Mechanism of Action of Ozempic (Semaglutide)
Semaglutide, the active ingredient in Ozempic, is a GLP-1 receptor agonist 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. 1
Primary Mechanism of Action
Semaglutide works through several key mechanisms:
GLP-1 Receptor Activation: Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1 that selectively binds to and activates the GLP-1 receptor 1
Glucose-Dependent Effects on Pancreatic Hormones:
- Stimulates insulin secretion when blood glucose is high
- Suppresses glucagon secretion in a glucose-dependent manner
- Preserves counter-regulatory glucagon response during hypoglycemia 1
Delayed Gastric Emptying: Causes a delay in early postprandial gastric emptying, reducing the rate at which glucose appears in circulation after meals 1, 2
Molecular Structure and Modifications
Semaglutide has been specifically engineered for extended duration of action through several modifications:
Modified at 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 a C18 fatty di-acid to facilitate albumin binding 1
Minor modification at position 34 to ensure attachment of only one fatty di-acid 1
These modifications result in:
- Decreased renal clearance
- Protection from metabolic degradation
- Extended half-life of approximately 1 week 1
Physiological Effects
Semaglutide treatment results in several measurable physiological changes:
Glucose Reduction: In patients with type 2 diabetes, semaglutide 1 mg reduces:
- Fasting glucose by 29 mg/dL (22%)
- 2-hour postprandial glucose by 74 mg/dL (36%)
- Mean 24-hour glucose concentration by 30 mg/dL (22%) 1
Effects on Glucagon: Treatment with semaglutide results in:
- 8% reduction in fasting glucagon
- 14-15% reduction in postprandial glucagon response
- 12% reduction in mean 24-hour glucagon concentration 1
Insulin Secretion: Both first- and second-phase insulin secretion are increased in patients with type 2 diabetes treated with semaglutide 1
Gastrointestinal Effects
GLP-1 receptor activation delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone 2
This delay is more pronounced in people with normal rapid gastric emptying 2
The mechanism appears to be mediated by the vagus nerve, as effects on gastric emptying are not present in patients who have had a vagotomy 2
Clinical Implications
The mechanism of action of semaglutide translates to several important clinical benefits:
Improved glycemic control without increased risk of hypoglycemia due to its glucose-dependent action 2, 1
Significant weight reduction through appetite suppression and delayed gastric emptying 3
Cardiovascular benefits demonstrated in multiple clinical trials 2
Important Considerations
The long half-life of approximately 1 week means that effects persist for an extended period after discontinuation 1
Gastrointestinal side effects (nausea, vomiting, diarrhea) are common due to the delay in gastric emptying 3
The drug should be discontinued at least 2 months before a planned pregnancy due to its long washout period 1