Indications
Glimepiride is prescribed for the management of type 2 diabetes in adults. It serves as an adjunct to diet and exercise, primarily to enhance glycemic control when used as a monotherapy. Additionally, glimepiride may be employed in combination with metformin or insulin for individuals with type 2 diabetes whose blood sugar levels remain elevated despite dietary adjustments and the use of an oral hypoglycemic agent alone.
Pharmacodynamics
Glimepiride functions by stimulating the secretion of insulin granules from the pancreatic beta cells, thereby enhancing the sensitivity of peripheral tissues to insulin. This action increases peripheral glucose uptake and consequently, lowers plasma blood glucose and glycated hemoglobin (HbA1C) levels. In a multi-center, randomized, placebo-controlled clinical trial, where glimepiride doses ranging from 1 to 8 mg were tested as monotherapy over 10 weeks, there was a notable reduction in fasting plasma glucose by 46 mg/dL, post-prandial glucose by 72 mg/dL, and HbA1c by 1.4% compared to placebo. Furthermore, another randomized study indicated that all doses of glimepiride (1, 4, or 8 mg) significantly improved FPG, PPG, and HbA1c values in contrast to placebo, with the 4- and 8-mg doses proving more effective, although the 4-mg dose yielded a nearly maximal antihyperglycemic effect.
Absorption
Glimepiride is completely absorbed following oral administration within one hour, exhibiting a linear pharmacokinetic profile. In both healthy subjects and individuals with type 2 diabetes, peak plasma concentrations (Cmax) are typically achieved 2 to 3 hours post-dose, with no accumulation following multiple doses. When administered with meals, glimepiride demonstrates an increased time to reach Cmax by 12%, and decreases in mean AUC by 8 to 9%. A pharmacokinetic study in Japanese patients with type 2 diabetes revealed higher Cmax values with once-daily dosing compared to twice-daily administration. The absolute bioavailability of glimepiride is considered complete upon oral administration.
Metabolism
Glimepiride undergoes hepatic metabolism, primarily through oxidative biotransformation mediated by the CYP2C9 enzyme, resulting in a major metabolite, the cyclohexyl hydroxymethyl derivative (M1), which retains pharmacological activity. M1 is further metabolized into an inactive metabolite, the carboxyl derivative (M2), by cytosolic enzymes. M1 maintains approximately one-third of the pharmacologic activity of its parent compound, with a half-life ranging from 3 to 6 hours; however, the clinical significance of M1's glucose-lowering effect remains uncertain.
Mechanism of Action
Glimepiride functions by modulating the activity of ATP-sensitive potassium channels located on pancreatic beta cells, which are crucial for regulating insulin secretion. These channels are composed of a hetero-octomeric complex, including four Kir6.2 pore-forming subunits and four regulatory sulfonylurea receptor (SUR) subunits. Different tissues express varying isoforms of these subunits due to alternative splicing. In pancreatic beta cells, these channels serve as vital metabolic sensors, linking membrane excitability with glucose-stimulated insulin secretion. In conditions where the ATP:ADP ratio drops, the channels open, allowing potassium ions to exit the cell. This results in membrane hyperpolarization and a subsequent decrease in insulin secretion. Conversely, increased glucose uptake elevates the ATP:ADP ratio, prompting channel closure and membrane depolarization. This depolarization activates voltage-dependent calcium channels, leading to an influx of calcium ions that trigger the actomyosin-mediated exocytosis of insulin granules. Glimepiride enhances insulin secretion by binding to specific sites on the sulfonylurea receptor subunits, including the B sites on both SUR1 and SUR2A, as well as the A site on SUR1, effectively blocking the ATP-sensitive potassium channels.
