WEGOVY Solution for injection Ref.[49657] Active ingredients: Semaglutide

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues
ATC code: A10BJ06

Mechanism of action

Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1.

GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation.

Animal studies show that semaglutide works in the brain through the GLP-1 receptor. Semaglutide has direct effects on areas in the brain involved in homeostatic regulation of food intake in the hypothalamus and the brainstem. Semaglutide may affect the hedonic reward system through direct and indirect effects in brain areas including the septum, thalamus and amygdala.

Clinical studies show that semaglutide reduces energy intake, increases feelings of satiety, fullness and control of eating, reduces feelings of hunger, and frequency and intensity of cravings. In addition, semaglutide reduces the preference for high fat foods.

Semaglutide orchestrates the homeostatic and hedonic contributions with executive function to regulate caloric intake, appetite, reward and food choice.

In addition, in clinical studies semaglutide have shown to reduce blood glucose in a glucose dependent manner by stimulating insulin secretion and lowering glucagon secretion when blood glucose is high. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. During hypoglycaemia, semaglutide diminishes insulin secretion and does not impair glucagon secretion.

GLP-1 receptors are also expressed in the heart, vasculature, immune system and kidneys. Semaglutide has a beneficial effect on plasma lipids, lowered systolic blood pressure and reduced inflammation in clinical studies. Furthermore, animal studies have shown that semaglutide attenuated the development of atherosclerosis and had an anti-inflammatory action in the cardiovascular system.

Pharmacodynamic effects

Appetite, energy intake and food choice

Semaglutide reduces appetite by increasing feelings of fullness and satiety, while lowering hunger and prospective food consumption. In a phase 1 trial, energy intake during an ad libitum meal was 35% lower with semaglutide compared to placebo after 20 weeks of dosing. This was supported by improved control of eating, less food cravings and a relative lower preference for high fat food. Food cravings were further assessed in STEP 5 by a Control of Eating Questionnaire (CoEQ). At week 104, the estimated treatment difference both for control of cravings and craving of savoury food significantly favoured semaglutide, whereas no clear effect was seen for craving of sweet food.

Fasting and postprandial lipids

Semaglutide 1 mg compared to placebo lowered fasting triglyceride and very low density lipoproteins (VLDL) concentrations by 12% and 21%, respectively. The postprandial triglyceride and VLDL response to a high fat meal was reduced with >40%.

Clinical efficacy and safety

The efficacy and safety of semaglutide for weight management in combination The efficacy and safety of semaglutide for weight management in combination with a reduced calorie intake and increased physical activity were evaluated in four 68 weeks double-blinded randomised placebo-controlled phase 3a trials (STEP 1-4). A total of 4,684 adult patients (2,652 randomised to treatment with semaglutide) were included in these trials. Furthermore, the two-year efficacy and safety of semaglutide compared to placebo were evaluated in a double-blinded randomised placebo-controlled phase 3b trial (STEP 5) including 304 patients (152 in treatment with semaglutide).

Treatment with semaglutide demonstrated superior, clinically meaningful, and sustained weight loss compared with placebo in patients with obesity (BMI ≥30 kg/m²), or overweight (BMI ≥27 kg/m² to <30 kg/m²) and at least one weight-related comorbidity. Furthermore, across the trials, a higher proportion of patients achieved ≥5%, ≥10%, ≥15% and ≥20% weight loss with semaglutide compared with placebo. The reduction in body weight occurred irrespective of the presence of gastrointestinal symptoms such as nausea, vomiting or diarrhoea.

Treatment with semaglutide also showed statistically significant improvements in waist circumference, systolic blood pressure and physical functioning compared to placebo.

Efficacy was demonstrated regardless of age, sex, race, ethnicity, baseline body weight, BMI, presence of type 2 diabetes and level of renal function. Variations in efficacy existed within all subgroups. Relatively greater weight loss was observed in women and in patients without type 2 diabetes as well as in patients with a lower versus higher baseline body weight.

STEP 1: Weight management

In a 68-week double-blind trial, 1,961 patients with obesity (BMI ≥30 kg/m²), or with overweight (BMI ≥27 kg/m² to <30 kg/m²) and at least one weight-related comorbidity were randomised to semaglutide or placebo. All patients were on a reduced-calorie diet and increased physical activity throughout the trial.

