Semaglutide Usage as a Weight Loss Management - Literature Review Volume 58- Issue 4

Hananeh Rahmanpoor*

• College of Pharmacy, Ajman University, U.A.E

Received: August 26, 2024; Published: September 13, 2024

*Corresponding author: Hananeh Rahmanpoor, College of Pharmacy, Ajman University, P.O.BOX:346, Ajman, U.A.E

DOI: 10.26717/BJSTR.2024.58.009179

Abstract PDF

ABSTRACT

Background: Obesity has become a global public health concern. Categorized by fat accumulation and body mass index (BMI ≥ 30 kg/m2). Weight management is crucial for a healthy lifestyle and for reducing obesity-related complications through several strategies: pharmacotherapy treatments along with lifestyle modifications. This literature review aimed to discuss selected studies and understand the role of semaglutide in weight loss management.
Methods: The articles have been searched through Google Scholar, Semantic Scholar, ResearchGate, PMC, and PubMed databases. Studies have been related to the benefits, formulations, adverse effects, clinical trials, and maintenance after discontinuation of semaglutide been accessed.
Results: Studies reveal the efficacy of semaglutide on weight loss. The adverse effects observed in patients treated with semaglutide include gastrointestinal adverse events, like nausea, vomiting, diarrhea, constipation, and abdominal cramps.
Conclusion: The review suggests that semaglutide appears to be beneficial in its contribution to weight loss management.

Keywords: Obesity; Weight Loss Management; Medication; Semaglutide

Abbreviations: BMI: Body Mass Index; FDA: Food and Drug Administration; NICE: National Institute for Health and Care Excellence; EMA: European Medicines Agency’s; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; AOMS: anti-obesity medications; GLP: Glucagon-like peptide; BS: bariatric surgery; SUSTAIN: Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes; STEP: Semaglutide Treatment Effect in People with Obesity; PIONEER: Peptide Innovation for Early Diabetes Treatment

Introduction

Obesity is a chronic disease with continuously rising prevalence that currently affects over a third of the world’s population [1,2]. Obesity means excessive fat accumulation, most commonly defines as body mass index (BMI) equal or higher than 30 kg/m², by calculating: weight (kg)/height² (m²) [3]. Obesity can be caused by unbalance between energy intake and energy expenditure [4]. Weight management through lifestyle modification includes reduced energy intake and increased physical activity [5]. Pharmacotherapy treatments, with lifestyle modifications, are required for effective body weight reduction [6,7]. There are different anti-obesity medications used in weight management to prevent obesity-related complications like cardiovascular risk factors and hyperglycemia [8,9]. Semaglutide belongs to incretin mimetic that binds to glucagon-like peptide-1 receptor, stimulates insulin secretion and inhibits glucagon secretion [10]. Semaglutide, a glucagon-like peptide-1 GLP-1 agonist, induces weight loss through central mechanisms by delaying gastric emptying, increasing satiety, decreasing appetite and reducing energy intake [11- 13]. Semaglutide was approved for weight loss by the UK Medicine and Health Products Regulations Agency in 2021, the Food and Drug Administration (FDA) in 2021, the National Institute for Health and Care Excellence (NICE) in 2022, and the European Medicines Agency’s (EMAs) Committee for Medicinal Products for Human Use in 2022 [14-16]. Semaglutide is used along with reduced-calorie diet and exercise programs to control weight loss in obese or overweight adults [17]. Semaglutide may cause side effects as nausea, vomiting, diarrhea, abdominal pain, constipation, heartburn, fainting or dizziness, rapid heartbeat, sweating, back pain, headache, and blurred vision [18,19]. Multiple papers provided essential insights into using semaglutide in managing obesity, with their potential benefits, side effects, and possible mechanisms of action [20]. This literature review aimed to discuss selected studies and understand the role of Semaglutide in weight loss management.

Methods

The articles have been searched through databases like Google Scholar, Semantic Scholar, ResearchGate, PMC, and PubMed. The results were in English and contains keywords of Semaglutide, Weight Management, Obesity. The study selection process flow chart was generated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [21].

Results

A total of 1977 articles have been identified via databases. After removing duplicate articles, 384 articles were evaluated for screening and 169 articles were assessed for eligibility. After excluding the duplicates and other parameters, 10 articles have been chosen to be included in the review (Figure 1). Studies have been related to the benefits, formulations, adverse effects, clinical trials, and maintenance after discontinuation of semaglutide been accessed as in Table 1 [22-31].

Discussion

Obesity is a chronic condition with increased risk of obesity-related comorbidities comprising type 2 diabetes, dyslipidemia, and cardiovascular events [32-34]. However, conservative approaches such as lifestyle modification, dietary control and physical activity are usually unsatisfactory to achieve satisfactory weight reduction in patients with obesity [35-37] Successful obesity management expands beyond weight loss, as it is important to highlight the assessment of the life quality and the prevention of obesity-related comorbidities [38]. The ideal treatment for obesity should be a highly individualized, personalized medicine. Treatment decisions will consider age, coexisting diseases, drug tolerance, and economic and local medical conditions [39].

Glucagon-like peptide-1 (GLP-1) is a gut hormone released in response to food intake that acts as a satiety signal, stimulates insulin release, inhibits glucagon secretion, and regulates gastric emptying [40-42]. GLP-1-RAs reduce weight, improve fasting and postprandial glucose and lipid metabolism, and decrease cardiovascular events [43-50]. In the field of anti-obesity medications (AOMs), GLP-1-RAs are the latest class of drugs to be approved for the treatment of obesity [51,52].

Combining obesity medications with different mechanisms of action might be beneficial for individuals with overweight or obesity, providing more effective treatment options for weight management [53]. Semaglutide is a GLP-1 analogue that binds to the GLP-1 receptor in pancreatic β-cells to induce insulin secretion through a glucose concentration-dependent mechanism [54-57]. Semaglutide is a long-acting Glucagon-like peptide-1receptor agonist (GLP-1Ra) that is available as a once-weekly subcutaneous (at doses up to 2.4 mg) and as a once-daily oral (at doses up to 14 mg) and has been shown to have the most potent effect on glucose lowering and weight loss within the class [58,59]. Semaglutide is illustrated as an adjunct to a reduced-calorie diet and increased physical activity for weight loss management in adults with Body Mass Index (BMI) of ≥ 30 kg/ m2 (obesity), or ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity [60].The efficacy and safety profiles of semaglutide have an overall beneficial risk/benefit in obese/overweight individuals [61-63].

Benefits of Semaglutide

Semaglutide has demonstrated substantial weight reduction in patients with obesity with type 2 diabetes (diabesity) and without as a weight loss adjuvant therapy [64-66]. Switching from other GLP-1 RAs to semaglutide resulted in a significant decrease in HbA1c and body weight [67-75]. Semaglutide provided significant weight loss due to a reduction in fat mass whilst improving body composition along with lifestyle intervention for overweight/obesity in people with and without diabetes [76-78]. results highlighted by Moiz A et al. [23] Semaglutide appears to be a promising agent and more potent than existing GLP-1 RAs for body weight control in obese type 2 diabetes patients as observed in Deng Y, et al. [28] and multiple studies conducted for comparative results between semaglutide and liraglutide [79-84]. Physiological actions of GLP-1 RAs as semaglutide have been discussed in Figure 2 [85] Semaglutide, a glucagon-like peptide- 1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes [86,87] as observed in hypothesis by Lincoff AM et al.29 Weight Reduction by ≥3%, ≥5%, ≥10%, ≥15%, and ≥20% is enough to achieve a significant improvement in cardiovascular events [88,89].Treatment options to manage post-surgery excess weight regain are scarce [90,91]. Kanai R et al. [24] and other studies [92,93] discussed that semaglutide was found to be more effective for treating patients with a history of bariatric surgery (BS),

who have not achieved sufficient weight loss or who have experienced weight regain, and also who are on a waiting list for a bariatric procedure to reduce perioperative complications [94] Treatment with semaglutide improved obese patients’ health and quality of life in people with overweight/obesity and at least one obesity-related comorbidity [95,96].

Formulations of Semaglutide

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) that, until recently, were only available for administration by subcutaneous injection, which frequently represented a treatment barrier for the patient [97]. Recently, oral semaglutide, the first GLP-1RA for oral administration, was made available for use in clinical practice worldwide, and it has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [98]. Oral semaglutide by using SNAC (sodium N-[8- (2-hydroxybenzoyl)amino] caprylate), an absorption enhancer, facilitates absorption across the gastric mucosa. Oral semaglutide is effective and safe, and associated with high patient satisfaction [99-103]. To reduce semaglutide exposure to gastric mucosa, the approved label instructs to take oral semaglutide with 4 fl oz (120 mL) of plain water on an empty stomach followed by fasting of at least 30 min [104-106]. Semaglutide, administered orally or subcutaneously, provided significant reductions in HbA1c and body weight in patients with type 2 diabetes and obesity [107-116]. Oral formulation of semaglutide, in addition to improving glucose control and body weight, exerts beneficial effects on body composition by reducing fat mass [117,118]. Semaglutide has a pharmacokinetic profile with a long half-life that allows for once-weekly subcutaneous administration. Oral semaglutide is significantly faster than subcutaneous administration [119].

Adverse Effects of Semaglutide

Semaglutide exhibits various adverse events as reported by Chiappini S et al. [22] The main adverse events were related to the gastrointestinal tract as: nausea, vomiting, diarrhea, pancreatitis, fatigue, and dehydration [120-123]. The increase in semaglutide consumption is associated with “off-label” prescribing of semaglutide for weight loss in people without type 2 diabetes [124]. To reduce the risks, especially of severe ADRs or unfavorable outcomes, stakeholders should promote the correct use and dispensing of drug with increased carefulness in patient counselling to improve healthcare outcomes [125].

Clinical Trials

Clinical trials evaluate the efficacy of GLP-1 agonists in weight management across various patient populations by examining the changes of weight, weight-related comorbidities, and associated adverse events [126]. Moreover, improvements in cardiometabolic risk factors, such as blood pressure, lipid levels, and glycemic control, have been observed alongside weight loss, highlighting the potential for comprehensive metabolic benefits [127]. Most of the studies demonstrated a positive effect of semaglutide for obesity treatment. Some studies also revealed a dose-dependent effect of the therapy in those with poorly controlled diabetes [128]. This literature review discusses the weight loss results from the STEP (Semaglutide Treatment Effect in People with Obesity), SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes), and PIONEER (Peptide Innovation for Early Diabetes Treatment) clinical trials [129,130].

Step Trial

The efficacy and safety of semaglutide for weight management was discussed in Alabduljabbar K et al.25 and multiple studies [131- 144] highlighting the Semaglutide Treatment Effect in People with Obesity (STEP) program, collection of phase-III trials, evaluating once-weekly subcutaneous semaglutide 2.4 mg in people with overweight or obesity. The phase III STEP clinical trials have shown that semaglutide provides remarkedly reduce body weight, improve glycemic control, and improve cardiometabolic risk factors in adult with overweight/obesity with or without type 2 diabetes [145-148]. The researchers conducted 10 trials of semaglutide efficacy in different populations, different measures of semaglutide intake, and different durations to determine semaglutide effectiveness in weight loss as in Table 2, Figures 3 & 4 [149]. The STEP 1 trial [150] (ClinicalTrials.gov identifier: NCT03548935) was a 68-week, randomized, double blind, placebo-controlled trial of once-weekly subcutaneous semaglutide 2.4 mg or placebo, plus lifestyle intervention for weight management in adults with obesity or overweight with type 2 diabetes. In STEP 1, mean weight loss was -14.9% with semaglutide 2.4 mg versus -2.4% with placebo from baseline to week 68. At week 68, more participants in the semaglutide group than in the placebo group achieved weight reductions of 5% (86.4% vs. 31.5%), 10% (69.1% vs. 12.0%), 15% (50.5% vs. 4.9%), and 20% (32.0% vs. 1.7%).

