CADTH Reimbursement Review

Semaglutide (Wegovy)

Sponsor: Novo Nordisk Canada Inc.

Therapeutic area: Weight management

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

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.

Stakeholder Perspectives

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.

Patient Input

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.

Clinician Input

Input From Clinical Experts Consulted by CADTH

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.

Clinician Group Input

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.

Drug Program Input

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.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

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.

Efficacy Results

Body Weight

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 ||||| || |||| ||| ||||| || |||||||

Body Mass Index

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).

Health-Related Quality of Life

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.

Normalization of Glucose Parameters

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.

Harms Results

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.

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.

Indirect Comparisons

Description of Studies

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 ||||||||| ||||||| |||| ||||||||| |||||||||| |||||||| |||||||| |||||||| |||| ||||||||| ||| |||||||||||| |||| |||| | |||||||| ||||||||| |||||||| | |||||||| ||||||||| |||||| ||||||| ||||||||| |||||||| ||| ||||||||||||

Efficacy Results

The models with the best fit (base-case models) are reported as follows:

• ||||||||||| ||| |||||||||| |||| ||||||| |||| || |||||||| ||||||||| || ||||| || |||||| |||| ||||| || ||||| || ||| |||| ||||||||||| |||||| |||||||| |||| ||||||||||| ||| || ||| |||||||| || || ||||| ||||| ||||| ||||||| ||||||| |||| ||||||| |||||||||||| ||| |||||||||| |||| | ||||||| ||||||| ||||||||| |||| |||||||| || |||||| |||||||| |||| ||||||||||| ||| ||| |||||||||| || || ||| ||||||||| ||| ||| |||||||||| || || ||| ||||||||| ||| ||| |||||||| ||| || ||||| ||||| |||||| ||| |||||||| || || ||||| ||||| ||||| ||| ||||||||||| ||||||||| ||||||| ||| ||||||||||| |||||| |||||||| ||||||||||| |||| ||||||||| ||||||| ||| |||| |||||||| || ||| |||| |||||||| |||||| |||||||||| |||||||| |||| ||| ||||| ||||||||||| || ||| |||||||| || |||||||| |||| ||||| ||||| ||| || |||||||| || | |||||||||| ||||||| ||||||||||| ||| ||||||||||| || |||||||||||||||||||| ||| |||||| ||||||Sensitivity analyses ||||||||| |||||| || ||||||||| ||||||||||| ||||||| ||||| |||| ||||||| |||||||||| |||| ||| |||| ||||||||.

Harms Results

There was no evidence for | |||||||||| || |||| || |||| ||||||| ||||||||||| ||| ||||||||||| ||| ||| |||| ||||||| || |||||||||| ||| ||||||||||| ||| |||||||| ||| || ||||| ||||| ||||| ||| |||||||

Critical Appraisal

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.

Other Relevant Evidence

Description of Studies

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.

Efficacy Results

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.

Harms Results

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, ||||||||||| ||||||||| |||||||| || || |||||| ||| || ||||||||| || ||| |||||| |||| |||||||||||| || || |||||| ||||| ||||||||| |||| ||||||||| || || |||||| |||| ||| ||||||||||| ||||||||| || ||| |||||| |||| ||||| |||| || ||||| || ||||| |||||||||||||

Critical Appraisal

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.

Conclusions

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 |||||||| |||| ||||||||||| ||| |||||| | ||||||| |||||| |||| |||| ||||||| ||||| |||||| |||| |||||| ||||||||| |||||||||||| ||||||||| ||| ||||||||||| ||| ||||||||.

Introduction

Disease Background

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

Standards of Therapy

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.

Drug

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.

Table 3: Key Characteristics of GLP-1 Agonists, Naltrexone-Bupropion, and Orlistat

BMI = body mass index; GI = gastrointestinal; GLP-1 = glucagon-like peptide 1; T2DM = type 2 diabetes mellitus.

^aHealth Canada–approved indication.

Source: Product monographs for semaglutide (2020),⁴ liraglutide (2021),¹¹ naltrexone-bupropion (2018),¹² and orlistat (2017).¹³

Stakeholder Perspectives

Patient Group Input

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.

Clinician Input

Input From Clinical Experts Consulted by CADTH

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.

Unmet Needs

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.

Place in Therapy

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.

Patient Population

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.

