合併使用clopidogrel 與 repaglinide 與低血糖風險

Abstract

背景： Repaglinide 為治療糖尿病的第二線藥品，其機轉可促使insulin分泌，進而達到控制血糖的療效。若將clopidogrel與repaglinide合併使用，clopidogrel會抑制repaglinide的排除，使repaglinide血中濃度上升，進而增加repaglinide導致低血糖的風險。已有研究觀察到此交互作用會導致健康受試者的血糖濃度下降。然而，進一步探討此交互作用於糖尿病病人身上可能導致的低血糖風險之研究仍然缺乏。 研究目的：欲了解repaglinide 和 clopidogrel 之間的藥物交互風險。 方法：本研究利用臺灣全民健康保險研究資料庫 (National Health Insurance Research Database , NHIRD) 以及巢氏病例對照研究(Nested Case-Control)方法。 本研究收納年齡大於20歲並且處方有至少一筆repaglinide或nateglinde的糖尿病病人，做為我們的 glinides 使用世代 (glinides users cohort)。其中，處方有repaglinide之研究對象會收納為repaglinide世代 (repaglinide cohort)，做為我們的主要研究對象；而處方有nateglinde之研究對象則會被收納成為nateglinde世代 (nateglinde cohort)，作為我們的陰性對照 (negative control)。在這兩個世代中，曾經因為低血糖事件住院的病人會被歸為病例組，針對每一個病例，會根據年齡、性別、glinides使用種類、糖尿病診斷年份以及追蹤時間來隨機配對最多四個對照病人。篩選完病例組以及對照組後，我們會分別在病例組與對照組中檢試clopidogrel之暴露情況 (定義為低血糖事件前三天內有使clopidogrel)。此外，我們會利用gemfibrozil作為陽性對照 (positive control) 以及aspirin作為陰性對照 (negative control)，因此gemfibrozil和aspirin的暴露情況亦會被檢視。最後，我們會使用條件式邏輯斯迴歸模式(Conditional Logistic Regression)來計算低血糖事件的勝算比 (odds ratios, ORs) 與95%信賴區間 (95% confidence intervals, CIs)。 結果：共有125,992名研究對象被收為glinides 使用世代，其中有 1,014 名研究對象被收為病例組，3,600 名研究對象收為對照組。從病人的第一筆 glinides 使用處方至發生低血糖事件的時間平均為1.58年。相比於沒有合併使用clopidogrel的組別，合併使用clopidogrel與repaglinide會有顯著增加的低血糖風險，校正後的勝算比為2.280 (95% 信賴區間：1.504, 3.457)。另外，在我們的陽性對照(gemfibrozil)分析中，也可觀察到與clopidogrel相應的結果。將gemfibrozil與repaglinide合用會顯著增加低血糖風險 (校正後勝算比: 6.143；95% 信賴區間：2.817, 13.394)。 陰性對照 (aspirin) 與 repaglinide合用亦沒有觀察到顯著的低血糖風險 (校正後勝算比: 1.170；95% 信賴區間：0.894, 1.533) 結論：此研究結果發現clopidogrel和repaglinide之間可能存在著具有臨床意義的交互作用，因此增加因低血糖住院的風險。因此，我們建議臨床醫師應該要重視此交互作用，並避免將clopidogrel和repaglinide合併使用，以避免可能產生的不良事件。

BACKGTOUND: Repaglinide is a second-line anti-diabetic agent with insulinotropic property. Additional use of clopidogrel to repaglinide may inhibit the excretion of repaglinide and thus prolong the action of repaglinide. The decreased glucose level of healthy subjects induced by this effect between clopidogrel and repaglinide has already been displayed in a small trial. However, evidence to judge the hypoglycemic risk in diabetic patients for this drug interaction is still lacking. OBJECTIVE: To examine the hypoglycemic risk of the drug-drug interaction between clopidogrel and repaglinide. METHODS: A nested case–control study was conducted based on Taiwan National Health Insurance Research Database (NHIRD) from 2001 to 2013. Diabetic patients aged over 20 years and with a least one prescription for repaglinide or nateglinide were identified as repaglinide cohort or nateglinide cohort (glinides users cohorts). Repaglinide cohort was our study of interest while nateglinde cohort severed as negative control. Within the glinides users cohorts, case were patients who were admitted to hospital with a primary diagnosis code for hypoglycemia. Four controls were randomly selected from the cohort and matched to each case by age, sex, glinides use type (repaglinide or nateglinde) and the duration of follow-up time. Exposure of interest were clopidogrel usage within 3 days before the hypoglycemic event date. Besides, exposure status for gemfibrozil and aspirin were also assessed for being our positive control and negative control. Conditional logistic regression analysis was conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 1,014 cases and 3,600 matched controls were identified from glinides users cohort (n= 125,992). The mean time from cohort entry (first prescription of glinides) to hypoglycemic event were approximately 1.58 years. The significantly increased hypoglycemic risk was noted in patients receiving repaglinide between clopidogrel users and non-clopidogrel users (adjusted odds ratio [AOR]: 2.280, 95% confidence interval [Cl]: 1.504, 3.457). Our positive control-gemfibrozil showed the consistent result with clopidogrel (repaglinide cohort: AOR: 6.143, 95% Cl: 2.817, 13.394; nateglinide cohort: AOR: 1.051, 95% Cl: 0.095, 11.591). And for our negative control-aspirin, we found no significant association between aspiring use and hypoglycemia in patients receiving repaglinide (AOR: 1.170, 95% Cl: 0.894, 1.533). CONCLUSION: The finding of our result suggested a clinically significant drug interaction between clopidogrel and repaglinide, which could lead to severe hypoglycemia. The clinicians should pay more attention on this vital drug interaction and avoid the combination use of clopidogrel and repaglinide.