEP 2 was –2.26 kg/m2 (95% CI, –2.63 to –1.88), in STEP 3 was – 3.77 kg/m2 (95% CI, –4.44 to –3.10), and in STEP 4 was –4.74 kg/m2 (95% CI, –5.16 to –4.32).
HRQoL was studied using the SF-36 in the STEP 1 to STEP 4 studies, and the mean change from baseline in physical functioning on the SF-36 was a confirmatory secondary outcome in each of these studies. There was a statistically significant improvement in change in the physical functioning score for semaglutide versus placebo in STEP 1 (1.80 [95% CI, 1.18 to 2.42; P < 0.0001]), STEP 2 (1.52 [95% CI, 0.44 to 2.61; P = 0.0061]), and STEP 4 (2.45 [95% CI, 1.59 to 3.32; P < 0.0001]). In STEP 3, the difference between groups was not statistically significant (0.84 [95% CI, –0.23 to 1.92; P = 0.1249]). The minimal important difference (MID) for the SF-36 physical function score is 3.
Responses on the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) scale physical function score were reported as confirmatory secondary outcomes in the STEP 1 and STEP 2 trials. The difference between semaglutide and placebo in the mean change from baseline to week 68 in scores in STEP 1 was 9.43 (95% CI, 7.50 to 11.35; P < 0.0001) and in STEP 2 was 4.83 (95% CI, 1.79 to 7.86; P = 0.0018). The MID for this instrument is not known.
Glycemic status (normoglycemic, prediabetes, diabetes) was assessed in all studies except STEP 2, which enrolled patients who already had type 2 diabetes. In STEP 8, in patients who were normoglycemic at baseline, the percentage of patients transitioning to prediabetes was ||| |||| ||| ||| for semaglutide, liraglutide, and placebo, respectively (Table 31). || |||||||| |||||||||| || ||||||||. In STEP 1, STEP 3, and STEP 4, 3% of semaglutide patients in each study progressed to prediabetes, while 6% to 13% of patients progressed to prediabetes in the placebo group.
In patients who were considered to have prediabetes at baseline, in STEP 8, ||| of semaglutide patients became normoglycemic by the end of the study, compared to ||| of liraglutide patients and ||| of placebo patients, while ||| ||| ||| ||| in the semaglutide, liraglutide, and placebo groups, respectively, progressed to diabetes. In the STEP 1, STEP 3, and STEP 4 trials, 83% to 90% of semaglutide patients became normoglycemic compared to 48% to 68% of placebo patients. In the semaglutide group, no patients in STEP 3 or STEP 4 and 1% of patients in STEP 1 progressed to diabetes while in the placebo group, no patients in STEP 4, 1% of patients in STEP 3, and 3% of patients in STEP 1 progressed to diabetes.
In the STEP 8 study, 95% of patients in each of the semaglutide and placebo groups and 96% of patients in the liraglutide group reported at least 1 adverse event (AE) while on treatment during the study. The most common AEs were GI-related, such as nausea (61% of semaglutide patients versus 59% of liraglutide patients versus 22% of placebo patients) and constipation (39% of semaglutide patients versus 32% of liraglutide patients versus 24% of placebo patients). In the placebo-controlled studies (STEP 1 to STEP 4), AEs occurred in 88% to 96% of semaglutide patients and between 75% and 96% of placebo patients. GI disorders were the most common AE in the semaglutide groups in these studies, including nausea (14% to 58% of semaglutide patients versus 5% to 22% of placebo patients) and diarrhea (14% to 36% of semaglutide patients versus 7% to 22% of placebo patients).
In STEP 8, serious adverse events (SAEs) occurred in 8% of semaglutide-treated patients, in 11% of liraglutide-treated patients, and in 7% of placebo-treated patients. The most common SAEs were in the category of neoplasms — benign, malignant, and unspecified, occurring in 2% of patients in each of the semaglutide and liraglutide groups, and in 1% in the placebo group. In the placebo-controlled studies (STEP 1 to STEP 4), SAEs occurred in 8% to 10% of patients in the semaglutide group and in 3% to 9% of patients in the placebo group.
In STEP 8, permanent discontinuation of trial treatment due to AEs occurred in 3% of semaglutide patients, 13% of liraglutide patients, and 4% of placebo patients. The most common reason for discontinuation of trial treatment was GI disorder, occurring in 1% in each of semaglutide and placebo patients, and 6% of liraglutide patients. Permanent discontinuation of trial treatment due to AEs occurred in 6% to 7% of semaglutide patients and in 3% to 4% of placebo patients in the STEP 1 to STEP 3 studies, and in 2% of semaglutide patients and in 3% of placebo patients in the STEP 4 study, where patients had a 20-week run-in period.
There was no more than 1 death in any group in any of the included trials.
GI disorders were the most common of all the notable harms, as noted previously. In the STEP 8 study, other notable harms included gallbladder-related disorders in 1% in each of semaglutide and placebo patients, and 3% of liraglutide patients. There were no cases of acute pancreatitis or hypoglycemia in the semaglutide or placebo groups, and 1 case of acute pancreatitis and 1 case of hypoglycemia in the liraglutide group. Other notable harms included cardiovascular disorders (13%, 14%, and 11% for semaglutide, liraglutide, and placebo, respectively), injection site reactions (0, 11%, and 6% for semaglutide, liraglutide, and placebo, respectively), and psychiatric disorders (6%, 15%, and 11% for semaglutide, liraglutide, and placebo, respectively).
In the placebo-controlled trials, gallbladder-related disorders occurred in between 0.2% and 5% of semaglutide patients versus between 1% and 3% of placebo patients, with the most common event being cholelithiasis (0.2% to 3% of semaglutide patients versus 1% to 3% of placebo patients). Very few patients had acute pancreatitis — between 0 and 0.2% of patients in each group. Cardiovascular disorders occurred in 5% to 12% of semaglutide patients versus 10% to 12% of placebo patients, adjudicated cardiovascular events occurred in 0.2% to 2% of semaglutide patients versus 0 to 1% of placebo patients, and hypoglycemia occurred in 0.5% to 0.6% of semaglutide patients versus 0 to 1% of placebo patients in the STEP 1, STEP 3, and STEP 4 studies, respectively. In the STEP 2 study, where patients also had type 2 diabetes, cardiovascular events occurred in 6% of semaglutide patients and 3% of placebo patients. Injection site reactions occurred in 3% to 5% of semaglutide patients versus 2% to 7% of placebo patients and psychiatric disorders occurred in 6% to 15% of semaglutide patients versus 4% to 13% of placebo patients.
Summary of Key Results From Pivotal and Protocol Selected Studies.
The included trials were reasonably well conducted with respect to randomization, blinding, and control for multiplicity in statistical testing. Blinding in the STEP 1 to STEP 4 trials may have been compromised somewhat, however, by the fact that the primary outcome is based on a readily measurable, objective measure (weight loss) that patients can self-monitor, and by the large imbalance in GI AEs, a well-known complication of GLP-1 agonists. The only active-controlled trial, STEP 8, lacked blinding between active groups (semaglutide and liraglutide). The relatively long run-in (20 weeks) in STEP 4 may have resulted in a selected population that was already responding to the drug and tolerating semaglutide before being randomized; it may also have resulted in biasing results in favour of semaglutide, as placebo patients experienced rebound weight gain from discontinuing semaglutide.
The structured diet and lifestyle measures that were background therapy in each of the STEP trials may present a generalizability issue, as these measures are unlikely going to be available for the majority of Canadian patients who start semaglutide. The included studies were all 68 weeks in duration, and this is unlikely to be of sufficient duration to assess the long-term efficacy and safety of semaglutide. Most notably, none of the included trials was able to formally assess the impact of semaglutide treatment on the development of comorbidities or the prevention of cardiovascular events.
One indirect treatment comparison (ITC), submitted by the sponsor, was reviewed and its objectives were to determine the efficacy and safety of weekly semaglutide 2.4 mg when compared to relevant pharmacological comparators for weight management in patients with overweight or obesity. The study authors conducted a systematic literature review and Bayesian network meta-analysis (NMA).
||||| RCTs of pharmacological interventions for the weight management in overweight or obese patients were included. These trials included comparison of semaglutide, |||||||||||| ||||||||| |||||||||| ||| |||||||||| ||||||||||| ||| ||||||||||| |||||||||||| || ||||||||| |||||||||| || |||| ||| |||||||| |||||||||| |||||||||| |||||||||||| Trials were assessed for risk of bias using the |||||||| ||||||||| ||| |||||| ||| |||| |||||||||| |||||| |||||||||||||| |||||||||. Assessment for network feasibility and heterogeneity were conducted before the ITC. Outcome-specific networks were created, and ||||| ||| |||||||||| |||| |||| || ||||||| |||||| ||| ||||| ||||||| ||||||. The planned efficacy outcomes were |||||||||| || |||||||| |||||| || ||||| ||| |||| ||| ||| || |||||||| ||||||| |||| ||||||| |||||| |||| |||||||| || ||||||| ||||||| |||||| |||| |||||||| || ||||||| |||||| |||| |||||||| || |||||||| ||||| ||||||||| ||||| ||||||||||| |||||||||||| ||| |||||| ||||||||| || |||||||| ||||||||| |||| ||||||||||| || |||||| ||||||| |||||||||| ||||||||| || |||||||| |||||||| |||||||||||||||| ||||||||| ||| ||||||| |||||||| |||||| ||| |||||| |||| |||||||| || ||||| |||||||||||||. The planned safety outcomes were ||||||||| || |||||||||||||| ||||||||| || ||||| ||| |||||||||||||||| ||| || ||||
Sensitivity analyses were conducted ||||||||| ||||||| |||| ||||||||| |||||||||| |||||||| |||||||| |||||||| |||| ||||||||| ||| |||||||||||| |||| |||| | |||||||| ||||||||| |||||||| | |||||||| ||||||||| |||||| ||||||| ||||||||| |||||||| ||| ||||||||||||
The models with the best fit (base-case models) are reported as follows:
There was no evidence for | |||||||||| || |||| || |||| ||||||| ||||||||||| ||| ||||||||||| ||| ||| |||| ||||||| || |||||||||| ||| ||||||||||| ||| |||||||| ||| || ||||| ||||| ||||| ||| |||||||
The reported ITC was based on a broad systematic literature review, with study inclusion criteria reported transparently. A study protocol was finalized between Novo Nordisk and Mtech Access before conducting the review. Data were extracted in duplicate. The analyses were appropriately conducted and reported. The patients in the included studies match the people who would use this intervention in the real world. Key efficacy and safety outcomes were reported. Follow-up duration was comparable across trials. There was some ||||||||||| |||||||| ||||||||||||| |||| ||||||| || ||| |||||||||||| || |||| ||||||| ||||||| |||| ||| ||| || ||||||| |||||||| ||| ||| |||||||||||||||| || |||| ||||||. Further, it is unclear how the different approaches || |||||||| ||||||| |||| |||||| |||||| might have impacted the results. No ||||||||||| ||||||||||||| was reported. In the event there was ||||||||||||| ||| || ||||||| ||||||| |||||||||||||||| |||||||| |||||||| |||| |||||||||. A sensitivity analysis was also conducted to assess the impact of ||||||||| ||||||| |||| ||| ||||||||||||| which may lead to a ceiling effect. No ||||||||||||||| was presented. |||||||| ||||||||| |||| ||||||||| ||||| |||||| ||| || ||| ||| || |||||| ||||||| ||||||. Reporting of methods was not comprehensive as ||||||| || ||| |||||||| ||||||| was not reported, making it challenging to assess the impact of risk of bias. Sensitivity analyses to explore the impact of outlier studies were not conducted.
STEP 5 was the only 2-year (104-week) RCT in the STEP series of studies. Like the STEP 1 to STEP 4 studies, STEP 5 was a DB placebo-controlled trial, although it was not pivotal and, thus, did not meet the inclusion criteria for the systematic review.
STEP 5 was conducted at 41 sites in Canada, the US and Europe, and randomized 304 patients with overweight or obesity, 1:1, to either semaglutide or placebo. Outcomes were similar to the other STEP trials, with the co-primary outcome being percentage change from baseline in body weight and the percentage of patients achieving a 5% or greater weight reduction. Confirmatory secondary outcomes included the percentage of patients who achieved a 10% or greater reduction in weight by week 104, a 15% or greater reduction in weight by week 104, and change from baseline to week 104 in waist circumference, systolic blood pressure, and SF-36 (physical functioning) score.
Inclusion and exclusion criteria were similar to the STEP 1, STEP 3, STEP 4, and STEP 8 studies. Adults with a BMI of 30.0 kg/m2 or greater or 27.0 kg/m2 or greater with at least 1 weight-related comorbidity and a history of at least 1 unsuccessful attempt at losing weight were included. To be randomized, patients also had to have kept a food diary, have a Patient Health Questionnaire-9 (PHQ-9) score of less than 15 at randomization, and no suicidal behaviour or ideation before randomization.
Patients received a semaglutide SC 2.4 mg injection once weekly as an adjunct to a reduced-calorie diet and increased physical activity, versus matching placebo.
Semaglutide evoked a statistically significantly greater percentage reduction in weight from baseline to week 104 versus placebo, with a treatment difference between groups of –12.55% (95% CI, –15.33 to –9.77; P < 0.0001). The other co-primary outcome was patients achieving a 5% or greater reduction in weight from baseline to week 104, and this was achieved by 77% of semaglutide patients and 34% of placebo patients, a statistically significant difference between groups. In patients who were normoglycemic at baseline, || of semaglutide patients and ||| of placebo patients were prediabetic by the end of the trial, and in patients with prediabetes at baseline, ||| in the semaglutide group and ||| in the placebo group became normoglycemic at week 104, and || of patients in the semaglutide group and || of patients in the placebo group went on to develop diabetes by end of trial.
AEs were experienced by ||| of semaglutide patients and ||| of patients in the placebo group, while 8% of semaglutide patients and 12% of placebo patients had an SAE. The most common AEs in terms of semaglutide versus placebo were GI disorders such as nausea (53% of semaglutide patients versus 22% of placebo patients) and diarrhea (35% of semaglutide patients versus 24% of placebo patients). Among other notable harms for semaglutide versus placebo, ||||||||||| ||||||||| |||||||| || || |||||| ||| || ||||||||| || ||| |||||| |||| |||||||||||| || || |||||| ||||| ||||||||| |||| ||||||||| || || |||||| |||| ||| ||||||||||| ||||||||| || ||| |||||| |||| ||||| |||| || ||||| || ||||| |||||||||||||
The limitations of this study are similar to those seen with the other STEP trials, such as the potential for unblinding to occur due to an obvious treatment effect or due to notable harms like GI AEs that occur much more frequently with semaglutide than placebo. The generalizability issues with STEP 5 mirror those of the other STEP trials — notably, the structured weight management regime that patients followed in the trial, which is unlikely to be available to patients in most areas of Canada. Despite the longer follow-up in STEP 5 (104 weeks versus 68 weeks in the other STEP trials), STEP 5 was again not designed or powered to assess the impact of semaglutide on the development of weight-related comorbidities such as cardiovascular disease.
Data from 4 placebo-controlled DB RCTs (the STEP 1, STEP 2, STEP 3, and STEP 4 trials) and 1 open-label RCT comparison to liraglutide (the STEP 8 trial) suggest that treatment with semaglutide injection 2.4 mg for 68 weeks produces a statistically significant weight loss compared to liraglutide and to placebo in patients with overweight or obesity, including patients with comorbid type 2 diabetes. Although the weight loss is considered clinically significant according to the clinical expert consulted by CADTH on this review, there is no clear evidence regarding whether this weight loss reduces the number of patients who may develop various weight-related comorbidities, including type 2 diabetes, cardiovascular disease, and osteoarthritis. There is some evidence of a statistically significant improvement in the physical component of HRQoL versus placebo; however, the clinical significance of this improvement is less clear because it did not meet the MID for 1 instrument (SF36) and the MID is not known for the other (IWQOL-Lite-CT). Longer-term evidence from the STEP 5 trial suggests that the weight loss observed at 104 weeks is consistent with that seen in the other trials at 68 weeks; however, it appears from all the STEP trials that weight loss with semaglutide plateaus before the end of 68 weeks of treatment, and that once patients stop semaglutide treatment, they may regain the majority of the weight lost. The most common tolerability issues with semaglutide are GI-related; these are common with this drug class. Evidence from a sponsor-submitted indirect comparison |||||||| |||| ||||||||||| ||| |||||| | ||||||| |||||| |||| |||| ||||||| ||||| |||||| |||| |||||| ||||||||| |||||||||||| ||||||||| ||| ||||||||||| ||| ||||||||.
