Meglitinides

Definition

Meglitinides are a class of oral antihyperglycemic agents used in the treatment of type 2 diabetes mellitus (T2DM). They act primarily by stimulating insulin secretion from pancreatic β-cells, but unlike sulfonylureas, they exhibit rapid onset and short duration of action, targeting postprandial glucose excursions more specifically.

Also referred to as "short-acting insulin secretagogues," meglitinides are structurally unrelated to sulfonylureas but share a similar mechanism at the cellular level. This unique pharmacokinetic profile allows for more flexible dosing, particularly in patients with irregular meal patterns.

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Available Meglitinide Agents

1. Repaglinide

   • Brand names: Prandin, NovoNorm

   • Approved globally (FDA, EMA)

2. Nateglinide

   • Brand names: Starlix, Fastic

   • Approved in many countries (FDA, EMA)

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Mechanism of Action

Meglitinides stimulate insulin release by targeting the ATP-sensitive potassium (K_ATP) channels in pancreatic β-cells. Their mechanism includes:

1. Binding to K_ATP channels on β-cell membrane

   • Causes channel closure, leading to membrane depolarization

   • Activates voltage-dependent calcium channels, increasing intracellular Ca²⁺

   • Promotes exocytosis of insulin-containing granules

2. Glucose-Dependent Insulin Secretion

   • At normal/low blood glucose, minimal insulin release occurs

   • This glucose-dependent profile reduces the risk of hypoglycemia compared to sulfonylureas

3. Postprandial Targeting

   • Rapid onset matches insulin demand after meals

   • Useful for controlling postprandial hyperglycemia

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Clinical Indications

• Primary indication: Type 2 diabetes mellitus (T2DM) in adults when diet, exercise, and monotherapy with metformin are insufficient

• Adjunctive use with metformin or thiazolidinediones in combination therapy

• Alternative to sulfonylureas in patients at higher risk for hypoglycemia or with erratic eating schedules

• May be considered in elderly patients or those with renal impairment (with caution)

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Pharmacokinetics

Repaglinide

• Absorption: Rapid (peak plasma levels in 1 hour)

• Bioavailability: ~56%

• Half-life: ~1 hour

• Metabolism: Hepatic via CYP3A4, CYP2C8

• Elimination: Primarily biliary

• Protein Binding: >98%

• Onset of Action: Within 30 minutes

• Duration: 4–6 hours

Nateglinide

• Absorption: Peak levels within 1 hour

• Bioavailability: ~72%

• Half-life: ~1.5 hours

• Metabolism: Hepatic via CYP2C9, CYP3A4

• Elimination: Renal (16%) and fecal

• Protein Binding: ~98%

• Onset of Action: 20 minutes

• Duration: 4 hours

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Dosing Guidelines

Repaglinide

• Starting dose: 0.5 mg orally 15–30 minutes before meals

• Adjustments: Based on blood glucose response at 1-week intervals

• Usual dose: 0.5–4 mg before each meal, maximum 16 mg/day

• Missed meal: Skip dose to avoid hypoglycemia

Nateglinide

• Typical dose: 120 mg orally before each meal

• In special populations (elderly, mild renal impairment): 60 mg may be used

• Maximum: 360 mg/day (divided preprandially)

• Missed meal: Skip dose

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Adverse Effects

Common Adverse Effects	Mechanism or Note
Hypoglycemia	Less frequent than sulfonylureas, but still possible
Weight gain	Due to increased insulin activity and anabolic effect
Gastrointestinal discomfort	Nausea, diarrhea, bloating in rare cases
Upper respiratory tract symptoms	Especially with nateglinide (e.g., rhinitis, bronchitis)
Headache, dizziness	Transient; not dose-limiting
Rare: liver enzyme elevation	Monitor with long-term use

Contraindications

• Known hypersensitivity to repaglinide or nateglinide

• Type 1 diabetes mellitus

• Diabetic ketoacidosis

• Severe hepatic impairment (risk of accumulation and hypoglycemia)

