1 WHAT IS KNOWN AND OBJECTIVE

According to the Obesity Medicine Association, obesity is chronic and treatable disease state from multiple factors with a complex pathophysiology leading to potential health consequences.1 Many factors affect the prevalence of obesity with the most common factors including age, gender, race and economic status.2 Health consequences of obesity can include type 2 diabetes (T2D), dyslipidaemia, hypertension, cardiovascular disease, osteoarthritis and obstructive sleep apnea.1

In 2015, it was estimated that 603.7 million adults had their weight classified as obesity, with an overall prevalence of 12% worldwide in adults.2 This study also discovered that approximately 4 million deaths and increasing rates of disability were associated with the negative health effects of a higher body mass index (BMI).2 In 2019, the Centers for Disease Control estimated the national prevalence of 31.4% for obesity in the United States.3 During 2020, it was noted that people with obesity were at an increased risk of mortality when infected with COVID-19.4 The health and cost burden of obesity on patients, families and health systems does not appear to be going away. It is projected that 1 in 2 adults will have obesity and 1 in 4 adults will have severe obesity in the United States by 2030.5 Therefore, new, innovative medications to treat both obesity and its weight-related comorbidities would be ideal for clinical practice.

The current clinical guidelines are all similar by recommending a goal to improve the health of the patient by preventing and/or treating weight-related complications through weight loss by non-pharmacologic, pharmacologic, or surgical measures when necessary. The short-term treatment goal is reduction of weight by 5%–10% over 3–6 months, with a long-term goal of maintenance of weight loss.6-8 The aggressiveness of a patient's weight loss is often driven by their BMI and other comorbidities. The guidelines define overweight as a BMI between 25 and 29.9 kg/m2 and obesity as a BMI of equal to or above 30 kg/m2.8 First-line therapy should be non-pharmacologic therapy such as behavioural therapy in conjunction with increased physical activity and significant caloric reduction for 6 months. If non-pharmacologic therapy is not adequate after 6 months, then pharmacotherapy with an anti-obesity agent can be initiated as adjunct therapy. The guidelines recommend the implementation of non-pharmacologic and pharmacologic therapy in people with BMI ≥30 kg/m2 or in those with a BMI ≥27 kg/m2 with one or more cardiovascular risk factors, such as hyperlipidaemia, hypertension or diabetes.6-8 The guidelines are limited when it comes to choosing an anti-obesity agent for weight management. However, the choice would be determined based on risks and benefits.9 With lorcaserin removed from the market in 2020, there are now only five medications, approved by the Food and Drug Administration (FDA), for long-term weight management: orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide and most recently semaglutide. The purpose of this review was to provide an analysis of subcutaneous semaglutide as a pharmacotherapeutic option for obesity.

2 METHODS

In people with diabetes, glucagon-like peptide-1 receptor agonists (GLP-1 RA) promote weight reduction. The weight loss benefits of this class of medications have led to the investigation of certain GLP-1 RA, at higher doses, for the treatment of obesity. For people with obesity, weight loss and glycaemic improvement from GLP-1 RA are not the only potential benefits. In clinical trials, long-acting GLP-1 RA appear to also be cardioprotective through the reduction of blood pressure and cholesterol.9 Due to the potential health care consequences from obesity, people at an increased risk for cardiovascular events may benefit from a GLP-1 RA for cardioprotection. The first GLP-1 RA approved by the FDA for the treatment of obesity was liraglutide, marketed by Novo Nordisk as Saxenda. Based on efficacy and safety outcomes from Phase 3 trials, subcutaneous semaglutide was approved by the FDA on 4 June 2021, for the indication of long-term weight management. A MEDLINE search (1970 to June 2021) was conducted to identify Phase 3 trials of subcutaneous semaglutide for obesity management. Published Phase 3 trials from The Semaglutide Treatment Effect in People with obesity (STEP) program were reviewed and summarized.