The WHO defines overweight and obesity as abnormal or excessive fat accumulation that poses a risk to health.1 A BMI of 25 kg/m2 to 30 kg/m2 is considered to be overweight and a BMI of more than 30 kg/m2 is considered obese.1 In addition to the increasingly recognized role of various biochemical factors in obesity, according to the clinical expert consulted by CADTH, multiple factors contribute to the condition, including socioeconomic factors, lack of access to healthy foods and easy access to highly palatable processed foods, and living environment. The gut microbiome may influence 1’s risk of developing obesity, as certain bacteria appear better at extracting calories from food than others, and epigenetics, genetics, and the impact of environmental factors on the endocrine system also play a role. The Canadian Health Measures Survey (2019) found that 35.5% of adults between the ages of 18 and 79 were in the overweight category and 24.3% were living with obesity2 while the Canadian Task Force on Preventive Health Care has reported that 67% of Canadian males and 54% of Canadian females were living with overweight or obesity.3
There is a wide range of comorbidities associated with obesity, including increased risk of type 2 diabetes, certain cancers, hypertension, cardiovascular disease, and gallstones, as well as psychological and psychiatric issues. For example, individuals with obesity are 1.5 times more likely than individuals of normal weight to suffer from anxiety and/or depression,5 and there is an established relationship between obesity and insomnia and obstructive sleep apnea.6 According to the WHO global burden of disease report, more than 4 million people die each year as a result of overweight or obesity, and median survival is reduced by 2 years to 4 years for those with a BMI of 30 kg/m2 to 35 kg/m2, and by 8 years to 10 years for those with a BMI of 40 kg/m2 to 50 kg/m2.1
The approach to management of overweight and obesity is multi-pronged, and includes modification of physical activity and behaviour, in addition to medical nutrition therapy. It is estimated that a diet that provides a deficit of 600 kcal per day may be expected to produce a weight loss of 5 kg over 1 year, whereas exercise and behavioural therapy may induce a weight loss of approximately 2 kg and 8 kg, respectively, when added to a calorie-restricted diet.7 Although it is recognized that these types of interventions are least likely to cause harm, their use alone is difficult to sustain and many individuals regain weight upon discontinuation. This is where drug therapy comes into play.
According to the Canadian Adult Obesity Clinical Practice Guidelines, drug therapy for overweight or obesity is indicated only for those with a BMI of 30 kg/m2 or more, or for those with a BMI of 27 kg/m2 or more with at least 1 comorbidity. Semaglutide joins 3 other weight-loss drugs approved in Canada — orlistat, liraglutide, and the combination of naltrexone and bupropion. Liraglutide is in the same class as semaglutide, a GLP-1 agonist, while orlistat is an older drug that acts locally in the gut, inhibiting GI lipase and preventing fat absorption. Naltrexone is an opioid antagonist that has also been used to treat addiction, and bupropion is an antidepressant, a noradrenaline-dopamine reuptake inhibitor that has been used in addiction disorders, most notably smoking cessation. Although it acts locally, orlistat is known to have a number of unpleasant GI side effects, while bupropion has a number of systemic side effects and is prone to interacting with other drugs. Bariatric surgery is an option for patients with a BMI of 40 kg/m2 or greater or patients with a BMI of 35 kg/m2 or greater and at least 1 weight-related comorbidity. According to the Canadian Adult Obesity Clinical Practice Guidelines, bariatric surgery may also be an option for patients with poorly controlled type 2 diabetes and a BMI of between 30 kg/m2 and 35 kg/m2, or in patients within that BMI range for whom optimal behavioural and medical management have been insufficient to produce significant weight loss.8
Given the significant comorbidities associated with overweight and obesity, the goal of weight management therapy is not simply to reduce weight but to reduce the risk of the patient developing these comorbidities, according to the clinical expert consulted by CADTH on this review. They note that targeting a “normal” BMI of under 25 kg/m2 is neither realistic nor appropriate for many patients living with obesity; rather, the emphasis should be on improving overall health and well-being as well as these weight-related comorbidities. They also note that a 5% to 10% reduction in body weight can result in improvement in clinically relevant parameters such as blood pressure, glycemic control in diabetes, lipids, and symptoms of osteoarthritis.
Semaglutide is administered by SC injection at a dosage of 2.4 mg once weekly. It is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial BMI of 30 kg/m2 or greater (obesity), or 27 kg/m2 or greater (overweight) in the presence of at least 1 weight-related comorbidity such as hypertension, type 2 diabetes, dyslipidemia, or obstructive sleep apnea.4 Semaglutide is also indicated for the management of type 2 diabetes and was previously reviewed by CADTH for that indication, both for a SC formulation (May 2019)9 and an oral formulation (June 2021),10 receiving a positive recommendation for each.
Semaglutide is a GLP-1 agonist. Among other actions, it is believed that this results in enhanced satiety, which reduces hunger and cravings. The sponsor has requested that semaglutide be reimbursed for patients who have a BMI of 35 kg/m2 or greater and prediabetes, which is narrower than the Health Canada indication. The drug was submitted post–Notice of Compliance and did not undergo expedited review at Health Canada.
Key Characteristics of GLP-1 Agonists, Naltrexone-Bupropion, and Orlistat.
This section was prepared by CADTH staff based on the input provided by patient groups. The full patient group submissions are included in the Stakeholder Input section at the end of this report.
A total of 5 patient groups provided 4 submissions (GI Society; Obesity Canada and the Canadian Liver Foundation, which provided a joint input; Diabetes Canada; and Obesity Matters). The GI Society is a national charity that focuses on providing Canadians with trusted, commercial-free, medically sound information on gut and liver diseases and disorders, including obesity. Data for its submission came from a variety of sources, including contact with patients and patient caregivers, the results of published studies, and a survey conducted from October 6, 2020, to January 10, 2021, open to individuals who had experienced obesity. The survey was open internationally, but the majority of the 2,050 (96%) respondents were from Canada. Obesity Canada and the Canadian Liver Foundation provided a joint input. Obesity Canada is Canada’s leading obesity registered charity association for health professionals, researchers, trainees, students, policy-makers, and Canadians living with obesity. The Canadian Liver Foundation is dedicated to supporting education and research into all forms of liver disease. Data for the joint submission was based on a survey conducted from February to March 2022, which was distributed throughout Obesity Canada and Canadian Liver Foundation networks, on social media, and via newsletter mailing lists as well as within Obesity Canada’s online patient support community. There was a total of 109 responses from Canadians living with obesity. More than half of respondents (66%) indicated past or present experience with prescription medications for obesity management, with 57% reporting experience specifically with semaglutide. Diabetes Canada is a national health charity representing the millions of Canadians who are affected by diabetes and leads the fight against diabetes by helping people live healthy lives, preventing the onset and consequences of diabetes, and discovering a cure. Its submission contains patient input from an online survey conducted in March 2022. A total of 29 people in Canada participated in the survey; 3 identified as living with prediabetes and 26 identified as living with type 2 diabetes. Among those who answered the question (n = 21), 19 (90%) respondents said they identify as living with overweight or obesity. Two people said they have experience with the drug under review. Obesity Matters is a group of people with common experiences and concerns. The goal of Obesity Matters is to provide an opportunity for communities across Canada to share personal feelings, experiences, and coping strategies, and offer support so they can take action and seek the help they deserve. The input from Obesity Matters was based on a survey conducted from March 2 to 15, 2022, with 104 respondents. A video was also provided in Obesity Matters’ input.
The 4 patient group inputs reported that overweight and obesity affect many areas of life and patients usually present with various comorbid conditions, such as arthritis, hypertension, sleep apnea, gastroesophageal reflux disease, irritable bowel syndrome, high cholesterol, diabetes, fatty liver disease, asthma, osteoarthritis, infertility, cancers, and mental health issues. Overweight and obesity lead to a multitude of negative impacts, including pain and impacts on mobility, regular activities, self image, and patients’ families and relationships. A common theme in the submissions was the stigma associated with the disease, with patients experiencing discrimination from physicians and employers. Regarding current management options, there are very few medication options, and those that are available do not have public or full private coverage. In addition, patients indicated that these drugs have side effects that include nausea, diarrhea, constipation, and headaches. Patients considered it important for them to have a medication for weight management with long-term effectiveness and fewer side effects that is also affordable and easy to administer. Key outcomes identified by the patient advocacy groups as important to patients with overweight or obesity were weight loss, reducing weight-related comorbidity, and improving HRQoL.
In the input by the GI Society, those who had tried semaglutide found it easier to adhere to lifestyle modifications while taking that medication. In the input by Diabetes Canada, both patients said their ability to maintain or lose weight and meet target blood sugar levels was “much better” on semaglutide injection 2.4 mg than before, though 1 patient indicated improved GI side effects on semaglutide injection while the other patient indicated “much worse” GI side effects. One patient from the Obesity Canada and the Canadian Liver Foundation input stated that semaglutide had been very effective and described increased energy and reduction in medication needed to control blood pressure and cholesterol.
All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, providing guidance on the potential place in therapy). The following input was provided by a clinical specialist with expertise in weight management.
There are 4 approved drugs for weight loss in Canada. However, access to these drugs is limited as none is covered by provincial drug plans. Access to bariatric surgery is very limited and differs depending on where the patient resides; there are also patients who are unwilling to undergo this invasive procedure. Access to lifestyle programs is also limited and, in many cases, patients have to pay out of pocket for weight-loss programs that are not always evidence-based or even to access the services of a registered dietitian.
Those patients who pursue lifestyle changes in their effort to lose weight can expect to lose 3% to 5% of their total body weight; however, there is a high risk of regaining the weight after 1 year to 2 years. This regaining of weight is also observed when drugs that are used as a means for weight loss are discontinued. Bariatric surgery remains the only intervention that induces a significant and consistent weight loss that is typically maintained for 8 years to 10 years post surgery.
Current therapies do not fully address the multifaceted nature of obesity as they are only able to target a few of the known pathways involved in managing weight.
There are a variety of stages of a patient’s weight-loss journey where semaglutide could be used, including first-line treatment, in combination with structured lifestyle changes. It may also be used in patients who have undergone bariatric surgery, where it would be third-line treatment, behind lifestyle changes (required before being considered for bariatric surgery) and surgery. Given the significant efficacy advantage of semaglutide over liraglutide, the clinical expert saw semaglutide replacing liraglutide completely. The clinical expert also noted that they are more comfortable prescribing GLP-1 agonists than naltrexone-bupropion as the latter has more drug interactions and side effects, and because a cardiovascular safety study was never completed for this combination.
The clinical expert also noted that given that weight reductions of 20% or greater are not uncommon with semaglutide, they are increasingly seeing bariatric surgeons recommending patients try semaglutide first as a potential alternative to bariatric surgery. This was not something that was ever considered with the other weight-loss drugs on the market.
The majority of patients who can tolerate semaglutide would be expected to have at least some weight loss from taking the drug, and according to the clinical expert, patients who report significant hunger and difficulty reducing portion sizes tend to be the patients who respond the most to the drug, although some weight loss is also seen in patients who do not report significant hunger or overeating. The clinical expert, therefore, believes that any patient living with obesity would be a potential candidate for semaglutide, although they avoid using it in patients with a history of certain types of pancreatitis and in the rare patient who has a personal history or family history of medullary thyroid carcinoma.
The patients most in need of intervention with weight-loss drugs are those who are experiencing weight-related comorbidities such as hypertension, type 2 diabetes or prediabetes, nonalcoholic fatty liver disease, polycystic ovary disease, infertility, osteoarthritis, and so forth. There are also patients who do not suffer from any of these comorbidities but who still feel very distressed and limited by higher body weight who may benefit from drug therapy.
Patients who have no weight-related comorbidities and who remain active and living a full life despite a BMI of more than 30 kg/m2 may be less likely to benefit from semaglutide. Using the Edmonton Obesity Staging System, a patient who is stage I to stage III would be most likely to benefit from drug therapy.
Diagnosis of obesity is not that difficult and can be performed in the primary care setting, as primary care physicians are very well versed in evaluating and screening for weight-related comorbidities.
There is no reliable way to predict which patients would respond best to semaglutide or other weight-loss drugs. With weight-loss medications, there is typically a trial period of 12 weeks to 16 weeks at the maximum tolerated dose of the medication, and if the patient’s weight is unchanged or does not reduce by at least 5% of total body weight, that is the generally accepted definition of a nonresponse.
There are numerous weight-related comorbidities and improvement in any of these comorbidities should be assessed. Important outcomes that the clinical expert considers clinically meaningful for their patients include the following:
The clinical expert identified the development of gallstones as 1 situation where they have had to discontinue GLP-1 agonists, although they noted that GLP-1 agonists could be re-initiated after surgical removal of the gallbladder (cholecystectomy). The GLP-1 agonists would also likely be stopped in patients who develop acute pancreatitis or in those who are unable to tolerate the drug (due to nausea, for example), although most patients can tolerate a lower dose and still obtain some weight-loss benefit. Patients with more severe GI side effects can also often tolerate the medication better when it is uptitrated more slowly than the typical titration protocol.
The drug would also likely be stopped in patients who continue to gain weight or in those who are not experiencing any weight loss on the drug.
The issue of whether to continue or stop semaglutide immediately after bariatric surgery has not been well studied and there is likely a difference in practice between different surgical centres. It is common to use semaglutide in the context of weight regain after bariatric surgery.
The clinical expert believed that specialist intervention would only be required for more complex cases where patients have undergone bariatric surgery and are experiencing weight regain; otherwise, primary care physicians should easily be able to manage patients on semaglutide. Monitoring factors would include weight as well as other metabolic parameters that are relevant to the patient’s pre-existing comorbidities, such as lipid profile, blood pressure, and glucose parameters. In addition, patients should be encouraged to engage in lifestyle modifications and the prescribing clinician should periodically assess patient engagement in these behaviours and provide support to patients to engage in further changes.
This section was prepared by CADTH staff based on the input provided by clinician groups. The full clinician group submissions are included in the Stakeholder Input section at the end of this report.
Four clinician groups provided input. These groups were the Calgary Weight Management Centre, Centre de Médecine Métabolique de Lanaudière, Obesity Canada and the Canadian Association of Bariatric Physicians and Surgeons Surgeons — the latter 2 of which provided a joint input. The input from the clinician groups was consistent with that provided by the clinical expert consulted by CADTH on this review. The clinician groups believed that semaglutide is likely to replace liraglutide and naltrexone-bupropion for many patients.
The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical expert consulted by CADTH are summarized in Table 4.
Summary of Drug Plan Input and Clinical Expert Response.
The clinical evidence included in the review of semaglutide is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.
To perform a systematic review of the beneficial and harmful effects of semaglutide 2.4 mg for SC injection as an adjunct to a reduced caloric diet and increased physical activity for chronic weight management in adult patients
Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.
Inclusion Criteria for the Systematic Review.
The literature search was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.14
Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946—) via Ovid and Embase (1974—) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the US National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Wegovy (semaglutide) and weight management. Clinical trials registries were searched: the US National Institutes of Health’s ClinicalTrials.gov, the WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.
No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.
The initial search was completed on April 5, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on July 27, 2022.
Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.15 Included in this search were the websites of regulatory agencies (the US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.
These searches were supplemented through contacts with appropriate experts. In addition, the sponsor of the drug was contacted for information regarding unpublished studies.
Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.
A total of 5 studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.
Flow Diagram for Inclusion and Exclusion of Studies.
Details of the STEP 1 Study (Any Weight-Related Comorbidity).
Details of the STEP 2 Study (Type 2 Diabetes).
Details of the STEP 3 Study (Concomitant Intensive Behavioural Therapy).
Details of the STEP 4 Study (Dose Escalation and Randomized Withdrawal).
Details of the STEP 8 Study (Comparison With Liraglutide).
Four pivotal multinational sponsor-funded DB RCTs and 1 open-label RCT were included in this review. The open-label RCT, STEP 8, compared semaglutide to liraglutide while the remaining studies, STEP 1 to STEP 4, compared semaglutide to placebo. All studies were 68 weeks in duration. Randomization was conducted centrally using an interactive web response system in all studies.
