糖尿病病人合併慢性腎臟病與否使用DPP-4 inhibitors之心血管事件風險

Abstract

目的: 心血管疾病為第二型糖尿病患者死亡主因之一，而糖尿病藥品心血管風險議題也逐漸成為治療裡的焦點。本研究係探討口服降血糖藥物 (oral hypoglycemic agent, 簡稱OHA) dipeptidyl peptidase-4 (DPP-4) inhibitors之心血管事件風險，並將有無慢性腎臟疾病 (chronic kidney disease, 簡稱CKD) 患者分開比較。 方法: 本研究為回溯性世代研究，以健保資料庫中的百萬歸人檔作為資料來源，將2009年3月至2012年12月年滿20歲、使用至少一種OHA之第二型糖尿病患者，依照有無CKD分為兩族群追蹤研究。研究組別分為DPP-4 inhibitors (DPP-4i) 組與非DPP-4 inhibitors (non-DPP-4i) 組，為消除兩組間差異可能造成之偏誤，以propensity score進行1:1配對。研究終點為因心衰竭入院 (hospitalization for heart failure, 簡稱hHF) 與由心肌梗塞、阻塞性中風、心血管死亡組成之綜合終點major adverse cardiovascular events (MACE)，並用COX proportional hazard model作為統計分析。追蹤採用as-treated與intention-to-treat (ITT) analysis，並以前者作為主要分析方法。 結果: 在2009年3月到2012年12月間，我們共篩選出37, 641位糖尿病併CKD患者與87,604位non-CKD糖尿病患者，經過1:1配對後，CKD族群得8,213對患者，non-CKD族群得12,313對患者。主要研究終點分析中，CKD族群DPP-4 inhibitors的使用與25% hHF風險上升相關 (DPP-4i組vs. non-DPP-4i組每一千人年發生率: 15.0 vs. 9.9，HR=1.25; 95% CI 1.01-1.54, p= 0.037)，達統計上顯著，若進一步將患者分為透析與未透析，則僅有未透析者達統計上顯著；而non-CKD族群中DPP-4 inhibitors的暴露則與27% MACE發生率降低顯著相關 (DPP-4i組vs. non-DPP-4i組每一千人年發生率: 9.8 vs. 12.6，HR=0.73; 95% CI 0.61-0.87, p= 0.0007)，其中與MACE風險降低之關聯性主要受DPP-4 inhibitors暴露與阻塞性中風發生率降低相關所致 (DPP-4i組vs. non-DPP-4i組每一千人年發生率: 7.4 vs. 10.0，HR=0.68; 95% CI 0.55-0.84, p= 0.0003)。在CKD族群之MACE與non-CKD族群之hHF則與藥品之暴露無顯著關聯。ITT分析中，除non-CKD族群DPP-4 inhibitors的使用對MACE (HR= 0.98; 95% CI 0.86-1.12, p= 0.7363) 與阻塞性中風 (HR= 0.95; 95% CI 0.82-1.11, p= 0.5339) 之影響變為不顯著外，其餘結果皆與as-treated分析結果相似。 結論: 第二型糖尿病併CKD患者使用DPP-4 inhibitors與較高的hHF有所關聯而與MACE無顯著相關。然而此風險增加未見於無CKD之第二型糖尿病患者，此一群族中DPP-4 inhibitors反而與MACE的降低有所關聯。本研究結果顯示，第二型糖尿病併CKD患者，特別是尚未進行腎臟透析之患者中，在有替代藥品的情況下不建議選用DPP-4 inhibitors，而可考慮使用短效sulfonylurea (SFU) 類、meglitinide類或insulin作為二線降血糖藥品。在non-CKD的第二型糖尿病且可以耐受的患者中，則建議選用DPP-4 inhibitors做為二線治療藥品。

OBJECTIVES: Cardiovascular events associated with oral hyperglycemic agents (OHA) have raised significant safety concerns. This study aims to assess whether there is an association between dipeptidyl peptidase-4 (DPP-4) inhibitors, a new class of OHA, and the risk of cardiovascular events in type 2 diabetic patients with or wihout chronic kidney disease (CKD). METHODS: The retrospective cohort study was conducted using the National Health Insurance Research Database (NHIRD) in Taiwan. From the NHIRD, we identified patients diagnosed as type 2 diabetes mellitus. We further selected those who received OHA between March 1st, 2009 and December 31st, 2012 as our study subjects and classified them into the CKD cohort and the non-CKD cohort. Within each cohort we then divided patients as two groups, the DPP-4 inhibitor (DPP-4i) users and non-DPP-4 inhibitor (non-DPP-4i) users . The two groups were 1:1 matched by propensity score to attenuate potential selection bias. Outcomes of interest included a composite endpoint of ischemic stroke, myocardial infarction and cardiovascular death (MACE) and hospitalization for heart failure (hHF). COX proportional hazard models were used to examine the association between DPP-4 inhibitor and outcomes of interest. RESULTS: Between March 2009 and December 2012, we identified a total of 37,641 and 87,604 type 2 diabetic patients with and without CKD, respectively. 12,821 patients in the CKD cohort and 19,821 patients in the non-CKD cohort were exposed to DPP-4 inhibitors, and 24,792 patients in the CKD cohort and 67,732 patients in the non-CKD cohort were not. After propensity score matching, we identified 8,213 pairs of CKD patients and 12,313 pairs of non-CKD patients for analysis. In the CKD cohort, exposure to DPP-4 inhibitors are associated with a 25% increase risk of hHF (DPP-4i vs. non-DPP-4i incidence/1000 person-year: 15.0 vs. 9.9，HR=1.25; 95% CI 1.01-1.54, p= 0.037) but not with the risk of MACE (HR=0.89, p=0.144). When further stratified according to dialysis status, only those not undergoing dialysis show an increase risk of hHF associated with DPP-4 inhibitors use. On the contrary, exposure to DPP-4 inhibitors are associated with a lower risk of MACE (DPP-4i vs. non-DPP-4i incidence/1000 person-year: 9.8 vs. 12.6，HR=0.73; 95% CI 0.61-0.87, p= 0.0007), but not the risk of hHF (HR=1.09, p=0.631) in the non-CKD cohort. The decrease risk of MACE in non-CKD population is mainly contributed by a decrease risk of ischemic stroke (DPP-4i vs. non-DPP-4i incidence/1000 person-year: 7.4 vs. 10.0，HR=0.68; 95% CI 0.55-0.84, p= 0.0003) related to exposure of DPP-4 inhibitors. CONCLUSIONS: Our study shows that exposure to DPP-4 inhibitors is associated with a higher risk of hHF but not the risk of MACE in type 2 diabetic patients with CKD. However, for type 2 diabetic patients without CKD, DPP-4 inhibitors exposure is associated with a lower risk of MACE and ischemic stroke, but not with the risk of hHF. Therefore, we recommended that for type 2 diabetic patients with CKD, especially those not undergoing dialysis, DPP-4 inhibitors should be substituted with other antidiabetic agents (ADA) such as relatively short-acting sulfonylureas (SFUs), meglitinides or insulin. For type 2 diabetic patient without CKD, we recommended the use of DPP-4 inhibitors as second-line therapy, if not otherwise contraindicated. Future study with more comprehensive lab data should be warranted.