• Co-administration with gemfibrozil (for repaglinide only — CYP2C8 inhibition ↑ toxicity)

• Pregnancy and lactation – safety not established; insulin is preferred

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Drug Interactions

Repaglinide

• ↑ Effect/toxicity:

  • Gemfibrozil: CYP2C8 inhibition → severe hypoglycemia risk

  • Clarithromycin, azole antifungals: CYP3A4 inhibitors

  • NSAIDs, beta-blockers, MAOIs: Potentiate hypoglycemic effects

• ↓ Effect:

  • Rifampin, barbiturates, carbamazepine: Induce metabolism

  • Corticosteroids, thiazides, sympathomimetics: Increase blood glucose

Nateglinide

• Interacts with CYP2C9 and CYP3A4 substrates or inhibitors

• Caution with warfarin, phenytoin, fluconazole

• Additive hypoglycemia risk with insulin or sulfonylureas

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Monitoring Parameters

• Fasting and postprandial blood glucose

• HbA1c every 3 months

• Signs of hypoglycemia, particularly in elderly or renally impaired

• Weight and BMI

• Liver function tests (especially during long-term repaglinide use)

• Kidney function in patients at risk of accumulation

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Advantages of Meglitinides

• Rapid onset of action allows targeted postprandial glucose control

• Flexible dosing – can skip doses with skipped meals

• Lower hypoglycemia risk than sulfonylureas

• Suitable alternative to sulfonylureas in patients with sulfa allergies

• Useful in early-stage T2DM with preserved β-cell function

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Limitations

• Require multiple daily dosing (pre-meal administration)

• Weight gain may limit use in obese patients

• Less effective in advanced diabetes or β-cell failure

• Not commonly used as first-line therapy (typically after metformin)

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Role in Therapy

Meglitinides are not first-line agents per ADA or EASD guidelines but are considered in the following scenarios:

• Patients with erratic eating patterns or at risk for hypoglycemia

• Elderly patients intolerant to metformin or sulfonylureas

• Adjunctive therapy with metformin when monotherapy fails

• Alternative in patients with sulfonylurea intolerance

• Low-cost option in resource-limited settings

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Comparative Efficacy

Parameter	Repaglinide	Nateglinide	Sulfonylureas
Postprandial control	Strong	Moderate	Less targeted
Onset of action	Rapid (~30 min)	Very rapid (~20 min)	Slower (~1 hour)
Hypoglycemia risk	Lower than sulfonylureas	Lower than sulfonylureas	Higher
Duration	4–6 hours	4 hours	12–24 hours
Dosing flexibility	High	High	Low
Cost	Moderate	Moderate	Generally low

Regulatory Status

Drug	FDA Approval	EMA Approval	Japan/Asia
Repaglinide	Yes (1997)	Yes	Yes
Nateglinide	Yes (2000)	Yes	Yes

Special Populations

• Geriatrics:

  • Monitor closely for hypoglycemia

  • Start at lowest effective dose

• Renal impairment:

  • Repaglinide: Use with caution; no dosage adjustment in mild/moderate renal dysfunction

  • Nateglinide: Can be used with dose adjustment; contraindicated in severe renal failure

• Hepatic impairment:

  • Avoid in severe cases due to reduced metabolism

• Pregnancy/Lactation:

  • Not recommended; insulin is safer

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Research and Development

• Combination fixed-dose therapy with metformin under investigation

• Exploration of dual secretagogues combining GLP-1 action with K_ATP channel modulation

• Biomarker studies underway to assess early predictors of response

• Interest in using meglitinides in pre-diabetes and early intervention models

• Development of repaglinide analogs with enhanced β-cell selectivity and reduced hypoglycemia risk

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Summary of Drug Profiles

Agent	Dose Range	Time to Peak	Duration	Unique Features
Repaglinide	0.5–4 mg before meals	~1 hour	4–6 hours	Stronger postprandial control, more potent
Nateglinide	60–120 mg before meals	~1 hour	~4 hours	Faster onset, lower efficacy than repaglinide