The objective of the STEP 1 study was to compare the effect of a semaglutide SC 2.4 mg injection once weekly versus placebo as an adjunct to a reduced-calorie diet and increased physical activity in patients with overweight or obesity on body weight (primary objective), and cardiovascular risk factors, clinical outcome assessment, glucose metabolism, and other factors related to body weight (secondary objectives). This was a DB RCT that randomized 1,961 patients with overweight or obesity, 2:1, to semaglutide 2.4 mg or placebo. No stratification was mentioned. Enrolment occurred at 129 sites in 16 countries, including Canada. The study began with a screening visit where inclusion and exclusion criteria were assessed and patient mental health was evaluated, followed by a randomization visit; then, visit 3 to visit 24 during the treatment period were clinical or phone visits. Visits occurred every 2 weeks during the dose escalation period up to week 20, then every 4 weeks during the maintenance period until week 68. Some assessments, such as assessment of diet and physical activity and body weight, occurred every second visit while other assessments, such as HRQoL, occurred less frequently. A final follow-up visit was conducted at week 75. Patients who withdrew consent during the study were asked if they were willing to undergo a final “end of treatment” visit, where final assessments were performed. Patients who discontinued the trial product were asked to continue with scheduled visits and assessments. The data cut-off date was May 11, 2020, and the date of publication of the Clinical Study Report was August 17, 2020.
The objectives of the STEP 2 study were to compare the effect of a semaglutide SC 2.4 mg injection once weekly versus placebo as an adjunct to a reduced-calorie diet and increased physical activity in patients with overweight or obesity and type 2 diabetes on body weight (primary objective) and cardiovascular risk factors, clinical outcome assessment, and glycemic control (secondary objectives). This DB RCT randomized 1,210 patients with overweight or obesity and type 2 diabetes, 1:1:1, to either semaglutide 1.0 mg, semaglutide 2.4 mg, or placebo, once weekly. Randomization was stratified according to background diabetes treatment: diet and physical activity only, or treatment with metformin or SGLT-2 inhibitor monotherapy, or sulfonylurea or glitazone monotherapy or combination therapy with up to 3 oral antidiabetic drugs (OADs) (metformin, sulfonylureas, SGLT-2 inhibitors, or glitazone). After stratification for background diabetes treatment, patients were further stratified by hemoglobin A1C at screening (lower than 8.5% or 8.5% and higher). It is only the semaglutide 2.4 mg weekly dosage that is of interest for this review, as it is the Health Canada–approved dose for this indication. Enrolment occurred at 149 sites in 12 countries, including Canada. Visits and assessments occurred at the same intervals as in STEP 1. Patients who withdrew consent or discontinued treatment were handled in a similar manner to the STEP 1 study. The data cut-off date was May 20, 2020, and the date of publication of the Clinical Study Report was August 28, 2020.
The objectives of the STEP 3 study were to compare the effect of a semaglutide SC 2.4 mg injection once weekly versus placebo as an adjunct to intensive behavioural therapy (IBT) in patients with overweight or obesity on body weight (primary objective), and cardiovascular risk factors, clinical outcome assessment, and glucose metabolism (secondary objectives). This DB RCT randomized 611 patients with overweight or obesity, 2:1, to either semaglutide 2.4 mg weekly or matched placebo. No stratification was mentioned. Enrolment occurred at 41 sites in the US. STEP 3 had more frequent study visits — weekly during the 16-week dose escalation period, every 2 weeks through week 24, then every 4 weeks until the end of the maintenance period. Assessment of body weight occurred at every visit, while assessment of other outcomes like HRQoL occurred 7 times over the course of the study. Patients who withdrew consent or discontinued treatment were handled in a similar manner to the STEP 1 and STEP 2 studies. The data cut-off date was May 19, 2020, and the date of publication of the Clinical Study Report was August 20, 2020.
The STEP 4 study had a different design feature in that it had a 20-week run-in period where all patients were titrated to the target dosage of semaglutide 2.4 mg once weekly. All patients started on semaglutide 0.25 mg once weekly, then increased their dose every 4 weeks to the maintenance dosage of 2.4 mg once weekly by week 16 (as per the Health Canada–approved dosage regimen), and they continued on this dosage until randomization occurred at week 20. Of the 902 patients who entered the run-in, 99 (11%) patients did not end up being randomized into the study, with the most common reason being an AE (5%). The primary objective of STEP 4 was to compare the effect of a semaglutide SC 2.4 mg injection once weekly versus placebo as an adjunct to a reduced-calorie diet and increased physical activity in patients with overweight or obesity who have reached the target dosage of semaglutide during the run-in period on body weight. There were multiple secondary objectives, divided up with respect to whether they were efficacy-related from randomization (week 20) to week 68 (cardiovascular risk factors, clinical outcome assessment, and glucose metabolism), efficacy-related from week 0 to week 68 (effects on body weight in patients who achieved the target dose during the run-in period), and safety and tolerability from week 0 to week 20 and from week 20 to week 75. This DB RCT randomized 803 patients in a 1:1 manner to either semaglutide 2.4 mg or placebo, and patients were enrolled at 73 sites across the US, Europe, South Africa, and Israel. No Canadian sites were identified. No stratification was mentioned. After the 20-week run-in, visits were conducted every 4 weeks from week 20 until end of treatment (week 68), followed by an end-of-trial visit at week 75. Body weight and waist circumference were assessed at every second visit while other outcomes like HRQoL were assessed 3 times during the run-in and 4 times during the treatment period. Patients who withdrew consent or discontinued treatment were handled in a similar manner to STEP 1 and STEP 2. The data cut-off date was April 16, 2020, and the date of publication of the Clinical Study Report was July 16, 2020.
STEP 8 was the only study that featured an active control. The primary objective of STEP 8 was to demonstrate the superiority of semaglutide 2.4 mg SC injection weekly versus liraglutide 3.0 mg SC injection daily as an adjunct to a reduced-calorie diet and increased physical activity in patients with obesity, or with overweight and at least 1 weight-related comorbidity on body weight. The trial also contained a placebo group, and the semaglutide and liraglutide groups were blinded versus placebo but not versus each other, as semaglutide is administered once weekly and liraglutide is administered daily. Patients were randomized 3:1:3:1 to semaglutide, matched placebo, liraglutide, matched placebo, and the study enrolled patients at 19 sites in the US. No stratification was described. After randomization, study visits occurred every 2 weeks for the first 20 weeks, then every 4 weeks until week 44, then every 6 weeks until the end of treatment (week 68), followed by an end-of-trial follow-up visit at week 75. Body weight was assessed every visit from week 0 to week 4, then every second visit through week 44, then every visit until end of study, while waist circumference was assessed every second visit throughout. The data cut-off date was May 31, 2021, and the date of publication of the Clinical Study Report was September 1, 2021.
All studies except STEP 2 included patients with a BMI of 30.0 kg/ m2 or greater, or 27.0 kg/m2 or greater with the presence of at least 1 of the following weight-related comorbidities (treated or untreated): hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease (Table 6, Table 8, Table 9, and Table 10). In STEP 2, all patients had to have type 2 diabetes to be enrolled, so the BMI cut-off for everyone was 27 kg/m2 (Table 7). Patients in all studies also had to have a history of at least 1 unsuccessful effort to lose weight through diet. Additionally, there were randomization criteria that needed to be met, including having the ability to keep a food diary, having a PHQ-9 score of less than 15 at randomization, and having no suicidal behaviour or ideation. Other than in STEP 2, which enrolled patients with type 2 diabetes, patients with a hemoglobin A1C of 6.5% or greater were excluded, as were patients who had a self-reported change in body weight of greater than 5 kg within 90 days of screening. STEP 8 also excluded patients with a history of type 1 or type 2 diabetes. Additionally, STEP 2 excluded patients with renal impairment (an estimated glomerular filtration rate less than 30 mL per minute per 1.73 m2, or an estimated glomerular filtration rate less than 60 mL per minute per 1.73 m2 in those treated with SGLT-2 inhibitors). STEP 2 also excluded patients with uncontrolled and potentially unstable diabetic retinopathy or maculopathy.
Across the studies (Table 11, Table 12, and Table 13), the mean age of patients was 46 years to 49 years with the exception of STEP 2, where the mean age was 55 years. The majority of patients (75% to 80%) was female, with the exception of STEP 2 where there was a roughly equal percentage of females and males in the study. The vast majority of patients was White across the studies (75% to 93%), with the exception of STEP 2, where about 60% of patients were White and 27% were Asian. Baseline body weight in STEP 1, STEP 3, and STEP 8 was approximately 105 kg, and slightly lower (approximately 100 kg) in STEP 2, which focused on patients with type 2 diabetes and even lower in STEP 4 (approximately 96 kg), which featured a 20-week run-in where all patients received semaglutide before randomization. Baseline hemoglobin A1C was around 5.7% in STEP 1 and STEP 3, 5.5% in STEP 8, and 5.4% in STEP 4, which featured the run-in, and much higher in STEP 2 (8.1%), which enrolled patients with type 2 diabetes.
In the STEP 1 and STEP 4 studies, baseline characteristics were well balanced between groups. In the STEP 2 study, there were greater proportions of females in the semaglutide group versus placebo (55% versus 47%) and patients who had never smoked (61% in the semaglutide group versus 55% in the placebo group). In STEP 3, there were fewer females in the semaglutide group than in the placebo group (77% versus 88%); otherwise, there were no other clear numerical differences between groups. In the STEP 8 study, there were more females in the semaglutide group versus the liraglutide or placebo groups (81% versus 76% versus 78%, respectively) and baseline body weight was lower with semaglutide and liraglutide when compared to placebo (103 kg versus 104 kg versus 109 kg, respectively). As well, the percentage of patients who had never smoked was different between groups |||| || ||| || ||| ||| ||||||||||| || ||||||||||| || ||||||||.
Summary of Baseline Characteristics for STEP 1 and STEP 2 Studies — Full Analysis Set.
Summary of Baseline Characteristics for STEP 3 and STEP 4 Studies — Full Analysis Set.
Summary of Baseline Characteristics, Full Analysis Set — STEP 8 Study.
In all the STEP trials, semaglutide and placebo injection devices were identical in appearance to facilitate blinding. Trial product was administered using a PDS290 pre-filled pen-injector with a 3 mL cartridge containing semaglutide 1.0 mg/mL or 3.0 mg/mL (depending on dose level) or placebo. To mitigate GI side effects with GLP-1 agonist treatment, dose escalation to the maintenance dose was required. Patients were initiated at a once weekly dose of 0.25 mg and followed a fixed-dose escalation regimen, with dose increases every 4 weeks (to dose levels of 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg per week), aiming at reaching the maintenance dose of 2.4 mg (or the corresponding volume of placebo) after 16 weeks. If a patient did not tolerate the maintenance dose of 2.4 mg, they could stay at a lower dose of 1.7 mg semaglutide once weekly. This was only allowed if the patient would otherwise discontinue trial product completely and only if considered safe. It was recommended that the patient make at least 1 attempt to re-escalate to the recommended maintenance dosage of 2.4 mg once weekly, as per the investigator’s discretion. STEP 4 had a 20-week run-in period that included 16 weeks of dose escalation, where all patients received semaglutide, and patients were randomized at the conclusion of this 20-week period.
If a single dose of trial product was missed, it was to be administered as soon as noticed, provided the time to the next scheduled dose was at least 2 days (48 hours) away. If a dose was missed and the next scheduled dose was less than 2 days (48 hours) away, the patient was not to administer a dose until the next scheduled dose. A missed dose was not to affect the scheduled dosing day of the week. If 2 or more consecutive doses of trial product were missed, the patient was encouraged to recommence the treatment if considered safe, as per the investigator’s discretion, and if the patient did not meet any of the discontinuation criteria. Recommencement of treatment was then to occur as early as the situation allowed.
All patients in STEP 2 had type 2 diabetes and were continued on their existing regimens for diabetes. To minimize risk of hypoglycemia, patients who were on sulfonylureas had their doses reduced by 50% at the discretion of the investigator, from randomization. Patients could switch their OAD within the same class, and if intensification of treatment was required outside of provisions for rescue therapy (fasting plasma glucose [FPG] greater than 15 mmol/L), this change in regimen was to follow the American Diabetes Association/European Association for the Study of Diabetes guidelines (excluding GLP-1 receptor agonists, dipeptidyl-peptidase IV inhibitors, and amylin analogues). If any drugs were added, they were to be weight-neutral as much as possible, and were to be first based on intensification of existing background therapy or addition of new background OADs. If insulin was required for rescue, it was to be used for as short a duration as possible.
All patients in the STEP trials received counselling regarding diet (typically, 500 kcal deficit per day relative to the estimated total energy expenditure calculated once at randomization) and physical activity (100 minutes to 150 minutes of physical activity per week, depending on the study). Counselling was done by a dietitian or a similar qualified health care professional (according to local requirements) every fourth week via visits or phone contacts. Patients were instructed to record their food intake and physical activity daily (via paper diary, digital app or similar tool) to assist and evaluate their lifestyle intervention. In STEP 3, the first 8 weeks of the study consisted of a 1,000 kcal per day to 1,200 kcal per day liquid calorie diet at the discretion of the investigator, provided as meal replacements and portion-controlled meals. After 8 weeks, patients were gradually transitioned to a less strict hypocaloric diet consisting of conventional foods. From week 8 to end of treatment, the daily caloric target was calculated based on body weight at randomization. For example, patients weighing under 200 pounds were restricted to 1,200 kcal per day, patients weighing more than 300 pounds were restricted to 1,800 kcal per day, and for patients between 200 pounds and 300 pounds, body weight (in pounds) was multiplied by 6 to arrive at the daily caloric restriction. The calculated caloric target was kept for the remainder of the trial except if a patient achieved a BMI of 22.5 kg/m2 or lower, in which case the recommended energy intake was recalculated with no caloric deficit for the remainder of the trial. STEP 3 also focused on interventions to influence patient behaviour, referred to as IBT. Patients were given a guide, which had a dietitian section, as well as a handout. Each IBT session covered a specific topic, such as advice on diet or physical activity, as well as lifestyle modification (challenging negative thoughts, obtaining social support). Initially, intensive behavioural support occurred weekly, delivered by a dietitian or similarly trained health care professional. Progress was discussed with reviews of the food diary, addressing any compliance or other issues, and patients were prepared for the next stage, the structured diet. Most topics were accompanied by a homework assignment from the handout that was to be completed for the next visit.
During the trials, patients were not to initiate any anti-obesity treatment (e.g., medication) that was not part of the trial procedures. If such treatment was initiated, patients were instructed to stop the treatment.
A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 14.
Summary of Outcomes of Interest Identified in the CADTH Review Protocol.
The percentage change from baseline to week 68 in body weight was the primary outcome (or a co-primary outcome) in all the included studies. Patients achieving at least a 5% reduction from baseline to week 68 in body weight was a co-primary outcome in the STEP 1 to STEP 4 studies, and patients achieving at least 10%, 15%, or 20% reductions were confirmatory secondary outcomes in some studies and supportive secondary outcomes in others (Table 14). Body weight was measured without shoes, on an empty bladder, and in light clothing. Measurements were to be recorded on a digital scale in kilograms or pounds (to 1 decimal place) using the same scale throughout the trial, calibrated yearly as a minimum.
The change from baseline to week 68 in waist circumference was a confirmatory secondary outcome in the STEP 1 to STEP 4 studies. Waist circumference was defined as the abdominal circumference located midway between the lower rib margin and the iliac crest and obtained in standing position with a non-stretchable measuring tape and to the nearest cm or inch. The tape had to touch the skin but not compress soft tissue and twists in the tape were to be avoided. The subject was asked to breathe normally. The same measuring tape was to be used throughout the trial. The measuring tape was provided by Novo Nordisk to ensure standardization.
Investigators periodically assessed glycemic status using medical records, concomitant medications, blood glucose parameters (hemoglobin A1C, FPG), and AEs. Patients were categorized as having normoglycemia or prediabetes, or were diagnosed with type 2 diabetes according to the American Diabetes Association definitions.
Physical function was assessed in STEP 2, using the 6MWT, in a subgroup of patients with BMI of 35 kg/m2 or greater. Patients were asked to walk as far as possible in 6 minutes, without running, along a marked walkway of 20 m, and the distance walked was reported.
Questionnaires were used for measurements of HRQoL and patients completed the questionnaires themselves. HRQoL was assessed using the SF-36 in the STEP 1 to STEP 4 studies, and the physical function dimension was assessed as a confirmatory secondary outcome in each of these studies. The SF-36 is a generic HRQoL instrument that measures scores for 8 different health domains: physical function, role physical, bodily pain, general health, vitality, social functioning, and role emotional. In addition, mental and physical and component summaries can be calculated (mental component summary [MCS] and physical component summary [PCS], respectively; refer to Appendix 4 for detailed summary). Scores on the domains and MCS and PCS range from 0 to 100, with higher scores indicating better health status, and the MID is 2 points for each of the PCS and MCS. MID estimates range from 2 points to 4 points for the individual domains, and for the physical function domain the MID is 3 points.28 There is some evidence for the validity of the SF-36 in overweight and obesity; however, no specific MID has been described for these conditions. In addition to change from baseline, the sponsor also reported results for binary data (“responders”) on the physical function component of the SF-36, using a cut-off for response of 4.3 — a cut-off that was determined in consultation with the FDA and is intended to represent patient perception of a meaningful improvement.
