Glimepiride is a second-generation sulfonylurea that has FDA approval in 1995 to use for the improvement of glycemic control in adults with type 2 diabetes mellitus.[1] It can serve as a second-line drug in the treatment of type 2 diabetes mellitus in the form of combination therapy in conjunction with metformin in patients that do not have any form of atherosclerotic cardiovascular disease and not at their target hemoglobin A1c.[2] Additionally, it is worth noting that glimepiride is the only sulfonylurea approved by the FDA for combination therapy with insulin in patients that are not responsive to combination therapy.[1] Glimepiride is also prescribable as monotherapy in patients that are unable to tolerate metformin.[3] 

Glimepiride is sometimes referred to as a third-generation sulfonylurea as it has a better safety profile and has a prolonged duration of action of up to 24 hours.[4][1] Glimepiride has few cardiovascular effects compared to other sulfonylureas, which primarily are notorious for its effects on myocytes due to the blockade of ATP-dependent potassium channels.[5] Furthermore, glimepiride, unlike other sulfonylureas, does not affect the ischemic preconditioning of cardiac myocytes, defined as an adaptive physiological mechanism in response to an ischemic event to delay infarction and limit cardiac tissue damage. Researchers postulate that glimepiride selectively blocks sarcolemmal ATP-dependent potassium channels in cardiac myocytes over mitochondrial potassium channels, maintaining myocardial preconditioning.[6] This difference from other drugs in the class means that the use of glimepiride may be safer and more ideal in patients with cardiovascular comorbidities.[1]

Glimepiride is an insulin secretagogue and, like other sulfonylureas, is only effective in patients with residual pancreatic beta-cell activity. They act at ATP-dependent potassium channels on the cell membrane of pancreatic beta cells, causing iatrogenic depolarization by preventing potassium from exiting the cell. The depolarization activates voltage-dependent calcium channels on the cell membrane, leading to a rise in intracellular calcium and subsequent exocytosis of insulin into the bloodstream.[7] Insulin then acts on cell membrane receptors triggering GLUT-4 expression and the movement of glucose into the cell, lowering blood glucose levels. Additionally, research has shown that glimepiride interacts with Epac3, a nucleotide exchanger that mediates the exocytosis of insulin granules.[8][9][10] Glimepiride's effectiveness was highlighted in a study conducted in healthy volunteers where results demonstrated that there is a linear relationship between serum glimepiride and insulin release in both euglycemic and hyperglycemic conditions.[11]  

The standard initial dose of glimepiride is between 1 and 2 mg once daily, taken orally before the patient's first meal. Patients who are prone to hypoglycemia should be started at 1 mg once daily and titrated slowly to an appropriate dose. Following initial therapy, the standard maintenance dosage is at 1 to 4 mg once daily; however, this can be gradually titrated up to 8 mg once daily, depending on the patient's blood glucose and hemoglobin A1c levels. It is important to note that current guidelines do not have a fixed dosage regimen for glimepiride, and the dose requires adjustment according to the patient's blood glucose levels and hemoglobin A1c.[1] 

When used for combination therapy with metformin, the clinician should attempt to identify the minimum effective dose of each drug as the risk of hypoglycemia increases with the use of metformin with glimepiride.[1] Dual therapy of glimepiride with insulin is an option in patients with chronic type 2 diabetes, whose initial response to blood glucose-lowering medication has diminished. The fasting glucose level requirement for providing this therapy is greater than 150 mg/dL. In this case, patients should start on glimepiride at 8 mg once daily with subsequent adjustments of insulin administration depending on the patient's blood glucose.

Glimepiride, like other sulfonylureas, has multiple adverse effects, the most deadly and notorious being its metabolic effects. As glimepiride increases endogenous insulin secretion, this can lead to hypoglycemia. In patients with long-standing diabetes mellitus, hypoglycemic unawareness can manifest where the autonomic symptoms of hypoglycemia are not experienced by the patient, leading to neuroglycopenia symptoms and potential hypoglycemic coma. This situation is particularly dangerous in drivers or those involved in skilled tasks, especially if other hypoglycemic agents are in concomitant use. Weight gain is another significant side effect of sulfonylureas such as glimepiride, which can interfere with management as weight loss is often a major target in the treatment of diabetes. Other adverse effects include vomiting, abdominal pain, diarrhea, erythema multiforme, and exfoliative dermatitis.[1][12]

Contraindications for glimepiride include the following patient groups and conditions: 

• Diabetic ketoacidosis
• Type I diabetes mellitus
• Hypersensitivity to glimepiride