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

Abstract

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.

Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency

“…Considering that the patient had mild anemia, probably because of severe renal insufficiency, and her actual HbA1c value was assumed to be slightly higher than the measured value (6.4%), we believe that our patient's condition was adequately controlled. It has recently been reported that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7,8). Wei et al reported that the concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone in a population-based study using real-world data in Taiwan (adjusted odds ratio: 2.42; 95% confidence interval: 1.75, 3.35).…”

“…It has recently been reported that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM ( 7 , 8 ). Wei et al reported that the concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone in a population-based study using real-world data in Taiwan (adjusted odds ratio: 2.42; 95% confidence interval: 1.75, 3.35).…”

“…In that study, hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, while it was observed only in 1 of 15 patients in the mitiglinide and clopidogrel group; no patients in the repaglinide alone group developed hypoglycemia. All patients who developed hypoglycemia had a plasma glucose level of ＜150 mg/dL measured 5 days before starting glinide ( 8 ). Based on this finding, our patient likely had hypoglycemia, since the preprandial plasma glucose level before starting clopidogrel was 112 mg/dL.…”

“…Recently, the concomitant use of repaglinide and clopidogrel has been shown to result in the elevation of blood concentration of repaglinide ( 6 ). In addition, few reports have shown that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM ( 7 , 8 ). However, there are no reports on the clinical course of hypoglycemia due to the interaction of these drugs in patients with T2DM and severe renal insufficiency.…”

Sleep disorders and risk of dementia in patients with new‐onset type 2 diabetes: A nationwide population‐based cohort study

“…Blood samples were gained following overnight fasting to measure total cholesterol and serum glucose. Hypoglycemia was defined as a plasma glucose level less than 70 mg/dL 23 . Comorbidities were estimated by screening before index date using medical records, and the comorbidities were composed of dyslipidemia (ICD‐10: E78), hypertension (ICD‐10: I10‐I15), chronic kidney disease (ICD‐10: N18), ischemic heart disease (ICD‐10: I20‐I25), stroke (ICD‐10: I60‐I63), cancer (ICD‐10: C00‐C99), and depressive disorders (ICD‐10: F32‐F33).…”