HRQoL was also assessed using the IWQOL-Lite-CT questionnaire, as a confirmatory secondary outcome in the STEP 1 and STEP 2 studies. The IWQOL-Lite-CT is a shorter version of the 74-item Impact of Weight on Quality of Life (IWQOL), an instrument that was developed to assess HRQoL specifically in patients living with moderate to severe obesity. The IWQOL-Lite-CT has 20 self-administered items, with 2 domains: physical (7 items) and psychosocial (13 items). The total score is simply the sum of all items, and higher scores indicate poorer HRQoL. There was no MID found for the IWQOL-Lite-CT. Total scores and scale scores on the Impact of Weight on Quality of Life–Lite (IWQOL-Lite) questionnaire are transformed to a range from 0 to 100, with 100 being the best quality of life and 0 being the poorest.29
For the STEP 1 to STEP 4 trials, the power calculations were based on the randomization ratio, the 5% significance level, the statistical tests chosen for continuous outcomes (t-test on the mean differences assuming equal variances) and binary outcomes (Pearson chi-square test for 2 independent proportions), and permanent discontinuations of 20% (5% for STEP 4), with 60% of those retrieved at week 68 (based on study NN9536 to 4153). Patients in the placebo group who discontinue are assumed to have the same effect as patients who complete the trial in the placebo group, retrieved patients in the semaglutide group are assumed to have an effect corresponding to half the treatment difference (compared to placebo) of patients who complete the trial in the semaglutide group, and non-retrieved patients in the semaglutide group are assumed to have an effect corresponding to placebo. Further assumptions made to calculate power were based on findings from other projects conducted by the sponsor, including the SCALE, SUSTAIN, and PIONEER studies. Specific differences between groups were provided for each outcome in the hierarchy. Given these assumptions, the sample size of 1,950 (semaglutide = 1,300; placebo = 650) was to provide an effective power of 99% for the first 7 outcomes in the hierarchy. For STEP 2, the sample of 1,200 (400 in each group) provided an effective power of 94% for the first 9 outcomes in the hierarchy. For STEP 3, the planned sample of 600 patients (semaglutide = 400; placebo = 200) provided a power of 86% for the 7 efficacy outcomes in the hierarchy. For STEP 4, the sample of 750 (semaglutide = 500; placebo = 250) provided an effective power of 95% for the first 4 outcomes in the hierarchy. STEP 4 also had an additional assumption that at least 80% of patients would be eligible for randomization after the 20-week run-in, meaning that 900 patients would be started on trial product.
For STEP 8, the study was designed with an effective power of ||| to detect differences on all outcomes in the hierarchy at a 1-sided alpha of 0.025 (equivalent to a 2-sided alpha of 0.05). The power calculations were based on the same statistical tests described earlier, and assumptions were based on the SCALE study and the NN9536 to 4153 trial. Once again, the sponsor reported expected differences for each of the first 4 outcomes in the hierarchy.
Analysis of covariance was used for all continuous outcomes using randomized treatment as factor and baseline value for the outcome being tested as covariate. For binary outcomes, binary logistic regression was used using randomized treatment as factor and baseline value for the outcome being tested as covariate (Table 15).
For the STEP 1 to STEP 4 trials, semaglutide was compared to placebo, and a hierarchical design was used to control for multiplicity. The outcomes identified in the hierarchy and their place in the hierarchy was fairly consistent between trials. In STEP 8, the primary comparison was between semaglutide and liraglutide, and multiplicity was also controlled for by use of a hierarchy; the outcomes in the hierarchy were generally consistent with those found in the placebo-controlled trials. It was not clear whether both co-primary outcomes had to be superior for overall superiority to be claimed.
The treatment policy or strategy estimand is used for confirmatory, multiplicity-controlled statistical evaluations. It estimates the population level treatment effect of semaglutide regardless of treatment adherence and/or other anti-obesity therapies and does not exclude data collected after discontinuation of treatment (e.g., due to tolerability issues) or after initiation of alternative treatment (e.g., due to lack of efficacy). The treatment policy estimand, according to the FDA guidance E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials, is therefore relevant for those such as regulatory authorities evaluating the actual impact of an overall treatment strategy or policy for the indicated patient population.
A number of imputation methods were used across trials to account for missing data, including multiple imputation using retrieved patients, jump to reference multiple imputation, and single imputation as done by Sacks. The multiple imputation using retrieved patients was the primary method of imputation for the primary estimand, and this is where missing body weight measurement at week 68 for non-retrieved patients is imputed using data from retrieved patients in each treatment group. This is done according to the timing of the last available observation of body weight. Missing body weight at week 68 for patients on randomized treatment were imputed by sampling from available measurements at week 68 from patients on randomized treatment in the relevant randomized treatment group. The approach of jump to reference multiple imputation assumes that patients instantly lose any effect from randomized treatment after discontinuation beyond what could be expected from placebo as an adjunct to diet and exercise.
To account for missing baseline data, if no eligible observation was available at or before randomization, the mean of baseline values across all patients in the study was used as the baseline value.
No preplanned subgroups of relevance to the systematic review protocol were described in any of the included studies.
The imputation methods described earlier were the sensitivity analyses performed during the STEP trials.
Statistical tests used for secondary outcomes were the same as those used for primary outcomes (refer to Table 15). The order of outcomes in the testing hierarchy is reported in the summary of outcomes table (refer to Table 14).
Statistical Analysis of Efficacy End Points.
The full analysis set included all randomized patients, according to the intention-to-treat principle. These patients were to contribute to the evaluation as randomized. The safety analysis set included all randomized patients exposed to at least 1 dose of study drug, and were analyzed as treated.
Study withdrawals were typically low across trials (7% or less) and there were no clear or consistent differences between groups within studies (Table 16 and Table 17). Treatment discontinuations were higher, ranging from 12% to 17% of patients with semaglutide and 14% to 22% of patients with placebo, except in the STEP 4 study, which featured the 20-week run-in and where treatment discontinuations were 6% with semaglutide and 12% with placebo. In the STEP 8 study, treatment discontinuations were ||| in the liraglutide group; the most common reason was AEs, which occurred in 2% of semaglutide patients and 12% of liraglutide patients. AEs were the most common reason for treatment discontinuations across the STEP trials.
Mean treatment duration was similar between groups within studies. It was generally between 57 weeks and 61 weeks in the STEP 1 to STEP 3 studies and the STEP 8 study, and around 65 weeks in the STEP 4 study, which had a 20-week run-in period.
Patient Disposition for STEP 1, STEP 2, and STEP 3 Studies.
Patient Disposition for STEP 4 and STEP 8 Studies.
Treatment Exposure for STEP 1, STEP 2, and STEP 3 Studies — Full Analysis Set.
Treatment Exposure for STEP 4 and STEP 8 Studies — Full Analysis Set.
Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported as follows. Refer to Appendix 3 for detailed efficacy data.
This outcome was not reported as an efficacy outcome but was captured under the category of harms (Table 36 and Table 37). There was no more than 1 death in any treatment group in any of the included studies.
Changes in body weight were reported both as continuous outcomes (mean change from baseline) and binary outcomes. The results for percentage change in body weight are presented in Table 20 and Table 21 and the results for the binary body weight outcomes are presented in Table 22 and Table 23.
Percentage change from baseline to week 68 in body weight versus placebo was a co-primary outcome of the STEP 1 to STEP 3 studies, and the primary outcome of the STEP 4 and STEP 8 studies. There was a statistically significant difference in percentage reduction in body weight for semaglutide versus placebo in each of STEP 1 (difference between groups of –12.44% [95% CI, –13.37 to –11.51; P < 0.0001]), STEP 2 (difference between groups of –6.21% [95% CI, –7.28 to –5.15; P < 0.0001]), STEP 3 (difference between groups of –10.27% [95% CI, –11.97 to –8.57; P < 0.0001]), and STEP 4 (difference between groups of –14.75% [95% CI, – 16.00 to –13.50; P < 0.0001]), and a statistically significant difference in percentage reduction in body weight for semaglutide versus liraglutide in STEP 8 (difference between groups of ||||| |||| ||| |||||||||||||| |||||||||. Graphical representations of percentage change from baseline in body weight over time can be found in Appendix 3 (Figure 3, Figure 4, Figure 5, Figure 6, and Figure 7). Several sensitivity analyses were conducted, and results for these analyses were consistent with the findings of the primary analysis. For example, for STEP 1, the findings for the difference for semaglutide versus placebo for percentage reduction in weight ranged from –11.94% to –12.83%, consistent with the magnitude of difference in the primary analysis, –12.44%.
The proportion of patients achieving a 5% reduction from baseline in body weight was a co-primary outcome in the STEP 1 to STEP 3 studies, and there were greater percentages of patients in the semaglutide group than in the placebo group who achieved a 5% weight loss by week 68 in each of STEP 1 (OR = 11.22 [95% CI, 8.88 to 14.19; P < 0.0001]), STEP 2 (OR = 4.88 [95% CI, 3.58 to 6.64; P < 0.0001]), and STEP 3 (OR = 6.11 [95% CI, 4.04 to 9.26; P < 0.0001]). In STEP 4, where it was a supportive secondary outcome, the OR was 8.52 (95% CI, 5.93 to 12.24) for semaglutide versus placebo (Table 23). Patients achieving a reduction from baseline of at least 10%, 15%, and 20% were confirmatory secondary outcomes in the STEP 1 to STEP 3 studies, and the differences between semaglutide and placebo were statistically significant at each of these thresholds, across all of the studies (Table 23).
Patients achieving a weight reduction from baseline of at least 10%, 15%, and 20% were confirmatory secondary outcomes in the STEP 8 trial, and greater percentages of patients in the semaglutide group than the liraglutide group achieved at least a 10% reduction (OR = |||| |||| ||| ||||| ||||||| |||||||), at least a 15% reduction (OR = |||| |||| ||| ||||||||||| ||||||||), and at least a 20% reduction (OR = |||| |||| ||| ||||| ||||||| ||||||||) (Table 23). Similarly, there were statistically significant differences in favour of semaglutide for percentages of patients with at least a 10%, 15%, and 20% reduction in the STEP 1 to 3 studies.
Percentage Change From Baseline to Week 68 in Body Weight for STEP 8 Study — Primary Analysis, In Trial, Full Analysis Set.
Percentage Change From Baseline to Week 68 in Body Weight for STEP 1 to STEP 4 Studies — Primary Analysis, In Trial, Full Analysis Set.
Patients With Reduction in Body Weight of 5% or More, 10% or More, 15% or More, and 20% or More for STEP 8 Study — In Trial, Full Analysis Set.
Patients With Reduction in Body Weight of 5% or More, 10% or More, 15% or More, and 20% or More for STEP 1 to STEP 4 Studies — In Trial, Full Analysis Set.
Change from baseline in waist circumference was also a confirmatory secondary outcome in the STEP 1 to STEP 4 studies (Table 25). The reduction in mean waist circumference was greater for semaglutide versus placebo in each of STEP 1 (treatment difference of – 9.42 cm [95% CI, –10.30 to –8.53; P < 0.0001]), STEP 2 (treatment difference of –4.88 cm [95% CI, –5.97 to –3.79; P < 0.0001]), STEP 3 (treatment difference of –8.34 cm [95% CI, –10.08 to –6.59; P < 0.0001]), and STEP 4 (treatment difference of –9.74 cm [95% CI, –10.94 to –8.54; P < 0.0001]). The change from baseline to week 68 was a supportive secondary outcome in the STEP 8 study, and the difference between semaglutide and liraglutide ||| ||||| || |||| ||| ||||||||||||(Table 24).
The mean change from baseline to week 68 in BMI was reported as a supportive secondary outcome in the STEP 1 to STEP 4 studies, and thus was not part of the statistical hierarchy (Table 26). The difference between groups with respect to mean change in BMI in STEP 1 was –4.61 kg/m2 (95% CI, –4.96 to –4.27), in STEP 2 was –2.26 kg/m2 (95% CI, –2.63 to –1.88), in STEP 3 was –3.77 kg/m2 (95% CI, –4.44 to –3.10), and in STEP 4 was –4.74 kg/m2 (95% CI, –5.16 to –4.32).
Change From Baseline to Week 68 in Waist Circumference for STEP 8 Study — In Trial, Full Analysis Set.
Change From Baseline to Week 68 in Waist Circumference for STEP 1 to STEP 4 Studies — In Trial, Full Analysis Set.
Mean Change From Baseline to Week 68 in Body Mass Index for STEP 1 to STEP 4 Studies — Full Analysis Set Population.
HRQoL was studied using the SF-36 in the STEP 1 to STEP 4 studies, and the mean change from baseline in physical functioning on the SF-36 was a confirmatory secondary outcome in each of these studies (Table 27). There was a statistically significant improvement in change in physical functioning score for semaglutide versus placebo in STEP 1 (1.80 [95% CI, 1.18 to 2.42; P < 0.0001]), STEP 2 (1.52 [95% CI, 0.44 to 2.61; P = 0.0061]), and STEP 4 (2.45 [95% CI, 1.59 to 3.32; P < 0.0001]). In STEP 3, the difference between groups was not statistically significant (0.84 [95% CI, –0.23 to 1.92; P = 0.1249]).
The proportion of patients achieving at least a 4.3-point increase from baseline in physical function, semaglutide versus placebo, was reported for STEP 1 (OR = 2.11 [95% CI, 1.53 to 2.91]), STEP 2 (OR = 1.72 [95% CI, 1.16 to 2.55]), STEP 3 (OR = 1.40 [95% CI, 0.80 to 2.44]), and STEP 4 (OR = 2.72 [95% CI, 1.18 to 6.29]) (Table 28).
Other domains of the SF-36 were reported descriptively for each group (refer to Appendix 4, Table 38).
Responses on the IWQOL-Lite-CT physical function score were reported as confirmatory secondary outcomes in the STEP 1 and STEP 2 studies. The difference between semaglutide and placebo in the mean change from baseline to week 68 in scores in STEP 1 was 9.43 (95% CI, 7.50 to 11.35; P < 0.0001) and in STEP 2 was 4.83 (95% CI, 1.79 to 7.86; P = 0.0018) (Table 29). Patients achieving at least a 20-point increase from baseline to week 68 were also reported; however, this outcome was not controlled for multiplicity. In STEP 1, 40% of semaglutide patients and 26% of placebo patients achieved this threshold (OR = 2.46 [95% CI, 1.90 to 3.18]) and in STEP 2, 35% of semaglutide patients and 23% of placebo patients achieved this threshold (OR = 1.73 [95% CI, 1.20 to 2.49]).
Mean Change From Baseline to Week 68 in SF-36 Physical Functioning Score for STEP 1 to STEP 4 Studies — In Trial, Full Analysis Set.
Patients Achieving At Least a 4.3-Point Increase in SF-36 Physical Functioning Score From Baseline for STEP 1 to STEP 4 Studies — In Trial, Full Analysis Set.
Mean Change From Baseline to Week 68 in IWQOL-Lite-CT Physical Function Score for STEP 1 and STEP 2 Studies — In Trial, Full Analysis Set.
Patients Achieving At Least a 20-Point Increase From Baseline to Week 68 for STEP 1 and STEP 2 Studies — In Trial, Full Analysis Set Population.
Glycemic status (normoglycemic, prediabetes, diabetes) was assessed in all studies except STEP 2, which enrolled patients who already had type 2 diabetes.
In the STEP 8 study, in patients who were normoglycemic at baseline, the percentage of patients transitioning to prediabetes was ||| |||| ||| ||| for semaglutide, liraglutide, and placebo, respectively (Table 31). || |||||||| |||||||||| || ||||||||| In the STEP 1, STEP 3, and STEP 4 studies, 3% of semaglutide patients in each study progressed to prediabetes, while 6% to 13% of patients progressed to prediabetes in the placebo group.