Assessing Response to Treatment

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:

• improved survival

• improved hemoglobin A1C by at least 0.5%

• improved blood pressure

• improvement/normalization of liver enzymes

• improvement in lipid profile (reduced triglycerides and low-density lipoprotein, in particular)

• the patient reporting reduced hunger or reduced food cravings and feeling more in control of their food intake

• reduced risk of weight-related cancers (e.g., endometrial, breast)

• the patient reporting improved mobility or ability to perform daily activities

• the resolution of prediabetes with glucose parameters returning to the “normal” range

• a total body weight loss of 5% or greater

• a plateau in weight regain or reversal of weight regain in a patient who has undergone bariatric surgery.

Discontinuing Treatment

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.

Prescribing Conditions

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.

Clinician Group Input

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.

Drug Program Input

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.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

ADA = American Diabetes Association; BMI = body mass index; CDEC = CADTH Canadian Drug Expert Committee; DC = Diabetes Canada; FPG = fasting plasma glucose.

Clinical Evidence

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.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

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

Methods

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.

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.

Findings From the Literature

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.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

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.

Populations

Inclusion and Exclusion Criteria

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.

Baseline Characteristics

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 |||| || ||| || ||| ||| ||||||||||| || ||||||||||| || ||||||||.

Table 11: Summary of Baseline Characteristics for STEP 1 and STEP 2 Studies — Full Analysis Set

BMI = body mass index; FPG = fasting plasma glucose; NA = not applicable; SD = standard deviation.

Source: Clinical Study Reports for STEP 1 (2020)¹⁷ and STEP 2 (2020).²¹

Table 12: Summary of Baseline Characteristics for STEP 3 and STEP 4 Studies — Full Analysis Set

BMI = body mass index; FPG = fasting plasma glucose; NA = not applicable; NR = not reported; SD = standard deviation.

Source: Clinical Study Reports for STEP 3 (2020)²³ and STEP 4 (2020).²⁵

Table 13: Summary of Baseline Characteristics, Full Analysis Set — STEP 8 Study

BMI = body mass index; FPG = fasting plasma glucose; SD = standard deviation.

Source: Clinical Study Report for STEP 8 (2021).²⁷

Interventions

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.

Outcomes

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.

Table 14: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

6MWT = six-minute walk test; BMI = body mass index; CFB = change from baseline; CV = cardiovascular; HCRU = health care resource utilization; HRQoL = health-related quality of life; IWQOL-Lite-CT = Impact of Weight on Quality of Life–Lite Clinical Trials Version; NR = not reported; SBP = systolic blood pressure; SF-36 = Short Form (36) Health Survey.

Note: Numbers in parentheses indicate ranking in the hierarchy.

Body Weight

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.

Assessment of Glycemic Status

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: Six-Minute Walk Test

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.

Health-Related Quality of Life

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

Statistical Analysis

Primary Outcomes of the Studies

Power Calculation

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.

Statistical Tests and Models

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.

Data Imputation Methods

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.

Subgroup Analyses

No preplanned subgroups of relevance to the systematic review protocol were described in any of the included studies.

Sensitivity Analyses

The imputation methods described earlier were the sensitivity analyses performed during the STEP trials.

Secondary Outcomes of the Studies

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).

Table 15: Statistical Analysis of Efficacy End Points

ANCOVA = analysis of covariance; IWQOL-Lite-CT = Impact of Weight on Quality of Life–Lite Clinical Trials Version; J2R-MI = jump to reference multiple imputation; LAO = last available observation; MMRM = mixed model of repeated measures; NR = not reported; SF-36 = Short Form (36) Health Survey.

^aJ2R-MI: Missing observations were multiple (1,000x), imputed from placebo patients based on a jump to reference approach.

^bS1-SI: Missing observations were imputed by adding a body weight regain rate of 0.3 kg per month to the LAO until baseline is reached.

^cS2-SI: Missing observations were imputed by adding a body weight regain rate of 0.3 kg per month to the LAO until baseline is reached for semaglutide 2.4 mg only.

^dMMRM: All responses were included in a MMRM with randomized treatment as factor and baseline body weight as covariate, all nested within visit. For binary outcomes, the MMRM was performed on body weight (kg) and individual missing week 68 responses were predicted from the MMRM; each subject was then classified for body weight loss of 5% or more and analyzed using a binary logistic regression model.