The STEP 2 trial [151] (ClinicalTrials.gov identifier: NCT03552757) was a 68-week, randomized, double blind, placebo- controlled trial of once-weekly subcutaneous semaglutide 2.4 mg, semaglutide 1.0 mg, or placebo for weight management in adults with obesity or overweight with type 2 diabetes. In STEP 2, mean weight loss was -9.6% with semaglutide 2.4 mg and -7.2% with Semaglutide 1.0 mg versus -3.4% with placebo from baseline to week 68. At week 68, more participants in the semaglutide groups (semaglutide 2.4 mg, 1.0 mg) respectively than in the placebo group achieved weight reductions of 5% (68.8%, 57.1% vs. 28.5%), 10% (45.6%, 28.7% vs. 8.2%), 15% (25.8%, 13.7% vs. 3.2%), and 20% (13.1%, 4.7% vs. 1.6%). The STEP 3 trial [152] (ClinicalTrials.gov identifier: NCT03611582) was a 68-week, randomized, double blind, parallel-group, placebo-controlled trial of once-weekly subcutaneous semaglutide 2.4 mg or placebo for weight management in adults with obesity or overweight with type 2 diabetes. In STEP 3, mean weight loss was -16.5% with semaglutide 2.4 mg versus -5.8% with placebo from baseline to week 68. At week 68, more participants in the semaglutide group than in the placebo group achieved weight reductions of 5% (86.6% vs. 47.6%), 10% (75.3% vs. 27.0%), 15% (55.8% vs. 13.2%), and 20% (35.7% vs. 3.7%).

The STEP 4 trial [153] (ClinicalTrials.gov identifier: NCT03548987) was a 68-week, randomized, double blind, placebo- controlled trial of once-weekly subcutaneous semaglutide 2.4 mg or placebo for weight management in adults with obesity or overweight with type 2 diabetes. Semaglutide was administered in a dose-escalated fashion for a 20-week run-in period. In STEP 4, mean weight loss was -8.3% with semaglutide 2.4 mg versus 6.5% with placebo from baseline to week 68. At week 68, more participants in the semaglutide group than in the placebo group achieved weight reductions of 5% (88.7% vs. 47.6%), 10% (79.0% vs. 20.4%), 15% (63.7% vs. 9.2%), and 20% (39.6% vs 4.8%).The STEP 5 trial [154] (Clinical- Trials.gov identifier: NCT03693430) was 104-week, randomized, placebo- controlled trial of once-weekly subcutaneous semaglutide 2.4 mg or placebo for weight management in adults with obesity or overweight with type 2 diabetes. In STEP 5, mean weight loss was -15.9% with semaglutide 2.4 mg versus -2.1% with placebo from baseline to week 104. At week 104, more participants in the semaglutide group than in the placebo group achieved weight reductions of 5% (77.1% vs. 34.4%), 10% (61.8% vs. 13.3%), 15% (52.1% vs. 7.0%), and 20% (36.1% vs 2.3%).The STEP 6 trial [155] (ClinicalTrials.gov identifier: NCT03811574) was a 68-week, randomized, placebo-controlled trial of either semaglutide 2.4 mg or placebo, or semaglutide 1.7 mg or placebo in east Asian adults, with or without type 2 diabetes: only 25% of the patients had diabetes.

In STEP 6, mean weight loss was -13.4% with semaglutide 2.4 mg and -9.9% with semaglutide 1.7 mg versus -1.9% with placebo from baseline to week 68. At week 68, more participants in the semaglutide groups (semaglutide 2.4 mg, 1.7 mg) respectively than in the placebo group achieved weight reductions of 5% (82.9%, 72.4% vs. 21.0%), 10% (60.6% , 41.8% vs. 5.0%), 15% (40.9%, 24.5% vs. 3.0%), and 20% (19.7%, 11.2% vs. 2.0%).The STEP 7 trial [156] (ClinicalTrials. gov identifier: NCT04251156) was a 44-week, randomized, placebo- controlled trial of once-weekly subcutaneous semaglutide 2.4 mg for weight management in people from east Asia with overweight or obesity and with or without type 2 diabetes. In STEP 7, mean weight loss was -12.1% with semaglutide 2.4 mg versus -3.6% placebo from baseline to week 44. At week 44, more participants in the semaglutide group than in the placebo group achieved weight reductions of 5% (85.3% vs. 31%), 10% (63.4% vs. 10.3%), 15% (34.5% vs. 6.0%), and 20% (14.3% vs 1.7%).The STEP 8 trial [157] (ClinicalTrials.gov identifier: NCT04074161) was a 68-week, randomized, placebo-controlled trial of either once-weekly semaglutide 2.4 mg, or once-daily liraglutide 3.0 mg, or placebo in adults with obesity or overweight with type 2 diabetes.. In STEP 8, mean weight loss was -16.4% with semaglutide 2.4 mg, -6.4% with liraglutide 3 mg and -1.4% with placebo from baseline to week 68. At week 68, more participants in the semaglutide, liraglutide groups respectively than in the placebo group achieved weight reductions of 10% (70.9%, 25.6% vs. 15.4%), 15% (55.6%, 12.0% vs. 6.4%), and 20% (38.5%, 6.0% vs 2.6%).

The STEP 10 trial [158] (ClinicalTrials.gov identifier: NCT05040971) was a 52-week, randomized, double-blind, placebo- controlled trial of once-weekly subcutaneous semaglutide 2.4 mg for weight management and glycaemic control in people with obesity and prediabetes. In STEP 10, mean weight loss was -13.9% with semaglutide 2.4 mg versus -2.7% placebo from baseline to week 52. At week 52, more participants in the semaglutide group than in the placebo group achieved weight reductions of 5%, 10%, 15% (50% vs. 1.5%), and 20% (24.8%).The STEP TEENS trial [159] (Clinical- Trials.gov identifier: NCT04102189) was a 68-week, randomized, double-blind, parallel-group, randomized, placebo-controlled trial of once-weekly subcutaneous semaglutide 2.4 mg in adolescents with obesity or overweight. In STEP TEENS, mean weight loss was -16.2% with semaglutide 2.4 mg versus 0.6% placebo from baseline to week 68. At week 68, more participants in the semaglutide group than in the placebo group achieved weight reductions of 5% (72.5% vs. 17.7%), 10% (61.8% vs. 8.1%), 15% (53.4% vs. 4.8%), and 20% (37.4% vs 3.2%).

Safety

In all the STEP studies, semaglutide was involved with more gastrointestinal- related side effects than placebo. The side effects were nausea, diarrhea, vomiting, constipation, and nasopharyngitis as in Table 3 [160,161] In STEP 1,150 the rate of any reported side effect was higher with semaglutide contrasted with placebo (80.55% vs. 68.24%). The number of reported serious side effects was greater in the semaglutide arm compared to the placebo arm (9.80% vs. 6.41%). In STEP 2,151 the rate of any reported side effect was higher with 70.47% in semaglutide 2.4 mg and 64.93% in semaglutide 1.0 mg contrasted with 47.26% in placebo. Moreover, the number of reported serious side effects was comparable between all treatment arms as 9.93% in semaglutide 2.4 mg, 7.71% in semaglutide 1.0 mg and 9.20% in placebo. In STEP 3,152 the rate of reported side effect was comparable between the semaglutide and placebo arms (93.12% vs. 86.76%). Moreover, the number of reported serious side effects was greater in the semaglutide arm contrasted with the placebo arm (9.09% vs. 2.94%). In STEP 4,153 the rate of any adverse event was greater in the continued semaglutide arm than the switched placebo arm (55.14% vs. 42.54%). The number of serious side effects was higher in the continued semaglutide arm contrasted with the switched placebo arm (7.66% vs. 5.60%).In STEP 5,154 the rate of any adverse event was greater after semaglutide compared to placebo (92.76% vs. 76.97%). The number of reported serious side effects was unexpectedly lower in the semaglutide arm contrasted with the placebo arm (7.89% vs. 11.84%).

In STEP 6,155 the rate of reported adverse events was 71.36% in the semaglutide 2.4 mg group, 73% in the semaglutide 1.7 mg group, and 48.51% in the placebo group. Unexpectedly, the percentage of serious adverse events was lower in the semaglutide 2.4 mg arm (5.03%) contrasted with semaglutide 1.7 mg and placebo arms (7% each).In STEP 7,156 adverse events were reported by 93% in the semaglutide 2.4 mg group and 86% in the placebo group. The number of reported serious side effects was unexpectedly lower in the semaglutide arm contrasted with the placebo arm (5.2% vs. 6.3%). In STEP 8,157 the rate of any reported adverse events was 91.27% with semaglutide 2.4 mg, 90.55% with liraglutide 3.0 mg, and 80.00% with placebo. The number of reported serious side effects was higher with liraglutide (11%) compared to semaglutide (7.9%) or placebo (7.1%). In STEP 10,158 serious adverse events occurred in 9% receiving semaglutide 2.4 mg versus 6% receiving placebo. In STEP TEENS,159 the rate of any reported adverse events was 67.67% with semaglutide 2.4 mg versus 59.70% with placebo. The number of reported serious side effects was 11.28% in semaglutide versus 8.96% in placebo.

Sustain Trial

The SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) clinical trials provide an outline of the efficacy and safety profile of semaglutide and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes as discussed in Capehorn M, et al. [26] and other studies [162- 165]. In the SUSTAIN trials, semaglutide has substantiated reductions in glycemic control and body weight compared with placebo and comparators. The researchers conducted 11 trials of semaglutide efficacy and safety and cardiovascular outcomes to determine semaglutide effectiveness in weight loss as in Table 4, Figures 5 & 6. The SUSTAIN 1 trial [166] (ClinicalTrials.gov identifier: NCT02054897) was a 30- week, double-blind, randomised, parallel-group, placebo-controlled trial of once-weekly subcutaneous semaglutide 0.5 mg, or semaglutide 1 mg compared with placebo in treatment-naive patients with type 2 diabetes. In SUSTAIN 1, mean weight loss was -3.68% with semaglutide 0.5 mg, -4.67% with semaglutide 1 mg and -0.89% placebo from baseline to week 30.The SUSTAIN 2 trial [167] (ClinicalTrials. gov identifier: NCT01930188) was a 56-week, randomised, double- blind, double-dummy, active-controlled, parallel-group trial in patients with type 2 diabetes inadequately controlled on metformin, thiazolidinediones, or both randomly assigned of treatment using semaglutide 0.5 mg plus sitagliptin 100 mg placebo, semaglutide 1.0 mg plus sitagliptin 100 mg placebo, sitagliptin 100 mg plus semaglutide 0.5 mg placebo, or sitagliptin 100 mg plus semaglutide 1.0 mg placebo. In SUSTAIN 2, mean weight loss was -4.28% with semaglutide 0.5 mg plus sitagliptin 100 mg placebo, -6.13% with semaglutide 1.0 mg plus sitagliptin 100 mg placebo and -1.93% sitagliptin 100 mg plus semaglutide 0.5mg and 1.0 mg placebo from baseline to week 56.