In patients who were considered to have prediabetes at baseline, in the STEP 8 study, ||| of semaglutide patients became normoglycemic by end of study, compared to ||| of liraglutide patients and ||| of placebo patients, while for those progressing to diabetes, the results for semaglutide patients, liraglutide patients, and placebo patients were 3%, 3%, and 10%, respectively. In the STEP 1, STEP 3, and STEP 4 trials, 83% to 90% of semaglutide patients became normoglycemic compared to 48% to 68% of placebo patients. In the semaglutide group, no patients in STEP 3 or STEP 4 and 1% of patients in STEP 1 progressed to diabetes while in the placebo group, no patients in STEP 4, 1% of patients in STEP 3, and 3% of patients in STEP 1 progressed to diabetes.
End-of-Study Status in Patients With Prediabetes or Normoglycemia at Baseline for STEP 8 Study.
End-of-Study Status in Patients With Prediabetes or Normoglycemia at Baseline for STEP 1 to STEP 4 Studies.
Patients With Increase, Decrease, or No Change in Dose for Antihypertensive and Lipid-Lowering Medications for STEP 8 Study.
This outcome was not specifically studied in any of the included trials.
This outcome was not reported as an efficacy outcome; however, these events were captured under the category of harms (Table 36 and Table 37). There were few non-fatal cardiovascular events across the studies and no clear differences in event rates between groups in any study.
This outcome was not specifically reported on in the included studies.
The percentage of patients who had a dose increase or decrease, or no change, from their baseline dosing of antihypertensive medication or lipid-lowering medication was an exploratory outcome of all the STEP trials. For the STEP 8 study, |||| of patients in the semaglutide group reduced their dose of antihypertensive medication versus |||| in each of the liraglutide and placebo groups, and |||| of patients in each of the semaglutide, liraglutide, and placebo groups increased their dose of antihypertensive medication (Table 33). In the STEP 1 to STEP 4 studies, dose decreases occurred in between 3% and 9% of semaglutide patients and between 2% and 4% of placebo patients, and dose increases occurred in between 4% and 7% of semaglutide patients and between 4% and 9% of placebo patients (Table 34).
Dose changes were also assessed for lipid-lowering medication. In the STEP 8 trial, |||| of semaglutide and liraglutide patients were able to reduce their dose versus no patients in the placebo group, and |||| of semaglutide patients, |||| of liraglutide patients, and |||| of placebo patients had a dose increase. In the STEP 1 to STEP 4 studies, 1% to 2% of semaglutide patients reduced their dose of lipid-lowering medication versus 0 to 1% with placebo, and 1% to 4% of patients in the semaglutide group had a dose increase versus 2% to 5% of placebo patients.
Physical function was assessed in the STEP 2 study using the 6MWT in patients with a BMI of 35 kg/m2 or greater (Table 35). The mean change (standard deviation [SD]) from baseline was 92.7 m (SD = 574.6) with semaglutide and 18.4 m (SD = 112.6) with placebo.
Patients With Increase, Decrease, or No Change in Dose for Antihypertensive and Lipid-Lowering Medications for STEP 1 to STEP 4 Studies.
Change From Baseline to Week 68 in Six-Minute Walk Test for STEP 2 Study Subgroup.
Only those harms identified in the review protocol are reported as follows. Refer to Table 36 for detailed harms data.
In the STEP 8 study, 95% of patients in the semaglutide and placebo groups and 96% of patients in the liraglutide group reported at least 1 AE while on treatment during the study (Table 37). The most common AEs were GI-related, such as nausea (61% of semaglutide patients versus 59% of liraglutide patients versus 22% of placebo patients) and constipation (39% of semaglutide patients versus 32% of liraglutide patients versus 24% of placebo patients).
Summary of Harms for STEP 1, STEP 2, and STEP 3 Studies — Safety Analysis Set.
In the placebo-controlled studies, STEP 1 to STEP 4, AEs occurred in 88% to 96% of semaglutide patients and between 75% and 96% of placebo patients (Table 36 and Table 37). GI disorders were the most common AEs in the semaglutide groups in these studies, including nausea (14% to 58% in the semaglutide groups versus 5% to 22% in the placebo groups) and diarrhea (14% to 36% in the semaglutide groups versus 7% to 22% in the placebo groups).
In the STEP 8 study, SAEs occurred in 8% of semaglutide-treated patients, 11% of liraglutide patients, and 7% of placebo patients (Table 37). The most common SAEs were in the category of neoplasms — benign, malignant, and unspecified, occurring in 2% of patients in each of the semaglutide and liraglutide groups, and 1% of patients in the placebo group.
In the placebo-controlled studies, STEP 1 to STEP 4, SAEs occurred in 8% to 10% of patients in the semaglutide group and 3% to 9% of patients in the placebo group (Table 36 and Table 37).
In the STEP 8 study, permanent discontinuation of trial treatment due to AEs occurred in 3% of semaglutide patients, 13% of liraglutide patients, and 4% of placebo patients (Table 37). The most common reason for discontinuation of trial treatment was GI disorder, occurring in 1% in each of semaglutide and placebo patients, and 6% of liraglutide patients.
Permanent discontinuation of trial treatment due to AEs occurred in 6% to 7% of semaglutide patients and 3% to 4% of placebo patients in the STEP 1 to STEP 3 studies, and in 2% of semaglutide patients and 3% of placebo patients in the STEP 4 study, where patients had a 20-week run-in period (Table 36 and Table 37).
Summary of Harms for STEP 4 and STEP 8 Studies — Safety Analysis Set.
There was no more than 1 death in any group in any of the included trials (Table 36 and Table 37).
GI disorders were the most common of all the notable harms, as noted previously.
In the STEP 8 study, other notable harms included gallbladder-related disorders in 1% of each of the semaglutide and placebo groups, and 3% of liraglutide patients (Table 37). There were no cases of acute pancreatitis or hypoglycemia in the semaglutide or placebo groups, and 1 case of acute pancreatitis and 1 case of hypoglycemia in the liraglutide group. Cardiovascular disorders occurred in 13% of semaglutide patients, 14% of liraglutide patients, and 11% of placebo patients. There were no injection site reactions in the semaglutide group, and injection site reactions in 11% of liraglutide patients and 6% of placebo patients. Psychiatric disorders occurred in 6% of semaglutide patients, 15% of liraglutide patients, and 11% of placebo patients. The most common psychiatric disorders were anxiety (in 2% of semaglutide patients versus 3% of liraglutide patients versus 2% of placebo patients), insomnia (in 2% of semaglutide patients versus 6% of liraglutide patients versus 2% of placebo patients), and depression (in 2% of semaglutide patients versus 2% of liraglutide patients versus 1% of placebo patients). There were no reported cases of thyroid carcinoma.
In the placebo-controlled studies, STEP 1 to 4, gallbladder-related disorders occurred in between 0.2% and 4.9% of semaglutide patients and 0.7% and 3.0% of placebo patients, with the most common event being cholelithiasis, occurring in 0.2% to 3.2% of semaglutide patients and 0.6% to 2.6% of placebo patients. Very few patients had acute pancreatitis — between 0 and 0.2% of semaglutide patients and between 0 and 0.2% of placebo patients. Cardiovascular disorders occurred in 5% to 12% of semaglutide patients and between 10% to 12% of placebo patients and adjudicated cardiovascular events occurred in 0.2% to 1.5% of semaglutide patients and 0 to 1.2% of placebo patients.
Hypoglycemia occurred in 0.5% to 0.6% of semaglutide patients and 0 to 1.1% of placebo patients in the STEP 1, STEP 3, and STEP 4 studies, while in the STEP 2 study, where patients also had type 2 diabetes, they occurred in 6% of semaglutide patients and 3% of placebo patients. Injection site reactions occurred in 3% to 5% of semaglutide patients and 2% to 7% of placebo patients. Psychiatric disorders occurred in 6% to 15% of semaglutide patients and 4% to 13% of placebo patients. The most common psychiatric disorders were anxiety (in 0.7% to 4.4% of semaglutide patients versus 1.0% to 3.9% of placebo patients), insomnia (in 1.7% to 4.7% of semaglutide patients versus 1.0% to 4.9% of placebo patients), and depression (in 0.5% to 3.9% of semaglutide patients versus 1.2% to 3.0% of placebo patients).
Withdrawals from study were less than 10% in all groups across all studies, and in many groups were less than 5%, with no clear and consistent differences in study withdrawals between groups. Treatment discontinuations were more common in the placebo group in the STEP 1 study (17% versus 22% for semaglutide versus placebo) and STEP 4 study (6% versus 12% for semaglutide versus placebo). The large number of treatment withdrawals in STEP 1, the largest of the included studies, does potentially compromise the quality of the trial and data from the trial. There were no clear or consistent imbalances between comparison groups within studies with respect to key baseline characteristics such as weight, and the relatively low number of withdrawals from the studies should have helped to maintain these balances between comparison groups. There was missing data for week 68 assessments of all outcomes, including the primary outcome of percentage change from baseline in weight. The amount of missing data was often slightly larger than the reported number of study withdrawals, and it is not clear why this was the case. For example, in STEP 1 in the placebo group, the sample reported for the week 68 percentage change from baseline in weight was 577 patients, which is 12% less than the original baseline sample of 655, despite the fact that 7% of patients were reported as having withdrawn from the study in this group, and 22% were reported as having stopped treatment. A number of sensitivity analyses were performed to account for missing data, and their results were consistent with that of the primary analysis. Even though the overall conclusions may remain unaffected, the exact estimates of weight change could have been biased.
In all trials, patients were blinded to whether they received placebo or the active drug, and this was facilitated by the use of injector devices that were similar in appearance. Weight is an easily perceivable or measured indicator of treatment success, and it is possible that patients who are experiencing significant weight loss may begin to modify their behaviour to further enhance their weight loss. This compromises our ability to delineate weight loss directly to actual drug effect. Another source of potential unblinding in the placebo-controlled studies is the well-known and frequently observed GI side effects associated with this class — namely, nausea, vomiting, and diarrhea. These were far more common in the semaglutide group than in the placebo group in each of the studies, and this may have led some patients to guess which group they were assigned to.
HRQoL was assessed using the SF-36, a well-established generic scale, and the IWQOL-Lite-CT, a newer instrument developed for patients with overweight or obesity. A detailed review of the validity of both instruments can be found in Appendix 4. There is some evidence for the validity of the SF-36 for patients with overweight or obesity for the PCS and MCS; however, the validity of the subscales for this population has not been confirmed. No MID has been established for this instrument in this specific population. The IWQOL-Lite-CT is a shorter version of the IWQOL instrument, and although there is an MID for the longer instrument, there is no MID yet for the IWQOL-Lite-CT; this is a limitation when trying to interpret data from this instrument.
The STEP 4 study began with a 20-week run-in period where all patients received semaglutide and had their doses titrated to the eventual target dosage of 2.4 weekly by week 16. Aside from the fact that this is now a selected population that has demonstrated that they are able to tolerate the drug, patients who were randomized to placebo had their semaglutide discontinued. This type of design does help to reduce the number of study withdrawals and also provides information about potential withdrawal and/or rebound from removal of the drug. However, due to the potential for rebound upon drug withdrawal, this approach may also exaggerate the treatment effect, biasing results in favour of the study drug. Indeed, the largest treatment effect was seen in STEP 4, and this was the only trial where patients in the placebo group gained weight.
The co-intervention that was employed in all the included trials was a diet and exercise regime. This is an issue when it comes to generalizability of findings from the STEP trials to how the drug may be used in clinical practice in Canada. Semaglutide is indicated as an adjunct to a reduced-calorie diet and physical activity. However, whether diet and exercise will be employed in a structured manner in real-world use and to the same extent that it was in the STEP trials is unclear. According to the clinical expert consulted by CADTH on this review, there is a lack of structured weight management programs that are financially accessible to patients in Canada. Therefore, it is not clear whether the weight loss achieved by semaglutide in the STEP trials will be of the same magnitude if these programs are not available to patients.
None of the trials included in this review were of sufficient size or duration to assess key clinical outcomes related to weight management — most notably, the risk of various weight-associated morbidities such as onset of type 2 diabetes and the risk of cardiovascular events. None of the morbidity-related outcomes in our review protocol were assessed as efficacy outcomes in the trials included in this review. The transition from normoglycemia to prediabetes, and the reverse, were assessed as exploratory outcomes; however, no conclusions can be drawn from this data. Cardiovascular events were not assessed as efficacy outcomes and when reported as harms, were uncommon. Therefore, although semaglutide clearly induces a statistically significant weight loss, the clinical significance of this weight loss, with respect to reducing the risk of various weight-related comorbidities, is uncertain and we do not know the long-term efficacy, or harms, of semaglutide.
HRQoL was assessed in the placebo-controlled trials but not versus liraglutide. Weight clearly has a significant impact on HRQoL and the impact on the physical function component of the SF-36 was formally assessed. However, other components, such as those related to mental health, were not, thus limiting any conclusions that can be drawn about this data. Given the impact that overweight and obesity have on mental health, the inability to draw conclusions about the impact of semaglutide on mental health is a limitation of the STEP trials.
There was 1 study, STEP 8, that compared semaglutide to an active comparator, liraglutide; the rest of the included trials were placebo-controlled. STEP 8 was, however, the smallest of the included trials, with only 125 patients in each of the 2 active groups. Therefore, there is limited direct evidence of the efficacy and harms of semaglutide compared to other drugs used for overweight or obesity.
In STEP 2, the clinical expert consulted by CADTH on this review noted that the inclusion criteria would not be generalizable to patients with type 2 diabetes who are receiving insulin, which could be a significant number of patients. They also noted that semaglutide is now approved as a 2.0 mg weekly dosage for type 2 diabetes and in the STEP 2 study, semaglutide was used at dosages of 1.0 mg weekly (previously the only dosage approved for type 2 diabetes) and 2.4 mg weekly. The clinical expert also noted that, other than in STEP 2, the populations were generally White females, which is not necessarily reflective of the general Canadian population with overweight and obesity but does tend to reflect the patients they see in their practice. The clinical expert also noted the fact that other than in STEP 2, patients were generally relatively free of comorbidities at baseline whereas patients with weight-related comorbidities are in greater need of an effective intervention.
The objective of this section is to summarize and appraise the evidence from ITCs for semaglutide versus relevant comparators for chronic weight management. Although semaglutide was compared with liraglutide in the STEP 8 trial, the sample size of the trial was small. Also, no direct evidence for semaglutide versus other relevant comparators was found. Therefore, evidence of efficacy and safety of semaglutide relative to active comparators is limited.
The sponsor submitted a systematic literature review and NMA to demonstrate the comparative effect of weekly semaglutide 2.4 mg when compared to relevant pharmacological comparators for weight management in patients with overweight or obesity.30 This ITC is summarized and appraised in this section.
A focused literature search for NMAs dealing with Wegovy (semaglutide) and weight management was run in MEDLINE All (1946-) on April 6, 2022. No limits were applied. One NMA comparing GLP-1 agents (dulaglutide, exenatide, efpeglenatide, liraglutide, lixisenatide, semaglutide, and taspoglutide) in terms of change in weight and AEs in adults with obesity or overweight was found31 and the results for semaglutide versus liraglutide 3.0 mg were consistent with the results for the sponsor-submitted NMA. Given the more comprehensive nature of the sponsor-submitted NMA, the published ITC is not described in this section.
The ITC included randomized trials of participants with a BMI of 27 kg/m2 or greater and 1 weight-related comorbidity, ||| || ||| ||||| || ||||||| |||| |||||||||||||| ||||||||||||||, or BMI of 30 kg/m2 or greater without weight-related comorbidities. The following interventions were of interest for the network: semaglutide 2.4 mg, || ||||||||| |||||||||| |||| ||| ||||||||| ||||||||||| ||| ||| |||||||| |||| |||||| |||||||||| ||| ||||||||| |||| |||||| ||||||||||| ||| |||||||||| |||| |||||| ||| |||||||||||||| |||||||| || ||||| ||||||||| Efficacy and safety outcomes were captured. Further details are reported in Table 38.
Study Selection Criteria and Methods for Indirect Treatment Comparison.