3 RESULTS AND DISCUSSION 3.1 GLP-1 RA

Semaglutide has shown improved weight reduction compared to liraglutide in patients with or without type 2 diabetes. Superiority of semaglutide to liraglutide in weight reduction was initially shown in a dose-finding trial for treatment of patients with T2D.10 In this trial, participants were treated with either semaglutide once weekly without dose escalation (0.1–0.8 mg), semaglutide once weekly with dose escalation (0.4 mg escalated every 1–2 weeks until reaching 0.8 or 1.6 mg), liraglutide once daily (1.2 or 1.8 mg) or placebo. At the end of the 12 weeks, participants in both the liraglutide and semaglutide experienced ≥5% dose-dependent weight reduction, however, only participants in the semaglutide group experienced ≥10% dose-dependent weight reduction.10 Results like this, began the investigation of semaglutide's therapeutic potential for the treatment of obesity.

In a trial investigating the efficacy of semaglutide compared with liraglutide and placebo, participants were treated with once daily semaglutide at varying doses (initiated at 0.05 mg per day, and escalated to 0.1, 0.2, 0.3 or 0.5 mg per day by 0.05 mg every 4 weeks), liraglutide (initiated at 0.6 mg per day, and escalated to 3.0 mg by 0.06 mg per week), or placebo.11 At the end of 52 weeks, semaglutide was shown to be superior to liraglutide 3.0 mg per day with a dose of 0.2 mg or more per day. In this study, the liraglutide group experienced a mean weight reduction of 7.8% at a dose of 3.0 mg per day which was significantly less than the semaglutide group which experienced weight reduction of 11%–14% at a dose of 0.2 mg per day or more.11 In both trials, both the liraglutide and semaglutide groups had discontinuation due to adverse effects. The most common adverse effects from these early trials were gastrointestinal-related, mainly nausea, vomiting and diarrhoea.10, 11 In the second trial, the semaglutide group experienced higher dose-related gastrointestinal adverse events than the liraglutide group.11 This could be potentially explained by the fact the semaglutide group experienced more dose titration over a longer period of time than the liraglutide group. The adverse events of GLP-1 RA are thought to be dose dependent, present during the titration phase and transient in nature.12 From these trials, it can be concluded that both liraglutide and semaglutide play a role in the treatment of obesity. In the future, the choice of which agent to use will likely be based on the individual weight reduction goals of each patient.

An endogenous hormone, GLP-1 is produced in response to the intake of food by the L cells within the intestinal mucosa.9 GLP-1 receptors are present throughout the body. However, the receptors within the pancreas, gastrointestinal tract, heart and brain are what potentially play a role in diabetes, weight management and the cardioprotective effects of GLP-1 RA.12 The exact mechanism behind how GLP-1 RA promote weight reduction is not entirely understood. Many potential mechanisms of action have been suggested. In the pancreas, GLP-1 upregulates the secretion of insulin from pancreatic beta cells, while increasing insulin sensitivity throughout the body. GLP-1 also acts on the alpha cells of the pancreas to simultaneously decrease the release of glucagon.9, 12 GLP-1 also appears to have other effects on metabolism such as promoting fat oxidation over carbohydrates and decreasing hepatic gluconeogenesis.9 In the gastrointestinal tract, GLP-1 works to slow down gastrointestinal motility, increase satiety, as well as potential protective effects of decreased acid production from the parietal cells and increased intestinal mucus secretion.12 In the heart, GLP-1 receptors are found mainly on the sinoatrial nodes and myocytes, which may be the cause of the sustained increase in heart rate with GLP-1 RA treatment.12 In the brain, GLP-1 communicates with the hypothalamus, regulating the appetite by increasing satiety signalling.9, 12 Semaglutide is thought to affect the brain with a unique mechanism apart from other GLP-1 receptor agonists. Treatment with semaglutide has been associated with the food/reward system, increasing an individual's ability to control food intake and altering food preferences (ie, a lower liking for high-fat foods).12 Taking all of these potential mechanisms of action into consideration, there does not appear to be just one main mechanism behind how GLP-1 RA promote weight reduction. It is most likely that each mechanism plays a role in a combined effect which ultimately leads to improved weight control.