The SUSTAIN 3 trial [168] (ClinicalTrials.gov identifier: NCT01885208) was a 56-week, open-label, parallel-group, randomized controlled trial of once-weekly semaglutide 1.0 mg subcutaneous with exenatide extended release 2.0 mg subcutaneous in patients with type 2 diabetes. In SUSTAIN 3, mean weight loss was -5.63 % with semaglutide 0.5 mg, -1.85% with exenatide extended release 2.0 mg from baseline to week 56. The SUSTAIN 4 trial [169] (ClinicalTrials. gov identifier: NCT02128932) was a 30-week, randomised, open-label, parallel-group trial of once-weekly subcutaneous semaglutide 0.5 mg, semaglutide 1.0 mg or once-daily insulin glargine in patients with type 2 diabetes who were inadequately controlled with metformin (with or without sulfonylureas). In SUSTAIN 4, mean weight loss was -3.47% with semaglutide 0.5 mg, -5.17% with semaglutide 1.0 mg or 1.15% with insulin glargine from baseline to week 30. The SUSTAIN 5 trial [170] (ClinicalTrials.gov identifier: NCT02305381) was a 30-week, double-blind, placebo-controlled trial of once-weekly subcutaneous semaglutide 0.5 mg or semaglutide 1.0 mg versus placebo in patients with type 2 diabetes. In SUSTAIN 5, mean weight loss was -3.67% with semaglutide 0.5 mg, -6.42% with semaglutide 1.0 mg versus -1.36% with placebo from baseline to week 30. The SUSTAIN 6 trial [171] (ClinicalTrials.gov identifier: NCT01720446) was a 104-week, randomised, double-blind, placebo-controlled trial of once-weekly subcutaneous semaglutide 0.5 mg or semaglutide 1.0 mg versus placebo in patients with type 2 diabetes. In SUSTAIN 6, mean weight loss was -3.57% with semaglutide 0.5 mg, -4.88% with semaglutide 1.0 mg versus -0.62% with placebo from baseline to week 104.

The SUSTAIN 7 trial [172] (ClinicalTrials.gov identifier: NCT02648204) was a 40-week, open-label, parallel-group trial of once-weekly subcutaneous semaglutide 0.5 mg, semaglutide 1.0 mg, dulaglutide 0.75 mg, or dulaglutide 1.5 mg in patients with type 2 diabetes. In SUSTAIN 7, mean weight loss was -4.56% with semaglutide 0.5 mg, -6.53% with semaglutide 1.0 mg, -2.30% with dulaglutide 0.75 mg, or -2.98% with dulaglutide 1.5 mg from baseline to week 40. At week 40, more participants in the semaglutide groups (semaglutide 0.5 mg, 1.0 mg) respectively than in the dulaglutide groups (dulaglutide 0.75 mg, 1.5 mg) respectively achieved weight reductions of 3% (64.5%, 76.7% vs. 36.5%, 44.6%), 5% (43.9%, 63.0% vs. 22.7%, 30.2%), and 10% (14.3%, 26.7% vs 3.3%, 7.7%).The SUSTAIN 8 trial [173] (ClinicalTrials.gov identifier: NCT03136484) was a 52- week, double-blind, parallel-group, randomised controlled trial of once-weekly subcutaneous semaglutide 1.0 mg versus oral canagliflozin 300 mg in patients with type 2 diabetes. In SUSTAIN 8, mean weight loss was -5.7% with semaglutide 1.0 mg versus -4.3% with canagliflozin 300 mg from baseline to week 52. At week 52, more participants in the semaglutide group than in the canagliflozin achieved weight reductions of 3% (68.8% vs. 64.9%), 5% (52.7% vs. 47.0%), and 10% (23.2% vs 8.9%).The SUSTAIN 9 trial [174] (ClinicalTrials. gov identifier: NCT03086330) was a 30-week, double-blind, parallel- group trial of once-weekly subcutaneous semaglutide 1.0 mg versus placebo in patients with type 2 diabetes. In SUSTAIN 9, mean weight loss was -4.7% with semaglutide 1.0 mg versus -1.0% with placebo from baseline to week 30. At week 30, more participants in the semaglutide group than in the placebo group achieved weight reductions of 3% (69.4% vs. 21.1%), 5% (50.4% vs. 7.8%), and 10% (15.7% vs 1.6%).

The SUSTAIN 10 trial [175] (ClinicalTrials.gov identifier: NCT03191396) was a 30-week, open-label trial of once-weekly subcutaneous semaglutide 1.0 mg versus once-daily subcutaneous liraglutide 1.2 mg in patients with type 2 diabetes. In SUSTAIN 10, mean weight loss was -5.8% with semaglutide 1.0 mg versus -2.0% with liraglutide 1.2 mg from baseline to week 30. At week 30, more participants in the semaglutide group than in the liraglutide group achieved weight reductions of 3% (72.7% vs. 33.9%), 5% (55.9% vs. 17.7%), and 10% (19.1% vs 4.4%).The SUSTAIN 11 trial [176] (ClinicalTrials. gov identifier: NCT03689374) was a 52-week, randomized, parallel, open-label trial of once-weekly subcutaneous semaglutide versus three times daily insulin aspart in patients with type 2 diabetes. In SUSTAIN 11, mean weight loss was -4.2% with semaglutide versus 2.9% with aspart from baseline to week 52.

Safety

The frequency of adverse events leading to treatment discontinuations was generally higher with semaglutide treatment than with comparators as observed across the SUSTAIN clinical trials. Gastrointestinal (GI) adverse events (AEs) are the most common AEs with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as in Table 5 [177-179]. In SUSTAIN 1,166 the rate of any reported adverse events was 41.41% with semaglutide 0.5 mg, 36.15% with semaglutide 1.0 mg, compared to 20.93% with placebo. The number of reported serious side effects was 5.47% with semaglutide 0.5 mg, 5.38% with semaglutide 1.0 mg, compared to 3.88% with placebo.

In SUSTAIN 2,167 the rate of any reported adverse events was 50.86% with semaglutide 0.5 mg plus sitagliptin 100 mg placebo, 48.17% with semaglutide 1.0 mg plus sitagliptin 100 mg placebo, 36.76% with sitagliptin 100 mg plus semaglutide 1.0 mg placebo and 41.87% sitagliptin 100 mg plus semaglutide 0.5mg placebo. The number of reported serious side effects was 7.33% with semaglutide 0.5 mg plus sitagliptin 100 mg placebo, 7.33% with semaglutide 1.0 mg plus sitagliptin 100 mg placebo, 6.37% with sitagliptin 100 mg plus semaglutide 1.0 mg placebo and 7.88% sitagliptin 100 mg plus semaglutide 0.5mg placebo.In SUSTAIN 3,168 the rate of any reported adverse events was 48.02% with semaglutide 1.0 mg versus 46.17% with exenatide extended release 2.0 mg. The number of reported serious side effects was 9.41% with semaglutide 1.0 mg versus 5.93% with exenatide extended release 2.0 mg.

In SUSTAIN 4,169 the rate of any reported adverse events was 47.51% with semaglutide 0.5 mg, 53.33% with semaglutide 1.0 mg and 29.72% with insulin glargine. The number of reported serious side effects was 6.08% with semaglutide 0.5 mg, 4.72% with semaglutide 1.0 mg and 5.00% with insulin glargine. In SUSTAIN 5,170 the rate of any reported adverse events was 39.39% with semaglutide 0.5 mg, 41.22% with semaglutide 1.0 mg and 25.56% with placebo. The number of reported serious side effects was 6.06% with semaglutide 0.5 mg, 9.16% with semaglutide 1.0 mg and 6.77% with placebo. In SUSTAIN 6,171 the rate of any reported adverse events was 69.37% with semaglutide 0.5 mg, 71.41% with semaglutide 1.0 mg and 63.52% with placebo. The number of reported serious side effects was 34.99% with semaglutide 0.5 mg, 33.58% with semaglutide 1.0 mg and 36.12% with placebo. In SUSTAIN 7,172 the rate of any reported adverse events was 43.85% with semaglutide 0.5 mg, 44.67% with semaglutide 1.0 mg, 35.45% with dulaglutide 0.75 mg and 46.49% with dulaglutide 1.5 mg. The number of reported serious side effects was 5.65% with semaglutide 0.5 mg, 7.67% with semaglutide 1.0 mg, 8.03% with dulaglutide 0.75 mg and 7.36% with dulaglutide 1.5 mg.

In SUSTAIN 8,173 the rate of any reported adverse events was 47.19% with semaglutide versus 30.46% with canagliflozin. The number of reported serious side effects was 4.59% with semaglutide versus 5.33% with canagliflozin. In SUSTAIN 9,174 the rate of any reported adverse events was 32.67% with semaglutide 1.0 mg versus 18.54% with placebo. The number of reported serious side effects was 4.67% with semaglutide 1.0 mg versus 3.97% with placebo. In SUSTAIN 10,175 the rate of any reported adverse events was 48.10% with semaglutide versus 39.37% with liraglutide 1.2 mg. The number of reported serious side effects was 5.88% with semaglutide 1.0 mg versus 7.67% with liraglutide 1.2 mg. In SUSTAIN 11,176 the rate of any reported adverse events was 25.74% with semaglutide versus 7.52% with insulin aspart. The number of reported serious side effects was 7.44 % with semaglutide versus 9.72% with insulin aspart.

Pioneer Trial

Oral formulation of GLP-1 RA was recently developed and based on the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) programme (PIONEER) program, phase III clinical trials showing the efficacy and safety of oral semaglutide in comparison with placebo or other medications. Oral semaglutide has been shown to be effective in reducing glycemia (HbA1c) and body mass, in the series of Peptide Innovation for Early Diabetes Treatment (PIONEER) studies as discussed in Pratley RE et al. [27] and other studies [180-184].The researchers conducted 10 trials of semaglutide efficacy to determine semaglutide effectiveness in weight loss as in Table 6, Figures 7 & 8.The PIONEER 1 trial [185] (ClinicalTrials.gov identifier: NCT02906930) was a 26-week, randomized, double-blind, placebo-controlled, parallel- group trial in adults with type 2 diabetes insufficiently controlled with diet and exercise were randomized to once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or placebo. In PIONEER 1, mean weight loss was -1.5% with semaglutide 3 mg, -2.6% with semaglutide 7 mg, -4.0% with semaglutide 14 mg and -1.4% with placebo from baseline to week 26. At week 26, more participants in the semaglutide groups (semaglutide 3 mg, 7 mg, and 14 mg) respectively than in the placebo group achieved weight reductions of 3% (18.0%, 36.9%, 50.6% vs. 10.7%), 5% (19.6%, 26.9%, 41.3% vs. 14.9%), and 10% (2.4%, 8.1%, 14.4% vs 1.2%).The PIONEER 2 trial [186] (ClinicalTrials.gov identifier: NCT02863328) was a 52-week, open-label, randomized trial with oral semaglutide 14 mg or empagliflozin 25 mg in patients with type 2 diabetes uncontrolled on metformin.