To determine the efficacy and safety of weekly semaglutide 2.4 mg when compared to relevant pharmacological comparators for weight management in patients with overweight or obesity
This systematic literature review involved searches from |||| |||||||||| ||||||||| ||| ||| |||| ||||||||| ||||||| ||||||| |||||||||| ||||||| |||| ||||| || |||||| ||||||| |||||||||| | ||||| ||||||||||| ||||||||| ||| ||||||| |||||| ||| ||| ||||||| |||||||||| ||| ||| ||||||||| ||| |||||||| |||||| ||||||| |||||||| |||||||||| ||||||||| |||||||| ||||||| |||||||| || |||||||||| |||||| |||||||||| |||||||| || ||||||||| || ||||||| || ||||||| |||||| ||| ||| |||||||| |||||||| || |||||||||| |||||||| The retrieved articles were reviewed by a single analyst and verified by a second in 2 stages (titles and abstracts, then full text) based on pre-specified inclusion criteria. Risk of bias was assessed using ||| |||||||| ||||||||| ||| |||||| ||| |||| |||||||||| |||||| |||||||||| ||||||||| |||| |||||||| |||||||||| || |||||||||||||| |||||||||| |||||||||||| |||||||| |||||||||||||||| ||||||||| ||||||||| || ||||||||| ||||||||| || ||||||| ||||||||| ||| |||||||||
Prior to conducting the ITC, a feasibility assessment was conducted. This included an assessment of trial comparability and generation of outcome-specific networks. The efficacy outcomes of interest were |||||||||| || |||||||| |||||| || ||||| ||| |||| ||| ||| || |||||||| ||||||| |||| ||||||| |||||| |||| |||||||| || |||||| || ||| ||||||| |||||| |||| |||||||| ||||||| |||||| |||| |||||||| || |||||||| ||||| |||||||| ||||| || ||||| |||||| |||| |||||||| || ||||| ||||||||||| || ||||| |||||||||||||||| ||||| || ||| ||| |||| |||||||| |||||| |||| |||||||| || |||| ||||||| ||||||||||| ||||| || ||||| |||||||||||||||| ||||| || ||| ||| |||| |||||||| |||||| |||| |||||||| || ||||| || || ||||||||| || |||||||| ||||||||| |||| ||||||||||| || |||||| ||||||| |||||||||| ||||||||| || |||||||| |||||||| |||||||||||||||| |||||||||| ||||||||| || |||||||| |||||||| ||||||| |||||||| |||||| ||| |||||| |||| |||||||| || ||||| ||||||||||||| || ||| ||| |||||| |||||||| || |||||||| |||| ||||||||| || |||||||||||||| ||||||||| || ||||| ||| ||||||||| |||||||||||||||| ||| || ||||
ITCs were conducted using a |||||||| ||||||||| ||| ||||||||||| |||||| ||||||||| |||||||| |||| | |||||| |||||||||| |||||||| |||| ||||| ||| |||||||||| |||||||| ||| ||| |||||||| |||||||||| ||||| |||| ||||| ||| |||||| ||||||||| |||| |||||| ||||||| |||| ||| ||||| ||||||| |||| |||||| |||| |||| ||| ||||| ||| ||| |||||||| || ||||||||| ||| |||||||| || ||||||| ||||| |||||||| ||||||||| || ||| || ||||| ||| || ||||||||| ||| |||||||| ||||||||||| ||||||||| |||||| ||||||||||| || | || | |||||| || ||| |||||||||| |||||||||| ||| ||| ||||| |||||||| ||||||||| Presented models were selected based on model fit.
The selection of priors, burn-in period, and number of iterations was not described.
Interstudy heterogeneity ||| |||||||| ||||||||||||| ||| ||||| ||||||| ||||||| |||||||||||||||| ||| ||||||| |||||||||||
Sensitivity analyses were conducted by excluding trials of ||||||||| ||||||||||| ||||||| ||||| ||||||| || ||||| ||||| ||||||||||||| |||||||| ||| |||||||| |||||| ||||||||||||| ||| ||||||||| || ||| ||| | ||||||| |||||| ||| ||||||||| |||||||| ||||||||| ||||||| ||||||| |||||||| |||| || ||||| |||||| |||||| |||| ||||||| ||||
Subgroup analyses were conducted for patients |||| |||| | |||||||| ||||||||| |||||||| ||||||| |||| | |||||||| ||||||||| |||||||| |||| |||||| ||||||| |||||||||| ||| |||||||| |||| ||||||||||||
||||||||||| ||| ||| ||||||||| ||| || | |||| || |||||| ||||| ||||| |||| ||||| |||||| || ||||||||| ||||||| No pairwise meta-analyses were presented.
|| |||||| ||| ||||||||||||| of pharmaceutical interventions were eligible. ||||| |||||| |||| ||||||| |||| ||| ||||||||||| |||||||||| ||||||| |||| |||| | |||||| |||||| || |||||||| |||||||||||| ||| ||| | ||| ||||||||| || ||||||| |||| ||||||| ||||||| || ||||||| ||||| |||||| ||| |||| | ||| | ||||||| |||| ||||| || |||| || ||||||||The main sources of ||||||||||| |||| |||| ||||||| || ||| ||||||||| ||||||||| || ||||||| |||| |||| || || ||||||| ||| ||||||||| || ||| || | ||||||||| |||||||||||| || |||| ||||||| ||||||| ||||| |||| |||| ||||||| |||||||||||| ||||| |||||| ||||| ||||||||| ||| ||||||||| || ||||| |||| ||| ||||| ||| ||| |||| ||| ||||| ||| |||||||| | |||||||||| |||| | |||||| |||| ||| || |||||||| |||||||| |||| ||| ||||| |||||||||| ||||| ||||| |||||||| |||||||| |||| ||| ||||| ||||||||| ||||| ||||||||| ||| ||||||||| |||||||| | |||||| |||| ||| || ||| |||||||| |||||||| |||| ||| ||||| |||||||There were insufficient data to permit the exploration of |||||||||| ||||||||||| || ||||| || |||| ||||||| |||||| ||| ||| ||||| |||||||| ||||||||| However, the impact of these factors across the trials (in addition to unknown patient characteristics) could be assessed via meta-regression based on the baseline risk in the control arms.
A summary of the heterogeneity among trials for key baseline characteristics and study design features are shown in Table 39.
Assessment of Homogeneity for Sponsor-Submitted Indirect Treatment Comparison.
A graphical depiction of the evidence network for the total population without consideration for availability of outcome data are shown in Figure 2.
Evidence Network for the Total Population — Non–Outcome Specific — Redacted.
||||| |||||||| |||| ||||||||| |||||| ||||||||| |||| | |||||||| ||||||||||||||||||| ||||.
The models with the best fit (base-case models) are reported as follows:
The results of the main analyses are summarized in Table 40.
Base-Case Analysis for Total Population of Semaglutide Versus Comparator — Redacted.
The reported ITC was based on a broad systematic literature review, with study inclusion criteria reported transparently. A study protocol was finalized between Novo Nordisk and Mtech Access before conducting the review. Data were extracted in duplicate. The analyses were appropriately conducted and reported. The patients in the included studies match the people who would use this intervention in the real world. Key efficacy and safety outcomes were reported. Follow-up duration ||| |||||||||| |||||| ||||||. There was some ||||||||||| |||||||| ||||||||||||| |||| ||||||| || ||| |||||||||||| || |||| ||||||| ||||||| |||| ||| ||| || ||||||| |||||||| ||| ||| |||||||||||||||| in some trials. Further, it is unclear how the ||||||||| |||||||||| || |||||||| ||||||| |||| |||||| |||||| ||||| |||| |||||||| ||| |||||||| || ||||||||||| ||||||||||||| ||| ||||||||| || ||| ||||| ||||| ||| ||||||||||||| ||| || ||||||| ||||||| |||||||||||||||| |||||||| |||||||| |||| |||||||||| A sensitivity analysis was also conducted to assess the impact of including studies |||| ||| ||||||||||||| ||||| ||| |||| || | ||||||| ||||||| || ||||||||||||||| ||| |||||||||| |||||||| ||||||||| |||| ||||||||| ||||| |||||| ||| || ||| ||| || |||||| ||||||| ||||||| Reporting of methods was ||| ||||||||||||| || ||||||| || ||| |||||||| ||||||| ||| ||| ||||||||| |||||| || ||||||||||| || |||||| ||| |||||| || |||| || ||||| ||||||||||| |||||||| || ||||||| ||| |||||| || ||||||| ||||||| |||| ||| ||||||||||
This section includes submitted long-term extension studies and additional relevant studies included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review.
STEP 5 was the only 2-year (104-week) study in the STEP series of studies, and the reviewers believed that this additional follow-up might be useful when assessing efficacy and harms associated with semaglutide treatment. Like the STEP 1 to STEP 4 studies, STEP 5 was a placebo-controlled trial, although it was not pivotal and thus did not meet the inclusion criteria for the systematic review.
STEP 5 was a DB RCT conducted at 41 sites in Canada, the US and Europe, and randomized 304 patients with overweight or obesity, 1:1, to either semaglutide or placebo. Outcomes were similar to the other STEP trials, with the co-primary outcomes being percentage change from baseline in body weight and the percentage of patients achieving a 5% or greater weight reduction. Confirmatory secondary outcomes included the percentage of patients who achieved a 10% or greater reduction in weight by week 104, a 15% or greater reduction in weight by week 104, and change from baseline to week 104 in waist circumference, systolic blood pressure, and SF-36 (physical functioning).
Inclusion and exclusion criteria were similar to the STEP 1, STEP 3, STEP 4, and STEP 8 studies. Included were adults with a BMI of 30.0 kg/m2 or greater, or 27.0 kg/m2 or greater with at least 1 weight-related comorbidity and a history of at least 1 unsuccessful attempt at losing weight. To be randomized, patients also had to have kept a food diary, have a PHQ-9 score of less than 15 at randomization, and have no suicidal behaviour or ideation before randomization.
Patients received a semaglutide SC 2.4 mg injection once weekly as an adjunct to a reduced-calorie diet and increased physical activity, versus matching placebo. The main co-intervention was diet and exercise, and these followed a protocol similar to those in the other STEP studies.
The efficacy outcomes were as described earlier and assessed as described previously for the STEP studies in the systematic review section of this report.
||||||||||| |||||||| |||| ||| |||| || ||||| ||||||||| ||||| ||| ||| |||| |||||| |||| |||| |||||||| || ||| |||||||||| ||||||| | |||||||||||| ||||||| ||||||||| ||| |||| || ||||||| ||| |||| | |||||| ||| ||| |||||||| |||| |||||||| || ||| ||||||||| ||| ||| ||||| |||| |||||||| |||| ||||||| || ||| |||| |||||| |||||||| || ||| |||||||||| ||||||| |||| ||| ||||||||||| ||||||||| ||| |||| |||||||| ||| |||||||| ||| |||||||||| ||||||||| ||| ||| |||||| |||||||| ||| |||||||| ||| |||||||||| |||||||| ||| |||||||| || ||||| | |||| || ||||| ||||| ||| ||||||||||| ||||||| |||| |||||||| ||| ||| |||||| |||||| ||| ||| |||| |||| ||||||||||||| || |||| ||||||| |||| ||| ||||| ||||| ||| ||| |||||||||||| |||||| ||| ||| |||||| |||| ||||| || |||| ||||||| ||||||||||||||| |||| | ||||| |||| ||||||||| |||| ||| |||||||| |||||| ||| ||| ||||||| |||| ||| |||| ||| |||||||||||| |||||||| |||| ||| |||||| || |||| | ||||| ||||| ||| ||||||| ||||||| |||||| ||| ||||||||||| ||||||||
Trial product was permanently discontinued in ||| of patients in the semaglutide group and ||| of patients in the placebo group. The most common reason for ||||||||||||| ||||| ||||||| || ||| ||||||||||| ||||| ||| ||||||| ||||| ||| ||| || ||| ||||||||||| ||| |||||||| |||||||||||||| while “lost to follow-up” ||| ||| |||| |||||| |||||| || ||| ||||||| ||||| ||| ||| |||| Withdrawals from trial occurred with || || ||||||||||| |||||||| and ||| || ||||||| ||||||||, and “lost to follow-up” was the |||| |||||| |||||| |||| ||||||||||| |||| ||| |||| ||||||| |||||
Patient Disposition.
The mean exposure to semaglutide was |||| ||||| || |||| ||||| for placebo, and the mean observation time was 110.5 weeks for semaglutide and 103.4 weeks for placebo.
Semaglutide evoked a statistically significantly greater percentage reduction in weight versus placebo, with a treatment difference between groups of –12.55% (95% CI, –15.33 to –9.77; P < 0.0001); this was the co-primary outcome of STEP 5. Figure 8 The other co-primary outcome was patients achieving a 5% or greater reduction in weight from baseline to week 104. This was achieved by 77% of semaglutide patients and 34% of placebo patients, a statistically significant difference between groups.
In patients who were normoglycemic at baseline| || || ||||||||||| |||||||| ||| ||| || ||||||| |||||||| were prediabetic by the end of trial, and in patients with prediabetes at baseline ||| || ||| ||||||||||| ||||| ||| ||| || ||| ||||||| ||||| |||||| ||||||||||||| || |||| |||, and || |||||||| || ||| ||||||||||| ||||| ||| || || |||||||| || ||| ||||||| ||||| |||| || || ||||||| |||||||| || ||| || |||||.
AEs were experienced by ||| of semaglutide patients and ||| of patients in the placebo group, while || of semaglutide patients and ||| in the placebo group had an SAE. As was the case with the STEP trials included in the systematic review, the most common AEs, semaglutide versus placebo, were || ||||||||| |||| || |||||| |||| || |||| and |||||||| |||| || ||||. Among other notable harms, semaglutide versus placebo, ||||||||||| ||||||||| |||||||| || || || ||| || ||||||||| || ||| || |||| |||||||||||| || || || ||||| ||||||||| |||| ||||||||| || || || |||| ||| ||||||||||| ||||||||| || ||| || |||| ||||| |||| || ||||| || ||||| |||||||||||||
Efficacy Results for STEP 5 Study — Full Analysis Set.
Harms in STEP 5 Study — Safety Analysis Set.
STEP 5 was reasonably well conducted, with proper procedures for randomization, blinding, and control for multiplicity. The limitations of this study were similar to those seen with the other STEP trials, such as the potential for unblinding to occur due to notable harms like GI AE that occur much more frequently with semaglutide than placebo. There were numerically more study withdrawals in the placebo group than with semaglutide, and a relatively large number of patients |||| || ||||||||| |||| || ||| ||||||| |||||, which may bias interpretation of both efficacy and harms outcomes.
The generalizability issues with STEP 5 mirror those of the other STEP trials — notably, the structured weight management regime that patients followed in the trial, which is unlikely to be available to patients in most areas of Canada. Despite the longer follow-up in STEP 5 (104 weeks versus 68 weeks in the other STEP trials), STEP 5 was again not designed or powered to assess the impact of semaglutide on the development of weight-related comorbidities such as cardiovascular disease.
Five pivotal, multinational, sponsor-funded, 68-week RCTs were included in the systematic review. Four of those trials were double-blinded and placebo-controlled: STEP 1 (N = 1,950, randomized 2:1, semaglutide to placebo), STEP 2 (N = 1,210, randomized 1:1:1 to semaglutide 1.0 mg, semaglutide 2.4 mg, or placebo weekly), STEP 3 (N = 611, randomized 2:1, semaglutide to placebo), and STEP 4 (N = 803, randomized 1:1, semaglutide to placebo). STEP 2 included patients who were in the overweight category with comorbid type 2 diabetes. The STEP 1, STEP 3, and STEP 4 studies included patients with overweight (BMI of at least 27 kg/m2) or obesity (BMI of at least 30 kg/m2); patients who were overweight had to have at least 1 weight-related comorbidity other than type 2 diabetes. STEP 8 (N = 338, randomized 1:1:1) was the only trial that included an active comparator, liraglutide, as well as corresponding placebo controls for each of the active treatment groups. Across the trials, the primary outcomes were typically the percentage reduction from baseline in body weight and the number of patients achieving at least a 5% weight loss from baseline. Secondary outcomes that were controlled for multiplicity included patients achieving weight loss of at least 10% or 15% from baseline, as well as changes from baseline in patient-reported outcomes such as the physical function component of the SF-36, as well as the IWQOL-Lite-CT. All trials were well conducted, with methods to maintain adequate blinding, allocation concealment during randomization, and control for multiplicity, among others. Additional evidence included in this review were from a longer-term placebo-controlled trial that was non-pivotal (STEP 5, 104 weeks) as well as a sponsor-submitted ITC.
Across the studies, the mean age of patients was 46 years to 49 years, with the exception of STEP 2, where the mean age was 55 years. The majority of patients (75% to 80%) was female, with the exception of STEP 2 where there was a roughly equal percentage of females and males in the study. The vast majority of patients across the studies was White (75% to 93%), with the exception of STEP 2, where about 60% of patients were White and 27% were Asian. Baseline body weight was typically around 105 kg, and slightly lower (approximately 100 kg) in STEP 2, which focused on patients with type 2 diabetes, and even lower in STEP 4 (approximately 96 kg), which featured a 20-week run-in where all patients received semaglutide before randomization. Baseline hemoglobin A1C was around 5.7% in the STEP 1 and STEP 3 studies, 5.5% in the STEP 8 study, and 5.4% in the STEP 4 study, and much higher (8.1%) in the STEP 2 study, which enrolled patients with type 2 diabetes.
