Semaglutide in Obesity Treatment: Mechanism, Efficacy, and Safety

Obesity has become a globally prevalent chronic disease, affecting approximately 650 million adults worldwide. It is closely associated with various complications, including cardiovascular disease, type 2 diabetes, and hypertension. A weight reduction of 5% or more can improve these associated health risks. While lifestyle intervention forms the cornerstone of obesity treatment, its weight loss effects are often limited and prone to rebound. Anti-obesity medications (AOMs) have therefore emerged as an important adjunctive treatment. Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, was approved by the US FDA in 2021 for chronic weight management. With its significant weight loss efficacy and cardiovascular protective properties, it represents a major breakthrough in obesity treatment. This article provides a systematic review of the mechanism of action, weight loss and cardiometabolic efficacy, and safety profile of semaglutide 2.4 mg/week for obesity treatment. By analyzing key clinical trials (the STEP program), it evaluates its clinical application value and future directions, offering a comprehensive reference for the pharmacotherapy of this chronic disease.

1. Background and Drug Profile

Approximately 650 million adults worldwide are affected by obesity, a condition closely linked to complications like cardiovascular disease and type 2 diabetes. Weight loss of 5% or more can mitigate associated risks. Lifestyle intervention is fundamental but often yields limited and unsustainable weight loss, making AOMs a crucial adjunct. Currently approved AOMs in various countries include liraglutide and orlistat. Semaglutide, a novel agent approved by the US FDA in 2021, has become a major focus of research due to its once-weekly dosing and pronounced weight loss effects.

Semaglutide is a long-acting GLP-1 receptor agonist with 94% homology to native human GLP-1. Structural modifications enable reversible albumin binding, reducing degradation by dipeptidyl peptidase-4 (DPP-4) and renal clearance, resulting in an extended half-life of 155-184 hours, allowing for once-weekly subcutaneous injection. The recommended dose for obesity treatment is 2.4 mg/week, achieved through a 16-week dose-escalation schedule starting at 0.25 mg/week. A 1.0 mg/week dose is approved for type 2 diabetes, and an oral formulation is also available (approved for diabetes).

2. Core Mechanism of Action

Semaglutide induces weight loss through multiple pathways, with its core mechanism centered on appetite and metabolic regulation:

 Reduced Energy Intake:​ Acts directly on hypothalamic appetite control pathways, decreasing hunger, enhancing satiety, and reducing food cravings. Laboratory studies show it can reduce ad libitum food intake by 35%.

 Glucose Metabolism Regulation:​ Stimulates glucose-dependent insulin secretion and suppresses glucagon release, minimizing hypoglycemia risk.

 Minor Gastrointestinal Effects:​ Has a limited impact on gastric emptying; gastrointestinal side effects are not the primary driver of weight loss.

No Significant Effect on Energy Expenditure:​ Weight loss primarily relies on reduced caloric intake.

 3. Efficacy from Key Clinical Trials (STEP Program)

The STEP Phase 3 trial series provides the core evidence for semaglutide in obesity, encompassing diverse populations and intervention models:

STEP 1 (Non-diabetic population):​ Over 68 weeks, the semaglutide group achieved an average weight loss of 14.9%, compared to 2.4% for placebo. 32% of participants lost ≥20% of body weight. Significant improvements were also seen in waist circumference, blood pressure, lipid profiles, and quality of life.

 STEP 2 (Population with type 2 diabetes):​ At 68 weeks, weight loss was 9.6%, superior to the 1.0 mg dose group (7.0%) and placebo (3.4%). HbA1c decreased by 1.6%, demonstrating benefits for both weight and glycemic control.

 STEP 3 (Intensive behavioral intervention combined with medication):​ Following an initial 8-week low-calorie meal replacement phase and 30 behavioral counseling sessions, the semaglutide group lost 16.0% of body weight vs. 5.7% for placebo. The results did not show a fully additive effect, suggesting the drug's potent appetite suppression is a dominant factor.

 STEP 4 (Weight maintenance trial):​ After an initial 20-week run-in period resulting in 10.6% weight loss, participants continuing semaglutide achieved a cumulative 17.4% weight loss at week 68. Those switched to placebo regained weight, ending at 5.7%, confirming the necessity of continued treatment for weight maintenance.

4. Safety and Tolerability

4.1 Common Adverse Events

Gastrointestinal reactions are most common, including nausea (33.7%-58.2%), diarrhea (21.3%-36.1%), and vomiting (21.8%-27.3%). These are typically mild to moderate, occur during the dose-escalation period (first 20 weeks), and are transient. Discontinuation rates due to adverse events were 5.9%-7.0%, higher than placebo (2.9%-3.5%).

4.2 Specific Risks and Contraindications

 Increased risk of gallbladder-related events (e.g., cholelithiasis), with an incidence of 2.6%-4.9%, associated with rapid weight loss.

 Contraindications include pregnancy, personal or family history of medullary thyroid carcinoma, and hypersensitivity to semaglutide or excipients.

 Rare risks: Acute pancreatitis, acute kidney injury, diabetic retinopathy (in patients with diabetes).

 4.3 Cardiovascular Safety

Semaglutide causes a small increase in heart rate (1-4 bpm). However, the SUSTAIN-6 trial confirmed it significantly reduces the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or stroke) in patients with type 2 diabetes (HR=0.74), indicating a favorable cardiovascular safety profile.

5. Key Insights and Future Directions

5.1 Core Advantages

 Significant Weight Loss:​ One of the most effective approved AOMs, achieving up to 15-16% weight loss in non-diabetic individuals, approaching the efficacy of sleeve gastrectomy.

 Multiple Benefits:​ Simultaneously improves various cardiometabolic parameters (blood pressure, lipids, glucose) and enhances quality of life.

 Convenient Dosing:​ Once-weekly injection improves adherence compared to daily agents like liraglutide.

 5.2 Key Considerations for Clinical Application

Reduced Efficacy in Diabetes:​ Weight loss is approximately one-third lower in patients with type 2 diabetes due to metabolic factors (e.g., lower basal metabolic rate, hypoglycemia concerns).

Long-Term Treatment Required:​ Obesity is a chronic disease; weight regain is likely upon discontinuation, necessitating long-term use similar to medications for hypertension or diabetes.

Ancillary Value of Behavioral Intervention:​ Moderate lifestyle counseling is beneficial, but intensive intervention does not significantly augment the weight loss effect of the drug itself.

5.3 Future Directions

Formulation Optimization:​ Development of oral formulations may improve acceptability for injection-averse individuals.

Combination Therapies:​ Exploring combinations with amylin analogues, GIP receptor agonists (e.g., tirzepatide), etc., to further enhance weight loss. 

Population Expansion:​ Conducting trials in special populations like adolescents and patients with heart failure and obesity.

Cost-Effectiveness Studies:​ Further analysis of the long-term health economic value is needed to balance drug cost against the benefits of preventing complications.

6. Summary

Semaglutide, with its potent and sustained weight loss effects and cardiovascular benefits, represents a significant advancement in obesity treatment. It is particularly suitable for individuals with obesity or overweight who have concomitant cardiometabolic risks. Its core value lies in the precise regulation of appetite and metabolism by mimicking physiological GLP-1 action, coupled with the clinical practicality of once-weekly dosing. However, management of gastrointestinal side effects, the necessity for long-term use, and contraindications in specific populations require careful attention. With future optimization of formulations and combination strategies, its application in the precision treatment of obesity is expected to expand further.

Original Article：

Chao, Ariana M., et al. "Semaglutide for the treatment of obesity." Trends in cardiovascular medicine 33.3 (2023): 159-166.