Weight loss occurred early and continued throughout the trial. At end of treatment (week 68), the weight loss was superior and clinically meaningful compared with placebo (see Table 4 and Figure 1). Furthermore, a higher proportion of patients achieved ≥5%, ≥10%, ≥15% and ≥20% weight loss with semaglutide compared with placebo (see Table 4). Among patients with prediabetes at baseline, a higher proportion of patients had a normo-glycaemic status at end of treatment with semaglutide compared to placebo (84.1% vs. 47.8%).

Table 4. STEP 1: Results at week 68:

^* p<0.0001 (unadjusted 2-sided) for superiority.
¹ Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment or initiation of other anti-obesity medication or bariatric surgery.
² During the trial, randomised treatment was permanently discontinued by 17.1% and 22.4% of patients randomised to semaglutide 2.4 mg and placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies, the estimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures including all observations until first discontinuation were -16.9% and -2.4% for semaglutide 2.4 mg and placebo respectively.
³ Estimated from binary regression model based on same imputation procedure as in primary analysis.

Figure 1. STEP 1: Mean change in body weight (%) from baseline to week 68:

Observed values for patients completing each scheduled visit, and estimates with multiple imputations (MI) from retrieved dropouts.

STEP 2: Weight management in patients with type 2 diabetes

In a 68-week, double-blind trial, 1,210 patients with overweight or obesity (BMI ≥27 kg/m²) and type 2 diabetes were randomised to either semaglutide 2.4 mg, semaglutide 1 mg once-weekly or placebo. Patients included in the trial had insufficiently controlled diabetes (HbA_1c 7–10%) and were treated with either: diet and exercise alone or 1–3 oral antidiabetic drugs. All patients were on a reduced-calorie diet and increased physical activity throughout the trial.

Treatment with semaglutide for 68 weeks resulted in superior and clinically meaningful reduction in body weight and in HbA_1c compared to placebo (see Table 5 and Figure 2).

Table 5. STEP 2: Results at week 68:

^* p<0.0001 (unadjusted 2-sided) for superiority; **p<0.05 (unadjusted 2-sided) for superiority
¹ Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment or initiation of other anti-obesity medication or bariatric surgery.
² During the trial, randomised treatment was permanently discontinued by 11.6% and 13.9% of patients randomised to semaglutide 2.4 mg and placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies, the estimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures including all observations until first discontinuation were -10.6% and -3.1% for semaglutide 2.4 mg and placebo respectively
³ Estimated from binary regression model based on same imputation procedure as in primary analysis.

Figure 2. STEP 2: Mean change in body weight (%) from baseline to week 68:

Observed values for patients completing each scheduled visit, and estimates with multiple imputations (MI) from retrieved dropouts.

STEP 3: Weight management with intensive behavioural therapy

In a 68-week double-blind trial, 611 patients with obesity (BMI ≥30 kg/m²), or with overweight (BMI ≥27 kg/m² to <30 kg/m²) and at least one weight-related comorbidity were randomised to semaglutide or placebo. During the trial, all patients received intensive behavioural therapy (IBT) consisting of a very restrictive diet, increased physical activity and behavioural counselling.

Treatment with semaglutide and IBT for 68 weeks resulted in superior and clinically meaningful reduction in body weight compared to placebo (see Table 6).

Table 6. STEP 3: Results at week 68:

^* p<0.005 (unadjusted 2-sided) for superiority
¹ Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment or initiation of other anti-obesity medication or bariatric surgery.
² During the trial, randomised treatment was permanently discontinued by 16.7% and 18.6% of patients randomised to semaglutide 2.4 mg and placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies, the estimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures including all observations until first discontinuation were -17.6% and -5.0% for semaglutide 2.4 mg and placebo respectively
³ Estimated from binary regression model based on same imputation procedure as in primary analysis.

STEP 4: Sustained weight management

In a 68-week double-blind trial, 902 patients with obesity (BMI ≥30 kg/m²), or with overweight (BMI ≥27 kg/m² to <30 kg/m²) and at least one weight-related comorbidity were included in the trial. All patients were on a reduced-calorie diet and increased physical activity throughout the trial. From week 0 to week 20 (run-in), all patients received semaglutide. At week 20 (baseline), patients who had reached the maintenance dose of 2.4 mg were randomised to continue treatment or switch to placebo. At week 0 (start of run-in period) patients had a mean body weight of 107.2 kg and a mean BMI of 38.4 kg/m².