There is clear and consistent evidence from 4 placebo-controlled DB RCTs that semaglutide evokes a statistically significant weight loss that is also clinically significant according to the clinical expert consulted by CADTH on this review. Semaglutide also resulted in a statistically and clinically significant weight loss versus liraglutide in a smaller study, STEP 8, where patients were not blinded with respect to their assigned active therapy, although they were blinded to their corresponding placebo group. However, none of these trials was designed to demonstrate a benefit for semaglutide over liraglutide or placebo with respect to key clinical outcomes such as reducing the number of patients developing weight-related comorbidity or cardiovascular events. While the included trials often measured changes in markers for comorbidities such as hypertension (blood pressure) or diabetes (hemoglobin A1C, FPG), these measurements were performed across the entire study population and thus do not provide any information about improvement in these parameters in patients who have these conditions, or, more importantly, whether treatment with semaglutide helps to reduce the risk of developing hypertension or diabetes. The only outcome that did report on this type of information looked at the number of patients who went from normoglycemia to prediabetes or from a prediabetic state to normoglycemia. These were not formal analyses, though, so although differences can be seen between groups, 1 cannot comment on the statistical significance of these differences. It is a well-established fact that patients with overweight or obesity are at a higher risk for a number of comorbidities; however, the impact of weight loss and, more notably, what constitutes a clinically significant weight loss is less clear. Guidelines produced by the UK and the FDA suggest that a weight loss of between 5% and 10% should be considered clinically meaningful33-35 (refer to Appendix 4 for a detailed review) and a 5% reduction from baseline was a co-primary outcome in 3 of the STEP trials. A retrospective observational study by Haase et al. (2021) found that for patients with a BMI of 40 kg/m2 or greater, a median 13% weight loss reduced their risk of type 2 diabetes by 41% and sleep apnea by 40% and reduced the risk of developing other conditions like hypertension, dyslipidemia, and asthma (refer to Appendix 4 for a detailed review).36 There do not appear to be other studies of this size or duration that attempt to demonstrate the benefits of weight loss, and the authors of Haase et al. (2021) noted that the lack of causative data limits any conclusions that can be drawn from their data. Overall, although guidelines and regulatory bodies appear to endorse a weight loss of 5% as clinically meaningful, the rigour with which this number was arrived at is unclear. The SELECT study is an ongoing trial with the objective of determining the superiority of semaglutide to placebo with respect to the prevention of major adverse cardiovascular events in patients with overweight or obesity who have established cardiovascular disease, but do not have diabetes. This event-driven trial is expected to past 5 years, and with an enrolment of 17,500 patients, this is the type of trial that would be needed to answer the types of questions that the STEP trials do not address.
From the input of patients to CADTH, it is clear that overweight and obesity have a significant impact on a patient’s HRQoL. Semaglutide did improve the physical function component of the SF-36 versus placebo in 3 of 4 STEP trials, suggesting that it may improve this component of HRQoL. However, the improvement over placebo did not meet the MID of 3 for this component of the SF-36, suggesting that these differences were of questionable clinical significance. Semaglutide also improved physical function scores on the physical function components of the IWQOL-Lite-CT in the 2 trials where it was assessed (STEP 1 and 2); however, there is no known MID for this scale and the clinical significance of this improvement cannot be determined. The remaining components of the SF-36 were not formally assessed and there was no assessment of HRQoL in STEP 8, the only trial that compared semaglutide to liraglutide. Although the lack of blinding between the semaglutide and liraglutide groups would have been a limitation of any analyses, the lack of HRQoL data comparing semaglutide to liraglutide is a limitation of this review.
The proposed listing criteria from the sponsor Is for use in patients with a BMI of 35 kg/m2 or greater and who are prediabetic.19 There were no preplanned subgroup analyses from any of the included studies that focused on this subgroup; however, the sponsor provided a post hoc subgroup analysis from |||| | in support of its proposed listing criteria.19 The mean percentage change from baseline body weight in this subgroup, over placebo, was |||||| |||| ||| |||||| |||||, compared to the weight loss of –12.4% (95% CI, –13.4 to –11.5), over placebo, reported for the overall population in |||| |. There were ||| of semaglutide-treated patients (||| with placebo) in this subgroup who achieved a 5% or greater reduction in weight compared to ||| (||| placebo) in the overall study population. Thus, the results in this subgroup appeared consistent with those reported for the entire population in |||| |. The fact that this was a post hoc analysis is a significant limitation; however, and it is not clear why only data from |||| | was presented. An additional complication with the proposed listing criteria is that there is not a single universal definition of prediabetes, and the American Diabetes Association definition differs from the Diabetes Canada definition. The clinical expert consulted by CADTH on this review was clear that the term prediabetes, using the Diabetes Canada definition, is widely accepted in their field of practice in the Canadian context.
Findings from the STEP 4 study suggest that patients who discontinue treatment with semaglutide are likely to regain a large portion of the weight they lost. In STEP 4, all patients were originally on semaglutide during a 20-week run-in period, and reached the target dosage of semaglutide 2.4 mg weekly by week 16. Randomization occurred at week 20, and after this time patients who were randomized to placebo began to gain weight. At week 68, the average increase in weight from week 20 in the placebo group was 6.5%, whereas patients in the placebo group in the other studies experienced weight losses of between 2% and 6%, depending on the study. Further evidence that discontinuing semaglutide results in weight regain was found in the extension to the STEP 1 study. In STEP 1, all patients were required to discontinue all interventions at week 68, including diet and lifestyle measures that were part of the study intervention. In the extension, a subset of 327 patients from sites in Canada, Germany, the UK, the US, and Japan were followed to week 120.37 Patients in the semaglutide group regained a mean (SD) of 11.6% (SD = 7.7%) of their body weight versus 1.9% (SD = 4.8%) in the placebo group from week 68 to week 120. Overall, it appears that the effects of semaglutide do not persist after the drug has been discontinued. It is not surprising that the pharmacological effects of semaglutide would not persist after drug discontinuation; however, any impact that semaglutide may have on patient behaviour does not appear to persist either. Given that the effects of semaglutide appear to plateau after around 60 weeks, patients will need to remain motivated to continue with therapy despite the fact that they may feel frustrated that weight loss has plateaued. This raises the concern that the use of semaglutide may result in significant fluctuations in weight for those patients who stop therapy, regain weight, then go back to taking semaglutide. There is evidence that these weight fluctuations can have a negative impact on a patient’s health, and might actually be worse than simply maintaining a consistently high BMI.38 The lack of data beyond 104 weeks, the long-term efficacy of semaglutide, and whether patients begin to gain weight at some point after that plateau at 60 weeks is also unknown.
The only drug that semaglutide has been directly compared to is liraglutide, another GLP-1 agonist. In the STEP 8 trial, semaglutide proved superior to liraglutide with respect to reducing weight; however, once again this trial was not designed to assess key clinically relevant outcomes such as the number of patients developing various comorbidities. One sponsor-submitted ITC compared semaglutide 2.4 mg to other pharmacological interventions, including ||||||||||| ||| ||| |||||||||| ||| ||||||||| |||| ||||||||| ||| |||||||| |||| |||||||| ||| ||||||| ||||||||| ||||||||| |||||| |||| ||| ||||| While the analysis appears robust, some pieces of information about the analyses (||||||||| ||||||| |||||||||| ||||||| || |||||||||| |||||||| ||||||| ||| ||||||||||| |||||||||||||) were not reported. There was some unaddressed |||||||| ||||||||||||| |||| ||||||| || ||| |||||||||||| || |||| ||||||| ||||||| |||| ||| ||||| |||||| and this contributes some uncertainty to the results. Consistency could not be assessed between |||||| ||| |||||||| |||||||| due to the structure of the evidence network. The results are || |||||| || ||||||||||| |||||| ||||||||||| ||| |||||||| ||| ||| |||||||||| || |||||||| ||||||||| || ||||| || |||||| |||| || || ||||| || |||| ||||||||||| |||||| ||| || |||||| || ||||||||||| |||||| |||||||||||| |||||||||| ||| |||||||||| ||| |||||||| ||| ||| ||||||| || ||||||| |||||| |||| |||||||| || ||||||. There was no evidence of a difference between ||||||||||| ||| ||||||||||| || |||||||||| ||| ||||||||| || ||| |||||||| || |||||||| |||| ||||. The consistency of the main results with the results of the sensitivity analyses excluding trials that included ||| increases confidence in the results.
GI AEs are the most common type of AE associated with the use of GLP-1 agonists and these were the most common AEs reported in all the STEP trials. These included both upper GI events (nausea, vomiting) and lower GI events (diarrhea, constipation), and are closely linked with the mechanism of the drug. These events lead to tolerability issues, with a numerically higher number of patients treated with semaglutide who withdrew from therapy due to a GI AE compared to placebo in each of the STEP trials. These withdrawals from treatment were typically in fewer than 5% of those treated with semaglutide, and in the STEP 8 trial, treatment discontinuations due to GI AEs were numerically lower in the semaglutide group |||||| than in the liraglutide group |||||||. In STEP 8, overall GI AEs were similar between the semaglutide and liraglutide groups (95% versus 96%, respectively); thus, it is not clear why discontinuations due to AEs may have been lower with semaglutide. The clinical expert consulted by CADTH on this review did note that, in their experience, if patients are seeing a benefit from drug therapy, they are more likely to put up with the GI side effects and that GI side effects do tend to improve with time or can be managed with a more gradual dose escalation than that stated in the product monograph. Additionally, a published pooled analysis of the STEP 1 to STEP 3 trials suggests that GI-related AEs appear to plateau beginning at around week 20, the end of the dose escalation phase.39 In their input to CADTH, patients highlighted the tolerability issues with current anti-obesity drugs as a limitation of this therapeutic area.
A number of the other safety and tolerability issues associated with the GLP-1 agonists either occurred in too few patients to see numerical differences in risk between semaglutide and placebo (such as acute pancreatitis) or are events that would likely require much longer follow-up to determine risk (such as medullary thyroid cancer). The product monograph for semaglutide, as is the case with other GLP-1 agonists, cautions against use in populations at higher risk of these disorders. Data from the 104-week STEP 5 trial did not suggest an increased risk of these longer-term safety issues with the additional follow-up; however, the difference in treatment duration was relatively modest (104 weeks versus 68 weeks) and unlikely to be of sufficient duration to add valuable information about the long-term safety of semaglutide.
In the sponsor-submitted ITC, there was || |||||||| ||| | |||||||||| || |||| || |||| ||||||| ||||||||||| ||| ||||||||||| ||| ||| |||| ||||||| || |||||||||| ||| ||||||||||| ||| |||||||| ||| || ||||| ||||| ||||||
Data from 4 placebo-controlled DB RCTs (the STEP 1, STEP 2, STEP 3, and STEP 4 trials) and 1 open-label RCT comparison to liraglutide (the STEP 8 trial) suggest that treatment with semaglutide injection 2.4 mg for 68 weeks produces a statistically significant weight loss compared to liraglutide and to placebo in patients with overweight or obesity, including patients with comorbid type 2 diabetes. Although the weight loss is considered clinically significant according to the clinical expert consulted by CADTH on this review, there is no clear evidence that this weight loss reduces the number of patients who may develop various weight-related comorbidities, including type 2 diabetes, cardiovascular disease, and osteoarthritis. There is some evidence of a statistically significant improvement in the physical component of HRQoL versus placebo; however, the clinical significance of this improvement is less clear because it did not meet the MID for 1 instrument and the MID is not known for the other. Longer-term evidence from the STEP 5 trial suggests that the weight loss observed at 104 weeks is consistent with that seen in the other trials at 68 weeks; however, it appears from all the STEP trials that weight loss with semaglutide plateaus before the end of 68 weeks of treatment, and that once patients stop semaglutide treatment, they may regain the majority of the weight lost. The most common tolerability issues with semaglutide are GI-related; these are common with this drug class. Evidence from a sponsor-submitted indirect comparison suggests that ||||||||||| ||| |||||| | ||||||| |||||| |||| |||| ||||||| ||||| |||||| |||| |||||| ||||||||| |||||||||||| ||||||||| ||| ||||||||||| ||| |||||||||
adverse event
body mass index
confidence interval
double-blind
fasting plasma glucose
gastrointestinal
Gastrointestinal Society
glucagon-like peptide 1
health-related quality of life
intensive behavioural therapy
indirect treatment comparison
Impact of Weight on Quality of Life
Impact of Weight on Quality of Life–Lite
Impact of Weight on Quality of Life–Lite Clinical Trials Version
mental component summary
minimal important difference
network meta-analysis
oral antidiabetic drug
odds ratio
physical component summary
Patient Health Questionnaire-9
randomized controlled trial
serious adverse event
subcutaneous
standard deviation
Short Form (36) Health Survey
Note that this appendix has not been copy-edited.
Interface: Ovid
Databases:
Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.
Date of search: April 5, 2022
Alerts: Weekly search updates until project completion
Search filters applied: No filters were applied to limit the retrieval by study type
Limits:
Syntax Guide.
Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.
Search: Wegovy (semaglutide), weight management
International Clinical Trials Registry Platform, produced by the WHO. Targeted search used to capture registered clinical trials.
Search: Wegovy (semaglutide), weight management
Produced by Health Canada. Targeted search used to capture registered clinical trials.
Search: Wegovy (semaglutide), weight management
European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.
Search dates: March 25-April 1, 2022
Keywords: Wegovy (semaglutide), weight management
Limits: Publication years: none
Updated: Search updated before the completion of stakeholder feedback period
Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:
Note that this appendix has not been copy-edited.
Excluded Studies.
Note that this appendix has not been copy-edited.
Change From Baseline to Week 68 in SF-36, Other Domains, for STEP 1 to STEP 4.
Change From Baseline to Week 68 in IWQOL-Lite-CT, Other Domains, for STEP 1 and STEP 2.
Percentage Change From Baseline in Body Weight Over Time for STEP 1.
Percentage Change From Baseline in Body Weight Over Time for STEP 2.
Percentage Change From Baseline in Body Weight Over Time for STEP 3.
Percentage Change From Baseline in Body Weight Over Time for STEP 4.
Redacted.
Redacted.
Note that this appendix has not been copy-edited.
To describe the outcome measures in Table 48 and review their measurement properties (validity, reliability, responsiveness to change, and MID).
Outcomes Reported in the Included Studies.
Summary of Outcome Measures and Their Measurement Properties.