Both liraglutide and semaglutide are modified to reversibly bind to serum albumin in the body, increasing the half-life of these agents through protecting the peptide from dipeptidyl peptidase-IV degradation and renal filtration.12 Semaglutide's structure is 94% homologous to the endogenous hormone GLP-1. Three modifications to semaglutide's structure improve it is half-life to 165 hours which is approximately 1 week.13 These modifications include, the substitution of alanine to alpha-aminoisobutyric acid at position eight, lysine to arginine at position thirty-four, and finally, acylation of the lysine in position twenty-six that includes a spacer consisting of two 8-amino-3,6-dioxaoctanoic acid moieties, a C-18 fatty di-acid side chain and a glutamic acid moiety.12, 13 Metabolism of semaglutide occurs slowly through proteolysis of the peptide backbone, as well as beta oxidation of the di-fatty acid side chain.13 The degradation products are then excreted through the urine and faeces, with a very limited amount of unchanged semaglutide excreted in the urine approximately three per cent.13 Due to no single organ being implicated in semaglutide's metabolism, dose adjustment may not be necessary for patients with hepatic or renal impairment.14, 15

3.2 Clinical trials

The FDA has a guiding document of clinical trials for obesity management.16 To determine effectiveness, the FDA suggested an endpoint of weight loss from baseline; clinical significance would be met if an active medication results in a 5% or more placebo-subtracted difference for the primary outcome. The guiding document also suggests additional endpoints, including percentage of participants achieving 5% or 10% of weight loss from baseline. This endpoint aligned with recommended weight loss from clinical practice guidelines. For this endpoint, clinical significance would be met if either the active medication had 35% or more of the participants have a weight loss of 5% or at least double the number of participants with the active medication had a weight loss of 5%, compared to placebo. Most likely these three outcomes would also be statistically significant upon analysis.16

In the Semaglutide Treatment Effect in People with obesity (STEP) program with semaglutide, all participants were adults with obesity or were overweight regardless of diabetes status.17-20 Counselling on lifestyle modifications were provided periodically by a dietitian or healthcare professional and throughout the trial. In addition, participants also received tools for physical activity, such as kettlebells and jump ropes. Lifestyle modification did vary though among the five clinical trials. In STEP 1, 2, 4 and 5, participants were advised on a daily 500 calorie reduction and 150 min of physical activity, whereas participants in STEP 3 were encouraged to follow intensive behavioural therapy with a low-calorie diet. Overall, there were more than 5000 participants in the STEP program to evaluate semaglutide versus placebo. In all clinical trials, semaglutide was titrated to a maximum dose of 2.4 mg subcutaneously per week. Refer to Table 1 for baseline characteristics of participants within STEP 1–4 trials.17-20

TABLE 1. Baseline characteristics of participants in STEP program

Step 1

N = 1961

Step 2

N = 1210

Step 3

N = 611

Step 4

N = 902

Female, n (%) 1453 (74.1) 616 (50.9) 495 (81.0) 717 (79.5) Age, y 46.5 ± 12.7 55.3 ± 10.6 46.2 ± 12.7 46.4 ± 11.9 Race, n (%) White 1472 (77.2) 751 (62.1) 465 (76.1) 751 (83.3) African American 111 (5.8) 100 (8.3) 116 (19.0) 123 (13.6) Asian 261 (13.7) 317 (26.2) 11 (1.8) 19 (2.1) Hispanic 236 (12.0) 155 (12.8) 121 (19.8) 70 (7.8) Other 62 (3.2) 42 (3.5) 19 (3.2) 9 (1.0) BMI, kg/m2 37.9 ± 6.7 35.7 ± 6.3 38.0 ± 6.7 38.3 ± 7.0 Waist Circumference, cm 114.7 ± 14.7 114.6 ± 14.1 113.0 ± 15.5 115.1 ± 15.6 Blood pressure, mmHg) Systolic 126.5 ± 14.3 130.0 ± 13.5 124.4 ± 14.8 126.4 ± 14.3 Diastolic 80.3 ± 9.6 79.8 ± 9.0 80.5 ± 9.7 80.9 ± 9.9 Cholesterol, mg/dl Total 4.9 ± 20.0 4.4 ± 23.3 4.8 ± 19.7 5.0 ± 19.5 HDL 1.3 ± 25.5 1.1 ± 24.5 1.3 ± 23.6 1.29 ± 24.6 LDL 2.9 ± 28.7 2.3 ± 35.6 2.8 ± 28.5 3.0 ± 27.3 VLDL 0.6 ± 51.1 0.8 ± 51.6 0.6 ± 48.1 0.6 ± 53.6 Triglycerides 1.4 ± 70.0 1.8 ± 64.2 1.2 ± 49.8 1.4 ± 54.9 Overall eGFR, ml/min/1.73 m2 96.6 ± 17.2 93.7 ± 19.5 96.8 ± 19.5 97.6 ± 17.8 3.3 Efficacy