Patients who had reached the maintenance dose of 2.4 mg at week 20 (baseline) and continued treatment with semaglutide for 48 weeks (week 20–68) continued losing weight and had a superior and clinically meaningful reduction in body weight compared to those switched to placebo (see Table 7 and Figure 3). The body weight increased steadily from week 20 to week 68 in patients switching to placebo at week 20 (baseline). Nevertheless, the observed mean body weight was lower at week 68 than at start of the run-in period (week 0) (see Figure 3). Patients treated with semaglutide from week 0 (run-in) to week 68 (end of treatment) achieved a mean change in body weight of 17.4%, with weight loss ≥5% achieved by 87.8%, ≥10% achieved by 78.0%, ≥15% achieved by 62.2% and ≥20% achieved by 38.6% of these patients.

Table 7. STEP 4: Results from week 20 to week 68:

^* p<0.0001 (unadjusted 2-sided) for superiority,
¹ Baseline = week 20
² Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment or initiation of other anti-obesity medication or bariatric surgery.
³ During the trial, randomised treatment was permanently discontinued by 5.8% and 11.6% of patients randomized to semaglutide 2.4 mg and placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies, the estimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures including all observations until first discontinuation were -8.1% and 6.5% for semaglutide 2.4 mg and placebo respectively.

Figure 3. STEP 4: Mean change in body weight (%) from week 0 to week 68:

Observed values for patients completing each scheduled visit, and estimates with multiple imputations (MI) from retrieved dropouts

STEP 5: 2-year data

In a 104-week double-blind trial, 304 patients with obesity (BMI ≥30 kg/m²), or with overweight (BMI ≥27 to <30 kg/m²) and at least one weight-related comorbidity, were randomised to semaglutide or placebo. All patients were on a reduced-calorie diet and increased physical activity throughout the trial. At baseline, patients had a mean BMI of 38.5 kg/m², a mean body weight of 106.0 kg.

Treatment with semaglutide for 104 weeks resulted in a superior and clinically meaningful reduction in body weight compared to placebo. Mean body weight decreased from baseline through to week 68 with semaglutide after which a plateau was reached. With placebo, mean body weight decreased less, and a plateau was reached after approximately 20 weeks of treatment (see Table 8 and Figure 4). Patients treated with semaglutide achieved a mean change in body weight of -15.2%, with weight loss ≥5% achieved by 74.7%, ≥10% achieved by 59.2% and ≥15% achieved by 49.7% of these patients. Among patients with prediabetes at baseline, 80% and 37% achieved a normo-glycaemic status at end of treatment with semaglutide and placebo, respectively.

Table 8. STEP 5: Results at week 104:

^* p<0.0001 (unadjusted 2-sided) for superiority.
¹ Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment or initiation of other anti-obesity medication or bariatric surgery.
² During the trial, randomised treatment was permanently discontinued by 13.2% and 27.0% of patients randomised to semaglutide and placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies, the estimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures including all observations until first discontinuation were -16.7% and -0.6% for semaglutide and placebo respectively.
³ Estimated from binary regression model based on same imputation procedure as in primary analysis.

Figure 4. STEP 5: Mean change in body weight (%) from week 0 to week 104:

Observed values for patients completing each scheduled visit, and estimates with multiple imputations (MI) from retrieved dropouts

STEP 8: Semaglutide vs liraglutide

In a 68-week, randomised, open-label, pairwise placebo-controlled trial, 338 patients with obesity (BMI ≥30 kg/m²), or with overweight (BMI ≥27 to <30 kg/m²) and at least one weight-related comorbidity, were randomised to semaglutide once weekly, liraglutide 3 mg once daily or placebo. Semaglutide once weekly and liraglutide 3 mg were open-label, but each active treatment group was double-blinded against placebo administered at the same dosing frequency. All patients were on a reduced-calorie diet and increased physical activity throughout the trial. At baseline, patients had a mean BMI of 37.5 kg/m², a mean body weight of 104.5 kg.

Treatment with semaglutide once weekly for 68 weeks resulted in superior and clinically meaningful reduction in body weight compared to liraglutide. Mean body weight decreased from baseline through to week 68 with semaglutide. With liraglutide, mean body weight decreased less (see Table 9). 37.4% of the patients treated with semaglutide lost ≥20%, compared to 7.0% treated with liraglutide. Table 9 shows the results of the confirmatory endpoints ≥10%, ≥15% and ≥20% weight loss.