The IWQOL-Lite questionnaire is a disease-specific questionnaire that was designed to assess the effect of obesity on quality of life in 8 key areas.47 The IWQOL-Lite-CT was developed in response to the limitations of the IWQOL-Lite version use among patients in clinical trials.48
The IWQOL-Lite is the shorter version of the full 74-item IWQOL questionnaire.47,49 The original 74-item IWQOL measures areas of quality of life identified by adult patients living with moderate to severe obesity as those of greatest concern to them (health, social/interpersonal, work, mobility, self-esteem, sexual life, activities of daily living, and comfort with food).47,49 The IWQOL-Lite has 31 self-administered items with 5 scales: self-esteem (7 items), sexual life (4 items), physical function (11 items), public distress (5 items), and work (4 items).29 The scale score consists of the sum of all the item scores, and all scale scores are added to create the total score.29 Total scores and scale scores on the IWQOL-Lite are transformed to a range from 0 to 100; on this scale, higher scores indicate a poorer quality of life.29 The IWQOL-Lite-CT is an even shorter version of the original IWQOL, with 20 self-administered items derived from the IWQOL-Lite in 2 domains (physical – 7 items and psychosocial – 13 items) scored in the same way as the IWQOL-Lite.48,50,48
In 1 of the studies that assessed the psychometric properties of the IWQOL-Lite questionnaire, a community-based sample of 492 individuals who are living with overweight or obesity (mean BMI 27.4 kg/m2) who were not undergoing weight-loss treatment completed the IWQOL-Lite.29 Convergent validity of the total score and subscale scores was assessed in individuals with a BMI of at least 25 kg/m2 using BMI, the SF-36 (including the MCS and PCS scores and each subscale score), the Rosenberg self-esteem scale, the Marlowe-Crowne social desirability scale, and ad hoc sexual life and public distress scales using items from the obesity quality of life instrument (OBQOL).29 The IWQOL-Lite total score demonstrated strong correlations (Pearson correlation coefficient R with a magnitude of more than 0.50)51 in the expected direction with BMI, the general health, vitality, and PCS scores of the SF-36, as well as the Rosenberg self-esteem score and the OBQOL-based measures.29 The IWQOL-Lite total score was weakly correlated (magnitude of R between 0.10 and 0.30) with the Marlowe-Crowne social desirability score and SF-36 role emotional score and moderately correlated (magnitude of R between 0.30 and 0.50) with the rest of the measures.29 The IWQOL-Lite physical function score was strongly correlated with the SF-36 physical functioning, role physical, bodily pain, general health, PCS scores, moderately correlated with the SF-36 vitality and social functioning scores, the OBQOL-based measures, and weakly correlated with the SF-36 MCS and role emotional scores.29 The IWQOL-Lite work score was weakly correlated with the SF-36 role emotional score and the Marlowe-Crowne score and moderately correlated with the rest of the measures.29 Internal consistency, as assessed with Cronbach’s alpha, was acceptable for the IWQOL-Lite subscale and total scores. Test-retest reliability was evaluated an average of 14 days apart (SD = 0.7 days) in 112 individuals. Intraclass correlation coefficients (ICCs) for test-retest reliability ranged from 0.81 (public distress) to 0.88 (physical function) for the subscale scores, and 0.94 for the total score.29 These measures of reliability are acceptable relative to the generally accepted threshold of 0.70 or higher.52
The content validity of the IWQOL-Lite was assessed through a study that compared it to the International Classification of Functioning, Disability and Health using the Delphi technique with 21 raters; this study found that content was compatible and had good content validity in English and French.53
In another validation study, IWQOL-Lite data were collected from 1,197 individuals (225 had type 2 diabetes) living with obesity who were seeking weight-loss treatment and gastric-bypass surgery in a clinical trial, to determine the impact of weight on quality of life and the psychometric properties of the IWQOL-Lite instrument.54 This study found that internal consistency was acceptable52 for the IWQOL-Lite total score and subscale scores in patients with and without diabetes.54 To test the scale structure and construct validity, confirmatory factor analysis was performed as part of the same study.54 These results found that there was comparable factor structure for patients with and without diabetes.54 Moderate to strong correlations51 were found between BMI and IWQOL-Lite for both patients with and without diabetes, which suggested the construct validity.54 The correlation coefficient ranged from –0.545 (sexual life) to –0.737 (public distress) for IWQOL-Lite subscale scores and BMI and was 0.705 for IWQOL-Lite total score and BMI among patients with diabetes.54 The correlation coefficient ranged from –0.458 (sexual life) to –0.749 (public distress) for IWQOL-Lite subscale scores and BMI and was 0.683 for IWQOL-Lite total score and BMI among patients without diabetes.54
An MID range was estimated for the IWQOL-Lite total score in patients living with obesity.55 This study used both anchor and distribution-based methods in a study of 1,476 patients in weight-loss trials and compared IWQOL-Lite total scores at baseline and 6 months.55 Patients were categorized according to baseline IWQOL-Lite total score using a normative mean (calculated from a sample of 534 individuals with a BMI of 18 to 29.9 kg/m2 not enrolled in any weight-loss treatment program) for comparison.55 The categories of baseline impairment were: none (less than 1 SD below the normative mean), mild (greater than or equal to 1 but less than 2 SDs from the normative mean), moderate (greater than or equal to 2 but less than 3 SDs from the normative mean), and severe (greater than 3 SDs from normative mean).55 Standard error of measurement corrected for regression to the mean was used to evaluate the precision of the IWQOL-Lite using the Edwards-Nunnally method for the distribution-based method.55 The anchor-based method considered a 5% to 9.9% decrease in weight to represent improvement and anything below this cut-off to represent no change.55 Discrepancies in the change in IWQOL-Lite score corresponding to improvement between the distribution-based and anchor-based methods were resolved by selecting the greater of the 2 cut-offs for a given category of baseline impairment.55 Greater quality of life change was observed with greater weight loss and more severe baseline quality of life impairments.55 The MIDs for improvement were 7.7 to 7.8 for patients with no impairment at baseline (depending on exact baseline score), 7.9 to 8.1 for patients with mild impairment, 8.1 to 8.4 for patients with moderate impairment, and 12.0 for patients with severe impairment.55 The MIDs for deterioration determined using the distribution-based method ranged from –7.8 to –4.4, depending on baseline severity of impairment.55
In terms of the IWQOL-Lite-CT, internal consistency reliability was found to be satisfactory. Kolotkin et al.48,56 evaluated the measurement properties of the IWQOL-Lite-CT using 2 different RCTs with semaglutide, 1 using a population of individuals living with obesity and 1 using a population of individuals with type 2 diabetes. It was reported that the Cronbach’s alpha values for total score at baseline and end of trial ranged from 0.93 and 0.96.48 The item and composite-level test-retest reliabilities were found to be satisfactory in both studies, with ICCs of 0.80 or more for all composite scores.48 For validity, the authors reported strong correlations with the SF-36 scales for physical and physical function scores, role physical, and vitality subscale score in both studies.48 Both studies also revealed positive construct validity of the composite scores through longitudinal analyses in comparison to changes in the SF-36 scale.48 The author reported that IWQOL-Lite-CT was able to discriminate between known groups. Effect sizes comparing baseline and week 68 IWQOL-Lite-CT scores were statistically significant for all composites (P < 0.0001). Anchor-based analyses indicated responder thresholds ranging from 13.5 to 16.6 in composite scores. The author concluded that the IWQOL-Lite-CT was an appropriate scale for clinical trials assessing the efficacy of new treatments for weight management.56
No MID was reported for IWQOL-Lite-CT version.
The 36-Item Short Form Survey (SF-36) is an instrument that measures general health that has been used extensively in clinical trials in a variety of population groups.57 There are 8 health domains in the SF-36 and for each of these a subscale score can be determined: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health.57,58 There are 2 component summaries of the SF-36, the PCS and the MCS, that are derived with a scoring algorithm from the 8 domains.57,59,60 Scores on the PCS and MCS range from 0 to 100, with higher scores indicating better health status.57 Scoring for the summary scales uses norm-based methods; the general US population is used to derive the regression weights and constants. The PCS and MCS scales are transformed to have a mean of 50 and an SD of 10 in the general US population.28
The SF-36 version 2 (SF-36v2) was a modified version. It was made available in 1996; it contains minor changes to the original survey. Changes included: reduced ambiguity in instructions, better layout, increased item-level response choices, increased cultural/language comparability, and elimination of a response option from the items in the mental health and vitality dimensions.28
The original version of the SF-36 has some evidence of validity among patients living with obesity. In a study of outpatients living with obesity (N = 475) seeking treatment, the construct validity of the SF-36 was explored through main component analysis.61 This study found that BMI was associated with most factors, but not the mental health, vitality, and social functioning-based factors.61 In a study of patients living with morbid obesity (mean BMI of 41.7 kg/m2) with a referral to a rehabilitation centre, a factor analysis suggested that the 2 summary scales (PCS and MCS) had adequate factor loading, but that the validity of the original 8 subscales was not confirmed in this population.62
The construct validity and reliability of the original version of the SF-36 among patients living with obesity scheduled for bariatric surgery (N = 365) was evaluated in another study.58 Principal component analysis revealed 6 factors with an estimated Eigen value of greater than 1, ensuring that 6 factors were obtained.58 The identified 6-factor model was tested for fit using confirmatory factor analysis, which exhibited a good fit.58 Using Pearson’s correlation, the authors found that the correlations were satisfactory, with all factors showing a correlation below 0.70.58 The overall internal consistency reliability was found to be greater than 0.70 (Cronbach’s alpha = 0.717).58 Overall, the authors found that the main components closely related to increased BMI were physical activity, general health and body pain, physical role, emotional role, and mental health,58 which was in agreement with previous studies.
One study found evidence of validity for the original version of the SF-36 scale score in a group of people with type 2 diabetes,63 although it is important to note that these findings may not be applicable to patients living with obesity that do not have type 2 diabetes. A Cronbach’s alpha consistency value greater than 0.80 was attained for 6 of the individual scales on the SF-36, the physical functioning, role physical, bodily pain, vitality, role emotional, and mental health scales.63 The authors assessed the external validity of the SF-36 by comparing the scale scores at the start of diabetes therapy and education and 4 weeks after completion with the Well-Being Questionnaire, the Diabetes Treatment Satisfaction Questionnaire, the Diabetes, and the Quality of Life with Diabetes questionnaire.63 They found that there were significant differences in treatment satisfaction, role physical, general health, vitality, and social functioning scores before and 4 weeks after education and diabetes therapy on the SF-36 scale score.63 The authors did note that the SF-36 has a positive bias, as the positive answers receive higher scores.63
In the general population, clinically meaningful improvement is generally indicated by a change of 2 points in the SF-36 PCS and 3 points in the SF-36 MCS.28 Based on anchor data, following minimal mean group differences, in terms of t score points are described for SF-36 individual dimension scores: physical functioning, 3; role functioning, 3; bodily pain, 3; general health, 2; vitality, 2; social functioning, 3; role emotional, 4; and mental health, 3.28 These MID values were determined as appropriate for groups with mean t score ranges of 30 to 40.28 For higher t score ranges, MID values may be higher.28 No information about the MID of the SF-36 in the population living with obesity was identified.
The 6MWT is a supervised test that measures the distance a patient can walk on a hard flat surface over a 6-minute period.64 The American Thoracic Society provides guidelines for standardization of this test to maximize reliability.64 Walk tests aim to evaluate global function of organ systems involved in exercise, namely the heart, lungs, peripheral circulation, blood, nervous system, muscles, bones, and joints, during walking, a self-paced activity.64 Walk tests were originally developed to primarily evaluate cardiopulmonary function in cardiac and pulmonary conditions (e.g., chronic obstructive pulmonary disease, heart failure, pulmonary hypertension), but studies have been performed to validate these tests in musculoskeletal conditions such as fibromyalgia.64
The reproducibility and validity of 6MWT in overweight or obese has been assessed in several studies.65-68 In a prospective repeated-measure validity study, Beriault et al. (2009) found that 6MWT was highly reproducible in obese adults.69 In 1 study, Elmahgoub et al. (2012)66 assessed the reproducibility and validity of the 6MWT in adolescent participants with overweight (N = 39). The adolescent participants performed the 6MWT twice with an interval of 1 week. The results showed a good reliability (intraclass correlation coefficient: 0.82). The smallest real difference was 82.6 m. The validity of 6MWT was demonstrated by the 6MWT distance was well correlated with relative peak oxygen uptake (beta = 0.69). The author concluded that 6MWT was a reliable and valid test in adolescents with overweight or obesity.66
The key limitations of the 6MWT, especially in pediatric patients, include: a learning effect with repeated testing; confounding effect of patient motivation, encouragement and cooperation; and impact of age, height, and weight on walk distance.64 The learning effect could result in performance and detection bias (i.e., false-positive apparent benefits) when evaluating an intervention using these walk tests in a non-blinded, uncontrolled study. Additionally, differences in patient motivation, encouragement and cooperation between assessments can impact walking distance by a similar magnitude as the effect of interventions,70 which can produce substantial variability and be a source of performance bias in a non-blinded, uncontrolled study. Finally, previous studies have identified that age, height and weight impact distance travelled in 6 minutes,71,72 which may affect 6MWT results obtained from trials of longer duration.
No MID has been identified or proposed in patient with overweight. MIDs for distances were reported for other conditions such as chronic obstructive pulmonary disease (43 m) and heart failure (54 m).
Obesity is a chronic disease associated with several health-related complications. The Canadian Adult Obesity Clinical Practice Guidelines released in 2020 indicated that obesity increases the risk of developing cardiovascular disease and certain types of cancers, which are some of the leading causes of early death in these patients.8 In addition, obesity is considered a risk factor for other serious conditions including type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea, knee osteoarthritis, urinary incontinence, asthma, nonalcoholic steatohepatitis, and heart failure.19 Guidelines from the UK33 and the US34 suggest that minimal weight loss of between 5 and 10% is sufficient to have a clinical impact on outcomes. A 5% for body weight reduction is generally considered “clinically meaningful.”35 One of the criteria for approval medications for management of obesity In The US FDA Draft Guidance is that the medication achieve an average weight loss of 5% or greater than a placebo.73,74
To describe the impact of body weight reduction on long-term weight-related comorbidities, a brief summary of a study by Haase et al. (2021)36 is presented in the following section.
Haase et al.36 conducted a retrospective study to assess the impact of the body weight reduction on 10 clinical outcomes. The data sources used in this analysis were from UK Clinical Practice Research Datalink (CPRD) GOLD database75 and merged with Hospital Episode Statistics linkage information and death registry data from the Office for National Statistics.75
Study design: The study included a 4-year “baseline period” (year 1 to year 4) and a subsequent follow-up period. Index date for each included participant was defined as the date of the earliest BMI assessment and indicated the beginning of year 1 of the study. BMI assessments were made during the baseline period (after index date, years 1 to 4). The incidence of weight-related comorbidities was assessed during the follow-up period. Follow-up period ended at the date of the first event, death, transfer-out, or the last data collection.36
Inclusion and exclusion criteria: To be included in the study, participants had to be older than 18 years at index date and 70 years or younger at start of follow-up, have 1 or more BMI assessments during the “baseline period” (year 1 and year 4), and a have mean BMI between 25 and 50 kg/m2 during year 4 after the index date. Based on the change in those participants’ mean BMI during the “baseline period,” participants were categorized into 2 cohorts: 1 was the stable-weight cohort (defined as −5% to +5% BMI change). The other was the weight-loss cohort (defined as −25% to −10% BMI change). In order to confirm the intention to lose weight, it was required that participants in the weight loss cohort had a Read code in CPRD GOLD database indicating either a weight-loss diet, weight-loss drug prescription, or referral to a dietitian or for bariatric surgery during the baseline period. Participants with BMI change outside the ranges for these cohorts, participants with malignant cancer or thyroid disorder before the start of follow-up, and those with a record of pregnancy or limb amputation during the baseline period were excluded to ensure no unintentional weight loss.
Outcomes: Risk before and after weight loss for the following weight-related comorbidities was assessed: type 2 diabetes, sleep apnea, hip or knee osteoarthritis, hypertension, dyslipidemia, unstable angina or myocardial infarction, asthma, atrial fibrillation, heart failure, and chronic kidney disease.
Statistical analyses: Cox proportional hazard models with calendar time as the underlying time variable were used to estimate the difference in risk between the stable-weight and weight-loss cohorts. Participants with a baseline history of the weight- related comorbidity were excluded from the risk analysis only for that outcome. All statistical analyses were performed using the R environment for statistical computing and visualization (R Foundation for Statistical Computing; version 3.6.2).
Baseline and demographic characteristics: A total of 571,961 participants was included in this analysis. Among them, 523,138 were in the stable-weight cohort and 48,823 were in the weight-loss cohort. A total of 49.2% of the population were men. The median age at the start of the follow-up period was 55 years and the median follow-up time was 6.3 years. In the stable-weight cohort, the median BMI was 29.9 kg/m2 during year 1 and 30.0 kg/m2 during year 4. The median BMIs in the weight-loss cohort were 35.3 kg/m2 during year 1 and 30.4 kg/m2 during year 4, respectively, which represented a median weight loss of 13%. In the weight-loss cohort, 57.6% of participants were given dietary advice at some time point during the 4-year baseline period, 52.7% reported that they initiated a weight-loss diet, 27.0% received a weight-loss medication and 1.1% were referred for bariatric surgery (CPRD GOLD) or underwent bariatric surgery (Hospital Episode Statistics).36
Risk reduction following weight loss: the detail of results of risk reduction in weight-loss group is presented in Table 50. It was reported that, for the group with index BMI 40 kg/m2, the relative risk reductions with median 13% weight loss were observed for type 2 diabetes (41%), and sleep apnea (40%), hypertension (22%), dyslipidemia (19%), and asthma (18%). Similar results were observed in the sensitive analysis by excluding participants who had received sibutramine.
Limitations: The author indicated that this was the first study to assess, in a single real-world population, the differential impact of intentional weight loss on a range of weight-related comorbidities, for different BMI profiles. As the author acknowledged, the findings observed in this study was unable to provide conclusive evidence of the causative nature of the observations because of the retrospective and observational nature of this analysis.
Outcome Risk Before and After Median 13% Weight Loss Starting at BMI of 35.0 kg/m2, 40.0 kg/m2, and 45.0 kg/m2 Relative to a Stable BMI of 30 kg/m2.
Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/
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