Mechanism of Action of Ozempic (Semaglutide)
Ozempic (semaglutide) is a GLP-1 receptor agonist that works by selectively binding to and activating GLP-1 receptors, stimulating glucose-dependent insulin secretion, suppressing glucagon release, delaying gastric emptying, and promoting satiety through central nervous system pathways. 1
Primary Molecular Mechanism
Semaglutide is a modified GLP-1 analogue with 94% sequence homology to human GLP-1, engineered with specific structural modifications that extend its duration of action 1. The molecule is modified at position 8 to provide stabilization against degradation by dipeptidyl-peptidase 4 (DPP-4) enzyme, and at position 26 with a hydrophilic spacer and C18 fatty di-acid chain to facilitate albumin binding 1.
The principal mechanism of protraction is albumin binding, which results in decreased renal clearance and protection from metabolic degradation, giving semaglutide an approximately 1-week half-life 1. This albumin binding is the key innovation that allows once-weekly dosing 1.
Glucose-Lowering Mechanisms
Semaglutide reduces blood glucose through glucose-dependent stimulation of insulin secretion and suppression of glucagon secretion 1. When blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited; conversely, during hypoglycemia, semaglutide does not impair counter-regulatory glucagon responses 1.
- Both first- and second-phase insulin secretion are increased in patients with type 2 diabetes treated with semaglutide compared to placebo 1
- Fasting glucagon is reduced by 8%, postprandial glucagon by 14-15%, and mean 24-hour glucagon by 12% compared to placebo 1
- The glucose-dependent nature of these effects explains the low risk of hypoglycemia with semaglutide monotherapy 2
Gastric Emptying Effects
Semaglutide causes a delay in early postprandial gastric emptying, reducing the rate at which glucose appears in circulation after meals 1. This mechanism contributes to both glucose control and satiety 3.
- During the first postprandial hour, gastric emptying is delayed by 31% (measured by paracetamol absorption) 3
- This delayed gastric emptying is most pronounced in the early postprandial phase and contributes to the blood glucose lowering mechanism 1
Weight Loss and Appetite Regulation
Semaglutide reduces body weight through multiple pathways including central appetite suppression, delayed gastric emptying, and increased energy expenditure 2. GLP-1 receptors are expressed in multiple organs including the pancreas, gastrointestinal tract, heart, brain, kidney, lung, and thyroid, explaining the pleiotropic effects 2.
- Semaglutide induces meal termination through hypothalamic suppression in parabrachial neurons and regulates energy intake through brainstem signaling 2
- Vagal nerve endings in the intestinal mucosa are activated, generating central nervous system signals that influence both insulin secretion and metabolism 2
- The anorexigenic effects are mediated through central appetite suppression pathways in the hypothalamus 2
Cardiovascular and Metabolic Effects
Semaglutide provides cardioprotective effects through improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, reduced myocardial ischemia injury, lower systemic and pulmonary vascular resistance, and improved lipid profiles 2.
- Fasting triglycerides, VLDL, and apolipoprotein B48 are significantly reduced with semaglutide treatment 3
- Postprandial lipid metabolism is improved, with significant reductions in triglyceride and VLDL area under the curve 3
Pancreatic Beta-Cell Effects
Semaglutide may promote pancreatic β-cell proliferation and protect against apoptosis, potentially preserving pancreatic function over time 2. This modulation of β-cell proliferation is a key metabolic effect that contributes to glucose regulation 2.
Clinical Pharmacodynamics
At steady state with semaglutide 1 mg, fasting glucose is reduced by 29 mg/dL (22%), 2-hour postprandial glucose by 74 mg/dL (36%), and mean 24-hour glucose by 30 mg/dL (22%) compared to placebo 1. These reductions reflect the integrated effects of enhanced insulin secretion, suppressed glucagon, and delayed gastric emptying 1.