Table 9. STEP 8: Results of a 68-week trial comparing semaglutide with liraglutide:

^* p<0.005 (unadjusted 2-sided) for superiority.
¹ Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment or initiation of other anti-obesity medication or bariatric surgery.
² During the trial, randomised treatment was permanently discontinued by 13.5% and 27.6% of patients randomised to semaglutide and liraglutide, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies, the estimated changes from randomisation to week 68 for body weight based on a Mixed Model for Repeated Measures including all observations until first discontinuation were -16.7% and -6.7% for semaglutide and liraglutide respectively.
³ Estimated from binary regression model based on same imputation procedure as in primary analysis.

Effect on body composition

In a sub-study in STEP 1 (N=140), body composition was measured using dual energy X-ray absorptiometry (DEXA). The results of the DEXA assessment showed that treatment with semaglutide was accompanied by greater reduction in fat mass than in lean body mass leading to an improvement in body composition compared to placebo after 68 weeks. Furthermore, this reduction in total fat mass was accompanied by a reduction in visceral fat. These results suggest that most of the total weight loss was attributable to a reduction in fat tissue, including visceral fat.

Improvement in physical functioning

Semaglutide showed small improvements in physical functioning scores. Physical functioning was assessed using both the generic health-related quality of life questionnaire Short Form-36v2 Health Survey, Acute Version (SF-36) and the obesity-specific questionnaire Impact of Weight on Quality of Life Lite Clinical Trials Version (IWQOL-Lite-CT).

Cardiovascular evaluation

In the SUSTAIN 6 trial, 3,297 patients with insufficiently controlled type 2 diabetes and at high risk of cardiovascular events were randomised to semaglutide s.c. 0.5 mg or 1 mg once-weekly or placebo in addition to standard-of-care. The treatment duration was 104 weeks. The mean age was 65 years and the mean BMI was 33 kg/m².

The primary endpoint was the time from randomisation to first occurrence of a major adverse cardiovascular event (MACE): cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. The total number of the MACE was 254, including 108 (6.6%) with semaglutide and 146 (8.9%) with placebo.

The cardiovascular safety of treatment with semaglutide 0.5 or 1 mg was confirmed as the hazard ratio (HR) for semaglutide vs. placebo was 0.74, [0.58, 0.95] [95% CI], driven by a decrease in the rate of non-fatal stroke and non-fatal myocardial infarction with no difference in cardiovascular death (see Figure 5).

Figure 5. Kaplan-Maier plot of time to first occurrence of the composite outcome: Cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (SUSTAIN 6):

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Wegovy in one or more subsets of the paediatric population in the treatment of weight management (see section 4.2 for information on paediatric use).

STEP TEENS: Weight management in adolescent patients

In a 68-week double-blind trial 201 pubertal adolescents, ages 12 to <18 years, with obesity or overweight and at least one weight-related comorbidity were randomised 2:1 to semaglutide or placebo. All patients were on a reduced-calorie diet and increased physical activity throughout the trial.

At end of treatment (week 68), the improvement in BMI with semaglutide was superior and clinically meaningful compared with placebo (see Table 10 and Figure 6). Furthermore, a higher proportion of patients achieved ≥5%, 10% and ≥15% weight loss with semaglutide compared with placebo (see Table 10).

Table 10. STEP TEENS: Results at week 68:

^* p<0.0001 (unadjusted 2-sided) for superiority.
¹ Estimated using an ANCOVA model using multiple imputation based on all data irrespective of discontinuation of randomised treatment or initiation of other anti-obesity medication or bariatric surgery.
² During the trial, randomised treatment was permanently discontinued by 10.4% and 10.4% of patients randomised to semaglutide 2.4 mg and placebo, respectively. Assuming that all randomised patients stayed on treatment and did not receive additional anti-obesity therapies, the estimated changes from randomisation to week 68 for BMI based on a Mixed Model for Repeated Measures including all observations until first discontinuation were -17.9% and 0.6% for semaglutide 2.4 mg and placebo respectively
³ Estimated from logistic regression model based on same imputation procedure as in primary analysis.

Figure 6. STEP TEENS: Mean change in BMI (%) from baseline to week 68:

Observed values for patients completing each scheduled visit, and estimates with multiple imputations (MI) from retrieved dropouts