STEP 1 was a randomized, double-blind, multi-centred, placebo-controlled trial. In this trial, adults with a BMI of ≥30 or a BMI of ≥27 kg/m2 with one or more treated or untreated weight-related co-existing conditions, such as hypertension, cardiovascular disease or obstructive sleep apnoea, who reported at least one unsuccessful dietary effort to lose weight were included in this trial.17 Individuals who had diagnosed diabetes, a haemoglobin A1C of ≥6.5%, a history of chronic pancreatitis, acute pancreatitis within 180 days before enrolment, previous surgical obesity treatment, or the use of anti-obesity medication within 90 days were all excluded from enrolment in this trial. Randomized in a 2:1 ratio, 1961 participants either received semaglutide at a dose of 2.4 mg administered subcutaneously once a week for 68 weeks or a matching placebo combined with lifestyle interventions. Lifestyle interventions include counselling sessions every 4 weeks to help participants adhere to a reduced calorie diet and increased physical activity of 150 min per week. The coprimary endpoints were the percentage change in body weight and a weight reduction of at least 5%. At week 68, in the semaglutide group, the mean change in body weight was −14.9% compared to −2.4% in the placebo group (p < 0.001). In the semaglutide group, 86.4% of participants achieved weight reductions of ≥5%, and 69.1% of participants achieved weight reductions of ≥10%, compared to 31.5% and 12.0% of participants within the placebo group (p < 0.001, NNT = 2).17 Limitations to consider are the relative short duration of the trial, the limited representation of minorities, and the higher percentage of women in participation of this study than men. In STEP 1, 2.4 mg of semaglutide once weekly was associated with clinically relevant reductions in body weight.

STEP 2 was a randomized, double-blind, multi-centred, placebo-controlled, superiority trial.18 Adults who were eligible for this trial must have reported at least one unsuccessful dietary effort to lose weight, a BMI of at least 27 kg/m2, a haemoglobin A1C of 7%–10% and had been diagnosed with T2D within 180 days before screening and were managed with diet and exercise alone or with up to three different oral glucose-lowering agents for at least 90 days before screening.18 Adults who reported body weight changes of more than 5 kg within 90 days before screening or who had previous or planned obesity treatment with surgery, or a weight loss device were excluded from this study. Randomized in a 1:1:1 ratio, 1210 participants, received once weekly either 2.4 mg of semaglutide, 1.0 mg of semaglutide or placebo subcutaneously for 68 weeks combined with lifestyle interventions. Lifestyle interventions were the same as those listed above in the STEP 1 trial. Patients were counselled every 4 weeks, by a qualified health professional and were encouraged to keep a food and activity diary. The coprimary endpoints were the percentage change in body weight and a weight reduction of at least 5%. At week 68, in the 2.4 mg semaglutide group, the mean change in body weight was −9.64% compared to −6.99% in the 1.0 mg semaglutide group, and −3.42% in the placebo group (p < 0.001). The percentages of participants who achieved weight reduction of ≥5% were 68.8%, in the 2.4 mg semaglutide group, 57.1% in the 1.0 mg semaglutide group, and 28.5% in the placebo group (p < 0.001). The percentages of participants who achieved weight reduction of ≥5% were 68.8%, in the 2.4 mg semaglutide group, 57.1% in the 1.0 mg semaglutide group, and 28.5% in the placebo group (p < 0.001, NNT = 4). The percentages of participants who achieved weight reduction of ≥10% were 45.6%, in the 2.4 mg semaglutide group, 28.7% in the 1.0 mg semaglutide group and 8.2% in the placebo group (p < 0.001).18 A limitation from the STEP 2 trial could be the exclusion of patients who are on insulin, as this patient population could benefit from the weight loss associated with the add on of semaglutide with insulin; this information is difficult to extrapolate to individuals on insulin therapy. In STEP 2, 2.4 mg of semaglutide once weekly achieved superior and clinically relevant reductions in body weight compared with placebo in participants who were overweight or obese, with T2D.

