Risk of hypoglycemia associated with repaglinide combined with clopidogrel, a retrospective cohort study

BACKGROUND: Repaglinide is widely prescribed to reduce postprandial hyperglycemia and elevated glycated hemoglobin (HbA1c) levels associated with type 2 diabetes, and clopidogrel is a thienopyridine antiplatelet agent and widely used in cardiovascular and cerebrovascular diseases. It has been suggested that the concomitant use of repaglinide with clopidogrel may inhibit repaglinide metabolism, because repaglinide is a substrate of cytochrome P450 2C8 (CYP2C8) and the main metabolite of clopidogrel acyl-β-D-glucuronide inhibits CYP2C8 activity. In this study, we retrospectively investigated the effect of clopidogrel with repaglinide on plasma glucose and the risk of hypoglycemia associated with the combination of both drugs. METHOD: Patients were taking clopidogrel (75 mg/day) and started taking glinide (1.5 mg/day repaglinide or 30 mg/day mitiglinide) for the first time from April 2012 to March 2017. We targeted subjects who were hospitalized at the start of glinide and whose preprandial plasma glucose was measured by a nurse. The glucose levels were collected for up to 5 days before and after the glinide start date. RESULTS: Average fasting plasma glucose levels (before breakfast) in the repaglinide and clopidogrel group before and after starting repaglinide were 180.1±35.5 and 136.5 ± 44.1 mg/dL, with a mean decrease of 43.6 ± 33.6 mg/dL. In contrast, there was only a moderate decrease of 11.6 ± 30.0 mg/dL in the mitiglinide and clopidogrel group. Minimum plasma glucose levels in the repaglinide and clopidogrel group before and after starting repaglinide were 145.2 ± 42.9 and 93.3 ± 36.3 mg/dL, respectively. Decrease in minimum levels after starting glinide in the repaglinide and clopidogrel group (51.9 ± 47.5 mg/dL) was more significant than those in the mitiglinide and clopidogrel group (only 2.1 ± 29.1 mg/dL), and the repaglinide group (without clopidogrel, 15.5 ± 20.0 mg/dL). Hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, but only 1 of 15 patients in the mitiglinide and clopidogrel group, and no patients in the repaglinide group. CONCLUSION: These findings indicate that minimum plasma glucose levels were significantly decreased in patients taking repaglinide and clopidogrel. Considering the risk of hypoglycemia associated with taking repaglinide and clopidogrel, when a glinide is required in patients taking clopidogrel, mitiglinide may be a better choice.