Mechanism of Action of Semaglutide (GLP-1 Receptor Agonist)
Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1 that selectively binds to and activates the GLP-1 receptor, reducing blood glucose primarily through glucose-dependent stimulation of insulin secretion and suppression of glucagon secretion, while also delaying gastric emptying and reducing appetite through central nervous system effects. 1
Primary Mechanisms
Semaglutide works through several key mechanisms:
Pancreatic Effects
- Insulin secretion: Stimulates insulin secretion from β-cells in a glucose-dependent manner 2, 1
- Glucagon suppression: Inhibits glucagon secretion from α-cells in a glucose-dependent manner 2, 1
- β-cell protection: May promote β-cell proliferation and protect against apoptosis 2
Gastrointestinal Effects
- Delayed gastric emptying: Inhibits gastric peristalsis while increasing pyloric tone 2, 1
- This effect is mediated by the vagus nerve 2
- GLP-1 receptors on the myenteric plexus activate nitrergic and cyclic adenosine monophosphate pathways to inhibit vagal activity 2
- This delay is more pronounced in people with normal rapid gastric emptying 2
- Note: Tachyphylaxis (diminishing response) to the gastric emptying effect can develop with continuous exposure 2
Central Nervous System Effects
- Appetite regulation: Acts on GLP-1 receptors in the hypothalamus and brainstem nuclei to reduce appetite and food intake 2
- Weight loss: Promotes significant weight loss (6.1-17.4% in non-diabetic individuals, 4-6.2% in diabetic patients) 2
Pharmacokinetic Properties
Semaglutide has been specifically engineered for prolonged action:
- Protection from degradation: Modified to prevent cleavage by dipeptidyl peptidase-4 (DPP-4) enzyme 2, 1
- Extended half-life: Achieved through high albumin binding, which:
- Decreases renal clearance
- Protects from metabolic degradation 1
- Dosing advantage: These modifications allow for once-weekly dosing 2
Cardiovascular Effects
Semaglutide has demonstrated cardioprotective effects through:
- Improved myocardial substrate utilization
- Anti-inflammatory and anti-atherosclerotic effects
- Reduced myocardial ischemia injury
- Lower systemic and pulmonary vascular resistance
- Improved lipid profiles 2
Clinical Implications
Understanding semaglutide's mechanism of action explains several important clinical observations:
- Low hypoglycemia risk: The glucose-dependent nature of insulin stimulation and glucagon suppression explains why hypoglycemia risk is low when used as monotherapy 2, 1
- Gastrointestinal side effects: Common adverse effects like nausea, vomiting, and diarrhea relate to the drug's effects on gastric emptying and GI motility 2
- Cardiovascular benefits: The LEADER trial demonstrated cardiovascular outcome benefits, consistent with the drug's multiple cardioprotective mechanisms 2
Important Considerations in Clinical Practice
- Gastroparesis: Avoid in patients with gastroparesis due to its effects on gastric emptying 3
- Dose titration: Start at a low dose and titrate upward slowly to minimize GI side effects 3
- Meal size: Recommend reducing meal size to help manage GI side effects 3
- Monitoring: Be aware of potential for gallbladder disorders, though these are rarely symptomatic 3
Understanding semaglutide's mechanism of action provides the foundation for its appropriate clinical use in type 2 diabetes management and obesity treatment, explaining both its beneficial effects and potential adverse reactions.