STEP 3 was a randomized, double-blind, placebo-controlled, multi-centred trial.19 In this trial, adults with a BMI of ≥30 kg/m2 or a BMI of ≥27 kg/m2 with one or more treated or untreated weight-related co-existing conditions, who reported at least one unsuccessful dietary effort to lose weight were included in this trial. Adults who had diagnosed diabetes, a haemoglobin A1C of ≥6.5%, who reported body weight changes of more than 5 kg within 90 days before screening or who had previous or planned obesity treatment with surgery, or a weight loss device were excluded from this study. In the trial, 611 participants were randomized 2:1 to receive either once weekly 2.4 mg of semaglutide subcutaneously or placebo, combined with a low-calorie diet for the first 8 weeks and behavioural therapy during the 68 weeks. For the first 8 weeks, participants received low-calorie (1000–1200 kcal/d) meal replacements provided by Nutrisystem. After 8 weeks, participants transitioned to a hypo-caloric diet (1200–1800 kcal/d) of conventional food for the remaining 68 weeks. Participants were also prescribed 100 min of physical activity per week which was increased weekly by 25 min until participants reached 200 min/wk. Participants also received 30 individual therapy visits with a registered dietician who counselled on diet, physical activity and behavioural strategies. The coprimary endpoints were the percentage change in body weight and a weight reduction of at least 5%. At week 68, the mean weight reduction in the semaglutide group was −16.0% compared to the placebo group which was −5.7% (p < 0.001). The percentage of those who achieved ≥5% weight reduction in the semaglutide group was 86.6% and 47.6% in the placebo group (p < 0.001, NNT = 3). The percentage of those who achieved ≥10% weight reduction in the semaglutide group was 75.3% and 27.0% in the placebo group (p < 0.001).18 Limitations of this trial include the short duration of the trial and the inability to identify the separate contributions to weight loss of the lifestyle modifications. Overall, semaglutide in combination with both a low-calorie diet and behavioural therapy resulted in significantly greater weight loss than placebo based on results from the STEP 3 trial.

The STEP 4 was a randomized, double-blind, placebo-controlled, multi-centred withdrawal study.20 Included in this trial was adults with a BMI of ≥30 kg/m2 or a BMI of ≥27 kg/m2 with one or more treated or untreated weight-related co-existing conditions, who reported at least one unsuccessful dietary effort to lose weight. Excluded were those who reported body weight changes of more than 5 kg within 90 days before screening or a haemoglobin A1C of ≥6.5%. For 20 weeks, all 803 individuals participated in a run-in period. During this period, participants received semaglutide starting at 0.25 mg and titrated up to 2.4 mg by week 16 and continued to week 20. At week 20, participants were randomized 2:1 to either continue the semaglutide 2.4 mg or to receive placebo for the remaining 48 weeks. All participants received behavioural therapy, a reduced calorie diet and increased physical activity during the 68 weeks. The primary endpoint of this study was the per cent change in body weight from week 20 to week 68. At week 68, the mean per cent body weight change in the semaglutide 2.4 mg group was −7.9% compared to 6.9% in the placebo group (p < 0.001).20 Limitations to consider in the STEP4 trial are the potential selection bias due to the run-in period and withdrawal design, and the lack of assessment of adherence to lifestyle modifications. In STEP 4, continued treatment with semaglutide showed sustained clinically relevant weight loss as compared to switching to placebo.