^eNR: Patients with missing week 68 response were considered as nonresponders.

Analysis Populations

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.

Results

Patient Disposition

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.

Exposure to Study Treatments

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.

Table 16: Patient Disposition for STEP 1, STEP 2, and STEP 3 Studies

Source: Clinical Study Reports for STEP 1 (2020),¹⁷ STEP 2 (2020),²¹ and STEP 3 (2020).²³

Table 17: Patient Disposition for STEP 4 and STEP 8 Studies

NA = not applicable.

Source: Clinical Study Reports for STEP 4 (2020)²⁵ and STEP 8 (2021).²⁷

Table 18: Treatment Exposure for STEP 1, STEP 2, and STEP 3 Studies — Full Analysis Set

SD = standard deviation.

Source: Clinical Study Reports for STEP 1 (2020),¹⁷ STEP 2 (2020),²¹ and STEP 3 (2020).²³

Table 19: Treatment Exposure for STEP 4 and STEP 8 Studies — Full Analysis Set

SD = standard deviation.

Source: Clinical Study Reports for STEP 4 (2020)²⁵ and STEP 8 (2021).²⁷

Efficacy

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.

Mortality

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.

Body Weight

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.

Table 20: Percentage Change From Baseline to Week 68 in Body Weight for STEP 8 Study — Primary Analysis, In Trial, Full Analysis Set

CI = confidence interval; FAS = full analysis set; SD = standard deviation; vs. = versus.

Note: Baseline sample sizes correspond to the FAS population. Week 68 responses were analyzed using an analysis of covariance model with randomized treatment as factor and baseline body weight as covariate.

Source: Clinical Study Report for STEP 8 (2021).²⁷

Table 21: Percentage Change From Baseline to Week 68 in Body Weight for STEP 1 to STEP 4 Studies — Primary Analysis, In Trial, Full Analysis Set

CI = confidence interval; FAS = full analysis set; SD = standard deviation; vs. = versus.

Note: Baseline sample sizes correspond to the FAS population. For STEP 4, the initial baseline value is the week 20 (randomization) value and change is from week 20 to week 68. Week 68 responses were analyzed using an analysis of covariance model with randomized treatment as factor and baseline body weight as covariate.

Source: Clinical Study Reports for STEP 1 (2020),¹⁷ STEP 2 (2020),²¹ STEP 3 (2020),²³ and STEP 4 (2020).²⁵

Table 22: 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

CI = confidence interval; FAS = full analysis set; OR = odds ratio; vs. = versus.

Note: Week 68 responses were analyzed using a binary logistic regression model with randomized treatment as factor and baseline body weight as covariate.

Source: Clinical Study Report for STEP 8 (2021).²⁷

Table 23: 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

CI = confidence interval; OR = odds ratio; vs. = versus.

Note: Week 68 responses were analyzed using a binary logistic regression model with randomized treatment as factor and baseline body weight as covariate. The denominator N values represent the number of observations at the relevant time point (68 weeks).

^aThe P value was not controlled for multiplicity.

Source: Clinical Study Reports for STEP 1 (2020),¹⁷ STEP 2 (2020),²¹ STEP 3 (2020),²³ and STEP 4 (2020).²⁵

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).

Body Mass Index

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).

Table 24: Change From Baseline to Week 68 in Waist Circumference for STEP 8 Study — In Trial, Full Analysis Set

CI = confidence interval; FAS = full analysis set; SD = standard deviation; vs. = versus.

Note: Baseline sample sizes correspond to the FAS population. Week 68 responses were analyzed using an analysis of covariance model with randomized treatment as factor and baseline waist circumference as covariate.

^aThe P value was not adjusted for multiplicity.

Source: Clinical Study Report for STEP 8 (2021).²⁷

Table 25: Change From Baseline to Week 68 in Waist Circumference for STEP 1 to STEP 4 Studies — In Trial, Full Analysis Set

CI = confidence interval; FAS = full analysis set; SD = standard deviation; vs. = versus.

Note: Baseline sample sizes correspond to the FAS population. For STEP 4, the initial baseline value is the week 20 (randomization) value and change is from week 20 to week 68. Week 68 responses were analyzed using an analysis of covariance model with randomized treatment as factor and baseline waist circumference as covariate.

