What is the interaction between repaglinide (oral anti-diabetic medication) and clopidogrel (antiplatelet agent)?

Repaglinide and Clopidogrel Interaction: Clinical Implications

Concomitant use of repaglinide with clopidogrel should be avoided due to a significant drug interaction that increases the risk of hypoglycemia by 2.4-fold compared to repaglinide alone. 1

Mechanism of Interaction

• Clopidogrel's active metabolite glucuronide is a strong inhibitor of CYP2C8, which is a primary enzyme responsible for repaglinide metabolism 2
• This inhibition significantly increases repaglinide's systemic exposure by 3.9-5.1 fold following clopidogrel loading (300 mg) and maintenance (75 mg) doses 2
• Unlike other drug interactions with clopidogrel that affect its efficacy, this interaction increases the effect of repaglinide, potentially leading to dangerous hypoglycemia 3

Clinical Evidence

• A retrospective cohort study demonstrated that patients taking both repaglinide and clopidogrel experienced a mean decrease in fasting plasma glucose of 43.6 mg/dL compared to only 11.6 mg/dL in patients taking mitiglinide with clopidogrel 3
• Minimum plasma glucose levels decreased significantly more (51.9 mg/dL) in the repaglinide-clopidogrel group compared to the mitiglinide-clopidogrel group (2.1 mg/dL) 3
• A population-based nested case-control study found that concomitant use of repaglinide and clopidogrel was associated with an adjusted odds ratio of 2.42 (95% CI: 1.75-3.35) for hypoglycemic events requiring emergency department visits or hospitalization 1

Management Recommendations

• Alternative antiplatelet therapy: If a patient requires repaglinide, consider using an alternative antiplatelet agent that does not inhibit CYP2C8 4
• Alternative antidiabetic medication: If a patient requires clopidogrel, mitiglinide may be a safer alternative to repaglinide, as it demonstrated significantly less risk of hypoglycemia when combined with clopidogrel 3
• Dose adjustment: If the combination cannot be avoided, consider reducing the repaglinide dose and monitor blood glucose levels more frequently 5
• Monitoring: For patients on this combination, implement more frequent blood glucose monitoring, especially during the first few days after initiating the combination 3

Common Pitfalls and Caveats

• The interaction between repaglinide and clopidogrel is among the most potent drug interactions involving clopidogrel, yet it is less well-known than the clopidogrel-PPI interaction 4
• Unlike the controversial clopidogrel-PPI interaction (which may reduce clopidogrel efficacy), the repaglinide-clopidogrel interaction has clear clinical consequences with documented cases of hypoglycemia 3, 1
• This interaction is specific to repaglinide and does not apply equally to all oral antidiabetic medications - nateglinide showed no significant interaction with clopidogrel in clinical studies 1
• The magnitude of this interaction (3.9-5.1 fold increase in repaglinide exposure) is substantially higher than many other drug interactions, making it particularly dangerous 2, 5

Comparison to Other Relevant Drug Interactions

• The repaglinide-clopidogrel interaction is more clinically significant than the well-known clopidogrel-PPI interaction, which has shown inconsistent effects on cardiovascular outcomes in clinical studies 6, 7
• While the clopidogrel-PPI interaction primarily affects clopidogrel's efficacy through CYP2C19 inhibition, the repaglinide-clopidogrel interaction affects patient safety through CYP2C8 inhibition 2, 4
• The magnitude of the repaglinide-clopidogrel interaction (3.9-5.1 fold increase) is second only to the repaglinide-gemfibrozil interaction (8-fold increase) among known repaglinide drug interactions 5