Continuing Education Activity

Glimepiride is a medication used in the management and treatment of type 2 diabetes mellitus. It is in the sulfonylurea class of drugs. This activity outlines the indications, mechanism of action, and contraindications for glimepiride as a valuable agent in managing type 2 diabetes mellitus. This activity will also highlight the mechanism of action, adverse event profile, and other key factors (e.g., dosing, pharmacodynamics, monitoring, relevant interactions) pertinent for interprofessional healthcare team members managing patients with type 2 diabetes mellitus and related conditions.

Objectives:

• Identify the mechanism of action of glimepiride.
• Describe the possible adverse effects of glimepiride.
• Review appropriate monitoring methods for patients on glimepiride, including management of complications of treatment.
• Explain the importance of collaboration and communication amongst the interprofessional team and patients to improve patient outcomes when receiving glimepiride therapy.

Indications

Glimepiride is a second-generation sulfonylurea that received 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 combination therapy in conjunction with metformin in patients who 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 are primarily notorious for their effects on myocytes due to the blockade of ATP-dependent potassium channels.[5] Furthermore, unlike other sulfonylureas, glimepiride 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]

Mechanism of Action

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 on healthy volunteers. Results demonstrated a linear relationship between serum glimepiride and insulin release in euglycemic and hyperglycemic conditions.[11]  

Administration

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.

Adverse Effects

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

Contraindications for glimepiride include the following patient groups and conditions: 

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

Monitoring

Monitoring methods for glimepiride include frequent self-glucose monitoring and hemoglobin A1c monitoring every 3 to 6 months. In those with renal pathology, monitoring of glomerular filtration rate may be recommended as glimepiride is primarily excreted via the kidneys. 

Toxicity

In cases of overdose of sulfonylureas such as glimepiride, hypoglycemia can occur. It is essential to recognize the signs and symptoms of hypoglycemia, which can fall into the following two categories:

1. Autonomic symptoms such as tremor, palpitations, nausea, tachycardia, diaphoresis, and anxiety
2. Neuroglycopenic symptoms such as confusion, fatigue, headache, drowsiness, coma, and seizures.

Rapid recognition and reversal of hypoglycemia are essential in improving prognosis in those that have overdosed on glimepiride.[13] Initial management is intravenous dextrose; however, this is quickly switched to octreotide (long-acting somatostatin analog) as many patients will have sufficient pancreatic function to stimulate endogenous insulin production in response leading to a cycle of dextrose infusion and rebound hypoglycemia. Additionally, activated charcoal should be given as soon as possible for decontamination. In an emergency or pre-hospital setting, intramuscular injections of glucagon can temporarily increase blood glucose via physiological glycogenolysis and gluconeogenesis. However, as glucagon stimulates insulin release, this is not recommended.[14]

Enhancing Healthcare Team Outcomes

Managing type 2 diabetes mellitus involves an interprofessional healthcare team approach involving various healthcare team members, including but not limited to the endocrinologist, family/primary care clinician (MDs, DOs, PAs, NPs), diabetes specialist nurse, podiatrist, and pharmacist. Its management involves the utilization of drugs that control blood glucose, which include glimepiride. Glimepiride is a second-line, FDA-approved drug to be used either in combination with metformin or as a monotherapy. Sulfonylureas augment and increase insulin release from the pancreas and, although effective, poses a threat to patient safety if used inappropriately. Sufficient communication is essential in delivering optimal care to patients, including providing information in aspects such as time and frequency of administration and associated sick day rules. Through a coordinated interprofessional team effort, diabetes management, including the use of glimepiride, can achieve better patient outcomes and limit the potential for therapeutic failure or adverse events. [Level 5]