Mechanism of Action of Semaglutide (Ozempic)
Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, reducing blood glucose by stimulating insulin secretion and lowering glucagon secretion in a glucose-dependent manner. 1
Primary Mechanism
Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Its mechanism involves several key actions:
- Receptor binding and activation: Selectively binds to and activates the GLP-1 receptor, the target for native GLP-1 1
- Glucose regulation: Reduces blood glucose through:
- Stimulating insulin secretion when blood glucose is high
- Lowering glucagon secretion in a glucose-dependent manner
- Delaying gastric emptying in the early postprandial phase 1
Molecular Structure and Modifications
Semaglutide has been specifically engineered for enhanced stability and extended duration of action:
- Produced by yeast fermentation with the peptide backbone 1
- Modified in position 8 to provide stabilization against degradation by dipeptidyl-peptidase 4 (DPP-4) enzyme 1
- Modified at position 26 lysine with a hydrophilic spacer and C18 fatty di-acid to facilitate albumin binding 1
- Minor modification at position 34 to ensure attachment of only one fatty di-acid 1
- Molecular formula: C187H291N45O59 with molecular weight of 4113.58 g/mol 1
Pharmacokinetic Properties
The principal mechanism of protraction resulting in semaglutide's long half-life includes:
- Albumin binding: Results in decreased renal clearance and protection from metabolic degradation 1
- DPP-4 resistance: Stabilized against degradation by the DPP-4 enzyme 1
- Half-life: Approximately 1 week, allowing for once-weekly dosing 1
- Bioavailability: 89% absolute bioavailability when administered subcutaneously 1
Pharmacodynamic Effects
Semaglutide produces several important physiological effects:
Glucose Regulation
- Reduces fasting glucose by 29 mg/dL (22%) compared to placebo 1
- Reduces 2-hour postprandial glucose by 74 mg/dL (36%) 1
- Reduces mean 24-hour glucose concentration by 30 mg/dL (22%) 1
Insulin and Glucagon Effects
- Increases both first- and second-phase insulin secretion 1
- Lowers fasting glucagon by 8% compared to placebo 1
- Reduces postprandial glucagon response by 14-15% 1
- Decreases mean 24-hour glucagon concentration by 12% 1
Gastric Emptying
- Delays early postprandial gastric emptying, reducing the rate at which glucose appears in circulation 1
- This delay is mediated by vagus nerve activity 2
Clinical Applications
The mechanism of action of semaglutide makes it particularly effective for:
- Type 2 diabetes management through improved glycemic control 3
- Weight reduction in patients with obesity 4
- Potential cardiovascular benefits through multiple mechanisms 3, 5
Safety Considerations Related to Mechanism
Understanding semaglutide's mechanism helps explain some safety considerations:
- Glucose-dependent action minimizes hypoglycemia risk when used as monotherapy 1, 6
- Gastrointestinal side effects (nausea, vomiting, diarrhea) relate to delayed gastric emptying 2, 6
- Does not impair counter-regulatory responses during hypoglycemia 1
Semaglutide's unique molecular modifications and mechanism of action contribute to its clinical efficacy and once-weekly dosing advantage over earlier GLP-1 receptor agonists, making it an important treatment option for patients with type 2 diabetes and obesity.