Continuing Education Activity

Repaglinide is a medication used in the management and treatment of diabetes mellitus Type 2. It is in the antihyperglycemic class of drugs. This activity outlines the indications, mechanism of action, and contraindications for repaglinide as a valuable agent in the management of diabetes mellitus type 2.

Objectives:

• Describe the mechanism of action of repaglinide.
• Identify the adverse drug reactions associated with repaglinide.
• Review the role of repaglinide in treatment algorithms for managing diabetes mellitus type 2.
• Outline the importance of collaboration and coordination among the interprofessional team and how it can enhance patient care when dosing and monitoring repaglinide. This will improve patient outcomes for patients receiving antihyperglycemic agents.

Indications

Repaglinide is a drug used in the treatment of diabetes mellitus type 2. It belongs to a class of antihyperglycemic agents known as meglitinides, along with nateglinide. Meglitinides work to reduce blood glucose levels by stimulating endogenous insulin production. The present recommended starting dose is dependent on hemoglobin A1c levels, with those below 8% (64 mmol/mol) urged to start with 0.5 mg pre-prandially and those above 8% to start with 1 to 2 mg. 

Repaglinide may be used as monotherapy (supplemental to exercise and diet control) or in combination with other antihyperglycemic agents (metformin or others, if metformin is not tolerated/contraindicated). The exception is using sulfonylureas (e.g., gliclazide, glipizide), which is a contraindication for dual therapy with meglitinides. Research has suggested that repaglinide is a favorable treatment choice in patients with chronic kidney disease and end-stage renal disease. 

Repaglinide is FDA class C during pregnancy, meaning its use requires caution. There has been no evidence to support its safe use during breastfeeding, and thus an alternative is recommended. 

The safety of repaglinide in children under the age of 18 has not been established and, as such, is not recommended. 

Repaglinide should be taken shortly before meals and should be omitted when skipping meals.[1][2][3][4][5][6]

Mechanism of Action

Repaglinide is an insulin secretagogue, meaning it binds to receptors on pancreatic beta cells and stimulates insulin release. Repaglinide binds to an ATP-dependent potassium channel on beta cells, known as SUR1, bringing about its closure. This mechanism of action is similar to that of the sulfonylureas, and as a result, the concurrent use of these therapies is contraindicated. 

Repaglinide demonstrates a concentration-response relationship in the presence of glucose, with a maximal secretory response of approximately 10 nmol/L. Studies suggest repaglinide reduces postprandial glucose in the order of around 5.8 mmol/L and fasting glucose around 3.1 to 3.4 mmol/L.

Repaglinide is rapidly absorbed, with a half-life of fewer than 60 minutes. The fast onset and short duration of action of repaglinide have made it one of the most appropriate therapies for managing postprandial glucose spikes, and as such, it is recommended approximately 30 minutes before an intended meal.

In the body, repaglinide binds to albumin at around 98% concentration and is associated with a more significant reduction in glycated albumin than sulfonylureas. 

Repaglinide is inactivated and excreted via the liver, and as such, concomitant use of other therapies associated with liver metabolism should be considered.[7][8][9][10][11][12]

Administration

Oral administration of repaglinide, between 0.5 to 4 mg twice to three times daily, to a maximum of 16 mg, produces glycemic control in a similar order to other antihyperglycemic agents. Repaglinide should be administered approximately 30 minutes before an intended meal, and the dose skipped if a scheduled mealtime is skipped. Dose adjustments should be reviewed a minimum of one week later.[2][5][13]

Adverse Effects

The most commonly reported side effect associated with repaglinide monotherapy is hypoglycemia (7% in a study of 76 patients), followed by weight gain (1.8 kg / 16 weeks). Whipple triad for hypoglycemia is defined as the presence of symptoms of hypoglycemia, presence of factual hypoglycemia (<50 mg/dl), and correction of the symptoms after administration of glucose. 

Repaglinide has reports showing it to be of greater risk of cardiovascular events than metformin but lesser than sulfonylureas.

Other adverse reactions of note included upper respiratory tract infection and sinusitis when trialed versus placebo. There are reports of weight gain, diarrhea, and joint pain. 

Reports of hypoglycemia are more frequent when repaglinide is used in combination with metformin, while studies suggest an increased risk of peripheral edema if used in combination with a thiazolidinedione.[14][15][16][17]

Contraindications

Repaglinide is not contraindicated in many instances - it has been utilized in patients with chronic kidney disease to good effect. It is deemed safer in such cases than metformin and sulfonylureas.

Contraindications does include[13][6][18]:

• Hypersensitivity to any of the components of the oral preparation
• Diabetes mellitus type 1 and diabetic ketoacidosis
• Severe liver dysfunction
• Concomitant use of gemfibrozil or clopidogrel
• Concomitant use of NPH insulin

Monitoring

Periodic measurements of fasting glucose and HBA1c are recommended for determining the efficacy of treatment. Dose adjustments should be monitored by fasting glucose alone for responsivity at a minimum of 1 week following the start of treatment.[5]

Repaglinide is metabolized by the hepatic isoenzymes CYP3A4 and CYP2C8. As such, it carries a low therapeutic index as a substrate for inactivation and clearance and is susceptible to concentration changes in the presence of hepatic inducers and inhibitors. 

Dose adjustment and closer monitoring may be necessary for concomitant use of the following therapeutic agents:

• Fenofibrate
• Ketoconazole
• Trimethoprim
• Cyclosporine
• Rifampin
• Estrogen-based therapies
• Simvastatin
• Nifedipine
• Clarithromycin

Besides, grapefruit juice may cause pharmacokinetic interactions.[19][20][5]

Toxicity

Severe hypoglycemia may induce seizures, coma, or other neurological impairments and requires immediate hospitalization and medical attention. 

Hypoglycemia without loss of consciousness may present with drowsiness, confusion, profuse sweating, agitation, abdominal pain, and tachycardia.

Intentional overdose in large quantities may be managed with activated charcoal if caught exceptionally early. In the asymptomatic patient, a watch-and-wait approach with repeated blood glucose measurements for 24 hours may suffice. It is important to note that despite the short duration of action, overdose with repaglinide may lead to more prolonged hypoglycemia.

In unintentional excessive ingestion, prompt feeding may be sufficient to alleviate symptoms. In more severe cases, glucagon subcutaneous or intramuscular injection is recommended (1 mg for weights greater than 25 kg). Failure to respond to glucagon should be addressed with a 20% glucose intravenous infusion.[21][22]

Enhancing Healthcare Team Outcomes

Management of diabetes mellitus type 2 is an interprofessional process with the patient at the center of care.

All treatment should consider the patients' preferences, and patients should always be well informed and encouraged to make their own decisions about their care.

Patient education is key to the management of diabetes mellitus type 2, and it is the healthcare professional's responsibility to ensure all guidance is evidence-based, goal-oriented, and suitably informative.[17][5]

Evidence has suggested that educating patients on the self-management of their diabetes leads to improved clinical outcomes, as does input from specialists outside of the medical team, including but not limited to dieticians and occupational therapists. Information regarding possible drug-drug interactions, dosing alterations, and organ failure prevention is provided by specialists.[23][24]

Research suggests there may be benefits in switching to repaglinide from other antihyperglycemic agents in the elderly. Pharmacists and specialists should be trained in providing adequate education, risks versus benefits, and support clinicians (MDs) DOs, NPs, PAs) in making this transition. The interprofessional approach will yield improved patient results with targeted medication management and reduce adverse events.[25][26] [Level 5]