What is the mechanism of action of acarbose?

Mechanism of Action of Acarbose

Acarbose works by competitively and reversibly inhibiting α-glucosidase enzymes in the small intestine, which delays the digestion of complex carbohydrates into absorbable monosaccharides, thereby reducing postprandial hyperglycemia. 1

Primary Enzymatic Inhibition

Acarbose targets two key enzyme systems in the gastrointestinal tract:

• Pancreatic α-amylase inhibition: Acarbose blocks this enzyme in the lumen of the small intestine, preventing the breakdown of complex starches into oligosaccharides 1

• Membrane-bound intestinal α-glucosidase hydrolase inhibition: The drug competitively inhibits these brush-border enzymes that normally convert oligosaccharides, trisaccharides, and disaccharides into glucose and other monosaccharides 1

• The inhibition is competitive and reversible, meaning carbohydrate conversion is delayed rather than completely blocked 2

Structural and Binding Characteristics

• Acarbose is a complex oligosaccharide with the structural features of a tetrasaccharide 2

• The molecule attaches to the carbohydrate binding sites of α-glucosidases with an affinity constant much higher than that of the normal substrate 2

• This high-affinity binding allows acarbose to effectively compete with dietary carbohydrates for enzyme access 3

Metabolic Effects

The enzymatic inhibition produces several downstream metabolic consequences:

• Delayed glucose absorption: By slowing carbohydrate digestion, acarbose causes a smaller and delayed rise in blood glucose following meals 1, 4

• Reduced postprandial hyperglycemia: The primary clinical effect is attenuation of the postprandial glucose spike 5, 6

• Blunted insulin response: Acarbose decreases the hyperinsulinemic response that typically follows carbohydrate-rich meals 5, 6

• Prevention of reactive hypoglycemia: By preventing the initial hyperglycemic spike, acarbose reduces subsequent hypoglycemia, particularly beneficial in dumping syndrome and post-bariatric hypoglycemia 6, 7

Hormonal Modulation

Acarbose affects multiple gastrointestinal hormones involved in glucose homeostasis:

• Reduces gastric inhibitory polypeptide (GIP) secretion 6

• Decreases glucagon-like peptide-1 (GLP-1) release 6

• Lowers postprandial insulin secretion 5, 4

Site of Action and Pharmacokinetics

• Local gastrointestinal action: Acarbose acts exclusively within the GI tract and does not cross enterocytes after ingestion 2

• Minimal systemic absorption: Less than 2% of an oral dose is absorbed as active drug, which is therapeutically desired since the drug acts locally 1

• No effect on lactase: Acarbose has no inhibitory activity against lactase and does not induce lactose intolerance 1

• Substrate specificity: The drug influences starch and sucrose digestion but does not affect lactose or glucose absorption 3

Distinction from Other Antidiabetic Agents

• Does not enhance insulin secretion: Unlike sulfonylureas, acarbose does not stimulate pancreatic insulin release 1

• Additive mechanism: Because its mechanism differs from other antidiabetic drugs, acarbose's effects are additive when combined with sulfonylureas, insulin, or metformin 1

• Reduces insulinotropic effects: When combined with sulfonylureas, acarbose diminishes their insulin-stimulating and weight-increasing effects 1

Clinical Implications of Mechanism

• The delayed carbohydrate absorption results in reduced glycosylated hemoglobin levels over time by decreasing average blood glucose concentrations 1, 4

• Approximately 34% of the dose is metabolized by intestinal bacteria and digestive enzymes, with metabolites absorbed and excreted in urine 1

• The plasma elimination half-life is approximately 2 hours, preventing drug accumulation with three-times-daily dosing 1