3.4 Other outcomes

In the STEP trials, confirmatory secondary endpoints were achievement of a reduction in body weight of ≥10% and ≥15% by week 68 and the change from baseline to week 68 in waist circumference, systolic blood pressure and physical function score on the Short Form Health Survey (SF-36) version 2 and on the Quality of Life-Lite Clinical Trials Version questionnaire (IWQOL-LiteCT).17-20 Table 2 summarizes the confirmatory secondary endpoints from the STEP program.

TABLE 2. Confirmatory secondary endpoints STEP 1 STEP 2 STEP 3 STEP 4

Semaglutide

(n = 1306)

Placebo

(n = 655)

Semaglutide 2.4 mg

(n = 403)

Semaglutide

1.0 mg

(n = 402)

Placebo

(n = 402)

Semaglutide

(n = 407)

Placebo

(n = 204)

Semaglutide

(n = 535)

Placebo

(n = 268)

Weight reduction of ≥10% (%) 69.1 12.0 45.6 28.7 8.2 75.3 27.0 N/A N/A Weight reduction of ≥15% (%) 50.5 4.9 25.8 13.7 3.2 55.8 13.2 N/A N/A Changes from baseline to week 68 WC (cm) −13.54 −4.13 −9.4 −6.7 −4.5 −14.6 −6.3 −6.4 3.3 SBP (mmHg) −6.16 −1.06 −3.9 −2.9 −0.5 −5.6 −1.6 0.5 4.4 SF-36 2.21 0.41 2.5 2.4 1.0 2.4 1.6 1.0 −1.5 IWQOL-Lite 14.67 5.25 10.1 8.7 5.3 N/A N/A N/A N/A Abbreviations: IWQOL-Lite, Impact of Weight on Quality of Life – Lite; SBP, systolic blood pressure; SF-36, Short Form 36; WC, waist circumference.

Supplementary secondary endpoints in all trials were changes from baseline to week 68 in BMI, body weight, A1C, fasting plasma glucose, diastolic blood pressure and a fasting lipid panel.17-20 Other supplementary secondary endpoints not included in every trial was a body weight reduction ≥20% in STEP 1 and 3, body composition changes in STEP 1 and changes in baseline C-reactive protein in STEP trials 1, 2 and 3.17-19

In STEP 1, other exploratory endpoints favoured the use of semaglutide. In the prediabetes subpopulation, 84.1% of participants had normoglycemia at week 68 compared to 47.8% in the placebo group.17 The comparison of A1C levels from baseline to week 68 showed a reduction of 0.52 percentage points in the semaglutide group compared to a reduction of 0.17 percentage points in the placebo group.17 In STEP 2, the exploratory endpoint focused around the potential reduction of other glucose-lowering medications with semaglutide use.18 In STEP 2, the 2.4 mg semaglutide group experienced a 28.6% reduction in concomitant use of glucose-lowering medication as compared to 25.1% in the 1.0 mg semaglutide group and 7.1% in the placebo group.18 Table 3 highlights secondary endpoints from the STEP 1–4 trials.

TABLE 3. Supplementary secondary endpoints STEP 1 STEP 2 STEP 3 STEP 4

Semaglutide

(n = 1306)

Placebo

(n = 655)

Semaglutide 2.4 mg

(n = 403)

Semaglutide

1.0 mg

(n = 402)

Placebo

(n = 402)

Semaglutide

(n = 407)

Placebo

(n = 204)

Semaglutide

(n = 535)

Placebo

(n = 268)

Changes from baseline to week 68 BMI −5.54 −0.92 −3.5 −2.5 −1.3 −6.0 −2.2 −2.6 2.2 Body weight (kg) −15.3 −2.6 −9.7 −6.9 −3.5 −16.8 −6.2 −7.1 6.1 Change in A1C (percentage points) −0.45 −0.15 −1.6 −1.5 −0.4 −0.51 −0.27 −0.1 0.1 Fasting plasma glucose (mg/dl) −8.35 −0.48 −2.1 −1.8 −0.1 −6.73 −0.65 −0.8 6.7 DBP (mmHg) −2.83 −0.42 −1.6 −0.6 −0.9 −3.0 −0.8 0.3 0.9 Cholesterol parameters (mg/dl) Total cholesterol 0.97 1.00 0.99 0.98 0.99 −3.8 2.1 5 11