In PIONEER 2, mean weight loss was -4.0% with semaglutide 14 mg versus -3.8% with empagliflozin 25 mg from baseline to week 26. Superior weight loss significantly better was 4.7% with semaglutide 7 mg versus 3.8% with empagliflozin 25 mg at week 52. At week 52, more participants in the semaglutide group than in the empagliflozin group achieved weight reductions of 3% (45.2% vs. 28.1%), 5% (41.2% vs. 36.1%), and 10% (12.5% vs 6.8%).The PIONEER 3 trial [187] (ClinicalTrials.gov identifier: NCT02607865) was a 78-week, randomized, double-blind, double-dummy, active-controlled, parallel- group trial in adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized to receive once-daily oral semaglutide 3 mg, semaglutide 7 mg, semaglutide 14 mg, or sitagliptin 100 mg. In PIONEER 3, mean weight loss was -1.3% with semaglutide 3 mg, -2.2% with semaglutide 7 mg, -3.2% with semaglutide 14 mg and -0.6% with sitagliptin from baseline to week 26. Mean weight loss was -1.6% with semaglutide 3 mg, -2.5% with semaglutide 7 mg, -3.5% with semaglutide 14 mg and -0.7% with sitagliptin at week 52. Greater weight loss significantly better was -1.8% with semaglutide 3 mg, -2.8% with semaglutide 7 mg, -3.2% with semaglutide 14 mg and -1.0% with sitagliptin at week 78. At week 26, more participants in the semaglutide groups (semaglutide 3 mg, 7 mg, and 14 mg) respectively than in the sitagliptin group achieved weight reductions of 3% (12.6%, 26.7%, 38.1% vs. 9.6%), 5% (12.1%, 18.4%, 29.8% vs. 10.1%), and 10% (1.1%, 5.2%, 6.6% vs. 1.8%).

At week 52, more participants in the semaglutide groups (semaglutide 3 mg, 7 mg, and 14 mg) respectively than in the sitagliptin group achieved weight reductions of 3% (17.1%, 24.6%, 37.8% vs. 11.7%), 5% (15.4%, 27.3%, 33.8% vs. 11.4%), and 10% (3.0%, 7.2%, 11.0% vs. 2.5%). At week 78, more participants in the semaglutide groups (semaglutide 3 mg, 7 mg, and 14 mg) respectively than in the sitagliptin group achieved weight reductions of 3% (18.1%, 26.7%, 35.1% vs. 13.7%), 5% (19.5%, 27.1%, 32.5% vs. 13.3%), and 10% (2.8%, 10.1%, 10.7% vs. 3.8%).The PIONEER 4 trial [188] (Clinical- Trials.gov identifier: NCT02863419) was a 52-week, randomized, double-blind, double-dummy trial in adults with type 2 diabetes were randomly assigned to once-daily oral semaglutide 14 mg, versus once-daily subcutaneous liraglutide 1.8 mg, or placebo. In PIONEER 4, mean weight loss was -4.7% with semaglutide 14 mg, versus -3.3% with liraglutide 1.8 mg, or -0.7% with placebo from baseline to week 26. Mean weight loss was -4.4% with semaglutide 14 mg, versus -3.1% with liraglutide 1.8 mg, or -1.2% with placebo at week 52. At week 26, more participants in the semaglutide, liraglutide groups respectively than in the placebo group achieved weight reductions of 3% (46.8%, 34.3% vs. 3.7%), 5% (43.5%, 27.7% vs. 7.5%), and 10% (14.0%, 5.9% vs. 0.0%). At week 52, more participants in the semaglutide, liraglutide groups respectively than in the placebo group achieved weight reductions of 3% (43.6%, 28.6% vs. 6.8%), 5% (44.7%, 24.5% vs. 12.0%), and 10% (16.4%, 7.4% vs. 3.0%).

The PIONEER 5 trial [189] (ClinicalTrials.gov identifier: NCT02827708) was a 26-week, randomised, double-blind, placebo- controlled trial in patients with type 2 diabetes and moderate renal impairment were assigned to once-daily oral semaglutide 14 mg versus placebo. In PIONEER 5, mean weight loss was -3.5% with semaglutide 14 mg versus -0.9% with placebo from baseline to week 26. At week 26, more participants in the semaglutide group than in the placebo group achieved weight reductions of 3% (39.0% vs. 7.7%), 5% (35.7% vs. 9.7%), and 10% (8.4% vs 0.0%).The PIONEER 6 trial [190] (ClinicalTrials.gov identifier: NCT02692716) was an 82-week, randomized, placebo-controlled, double-blind trial in patients with type 2 diabetes at high risk of cardiovascular events were assigned to once-daily oral semaglutide 14 mg versus placebo. In PIONEER 6, mean weight loss was -4.2% with semaglutide 14 mg versus -0.8% with placebo from baseline to week 82. The PIONEER 7 trial [191] (ClinicalTrials.gov identifier: NCT02849080) was a 52-week, open-label, randomized trial in patients with type 2 diabetes were assigned to once-daily oral semaglutide flex (with flexible dose adjustments to 3, 7, or 14 mg) versus sitagliptin 100 mg. In PIONEER 7, mean weight loss was -2.9% with semaglutide flex versus -0.8% with sitagliptin 100 mg from baseline to week 52. At week 52, more participants in the semaglutide group than in the sitagliptin group achieved weight reductions of 3% (34.8% vs. 10.5%), 5% (27.0% vs. 12.1%), and 10% (6.4% vs 2.1%).

The PIONEER 8 trial [192] (ClinicalTrials.gov identifier: NCT03021187) was a 52-week, double-blind trial in patients with type 2 diabetes uncontrolled on insulin with or without metformin were assigned to once-daily oral semaglutide 3 mg, semaglutide 7 mg, semaglutide 14 mg or to placebo. In PIONEER 8, mean weight loss was -1.4% with semaglutide 3 mg, -2.6% with semaglutide 7 mg, -3.7% with semaglutide 14 mg and -0.5% with placebo from baseline to week 26. Mean weight loss was -0.9% with semaglutide 3 mg, -2.2% with semaglutide 7 mg, -3.8% with semaglutide 14 mg and 0.5% with placebo at week 52. At week 26, more participants in the semaglutide groups (semaglutide 3 mg, 7 mg, and 14 mg) respectively than in the placebo group achieved weight reductions of 3% (15.9%, 29.3%, 43.9% vs. 4.0%), 5% (13.0%, 30.5%, 38.7% vs. 2.8%), and 10% (1.1%, 6.9%, 11.0% vs 0.6%). At week 52, more participants in the semaglutide groups (semaglutide 3 mg, 7 mg, and 14 mg) respectively than in the placebo group achieved weight reductions of 3% (11.6%, 21.9%, 38.1% vs. 2.9%), 5% (17.2%, 28.1%, 39.4% vs. 5.2%), and 10% (2.3%, 9.9%, 12.4% vs 0.6%).The PIONEER 9 trial [193] (ClinicalTrials. gov identifier: NCT03018028) was a 52-week, randomised, controlled trial in patients with type 2 diabetes in a Japanese population were randomly assigned to receive once-daily oral semaglutide 3 mg, semaglutide 7 mg, semaglutide 14 mg, versus placebo, or subcutaneous once-daily liraglutide 0.9 mg. In PIONEER 9, mean weight loss was -0.4% with semaglutide 3 mg, -1.2% with semaglutide 7 mg, -2.4% with semaglutide 14 mg, 0.1% with liraglutide 0.9 mg and -1.1% with placebo from baseline to week 26.

Mean weight loss was 0.0% with semaglutide 3 mg, -0.8% with semaglutide 7 mg, -2.9% with semaglutide 14 mg, 0.5% with liraglutide 0.9 mg and -1.0% with placebo at week 52. At week 26, more participants in the semaglutide groups (semaglutide 3 mg, 7 mg, and 14 mg) respectively than in the liraglutide, or placebo group respectively achieved weight reductions of 3% (16.3%, 24.4%, 47.7% vs. 11.1%, 7.3%), 5% (2.3%, 11.1%, 36.4% vs. 0.0%, 7.3%), and 10% (0.0%, 0.0%, 6.8% vs 0.0%, 0.0%). At week 52, more participants in the semaglutide groups (semaglutide 3 mg, 7 mg, and 14 mg) respectively than in the liraglutide, or placebo group respectively achieved weight reductions of 3% (21.1%, 16.3%, 48.8% vs. 4.9%, 2.9%), 5% (2.6%, 11.6%, 41.5% vs. 4.9%, 5.9%), and 10% (0.0%, 2.3%, 14.6% vs 0.0%, 0.0%).The PIONEER 10 trial [194] (ClinicalTrials.gov identifier: NCT03015220) was a 52-week, open-label, randomised, active-controlled trial in patients with type 2 diabetes in a Japanese population were randomly assigned to receive once-daily oral semaglutide 3 mg, semaglutide 7 mg, semaglutide 14 mg, or once-weekly subcutaneous dulaglutide 0.75 mg. In PIONEER 10, mean weight loss was -0.1% with semaglutide 3 mg, -1.0% with semaglutide 7 mg, -2.2% with semaglutide 14 mg, 0.3% with dulaglutide 0.75 mg from baseline to week 26. Mean weight loss was 0.00% with semaglutide 3 mg, -0.9% with semaglutide 7 mg, -1.7% with semaglutide 14 mg, 1.0% with dulaglutide 0.75 mg at week 52. At week 26, more participants in the semaglutide groups (semaglutide 3 mg, 7 mg, and 14 mg) respectively than in the dulaglutide group achieved weight reductions of 3% (11.7%, 26.6%, 48.4% vs. 12.5%), 5% (4.7%, 18.0%, 30.5% vs. 6.3%), and 10% (0.0%, 4.7%, 6.3% vs 1.6%). At week 52, more participants in the semaglutide groups (semaglutide 3 mg, 7 mg, and 14 mg) respectively than in the dulaglutide group achieved weight reductions of 3% (8.7%, 24.8%, 33.1% vs. 11.1%), 5% (5.5%, 16.3%, 22.0% vs. 6.3%), and 10% (0.0%, 7.0%, 5.5% vs 0.0%).

Safety

The overall safety profile of oral semaglutide was similar in all PIONEER trials and was not unexpected, considering subcutaneous semaglutide and other GLP-1 RAs. The main adverse events reported in the PIONEER program were related to the GI tract, but of mild or moderate severity, and most were transient [195] as in Table 7. In PIONEER 1,185 the rate of adverse side effect was 27.43% with semaglutide 3 mg, 21.14% with semaglutide 7 mg, 25.71% with semaglutide 14 mg and 14.61% with placebo. The number of reported serious side effects was 2.9% with semaglutide 3 mg, 1.7% with semaglutide 7 mg, 1.1% with semaglutide 14 mg and 4.5% with placebo.In PIONEER 2,186 the rate of adverse side effect was 31.22% with semaglutide 14 mg and 10.76% with empagliflozin 25 mg. The number of reported serious side effects was 6.6% with semaglutide 14 mg and 9.0% with empagliflozin 25 mg.In PIONEER 3,187 the rate of adverse side effect was 47.64% with semaglutide 3 mg, 50.43% with semaglutide 7 mg, 49.89% with semaglutide 14 mg, and 51.29% with sitagliptin 100 mg. The number of reported serious side effects was 13.73% with semaglutide 3 mg, 10.13% with semaglutide 7 mg, 9.46% with semaglutide 14 mg, and 12.45% with sitagliptin 100 mg.In PIONEER 4,188 the rate of adverse side effect was 51.93% with semaglutide 14 mg, 42.25% with liraglutide 1.8 mg and 33.10% with placebo The number of reported serious side effects was 10.88% with semaglutide 14 mg, 7.75% with liraglutide 1.8 mg and 10.56% with placebo.

