What is the mechanism of action of semaglutide (glucagon-like peptide-1 receptor agonist)?

Mechanism of Action of Semaglutide

Semaglutide is a GLP-1 receptor agonist with 94% sequence homology to human GLP-1 that works by selectively binding and activating GLP-1 receptors throughout the body, producing glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, and central appetite regulation. 1

Primary Molecular Mechanism

Receptor Binding and Activation

• Semaglutide acts as a selective GLP-1 receptor agonist that binds to and activates GLP-1 receptors, which are the same targets as native GLP-1 hormone 1
• The drug achieves its prolonged action through albumin binding, which decreases renal clearance and protects against metabolic degradation by the DPP-4 enzyme 1
• This albumin affinity is greater than other GLP-1 agonists like liraglutide, contributing to its once-weekly dosing capability 2

Pancreatic Effects

Glucose-Dependent Insulin and Glucagon Regulation

• Semaglutide stimulates insulin secretion from pancreatic β-cells in response to elevated plasma glucose levels, with this effect significantly attenuated when glucose is not elevated, explaining the low hypoglycemia risk 2, 1
• The drug enhances both first- and second-phase insulin secretion compared to placebo 1
• Glucagon secretion is inhibited in a glucose-dependent manner, with reductions of 8% in fasting glucagon, 14-15% in postprandial glucagon response, and 12% in mean 24-hour glucagon concentration 1
• During induced hypoglycemia, semaglutide does not impair counter-regulatory glucagon responses, preserving protective mechanisms 1
• GLP-1 receptor agonists may promote β-cell proliferation and protect against apoptosis 2

Gastrointestinal Effects

Gastric Emptying Modulation

• Much of the glucose-lowering effect comes from delayed gastric emptying rather than pancreatic effects alone 2
• Semaglutide delays early postprandial gastric emptying, reducing the rate at which glucose appears in circulation after meals 1
• The mechanism involves GLP-1 receptors on the myenteric plexus activating nitrergic and cyclic adenosine monophosphate pathways to inhibit vagal activity on the gut 2
• This leads to reduced phasic gastric contractions, delayed gastric emptying, reduced gastric acid secretion, and increased fasting and postprandial gastric volumes 2
• The vagus nerve mediates these effects; patients who have undergone vagotomy do not experience GLP-1's effects on gastric emptying 2

Important Caveat on Gastric Emptying

• Tachyphylaxis (tolerance) to gastric emptying effects may develop with continuous long-acting exposure to semaglutide (12-20 weeks), though scintigraphy studies still demonstrate delayed gastric emptying in patients with diabetes and obesity on semaglutide 2
• Acute and intermittent GLP-1 exposure has more pronounced effects on delaying gastric emptying than continuous infusion 2

Central Nervous System Effects

Appetite and Satiety Regulation

• GLP-1 receptors in the hypothalamus (arcuate nucleus) and brainstem nuclei (area postrema and nucleus tractus solitarius) mediate appetite suppression, satiety, and energy intake/expenditure 2
• Semaglutide reaches these central centers where the arcuate nucleus is suppressed and meal termination is induced in parabrachial neurons, either directly or indirectly via the nucleus tractus solitarius and area postrema 2
• GLP-1 receptors are also distributed in the hippocampus, neocortex, spinal cord, and cerebellum 2
• Receptors in the hepatoportal region and on afferent vagal nerve endings in the intestinal mucosa generate central nervous system signals that influence insulin secretion and metabolism 2

Cardiovascular Effects

Cardioprotective Mechanisms

• GLP-1 receptors are localized primarily to the sinoatrial node and arterial walls, where they are important for endothelial function and autonomic nervous system regulation 2
• Cardioprotective effects are mediated through improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, reduced myocardial ischemia injury, and lower systemic and pulmonary vascular resistance 2
• Semaglutide does not prolong QTc intervals to any clinically relevant extent at doses 1.5 times the maximum recommended dose 1

Clinical Outcomes from Mechanism

Glycemic Control

• Treatment with semaglutide 1 mg produces absolute reductions of 29 mg/dL (22%) for fasting glucose, 74 mg/dL (36%) for 2-hour postprandial glucose, and 30 mg/dL (22%) for mean 24-hour glucose concentration 1
• The insulin secretion rate in patients with type 2 diabetes treated with semaglutide becomes similar to that of healthy subjects 1

Weight Loss

• Semaglutide produces mean weight loss of 14.9% in non-diabetic, overweight or obese patients, a degree previously only reported with bariatric surgery 2, 3
• GLP-1 receptor agonists result in substantially greater weight loss in those without diabetes (6.1-17.4%) compared to patients with diabetes (4-6.2%) 2