What is the recommended treatment protocol for type 2 diabetes using Repaglinide (meglitinide)?

Repaglinide Treatment Protocol for Type 2 Diabetes

Repaglinide should be initiated at 0.5 mg before each meal for patients with HbA1c <8% or those previously treated with other glucose-lowering agents, and at 1-2 mg before each meal for patients with HbA1c ≥8%, with dose titration up to 4 mg per meal (maximum 16 mg daily) based on glycemic response. 1

Positioning in Treatment Algorithm

Repaglinide is a second-line agent, reserved for specific clinical situations rather than routine first-line therapy. 2

• Metformin remains the preferred initial pharmacologic agent for type 2 diabetes 2
• Repaglinide serves as an alternative to sulfonylureas when monotherapy with metformin at maximum tolerated dose fails to achieve HbA1c targets over 3 months 2
• Repaglinide is specifically indicated for patients with erratic meal schedules or those experiencing late postprandial hypoglycemia on sulfonylurea therapy 2

Dosing Protocol

Initial Dosing

• Start at 0.5 mg before each meal if HbA1c <8% 1
• Start at 1-2 mg before each meal if HbA1c ≥8% 1
• Administer within 30 minutes before meals 1
• Skip the dose entirely if a meal is skipped 1

Dose Titration

• Double the dose up to 4 mg per meal until satisfactory glycemic control is achieved 1
• Wait at least one week between dose adjustments to assess response 1
• Dose range: 0.5-4 mg before meals, maximum daily dose 16 mg 1
• If hypoglycemia occurs, reduce the dose immediately 1

Expected Efficacy

Repaglinide reduces HbA1c by 0.5-1.5% when used as monotherapy or in combination therapy. 2

• Comparable efficacy to sulfonylureas for HbA1c and fasting glucose reduction 3, 4
• Superior postprandial glucose control compared to some sulfonylureas 4, 5
• When combined with metformin in newly diagnosed patients, repaglinide provides greater HbA1c reduction than repaglinide alone, though with increased hypoglycemia risk 2

Special Populations

Renal Impairment

Repaglinide is advantageous in renal impairment because it does not accumulate with declining kidney function. 2

• For severe renal impairment (CrCl 20-40 mL/min), start at 0.5 mg before each meal 1
• Unlike sulfonylureas, repaglinide has no active metabolites that accumulate in renal dysfunction 2
• Can be used safely when metformin is contraindicated (serum creatinine ≥1.5 mg/dL in men, ≥1.4 mg/dL in women) 2

Elderly Patients

Use repaglinide cautiously in older adults due to hypoglycemia and fracture risk. 2

• Sulfonylureas and meglitinides (including repaglinide) are associated with hypoglycemia, bone loss, and fracture risk 2
• Monitor frequency of hypoglycemia at each visit 2
• The meal-related dosing provides flexibility for elderly patients with irregular eating patterns 6

Combination Therapy

Repaglinide demonstrates additive effects when combined with metformin, thiazolidinediones, or basal insulin. 4

• Combination with metformin is particularly effective, though increases hypoglycemia risk 2
• Can be combined with DPP-4 inhibitors (sitagliptin, saxagliptin) for further HbA1c reduction 2
• NOT indicated for combination with NPH insulin due to serious cardiovascular adverse reactions 1

Critical Drug Interactions

Contraindicated

Concomitant use with gemfibrozil is contraindicated 1

• Gemfibrozil increases repaglinide concentrations and half-life, significantly raising hypoglycemia risk 2

Dose Limitations Required

Limit daily dose to 6 mg when co-administered with cyclosporine 1

• Increase frequency of glucose monitoring 1

Avoid concomitant use with clopidogrel; if necessary, initiate at lowest dose 1

Dose Adjustments May Be Needed

• CYP2C8 and CYP3A4 inhibitors may require dose reductions 1
• CYP2C8 and CYP3A4 inducers may require dose increases 1
• Antimicrobials (fluoroquinolones, sulfamethoxazole-trimethoprim) increase effective dose and may precipitate hypoglycemia 2

Adverse Effects

The most common adverse reactions are hypoglycemia (16%), upper respiratory infection (10%), headache (9%), rhinitis (7%), and bronchitis (6%). 1, 4

• Overall hypoglycemia incidence similar to sulfonylureas, but serious hypoglycemia episodes are less frequent 4, 5
• Risk of hypoglycemia is reduced when meals are skipped, unlike with sulfonylureas 4, 5
• Weight gain occurs but is less than with sulfonylureas or thiazolidinediones 2, 6

Clinical Advantages

Repaglinide's rapid onset and short duration of action provide physiologic mimicry of meal-related insulin secretion. 5

• Flexibility for patients with irregular meal schedules 6, 5
• Lower risk of serious hypoglycemia compared to long-acting sulfonylureas 4, 5
• Safe in renal impairment where metformin is contraindicated 2, 6
• Suitable during Ramadan fasting when flexible dosing is needed 6

Important Caveats

• No clinical studies have established macrovascular risk reduction with repaglinide 1
• Requires three-times-daily dosing before meals, which may reduce adherence 6
• More expensive than sulfonylureas, potentially limiting use in cost-sensitive populations 2, 6
• Must be taken within 30 minutes before meals; skip dose if meal is skipped 1