In PIONEER 5,189 the rate of adverse side effect was 46.01% with semaglutide 14 mg versus 19.88% with placebo. The number of reported serious side effects was 10.43% with semaglutide 14 mg versus 10.56% with placebo.In PIONEER 6,190 the rate of serious adverse side effect was 18.92% with semaglutide 14 mg and 22.50% with placebo.In PIONEER 7,191 the rate of adverse side effect was 49.80% with semaglutide 14 mg versus 28.00% with sitagliptin 100 mg. The number of reported serious side effects was 9.49% with semaglutide flex versus 9.60% with sitagliptin 100 mg. In PIONEER 8,192 the rate of adverse side effect was 41.85% with semaglutide 3 mg, 47.51% with semaglutide 7 mg, 55.25% with semaglutide 14 mg, and 39.67% with placebo. The number of reported serious side effects was 13.59% with semaglutide 3 mg, 10.50% with semaglutide 7 mg, 6.63% with semaglutide 14 mg and 9.24% with placebo.In PIONEER 9,193 the rate of adverse side effect was 59.18% with semaglutide 3 mg, 42.86% with semaglutide 7 mg, 52.08% with semaglutide 14 mg, 47.92% with liraglutide 0.9 mg and 55.10% with placebo. The number of reported serious side effects was 4.08% with semaglutide 3 mg, 6.12% with semaglutide 7 mg, 0.00% with semaglutide 14 mg, 0.00% with liraglutide 0.9 mg and 6.12% with placebo.In PIONEER 10,194 the rate of adverse side effect was 49.62% with semaglutide 3 mg, 59.85% with semaglutide 7 mg, 64.62% with semaglutide 14 mg and 55.38% with dulaglutide 0.75 mg. The number of reported serious side effects was 6.87% with semaglutide 3 mg, 3.03% with semaglutide 7 mg, 5.38% with semaglutide 14 mg and 1.54% with dulaglutide 0.75 mg.

Cost-Effectiveness of Semaglutide

Semaglutide 2.4 mg subcutaneous injection as adjunct to diet and exercise (D&E) is a cost-effective therapy in patients with overweight and obesity [196,197]. Subcutaneous semaglutide is more cost-effective than other comparators as discussed in Alshahawey M et al. [30] and other studies [198-205]. The additional costs to produce semaglutide for the oral formulation are cost-effective over a weekly injection [206]. Oral semaglutide represents a cost-effective treatment option versus other comparators for patients with type 2 diabetes and obesity [207,208].

Maintenance after Discontinuation of Semaglutide

The optimization and maintenance of weight loss are key goals for obesity management, but individuals can vary in their response to treatment [209]. CarrisNW et al. [31] discussed the subsequent longer duration of weight control with semaglutide benefitted the patient’s abilities to maintain goal weight when an approach is used. Multiple factors potentially supporting weight maintenance following semaglutide discontinuation were early drug treatment for new-onset obesity, non-geriatric age, strength training, standard lifestyle counseling and diet modification. Maintaining treatment with semaglutide compared with placebo resulted in continued weight loss over the following 48 week as in STEP 4 Rubino D et al. [153] and other study [210] shows weight loss continued over 65 weeks and was sustained for up to 4 years. After a substantial reduction in body weight during 68 weeks of treatment with once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, withdrawal led to most of the weight loss being regained within 1 year, reinforcing the need for continued treatment to maintain weight loss and cardiometabolic benefits [211].

Conclusion

The efficacy of semaglutide on body weight reduction among patients with overweight/obesity with or without diabetes mellitus have been observed in multiple studies. While semaglutide resulted in more gastrointestinal-related side effects, the medication appeared to be generally safe and well tolerated. Clinicians play a crucial role in choosing suitable treatment designs based on varied individual situations, providing comprehensive education, and monitoring the adverse events to ensure the safe and effective use of semaglutide in weight loss management.

