What is the mechanism of action of semaglutide in adults with type 2 diabetes and obesity?

Mechanism of Action of Semaglutide

Semaglutide is a GLP-1 receptor agonist with 94% sequence homology to human GLP-1 that reduces blood glucose by stimulating insulin secretion and suppressing glucagon secretion in a glucose-dependent manner, while also delaying gastric emptying and promoting weight loss through central appetite suppression. 1

Core Pharmacologic Mechanism

• Semaglutide selectively binds to and activates the GLP-1 receptor, which is the target for native GLP-1, a physiological incretin hormone with multiple glucose-regulatory actions. 1

• The principal mechanism of protraction is albumin binding, which results in decreased renal clearance, protection from metabolic degradation, and stabilization against degradation by the DPP-4 enzyme—yielding a half-life of approximately one week. 1

Glucose-Lowering Mechanisms

Pancreatic Effects

• Semaglutide stimulates insulin secretion in a glucose-dependent manner, increasing both first- and second-phase insulin release when blood glucose is elevated. 1

• Glucagon secretion is suppressed in a glucose-dependent fashion, with reductions of 8% in fasting glucagon, 14–15% in postprandial glucagon response, and 12% in mean 24-hour glucagon concentration. 1

• The glucose-dependent nature of insulin stimulation and glucagon suppression explains the low intrinsic hypoglycemia risk with GLP-1 receptor agonists, as the counter-regulatory responses remain intact during induced hypoglycemia. 1, 2

• Semaglutide may promote β-cell proliferation and protect against apoptosis, potentially preserving pancreatic function over time, though this effect is primarily demonstrated in preclinical models. 2

Gastric Emptying

• Semaglutide causes a delay of early postprandial gastric emptying, reducing the rate at which glucose appears in the circulation after meals. 1

• Much of the glucose-lowering and weight-loss effect is attributable to delayed gastric emptying rather than pancreatic islet effects alone, as the slowing of gastric peristalsis and increased pyloric tone (mediated through vagal pathways) mechanically prolongs food residence time in the stomach. 2

• Scintigraphic studies demonstrate persistent gastric-emptying delays with long-acting semaglutide, with retained gastric contents documented in approximately 24% of users versus 5% of controls even after extended fasting periods. 2

Weight-Loss Mechanisms

Central Nervous System Effects

• GLP-1 receptors are widely distributed in the hypothalamus, brainstem, hippocampus, neocortex, spinal cord, and cerebellum, providing the neuroanatomical basis for potent satiety signals that terminate meals early and lower overall caloric intake. 2

• Activation of hypothalamic GLP-1 receptors triggers neuronal pathways (including parabrachial neurons) that induce meal termination and generate robust satiety signals, representing a primary mechanism of appetite suppression. 2

• Vagal nerve endings in the intestinal mucosa are activated by semaglutide, generating central nervous system signals that influence both insulin secretion and metabolism. 2

Peripheral Metabolic Effects

• Delayed gastric emptying produces prolonged feelings of fullness, reduces phasic gastric contractions, increases fasting gastric volumes, and diminishes gastric acid secretion. 2

• Semaglutide increases energy expenditure through mechanisms that extend beyond simple caloric restriction, contributing to the superior efficacy compared with older appetite-suppressant agents. 2

• The combined effects on appetite, gastric emptying, and energy metabolism explain why weight loss is not solely attributable to reduced food intake, distinguishing GLP-1 agonists from traditional appetite suppressants. 2

Cardiovascular and Metabolic Benefits

• Cardioprotective effects are mediated through improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic actions, reduced myocardial ischemia injury, lower systemic and pulmonary vascular resistance, and improved lipid profiles. 2

• Semaglutide modestly lowers systolic and diastolic blood pressure, with clinically meaningful reductions observed across multiple trials. 2

• Improvements in inflammatory markers such as C-reactive protein occur with semaglutide treatment, contributing to broader cardiometabolic benefits. 2

Renal Effects

• Semaglutide reduces albuminuria and slows eGFR decline, with pronounced benefit in patients whose eGFR is 20–60 mL/min/1.73 m². 2

• No dose adjustment is required across all stages of chronic kidney disease, including end-stage renal disease, making semaglutide a preferred option in advanced CKD. 2, 1

Clinical Pharmacodynamics

• At steady state (after 12 weeks of treatment 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 concentration by 30 mg/dL (22%). 1

• The insulin secretion rate in patients with type 2 diabetes treated with semaglutide becomes similar to that of healthy subjects, demonstrating restoration of near-normal glucose-dependent insulin response. 1

Important Mechanistic Considerations

• Continuous exposure to semaglutide leads to partial tachyphylaxis of the gastric-emptying effect, reflecting autonomic adaptation over time, though patients continue to achieve clinically meaningful weight loss through other operative mechanisms. 2

• The delayed gastric-emptying effect persists for 10–14 days after drug discontinuation, raising perioperative aspiration risk independent of appetite-suppression effects. 2

• Common gastrointestinal adverse events (nausea, vomiting) are mechanistically linked to the therapeutic gastric-slowing effect rather than representing separate safety concerns. 2