Mechanism of Action of Semaglutide
Primary Mechanism: GLP-1 Receptor Activation
Semaglutide is a GLP-1 receptor agonist with 94% sequence homology to human GLP-1 that selectively binds to and activates GLP-1 receptors throughout the body, triggering glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, and central appetite suppression. 1
Pancreatic Effects
Glucose-dependent insulin stimulation: When blood glucose is elevated, semaglutide activates GLP-1 receptors on pancreatic β-cells, increasing intracellular calcium and triggering insulin exocytosis. 2, 1
Glucagon suppression: Semaglutide inhibits glucagon secretion from pancreatic α-cells in a glucose-dependent manner, reducing hepatic glucose production when blood glucose is high. 2, 1
Low hypoglycemia risk: Because both insulin stimulation and glucagon suppression are glucose-dependent, semaglutide carries minimal intrinsic hypoglycemia risk when used as monotherapy—the effects attenuate when plasma glucose falls. 2, 3
β-cell protection: GLP-1 receptor activation may promote β-cell proliferation and protect against apoptosis, potentially preserving pancreatic function over time. 2, 3
Gastric Emptying and Satiety
Delayed gastric emptying is the primary driver of glucose lowering: Much of semaglutide's glucose-lowering effect results from slowing gastric emptying rather than direct pancreatic actions. 2
Vagal-mediated mechanism: Semaglutide delays gastric emptying by inhibiting gastric peristalsis and increasing pyloric tone through vagal nerve pathways—patients who have undergone vagotomy do not experience this effect. 2
Prolonged fullness: The delayed gastric emptying produces prolonged feelings of fullness, reduced phasic gastric contractions, increased fasting gastric volumes, and reduced gastric acid secretion. 2, 3
Persistent effect despite tachyphylaxis: Although some tachyphylaxis to gastric-emptying effects develops with continuous exposure, patients continue to experience significant weight loss, indicating multiple mechanisms remain active. 2, 3
Central Nervous System Effects
Hypothalamic appetite suppression: Semaglutide activates GLP-1 receptors in the hypothalamus, triggering neuronal pathways (including parabrachial neurons) that terminate meals and generate robust satiety signals. 3, 4
Distributed neural pathways: GLP-1 receptors are expressed in the hypothalamus, brainstem, hippocampus, neocortex, spinal cord, and cerebellum, providing the neuroanatomical basis for potent appetite suppression and meal termination. 2, 3, 4
Indirect neural activation: Semaglutide induces c-Fos activation in at least 10 brain areas, including both areas with direct GLP-1 receptor interaction and secondary areas without direct receptor contact, such as the lateral parabrachial nucleus involved in meal termination. 4
Limited blood-brain barrier penetration: Semaglutide does not cross the blood-brain barrier; instead, it interacts with the brain through circumventricular organs and select sites adjacent to the ventricles. 4
Cardiovascular and Metabolic Effects
Cardioprotective mechanisms: Semaglutide provides cardiovascular benefits 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. 3
Blood pressure reduction: Treatment produces clinically meaningful decreases in both systolic and diastolic blood pressure, mediated through weight loss and broader metabolic improvements. 3
Renal protection: Semaglutide reduces albuminuria and slows eGFR decline, with pronounced benefit in patients with eGFR 20–60 mL/min/1.73 m². 3, 5
Pharmacokinetic Properties Enabling Once-Weekly Dosing
Albumin binding for protraction: The principal mechanism of semaglutide's long half-life (approximately 1 week) is extensive albumin binding (>99%), which decreases renal clearance and protects against metabolic degradation. 2, 1
DPP-4 resistance: Semaglutide is modified at position 8 to provide stabilization against degradation by dipeptidyl peptidase-4 enzyme, further prolonging its duration of action. 2, 1
Steady-state achievement: Steady-state exposure is achieved after 4–5 weeks of once-weekly administration, with mean concentrations of approximately 65.0 ng/mL at 0.5 mg and 123.0 ng/mL at 1 mg doses. 1
Clinical Implications of the Mechanism
Weight loss through multiple pathways: Semaglutide reduces body weight via at least four distinct mechanisms: (1) central appetite suppression, (2) delayed gastric emptying, (3) increased energy expenditure, and (4) improved glucose metabolism—not simply "making you less hungry." 2, 3
Food preference modulation: Preclinical studies show semaglutide modulates food preference and reduces food intake without decreasing energy expenditure, suggesting selective effects on reward pathways. 4
Peri-operative aspiration risk: The delayed gastric-emptying effect persists for 10–14 days after discontinuation, creating aspiration risk during anesthesia independent of appetite-suppression effects. 2, 3