References

1. Ng M, Fleming T, Robinson M (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study. Lancet 384(9945): 766-781.
2. Hu FB (2008) Obesity epidemiology. Oxford University Press Oxford New York, pp. 498.
3. (2024) World Health Organization. Obesity and overweight.
4. Jensen MD (2020) Obesity In: Goldman L, Schafer AI, (Eds.)., Goldman-Cecil Medicine (26^th)., Philadelphia, PA Elsevier chap, pp. 227.
5. Fruh SM (2017) Obesity: Risk factors, complications, and strategies for sustainable long-term weight management. J Am Assoc Nurse Pract 29: 3-14.
6. Bhat SP, Sharma A (2017) Current drug targets in obesity pharmacotherapy – a review Curr Drug Targets 18(8): 983-993.
7. Pilitsi E, Farr OM, Polyzos SA (2019) Pharmacotherapy of obesity: Available medications and drugs under investigation. Metabolism 92: 170-192.
8. Oh TJ (2019) The Role of Anti-Obesity Medication in Prevention of Diabetes and Its Complications. J Obes Metab Syndr 28(3): 158-166.
9. Jensen MD, Ryan DH, Apovian CM (2014) AHA/ACC/ TOS guideline for the management of overweight and obesity in adults Circulation 129(2): S102-S138.
10. Ryan DH (2022) Drugs for Treating Obesity. Handb. Exp Pharmacol 274: 387-414.
11. Friedrichsen M, Breitschaft A, Tadayon S (2021) The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity Diabetes. Obes Metab 23(3): 754-762.
12. Blundell J, Finlayson G, Axelsen M (2017) Effects of onceweekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes. Obes Metab 19: 1242-1251.
13. Trujillo JM, Nuffer W, Smith BA (2021) GLP-1 receptor agonists: an updated review of head-to-head clinical studies. Ther Adv Endocrinol Metab 9(12): 2042018821997320.
14. Tucker ME (2021) Europe Gives Green Light to Once-Weekly Semaglutide for Weight Loss Medscape.
15. Ryan DH (2021) Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?. Journal of Obesity & Metabolic Syndrome. 30: 196-208.
16. Richards R, Wren GM, Campion P (2023) A Remotely Delivered, Semaglutide-Supported Specialist Weight Management Program: Preliminary Findings from a Retrospective Service Evaluation. JMIR Form Res 7: e53619.
17. Ghusn W, De la Rosa A, Sacoto D (2022) Weight Loss Outcomes Associated with Semaglutide Treatment for Patients with Overweight or Obesity. JAMA Netw Open 5(9): e2231982.
18. Shu Y, He X, Wu P (2022) Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system. Front Public Health 10: 996179.
19. Xiong S, Gou R, Liang X (2024) Adverse Events of Oral GLP-1 Receptor Agonist (Semaglutide Tablets): A Real-World Study Based on FAERS from 2019 to 2023. Diabetes Ther 15: 1717-1733.
20. Dagli N, Kumar S, Ahmad R (2023) An Update on Semaglutide Research: A Bibliometric Analysis and a Literature Review. Cureus 15(10): e46510.
21. Page MJ, McKenzie JE, Bossuyt PM (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372: n71.
22. Chiappini S, Vickers-Smith R, Harris D (2023) Is There a Risk for Semaglutide Misuse? Focus on the Food and Drug Administration’s FDA Adverse Events Reporting System (FAERS) Pharmacovigilance Dataset. Pharmaceuticals 16(7): 994.
23. Moiz A, Levett JY, Filion KB (2024) Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Am J Cardiol 222: 121-130.
24. Kanai R, Kinoshita S, Kanbe I (2024) Onceweekly semaglutide administered after laparoscopic sleeve gastrectomy: Effects on body weight, glycemic control, and measured nutritional metrics in Japanese patients having both obesity and type 2 diabetes. Obesity Pillars 9: 100098.
25. Alabduljabbar K, Al-Najim W, le Roux CW (2022) The Impact Once-Weekly Semaglutide 2.4 mg Will Have on Clinical Practice: A Focus on the STEP Trials Nutrients. 14: 2217.
26. Capehorn M, Ghani Y, Hindsberger C (2020) Once-Weekly Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Common OAD: a Subgroup Analysis from SUSTAIN 2–4 and 10. Diabetes Ther 11: 1061-1075.
27. Pratley RE, Crowley MJ, Gislum M (2021) Oral Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Glucose-Lowering Medication: PIONEER Subgroup Analyses. Diabetes Ther 12: 1099-1116.
28. Deng Y, Park A, Zhu L (2022) Effect of semaglutide and liraglutide in individuals with obesity or overweight without diabetes: a systematic review. Ther Adv Chronic Dis 13: 1-14.
29. Lincoff AM, Brown Frandsen K, Colhoun HM (2023) Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 389(24): 2221-2232.
30. Alshahawey M, Ghazy M, El Morshedy M (2024) Cost-effectiveness analysis of once-weekly semaglutide vs. once-daily liraglutide administered subcutaneously in patients with overweight and obesity: a decision analysis. European Review for Medical and Pharmacological Sciences 28: 3365-3374.
31. Carris NW, Wallaceb S, DuCoin CG (2024) Discontinuing semaglutide after weight loss: strategy for weight maintenance and a possible new side effect. Can J Physiol Pharmacol 102: 391-395.
32. Abdullah A, Peeters A, de Courten M (2010) The magnitude of association between overweight and obesity and the risk of diabetes: a meta-analysis of prospective cohort studies. Diabetes Res Clin Pract 89(3): 309-319.
33. Guh DP, Zhang W, Bansback N (2009) The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health 9: 88.
34. Ghusn W, Anazco D, Fansa S (2024) Weight loss outcomes with semaglutide based on diabetes severity using the individualized metabolic surgery score. eClinicalMedicine 72: 102625.
35. Pi-Sunyer X, Blackburn G, Brancati F L (2007) Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look. AHEAD trial Diabetes Care 30(6): 1374-1383.
36. Anyiam O, Phillips B, Quinn K (2024) Metabolic effects of very-low calorie diet, Semaglutide, or combination of the two, in individuals with type 2 diabetes mellitus. Clinical Nutrition 43: 1907-1913.
37. Cornier MA (2022) A review of current guidelines for the treatment of obesity. Am J Manag Care 28(15): 288-296.
38. Wharton S, Lau DCW, Vallis M (2020) Obesity in adults: a clinical practice guideline. CMAJ 192: 875-891.
39. Ozeki Y, Masaki T, Kamata A (2022) The Effectiveness of GLP-1 Receptor Agonist Semaglutide on Body Composition in Elderly Obese Diabetic Patients: A Pilot Study. Medicines 9: 47.
40. Ryan DH, Lingvay I, Colhoun HM (2020) Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) rationale and design. Am Heart J 229: 61-69.
41. Gibbons C, Blundell J, Hoff ST (2021) Effects of oral semaglutide on energy intake, food preference, appetite, control of eating and body weight in subjects with type 2 diabetes. Diabetes Obes Metab 23: 581-588.
42. Gabe MBN, Breitschaft A, Knop FK (2024) Effect of oral semaglutide on energy intake, appetite, control of eating and gastric emptying in adults living with obesity: A randomized controlled trial. Diabetes Obes Metab, p. 1‐
43. Hjerpsted JB, Flint A, Brooks A (2018) Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity. Diabetes Obes Metab 20: 610-619.
44. Tamayo-Trujillo R, Ruiz-Pozo VA, Cadena-Ullauri S (2024) Molecular mechanisms of semaglutide and liraglutide as a therapeutic option for obesity. Front Nutr 11: 1398059.
45. Matovinović M, Belanĉić A, Jug J (2024) Does the Efficacy of Semaglutide Treatment Differ between Low-Risk and High-Risk Subgroups of Patients with Type 2 Diabetes and Obesity Based on SCORE2, SCORE2-Diabetes, and ASCVD Calculations?. Diabetology 5: 26-39.
46. Dahl K, Brooks A, Almazedi F (2021) Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes. Diabetes Obes Metab 23: 1594-1603.
47. Ruseva A, Michalak W, Zhao Z (2024) Semaglutide 2.4 mg clinical outcomes in patients with obesity or overweight in a real‐world setting: a 6‐month retrospective study in the United States (SCOPE). Obes Sci Pract 10(1): e737.
48. Lingvay I, Deanfield J, Kahn SE (2024) Semaglutide and Cardiovascular Outcomes by Baseline HbA1c and Change in HbA1c in People With Overweight or Obesity but Without Diabetes in SELECT. Diabetes Care 47: 1360-1369.
49. Lingvay I, Brown-Frandsen K, Colhoun HM (2023) Semaglutide for cardiovascular event reduction in people with overweight or obesity: SELECT study baseline characteristics. Obesity (Silver Spring) 31(1): 111‐
50. Masaki T, Ozeki Y, Yoshida Y (2022) Glucagon-Like Peptide-1 Receptor Agonist Semaglutide Improves Eating Behavior and Glycemic Control in Japanese Obese Type 2 Diabetic. Patients Metabolites 12: 147.
51. Knudsen LB, Lau J (2019) The discovery and development of liraglutide and semaglutide. Front Endocrinol (Lausanne) 10: 155.
52. O Neil PM, Birkenfeld AL, McGowan B (2018) Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet 392(10148): 637-649.
53. Enebo LB, Berthelsen LK, Kankam M (2021) Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet 397: 1736-1748.
54. Marso SP, Bain SC, Consoli A (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375(19): 1834-1844.
55. Kahn SE, Deanfield JE, Jeppesen OK (2024) Effect of Semaglutide on Regression and Progression of Glycemia in People with Overweight or Obesity but Without Diabetes in the SELECT Trial. Diabetes Care 47: 1350-1359.
56. Lee YS, Jun HS (2014) Anti diabetic actions of glucagon like peptide 1 on pancreatic beta cells. Metabolism 63: 9-19.
57. Liu Y, Luo X (2022) New practice in semaglutide on type-2 diabetes and obesity: clinical evidence and expectation. Front Med 16(1): 17-24.
58. Lau J, Bloch P, Schäffer L (2015) Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem 58(18): 7370-7380.
59. Christou GA, Katsiki N, Blundell J (2019) Semaglutide as a promising antiobesity drug. Obes Rev 20: 805-815.
60. (2023) The National Institute for Health and Care Excellence (NICE) Semaglutide for managing overweight and obesity.
61. Alorfi NM, Algarni AS (2022) Clinical Impact of Semaglutide, A Glucagon-Like Peptide-1 Receptor Agonist, on Obesity Management: A Review. Clinical Pharmacology: Advances and Applications 14: 61-67.
62. Tzoulis P, Baldeweg SE (2024) Semaglutide for weight loss: unanswered questions. Front Endocrinol 15:1382814.
63. Kyrillos JV, Skolnik NS, Mukhopadhyay B, Pennings N (2022) Integrating semaglutide into obesity management – a primary care perspective. Postgraduate Medicine 134(1): 37-49.
64. Alkhalifah M, Afsar H, Shams A (2024) Semaglutide for the management of diabesity: The real-world experience. World J Methodol 14(3): 91832.
65. Gad H, Malik R A (2024) Rapid Improvement in Weight, Body Composition, and Glucose Variability with Semaglutide in Type 1 Diabetes. Cureus 16(6): e61577.
66. Pantanetti P, Cangelosi G, Alberti S (2024) Changes in body weight and composition, metabolic parameters, and quality of life in patients with type 2 diabetes treated with subcutaneous semaglutide in real-world clinical practice. Front Endocrinol 15: 1394506.
67. Serpa Díaz D, Llanos Florez CA, Uribe RS (2024) Glycemic Control and Body Weight Reduction with Once Weekly Semaglutide in Colombian Adults with Type 2 Diabetes: Findings from the COLIBRI Study Diabetes. Ther 15: 1451-1460.
68. Okamoto A, Yokokawa H, Nagamine T (2021) Efficacy and safety of semaglutide in glycemic control, body weight management, lipid profiles and other biomarkers among obese type 2 diabetes patients initiated or switched to semaglutide from other GLP 1 receptor agonists. Journal of Diabetes & Metabolic Disorders 20: 2121-2128.
69. Baldassarre MPA, Di Dalmazi G, Coluzzi S (2024) Oral Semaglutide in Routine Clinical Practice: Characteristics of People with Type 2 Diabetes Started on the Drug and Changes in Their Clinical Parameters after 24 Weeks of Treatment. J Clin Med 13: 3054.
70. Crabtree TSJ, Adamson K, Reid H (2022) Injectable semaglutide and reductions in HbA1c and weight in the real world in people switched from alternative glucagon-like peptide-1 receptor agonists. Diabetes. Obes Metab 24: 1398-1401.
71. Borlaug BA, Kitzman DW, Davies MJ (2023) Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial. Nature Medicine 29: 2358-2365.
72. Xiang J, Ding XY, Zhang W (2023) Clinical effectiveness of semaglutide on weight loss, body composition, and muscle strength in Chinese adults. European Review for Medical and Pharmacological Sciences 27: 9908-9915.
73. Pèrez-Belmonte LM, Sanz-Cánovas J, Garcia de Lucas MD (2022) Efficacy and Safety of Semaglutide for the Management of Obese Patients with Type 2 Diabetes and Chronic Heart Failure in Real-World Clinical Practice. Front Endocrinol 13: 851035.
74. McGowan BM, Houshmand-Oeregaard A, Laursen PN (2023) Impact of BMI and comorbidities on efficacy of once-weekly semaglutide: Post hoc analyses of the STEP 1 randomized trial. Obesity (Silver Spring) 31(4): 990‐
75. Kelly AS, Arslanian S, Hesse D (2023) Reducing BMI below the obesity threshold in adolescents treated with once-weekly subcutaneous semaglutide 2.4 mg. Obesity (Silver Spring) 31(8): 2139‐
