What is the biochemical mechanism of Semaglutide (GLP-1 receptor agonist) 2.4mg?

Biochemical Mechanism of Semaglutide 2.4mg

Molecular Structure and Receptor Binding

Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1 that acts as a GLP-1 receptor agonist, selectively binding to and activating the GLP-1 receptor, which is the target for native GLP-1. 1

• The drug functions as a peptidic GLP-1 receptor agonist with structural modifications that enhance its pharmacological properties compared to native GLP-1 2
• GLP-1 receptors are expressed ubiquitously throughout multiple organs including the pancreas, gastrointestinal tract, heart, brain, kidney, lung, and thyroid, explaining its pleiotropic metabolic effects 3
• Within the central nervous system, GLP-1 receptors are found in the hypothalamus, brainstem nuclei, hippocampus, neocortex, spinal cord, and cerebellum 4

Protraction Mechanism and Pharmacokinetics

The principal mechanism of protraction resulting in semaglutide's long half-life is albumin binding, which decreases renal clearance and provides protection from metabolic degradation. 1

• Semaglutide is stabilized against degradation by the DPP-4 enzyme, further extending its duration of action 1
• The absolute bioavailability of semaglutide is 89%, with maximum concentration reached 1 to 3 days post-dose 1
• Exposure increases in a dose-proportional manner for once-weekly doses 1

Glucose-Dependent Mechanisms

Semaglutide reduces blood glucose through glucose-dependent stimulation of insulin secretion and suppression of glucagon secretion, meaning these effects only occur when blood glucose is elevated. 1

• Both first- and second-phase insulin secretion are increased in patients with type 2 diabetes treated with semaglutide compared to placebo 1
• The insulin secretion rate in patients with type 2 diabetes treated with semaglutide becomes similar to that of healthy subjects 1
• Semaglutide lowers fasting glucagon by 8%, postprandial glucagon response by 14-15%, and mean 24-hour glucagon concentration by 12% 1
• During induced hypoglycemia, semaglutide does not alter counter-regulatory responses of increased glucagon and does not impair the decrease of C-peptide, preserving protective mechanisms 1

Gastric Emptying Effects

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

• This delayed gastric emptying is particularly pronounced during initial therapy, though tachyphylaxis may develop with continued use 5
• The effect on gastric emptying contributes to both glucose control and satiety mechanisms 1

Weight Loss Mechanisms

Semaglutide reduces body weight through multiple mechanisms including delayed gastric emptying, inhibition of food intake, and direct effects on adipose tissue. 3, 1

• GLP-1 has numerous metabolic effects including glucose-dependent stimulation of insulin secretion, delayed gastric emptying, inhibition of food intake, and modulation of β-cell proliferation 3
• In preclinical studies, semaglutide stimulates browning of subcutaneous fat adipocytes, enhancing UCP1 expression, mitochondrial biogenesis, and thermogenic marker expressions 6
• The drug increases expression of peroxisome proliferator-activated receptor-alpha (+560%) and gamma (+150%), fibronectin type III domain-containing protein 5 (+215%), and beta-3 adrenergic receptor (+520%) in adipose tissue 6
• Semaglutide reduces inflammation in visceral adipose tissue by decreasing tumor necrosis factor-alpha (-60%), interleukin-6 (-55%), and monocyte chemoattractant protein-1 (-90%) 6
• The drug lessens endoplasmic reticulum stress in adipocytes by reducing activating transcription factor-4 (-85%) and CCAAT enhancer-binding protein homologous protein (-55%) 6

Clinical Glucose Effects

At the 2.4mg dose, semaglutide produces substantial reductions in both fasting and postprandial glucose concentrations. 1

• Treatment results in absolute reductions of 29 mg/dL (22% relative reduction) for fasting glucose, 74 mg/dL (36% relative reduction) for 2-hour postprandial glucose, and 30 mg/dL (22% relative reduction) for mean 24-hour glucose concentration 1
• These effects are mediated through the glucose-dependent mechanisms described above, minimizing hypoglycemia risk when used as monotherapy 1

Cardiovascular and Metabolic Effects

Beyond glucose control, semaglutide improves insulin resistance, insulin signaling pathways, and cardiovascular risk factors through its widespread GLP-1 receptor activation. 2

• The drug improves cardiovascular risk factors including cholesterol profiles, blood pressure, and inflammatory markers 7
• Semaglutide has inherent glucoregulatory properties and provides cardioprotection in select populations 3
• In patients with obesity and heart failure with preserved ejection fraction (HFpEF), semaglutide improves symptoms through weight loss and direct cardiovascular effects 3

Cardiac Electrophysiology

At doses 1.5 times the maximum recommended dose, semaglutide does not prolong QTc intervals to any clinically relevant extent. 1

• This favorable cardiac safety profile was established in thorough QTc trials 1