Semaglutide

Semaglutide represents a breakthrough in metabolic medicine as a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. Originally developed for type 2 diabetes management, its remarkable weight loss effects in clinical trials led to its approval specifically for chronic weight management. The peptide is a modified analog of native human GLP-1, engineered with specific amino acid substitutions and a fatty acid chain that dramatically extends its half-life from minutes to approximately one week. This allows for convenient once-weekly dosing while maintaining consistent therapeutic levels. Semaglutide's efficacy in weight management has been demonstrated in the landmark STEP (Semaglutide Treatment Effect in People with obesity) clinical trial program, which showed unprecedented weight loss results compared to previous pharmacological interventions.

Semaglutide achieves its metabolic effects through multiple mechanisms: **GLP-1 Receptor Activation**: The peptide binds to and activates GLP-1 receptors throughout the body, particularly in the pancreas, brain, and gastrointestinal tract. **Appetite Regulation**: By acting on GLP-1 receptors in the hypothalamus and brainstem, semaglutide reduces hunger and increases feelings of satiety, leading to decreased caloric intake. **Glucose-Dependent Insulin Secretion**: In the pancreas, GLP-1 receptor activation enhances insulin secretion in response to elevated blood glucose, while suppressing glucagon release. **Gastric Emptying**: Semaglutide slows gastric emptying, contributing to prolonged satiety after meals and reduced postprandial glucose spikes. **Reward System Modulation**: Emerging research suggests effects on brain reward centers, potentially reducing food cravings and hedonic eating behaviors.

The clinical evidence for semaglutide is extensive and compelling: **STEP Trials**: The STEP clinical trial program demonstrated that 2.4mg weekly semaglutide produced average weight loss of 15-17% of body weight over 68 weeks, with approximately one-third of participants achieving ≥20% weight loss. **STEP 1**: In adults with obesity without diabetes, mean weight loss was 14.9% versus 2.4% for placebo. **STEP 2**: In adults with type 2 diabetes, mean weight loss was 9.6% with improvements in HbA1c. **SELECT Trial**: Demonstrated 20% reduction in major cardiovascular events in people with obesity and established cardiovascular disease. **Sustained Effects**: Studies show weight loss is maintained with continued treatment, with weight regain observed upon discontinuation.

Semaglutide for weight management follows a specific titration schedule: **Approved Dosing (Wegovy)**: - Weeks 1-4: 0.25mg once weekly - Weeks 5-8: 0.5mg once weekly - Weeks 9-12: 1.0mg once weekly - Weeks 13-16: 1.7mg once weekly - Week 17+: 2.4mg once weekly (maintenance dose) **Administration**: Subcutaneous injection in the abdomen, thigh, or upper arm. Can be administered any time of day, with or without food. **Titration Importance**: Gradual dose escalation is essential to minimize gastrointestinal side effects and improve tolerability.

Semaglutide's side effect profile is well-characterized from clinical trials: **Common (>10%)**: - Nausea (most common, typically improves over time) - Diarrhea - Vomiting - Constipation - Abdominal pain **Less Common**: - Fatigue - Dizziness - Injection site reactions **Serious (Rare)**: - Pancreatitis - Gallbladder disease - Hypoglycemia (mainly with concurrent diabetes medications) **Contraindications**: Personal or family history of medullary thyroid carcinoma, Multiple Endocrine Neoplasia syndrome type 2.