76. Volpe S, Lisco G, Racaniello D (2022) Once-Weekly Semaglutide Induces an Early Improvement in Body Composition in Patients with Type 2 Diabetes: A 26-Week Prospective Real-Life Study. Nutrients 14: 2414..
77. Smith I, Hardy E, Mitchell S (2022) Semaglutide 2.4 Mg for the Management of Overweight and Obesity: Systematic Literature Review and Meta-Analysis. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 15: 3961-3987.
78. Powell W, Song X, Mohamed Y (2023) Medications and conditions associated with weight loss in patients prescribed semaglutide based on real-world data. Obesity (Silver Spring) 31(10): 2482‐
79. Xie Z, Yang S, Dend W (2022) Efficacy and Safety of Liraglutide and Semaglutide on Weight Loss in People with Obesity or Overweight: A Systematic Review. Clinical Epidemiology 14: 1463-1476.
80. Murvelashvili N, Xie L, Schellinger JN (2023) Effectiveness of semaglutide versus liraglutide for treating post-metabolic and bariatric surgery weight recurrence. Obesity (Silver Spring) 31(5): 1280‐
81. Stretton B, Kovoor J, Bacchi S (2023) Weight loss with subcutaneous semaglutide versus other glucagon-like peptide 1 receptor agonists in type 2 diabetes: a systematic review. Internal Medicine Journal 53: 1311-1320.
82. Hepprich M, Zillig D, Florian-Reynoso MA (2021) Switch-to-Semaglutide Study (STS-Study): a Retrospective Cohort Study. Diabetes. Ther 12: 943-954.
83. Iijima T, Shibuya M, Ito Y (2023) Effects of switching from liraglutide to semaglutide or dulaglutide in patients with type 2 diabetes: A randomized controlled trial J Diabetes. Investig 14: 774-781.
84. Alsugair HA, Alshugair IF, Alharbi TJ (2021) Weekly Semaglutide vs. Liraglutide Efficacy Profile: A Network Meta-Analysis. Healthcare 9: 1125.
85. Drucker DJ (2016) The cardiovascular biology of glucagon-like peptide-1 Cell. Metab 24(1): 15-30.
86. Wong ND, Karthikeyan H, Fan W (2023) US Population Eligibility and Estimated Impact of Semaglutide Treatment on Obesity Prevalence and Cardiovascular Disease Events. Cardiovascular Drugs and Therapy.
87. Zhang R, Hou Q-c, Li B-h (2023) Efficacy and safety of subcutaneous semaglutide in adults with overweight or obese: a subgroup meta-analysis of randomized controlled trials. Front Endocrinol 14: 1132004.
88. Gao X, Hua X, Wang X (2022) Efficacy and safety of semaglutide on weight loss in obese or overweight patients without diabetes: A systematic review and meta-analysis of randomized controlled trials. Front Pharmacol 13: 935823.
89. Tzoulis P, Batavanis M, Baldeweg S (2024) A Real-World Study of the Effectiveness and Safety of Semaglutide for Weight Loss. Cureus 16(5): e59558.
90. Lautenbach A, Wernecke M, Huber TB (2022) The Potential of Semaglutide Once Weekly in Patients Without Type 2 Diabetes with Weight Regain or Insufcient Weight Loss After Bariatric Surgery—a Retrospective Analysis. Obesity Surgery 32: 3280-3288..
91. Jensen AB, Renström F, Aczél S (2023) Efficacy of the Glucagon Like Peptide 1 Receptor Agonists Liraglutide and Semaglutide for the Treatment of Weight Regain After Bariatric surgery: a Retrospective Observational Study. Obesity Surgery 33: 1017-1025.
92. Lautenbach A, Kantowski T, Wagner J (2023) Sustained weight loss with semaglutide once weekly in patients without type 2 diabetes and post-bariatric treatment failure. Clinical Obesity 13: e12593.
93. Bonnet J-B, Tournayre S, Anitcheou J (2024) Semaglutide 2.4 mg/wk for weight loss in patients with severe obesity and with or without a history of bariatric surgery. Obesity (Silver Spring) 32(1): 50‐
94. Rubio-Herrera MA, Mera-Carreiro S, Sánchez-Pernaute A (2023) Impact of Treatment with GLP1 Receptor Agonists, Liraglutide 3.0 mg and Semaglutide 1.0 mg, While on a Waiting List for Bariatric Surgery. Biomedicines 11: 2785.
95. Kolotkin RL, Jeppesen OK, Baker-Knight J (2022) Effect of once-weekly subcutaneous semaglutide 2.4 mg on weight- and health-related quality of life in an East Asian population: Patient-reported outcomes from the STEP 6 trial. Clinical Obesity 13: e12589.
96. Rubino D, Bjorner JB, Rathor N (2024) Effect of semaglutide 2.4 mg on physical functioning and weight- and health-related quality of life in adults with overweight or obesity: Patient-reported outcomes from the STEP 1–4 trials. Diabetes Obes Metab 26(7): 2945‐
97. Byrne J, Willis A, Dunkley A (2022) Individual, healthcare professional and system-level barriers and facilitators to initiation and adherence to injectable therapies for type 2 diabetes: a systematic review and meta-ethnography. Diabet Med 39: e14678.
98. Aroda VR, Faurby M, Lophaven S (2021) Insights into the early use of oral semaglutide in routine clinical practice: The IGNITE study. Diabetes Obes Metab 23: 2177-2182.
99. Alhindi Y, Avery A (2022) The efficacy and safety of oral Semaglutide for glycaemic management in adults with type 2 diabetes compared to subcutaneous Semaglutide, placebo, and other GLP-1 RA comparators: A systematic review and network meta-analysis. Contemp Clin Trials Commun 28: 100944.
100. Bækdal TA, Donsmark M, Hartoft-Nielsen ML (2021) Relationship Between Oral Semaglutide Tablet Erosion and Pharmacokinetics: A Pharmacoscintigraphic Study. Clinical Pharmacology in Drug Development 10(5): 453-462.
101. Overgaard RV, Navarria A, Ingwersen SH (2021) Clinical Pharmacokinetics of Oral Semaglutide: Analyses of Data from Clinical Pharmacology Trials. Clinical Pharmacokinetics 60: 1335-1348.
102. Bonora BM, Russo G, Leonetti F (2024) Effectiveness of oral semaglutide on glucose control and body weight up to 18 months: a multicentre retrospective realworld study. Journal of Endocrinological Investigation 47: 1395-1403.
103. Janić M, Jovanović M, Janež A (2023) Efficacy, safety, and patient satisfaction with oral semaglutide: first single-centre clinical experience. J Int Med Res 51(11): 1-13.
104. Hout M, Forte P, Jensen TB (2023) Effect of Various Dosing Schedules on the Pharmacokinetics of Oral Semaglutide: A Randomised Trial in Healthy Subjects. Clinical Pharmacokinetics 62: 635-644.
105. Candido R, Di Loreto C, Desenzani P (2024) Suitability and Usefulness of a Flexible Dosing Timing of Oral Semaglutide to Maximize Benefit in Clinical Practice: An Expert Panel. Diabetes Ther 15(9): 1963-1977.
106. Bækdal TA, Breitschaft A, Donsmark M (2021) Effect of Various Dosing Conditions on the Pharmacokinetics of Oral Semaglutide, a Human Glucagon-Like Peptide-1 Analogue in a Tablet Formulation. Diabetes Ther 12: 1915-1927.
107. Meier JJ (2021) Efficacy of Semaglutide in a Subcutaneous and an Oral Formulation Front Endocrinol 12: 645617.
108. Jiménez RB, de Vera Gómez RP, Lomas BS (2024) Transforming body composition with semaglutide in adults with obesity and type 2 diabetes mellitus. Front Endocrinol 15: 1386542.
109. Overgaard RV, Hertz CL, Ingwersen SH (2021) Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes. Cell Reports Medicine 2: 100387.
110. Tan HC, Dampil OA, Marquez MM (2022) Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis. Journal of ASEAN Federation of Endocrine societies 37(2): 65-72.
111. Chowdhury SR, Sadouki F, Collins E (2024) Real World Use of Oral and Subcutaneous Semaglutide in Routine Clinical Practice in the UK: A Single Centre, Retrospective Observational Study. Diabetes Ther 15: 869-881.
112. Alsheikh A, Alshehri A, Alzahrani S (2024) Oral Semaglutide effectiveness and safety in real world practice; The REVOLUTION study. Diabetes Epidemiology and Management 14: 100209.
113. Wang S, Wang S, Wang Y (2024) Glycemic Control, Weight Management, Cardiovascular Safety, and Cost-Effectiveness of Semaglutide for Patients with Type 2 Diabetes Mellitus: A Rapid Review and Meta-analysis of Real-World Studies. Diabetes Ther 15: 497-519.
114. Milluzzo A, Manuella L, Sciacca L (2022) Semaglutide: a game changer for metabolic diseases? Explor Med 3: 173-180.
115. Gallwitz B, Giorgino F (2021) Clinical perspectives on the use of subcutaneous and oral formulations of semaglutide. Front Endocrinol (Lausanne) 12: 645507.
116. Chaudhuri SR, Majumder A, Mukherjee P (2023) Glycemic Control and the Weight Benefit of a Daily 7 mg Dose of Oral Semaglutide Versus an Alternate-Day 14 mg Dose of Oral Semaglutide from an Ambulatory Glucose Monitoring Data: A Retrospective Cohort Study From Eastern India. Cureus 15(6): e40179.
117. Volpe S, Lisco G, Fanelli M (2023) Oral semaglutide improves body composition and preserves lean mass in patients with type 2 diabetes: a 26-week prospective real-life study. Front Endocrinol 14: 1240263.
118. Uchiyamaa S, Sadaa Y, Mihara S (2023) Oral Semaglutide Induces Loss of Body Fat Mass Without Affecting Muscle Mass in Patients With Type 2 Diabetes. J Clin Med Res 15(7): 377-383.
119. Yang XD, Yang YY (2024) Clinical Pharmacokinetics of Semaglutide: A Systematic Review. Drug Design. Development and Therapy 18: 2555-2570.
120. Niu K, Fan M, Gao W (2024) Adverse events in different administration routes of semaglutide: a pharmacovigilance study based on the FDA adverse event reporting system. Front Pharmacol 15: 1414268.
121. Du Y, Zhang M, Wang Z (2024) A real-world disproportionality analysis of semaglutide: Post-marketing pharmacovigilance data. J Diabetes Investig.
122. Kalra S, Kapoor N (2022) Oral Semaglutide: Dosage in Special Situations. Diabetes Ther 13: 1133-1137.
123. Feier CVI, Vonica RC, Faur AM (2024) Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review. Int J Mol Sci 25: 4346.
124. Mailhac A, Pedersen L, Pottegård A (2024) Semaglutide (Ozempic®) Use in Denmark 2018 Through 2023 ‒ User Trends and off-Label Prescribing for Weight Loss. Clinical Epidemiology 16: 307-
125. Butuca A, Dobrea CM, Arseniu AM (2024) An Assessment of Semaglutide Safety Based on Real World Data: From Popularity to Spontaneous Reporting in EudraVigilance Database. Biomedicines 12: 1124.
126. Aroda VR, Erhan U, Jelnes P (2023) Safety and tolerability of semaglutide across the SUSTAIN and PIONEER phase IIIa clinical trial programmes. Diabetes Obes Metab 25: 1385-1397.
127. Kute SA, Chothave MS, Rote PR M (2024) Exploring the unintended consequences of misuse of wegovy and Ozempic in weight management: A comprehensive Review. Int J Pharm Sci 16(6): 10-13.
128. Anam M, Maharjan S, Amjad Z (2022) Efficacy of Semaglutide in Treating Obesity: A Systematic Review of Randomized Controlled Trials (RCTs). Cureus 14(12): e32610.
129. Kurtzhals P, Kreiner FF, Bindra RS (2023) The role of weight control in the management of type 2 diabetes mellitus: Perspectives on semaglutide. Diabetes Research and Clinical Practice 203: 110881.
130. Singh G, Krauthamer M, Bjalme-Evans M (2022) Wegovy (semaglutide): a new weight loss drug for chronic weight management. J Investig Med 70: 5-13.
131. Chao AM, Tronieri JS, Amaro A (2022) Clinical Insight on Semaglutide for Chronic Weight Management in Adults: Patient Selection and special Considerations. Drug Design, Development and Therapy 16: 4449-4461.
132. Chao AM, Tronieri JS, Amaro A (2023) Semaglutide for the treatment of obesity. Trends Cardiovasc Med 33(3): 159-166.
133. Mahapatra MK, Karuppasamy M, Sahoo BM (2022) Therapeutic Potential of Semaglutide, a Newer GLP 1 Receptor Agonist, in Abating Obesity, NonAlcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review. Pharmaceutical Research 39: 1233-1248.
134. Lau DCW, Batterham RL, le Roux CW (2022) Pharmacological profile of once-weekly injectable semaglutide for chronic weight management. Expert Review of Clinical Pharmacology 15(3): 251-268.
135. Jung HN, Jung CH (2022) The Upcoming Weekly Tides (Semaglutide vs. Tirzepatide) against Obesity: STEP or SURPASS?. J Obes Metab Syndr 31: 28-36.
136. Phillips A, Clements JN (2022) Clinical review of subcutaneous semaglutide for obesity. J Clin Pharm Ther 47: 184-193.
137. Kyrillos J (2022) Semaglutide 2.4-mg injection as a novel approach for chronic weight management. Am J Manag Care 28(15): 297-306.
138. Verma S, Bhatta M, Davies M (2023) Effects of once-weekly semaglutide 2.4 mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials. EClinical Medicine 55: 101737.
139. Kushner RF, Calanna S, Davies M (2020) Semaglutide 2.4 mg for the treatment of obesity: key elements of the STEP trials 1 to 5. Obesity 28(6): 1050-1061.
140. Jensterle M, Rizzo M, Janez A (2023) Semaglutide in Obesity: Unmet Needs in Men. Diabetes Ther 14: 461-465.
141. Müllertz ALO, Sandsdal RM, Jensen SBK (2024) Potent incretin-based therapy for obesity: A systematic review and meta-analysis of the efficacy of semaglutide and tirzepatide on body weight and waist circumference, and safety. Obesity Reviews 25(5): e13717.