Source: Clinical Study Reports for STEP 1 (2020),¹⁷ STEP 2 (2020),²¹ STEP 3 (2020),²³ and STEP 4 (2020).²⁵

Table 26: Mean Change From Baseline to Week 68 in Body Mass Index for STEP 1 to STEP 4 Studies — Full Analysis Set Population

CI = confidence interval; FAS = full analysis set; SD = standard deviation; vs. = versus.

Note: Baseline sample sizes correspond to the FAS population. For STEP 4, the initial baseline value is the week 20 (randomization) value and change is from week 20 to week 68. Week 68 responses were analyzed using an analysis of covariance model with randomized treatment as factor and baseline BMI as covariate. P values were not adjusted for multiple comparisons.

Source: Clinical Study Reports for STEP 1 (2020),¹⁷ STEP 2 (2020),²¹ STEP 3 (2020),²³ and STEP 4 (2020).²⁵

Health-Related Quality of Life

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]).

Table 27: 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

CI = confidence interval; FAS = full analysis set; SD = standard deviation; SF-36 = Short Form (36) Health Survey; vs. = versus.

Note: For STEP 4, the initial baseline value is the week 20 (randomization) value and change is from week 20 to week 68. Week 68 responses were analyzed using an analysis of covariance model with randomized treatment as factor and baseline SF-36 physical function score as covariate. The N values (aside from those for the FAS) represent the number of observations at the relevant time point (68 weeks).

Source: Clinical Study Reports for STEP 1 (2020),¹⁷ STEP 2 (2020),²¹ STEP 3 (2020),²³ and STEP 4 (2020).²⁵

Table 28: 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

CI = confidence interval; FAS = full analysis set; SF-36 = Short Form (36) Health Survey; vs. = versus.

Note: Week 68 responses were analyzed using a binary logistic regression model with randomized treatment as factor and baseline SF-36 physical functioning score as covariate. The denominator N values represent the number of observations at the relevant time point (68 weeks). P values were not adjusted for multiple comparisons.

Source: Clinical Study Reports for STEP 1 (2020),¹⁷ STEP 2 (2020),²¹ STEP 3 (2020),²³ and STEP 4 (2020).²⁵

Table 29: 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

CI = confidence interval; FAS = full analysis set; IWQOL-Lite-CT = Impact of Weight on Quality of Life–Lite Clinical Trials Version; SD = standard deviation; vs. = versus.

Note: Week 68 responses were analyzed using an analysis of covariance model with randomized treatment as factor and baseline IWQOL-Lite-CT as covariate. The N values (aside from those for the FAS) represent the number of observations at the relevant time point (68 weeks).

Source: Clinical Study Reports for STEP 1 (2020)¹⁷ and STEP 2 (2020).²¹

Table 30: 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

CI = confidence interval; FAS = full analysis set; IWQOL-Lite-CT = Impact of Weight on Quality of Life–Lite Clinical Trials Version; vs. = versus.

Note: Week 68 responses were analyzed using a binary logistic regression model with randomized treatment as factor and baseline IWQOL-Lite-CT score as covariate. The aforementioned P values were not adjusted for multiple comparisons. The denominator N values represent the number of observations at the relevant time point (68 weeks).

Source: Clinical Study Reports for STEP 1 (2020)¹⁷ and STEP 2 (2020).²¹

Normalization of Blood Glucose

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.

Table 31: End-of-Study Status in Patients With Prediabetes or Normoglycemia at Baseline for STEP 8 Study

Note: The N values in Table 31 represent the number of observations at the relevant time point (68 weeks).

Source: Clinical Study Reports for STEP 1 (2020),¹⁷ STEP 2 (2020),²¹ STEP 3 (2020),²³ STEP 4 (2020),²⁵ and STEP 8 (2021).²⁷

Table 32: End-of-Study Status in Patients With Prediabetes or Normoglycemia at Baseline for STEP 1 to STEP 4 Studies

NR = not reported.

Note: The N values in Table 32 represent the number of observations at the relevant time point (68 weeks).

Source: Clinical Study Reports for STEP 1 (2020),¹⁷ STEP 2 (2020),²¹ STEP 3 (2020),²³ and STEP 4 (2020).²⁵

Table 33: Patients With Increase, Decrease, or No Change in Dose for Antihypertensive and Lipid-Lowering Medications for STEP 8 Study