142. Amaro A, Sugimoto D, Wharton S (2022) Efficacy and safety of semaglutide for weight management: evidence from the STEP program. Postgraduate Medicine 134(1): 5-17.
143. O Neil PM, Domenica M, Rubino DM (2022) Exploring the wider benefits of semaglutide treatment in obesity: insight from the STEP program. Postgraduate Medicine 134(1): 28-36.
144. Qin W, Yang J, Deng C (2024) Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta-analysis including the 2-year STEP 5 trial. Diabetes Obes Metab 26(3): 911‐
145. Colin IM, Gérard AC (2022) Once-weekly 2.4 mg Semaglutide for Weight Management in Obesity: A Game Changer?. Touch REVIEWS in Endocrinology 18(1): 35-42.
146. Bergmann NC, Davies MJ, Lingvay I (2023) Semaglutide for the treatment of overweight and obesity: A review. Diabetes Obes Metab 25: 18-35.
147. Kosiborod MN, Bhatta M, Davies M (2023) Semaglutide improves cardiometabolic risk factors in adults with overweight or obesity: STEP 1 and 4 exploratory analyses. Diabetes Obes Metab 25: 468-478.
148. Heerspink HJL, Apperloo E, Davies M (2023) Effects of Semaglutide on Albuminuria and Kidney Function in People With Overweight or Obesity With or Without Type 2 Diabetes: Exploratory Analysis From the STEP 1, 2, and 3 Trials. Diabetes Care 46: 801-810.
149. Liu Y (2024) Analysis of the therapeutic effect of semaglutide. Proceedings of the 2nd International Conference on Modern Medicine and Global Health, pp. 280-286.
150. Wilding JPH, Batterham RL, Calanna S (2021) Once weekly semaglutide in adults with overweight or obesity. N Engl J Med 384(11): 989-1002.
151. Davies M, Faerch L, Jeppesen OK (2021) Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 397(10278): 971-984.
152. Wadden TA, Bailey TS, Billings LK (2021) Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA 325(14): 1403-1413.
153. Rubino D, Abrahamsson N, Davies M (2021) Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA 325(14): 1414-1425.
154. Garvey WT, Batterham RL, Bhatta M (2022) Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med 28(10): 2083-2091.
155. Kadowaki T, Isendahl J, Khalid U (2022) Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): A randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial. Lancet Diabetes Endocrinol 10: 193-206.
156. Mu Y, Bao X, Eliaschewitz FG (2024) Efficacy and safety of once weekly semaglutide 2·4 mg for weight management in a predominantly east Asian population with overweight or obesity (STEP 7): a double-blind, multicentre, randomised controlled trial. Lancet Diabetes Endocrinol 12(3): 184-195.
157. Rubino DM, Greenway FL, Khalid U (2022) Effect of Weekly Subcutaneous Semaglutide vs. Daily Liraglutide on Body Weight in Adults with Overweight or Obesity without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA 327: 138-150.
158. McGowan BM, Bruun JM, Capehorn M (2024) Efficacy and safety of once-weekly semaglutide 2·4 mg versus placebo in people with obesity and prediabetes (STEP 10): a randomised, double-blind, placebo-controlled, multicentre phase 3 trial. Lancet Diabetes Endocrinol 2(9): 631-642.
159. Weghuber D, Barrett T, Barrientos-Pérez M (2022) Once-Weekly Semaglutide in Adolescents with Obesity. N Engl J Med 387: 2245-2257.
160. Kommu S, Berg RL (2024) Efficacy and safety of once-weekly subcutaneous semaglutide on weight loss in patients with overweight or obesity without diabetes mellitus—A systematic review and meta-analysis of randomized controlled trials. Obesity Reviews 25(9): e13792.
161. Wharton S, Calanna S, Davies M (2022) Gastrointestinal tolerability of once weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. Diabetes Obes Metab 24: 94-105.
162. Tham LS, Pantalone KM, Dungan K (2022) A model-based simulation of glycaemic control and body weight when switching from semaglutide to 3.0- and 4.5-mg doses of once-weekly dulaglutide. Diabetes Obes Metab 24: 302-311.
163. Warren M, Chaykin L, Trachtenbarg D (2018) Semaglutide as a therapeutic option for elderly patients with type 2 diabetes: Pooled analysis of the SUSTAIN 1-5 trials. Diabetes Obes Metab 20: 2291-2297.
164. Overgaard RV, Lindberg S, Thielke D (2018) Impact on HbA1c and body weight of switching from other GLP-1 receptor agonists to semaglutide: A model-based approach. Diabetes Obes Metab 21: 43-51.
165. Holst JJ, Madsbad S (2017) Semaglutide seems to be more effective than the other GLP-1Ras. Ann Transl Med 5(24): 505.
166. Sorli C, Harashima SI, Tsoukas GM (2017) nEfficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol 5(4): 251-260.
167. Ahrén B, Masmiquel L, Kumar H (2017) Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol 5(5): 341-354.
168. Ahmann AJ, Capehorn M, Charpentier G (2018) Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes Care 41(2): 258-266.
169. Aroda VR, Bain SC, Cariou B (2017) Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol 5(5): 355-366.
170. Rodbard HW, Lingvay I, Reed J (2018) Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial. J Clin Endocrinol Metab 103(6): 2291-2301.
171. Jódar E, Michelsen M, Polonsky W (2020) Semaglutide improves health-related quality of life versus placebo when added to standard of care in patients with type 2 diabetes at high cardiovascular risk (SUSTAIN 6). Diabetes Obes Metab 22(8): 1339-1347.
172. Pratley RE, Aroda VR, Lingvay I (2018) Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol 6(4): 275-286.
173. Lingvay I, Catarig AM, Frias JP (2019) Efficacy and safety of once weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. Lancet Diabetes Endocrinol 7(11): 834-844.
174. Zinman B, Bhosekar V, Busch R (2019) Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 7(5): 356-367.
175. Capehorn MS, Catarig AM, Furberg JK (2020) Efficacy and safety of once-weekly semaglutide 1.0mg vs once-daily liraglutide 1.2mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). Diabetes Metab 46(2): 100-109.
176. Kellerer M, Kaltoft MS, Lawson J (2022) Effect of once-weekly semaglutide versus thrice-daily insulin aspart, both as add-on to metformin and optimized insulin glargine treatment in participants with type 2 diabetes (SUSTAIN 11): A randomized, open-label, multinational, phase 3b trial. Diabetes Obes Metab 24(9): 1788-1799.
177. Smits MM, Van Raalte DH (2021) Safety of Semaglutide. Front Endocrinol 12: 645563.
178. Fonseca VA, Capehorn MS, Garg SK (2019) Reductions in Insulin Resistance are Mediated Primarily via Weight Loss in Subjects with Type 2 Diabetes on Semaglutide. J Clin Endocrinol Metab 104: 4078-4086.
179. Lingvay I, Hansen T, Macura S (2020) Superior weight loss with once-weekly semaglutide versus other glucagon-like peptide-1 receptor agonists is independent of gastrointestinal adverse events. BMJ Open Diab Res Care 8: e001706.
180. Morales J, Shubrook JH, Skolnik N (2020) Practical guidance for use of oral semaglutide in primary care: a narrative review. Postgraduate Medicine 132(8): 687-696.
181. Thethi TK, Pratley R, Meier JJ (2002) Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: the PIONEER programme. Diabetes Obes Metab 22: 1263-1277.
182. Rodbard HW, Dougherty T, Taddei-Allen P (2020) Efficacy of Oral Semaglutide: Overview of the PIONEER Clinical Trial Program and Implications for Managed Care. Am J Manag Care 26: 335-343.
183. Brunton SA, Mosenzon O, Wright Jr EF (2020) Integrating oral semaglutide into clinical practice in primary care: for whom, when, and how?. Postgraduate Medicine 132(2): 48-60.
184. Aroda VR, Bauer R, Christiansen E (2022) Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Diabetes Obes Metab 24(7): 1338‐
185. Aroda VR, Rosenstock J, Terauchi Y (2019) PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison with Placebo in Patients with Type 2 Diabetes. Diabetes Care 42(9): 1724-1732.
186. Rodbard HW, Rosenstock J, Canani LH (2019) Oral Semaglutide Versus Empagliflozin in Patients with Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial. Diabetes Care 42(12): 2272-2281.
187. Rosenstock J, Allison D, Birkenfeld AL (2019) Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA 321(15): 1466-1480.
188. Pratley R, Amod A, Hoff ST (2019) Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet 394(10192): 39-50.
189. Mosenzon O, Blicher TM, Rosenlund S (2019) Efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment (PIONEER 5): a placebo-controlled, randomised, phase 3a trial. Lancet Diabetes Endocrinol 7(7): 515-527.
190. Bain SC, Mosenzon O, Arechavaleta R (2019) Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial. Diabetes Obes Metab 21(3): 499-508.
191. Pieber TR, Bode B, Mertens A (2019) Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, openlabel, randomised, phase 3a trial. Lancet Diabetes Endocrinol 7(7): 528-539.
192. Zinman B, Aroda VR, Buse JB (2019) Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin with or Without Metformin in Patients with Type 2 Diabetes: The PIONEER 8 Trial. Diabetes Care 42(12): 2262-2271.
193. Yamada Y, Katagiri H, Hamamoto Y (2020) Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial. Lancet Diabetes Endocrinol 8(5): 377-391.
194. Yabe D, Nakamura J, Kaneto H (2020) Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial. Lancet Diabetes Endocrinol 8(5): 392-406.
195. Eliaschewitz FG, Canani LH (2021) Advances in GLP-1 treatment: focus on oral semaglutide. Diabetol Metab Syndr 13: 99
196. Sandhu H, Xu W, Olivieri AV (2023) Once-Weekly Subcutaneous Semaglutide 2.4 mg Injection is Cost-Effective for Weight Management in the United Kingdom. Adv Ther 40: 1282-1291.
197. Miguel LS, Soares M, Olivieri A (2024) Cost-effectiveness of semaglutide 2.4 mg in chronic weight management in Portugal. Silva Miguel et al. Diabetology & Metabolic Syndrome 16: 97.
198. Reitzel SB, Bøgelund M, Basse A, Olga Barszczewska, Hongye Ren (2023) Semaglutide versus tirzepatide for people with type 2 diabetes: cost of glycemic control in Austria, the Netherlands, Lithuania, and the United Arab Emirates. Current Medical Research and Opinion 39(8): 1055-1060.
199. Evans M, Berry S, Malkin SJP (2023) Evaluating the Long-Term Cost-Effectiveness of Once-Weekly Semaglutide 1mg Versus Liraglutide 1.8 mg: A Health Economic Analysis in the UK. Diabetes Ther 14: 1005-1021.
200. Gæde P, Johansen P, Tikkanen CK (2019) Management of Patients with Type 2 Diabetes with Once-Weekly Semaglutide Versus Dulaglutide, Exenatide ER, Liraglutide and Lixisenatide: A Cost-Effectiveness Analysis in the Danish Setting. Diabetes Ther 10: 1297-1317.
201. Azuri J, Hammerman A, Aboalhasan E (2023) Liraglutide versus semaglutide for weight reduction a cost needed to treat analysis. Obesity (Silver Spring) 31(6): 1510‐
202. Hu Y, Zheng SL, Ye XL (2022) Cost-effectiveness analysis of 4 GLP-1RAs in the treatment of obesity in a US setting. Ann Transl Med 10(3): 152.
203. Wilkinson L, Hunt B, Johansen P (2018) Cost of Achieving HbA1c Treatment Targets and Weight Loss Responses with Once-Weekly Semaglutide Versus Dulaglutide in the United States. Diabetes Ther 9: 951-961.
204. Johansen P, Hunt B, Iyer NN (2019) A Relative Cost of Control Analysis of Once-Weekly Semaglutide Versus Exenatide Extended-Release and Dulaglutide for Bringing Patients to HbA1c and Weight Loss Treatment Targets in the USA. Adv Ther 36: 1190-1199.
205. Kim N, Wang J, Burudpakdee C (2022) Cost-effectiveness analysis of semaglutide 2.4 mg for the treatment of adult patients with overweight and obesity in the United States. JMCP 28(7): 740-752.
206. Abramson A, Halperin F, Kim J, Traverso G (2019) Quantifying the value of orally delivered biologic therapies: A cost-effectiveness analysis of oral semaglutide. J Pharm Sci 108(9): 3138-3145.
207. Hunt B, Hansen BB, Ericsson A (2019) Evaluation of the Cost Per Patient Achieving Treatment Targets with Oral Semaglutide: A Short-Term Cost-Effectiveness Analysis in the United States. Adv Ther 36: 3483-3493.
208. Hansen BB, Nuhoho S, Ali SN (2020) Oral semaglutide versus injectable glucagon-like peptide-1 receptor agonists: a cost of control analysis. Journal of Medical Economics 23(6): 650-658.
209. Apovian CM, Garvey WT, Ryan DH (2015) Challenging obesity: patient, provider, and expert perspectives on the roles of available and emerging nonsurgical therapies. Obesity (Silver Spring) 23(2): 1-26.
210. Ryan DH, Lingvay I, Deanfield J (2024) Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nature Medicine 30: 2049-2057.
211. Wilding JP, Batterham RL, Davies M (2022) Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes Metab 24: 1553-1564.