| 摘要: | 背景和目的
2012年，癌症及糖尿病分別名列臺灣十大死因的首位及第五位。近年來，無論是全球或是臺灣的流行病學統計，癌症及糖尿病的發生率與盛行率皆呈現逐年上升的趨勢，此外，大量文獻顯示糖尿病會增加多種癌症的罹癌風險。TZDs為核轉錄因子過氧化酶體增生活化受體γ (peroxisome proliferator-activated receptor gamma, PPARγ) 的選擇性配體，用於治療糖尿病。研究顯示TZDs可能具有抑制腫瘤活性的功能，因其能夠使細胞週期停滯 (cell cycle arrest)、誘導細胞凋亡 (induction of apoptosis)，並且抑制細胞入侵 (inhibition of cell invasion)，由於至今仍缺乏探討TZDs與罹癌風險之間相關性的臨床試驗，尤其是針對亞洲人的研究，因此我們執行了這項在台灣的回溯性世代研究，以比較使用TZDs、使用其他糖尿病藥物及未使用糖尿病藥物之糖尿病人的罹癌風險。
研究方法
本研究納入32,891位糖尿病人，分析資料取樣自國家衛生研究院所提供之全民健康保險資料庫承保抽樣歸人檔 (Longitudinal Health Insurance Database, LHID)，篩選出1998年1月1日至2002年12月31日之間至少經過三次確診為糖尿病之病人，並且僅納入1998年1月1日前未被診斷罹患糖尿病或癌症者，以確保所納入之病人皆為新診斷的案例，我們將第二型糖尿病人分為以下組別：使用rosiglitazone或pioglitazone者；使用除TZDs以外之其他糖尿病藥物者，這些藥物包含metformin、sulfonylurea類藥物、acarbose、胰島素類似物及其他；未使用任何糖尿病藥物者；對照組則使用SAS軟體隨機選取四位未罹患癌症之非糖尿病人，來與一位糖尿病人做配對，共計有131,564位。
研究結果
使用TZDs者分別對照於非糖尿病人、使用除TZDs以外之其他糖尿病藥物組及未使用任何糖尿病藥物組之校正後罹癌率hazard ratio (HR) 分別為0.74 (95%CI 0.43-1.26, p<0.001)、0.39 (95%CI 0.33-0.45, p<0.001) 及0.49 (95%CI 0.27-0.89, p=0.02)。進一步分析TZDs使用劑量對於罹癌風險的影響，發現具有顯著的劑量效應 (p值趨勢檢定<0.001)，此外，癌症開始發生的時間也有明顯的延遲現象。分析TZDs對於不同種類癌症的影響，結果顯示使用TZDs的病人，乳癌、腦癌、大腸直腸癌、耳鼻喉部癌、腎癌、肝癌、肺癌、前列腺癌、胃癌及子宮癌的發生率皆顯著降低。
結論
本研究結果指出TZDs可能可以降低整體罹癌率，並且具有顯著的劑量效應，許多癌症的罹癌風險可能因使用TZDs而降低。但目前仍需有更多的研究來加以佐證，以驗證TZDs是否可於臨床用作癌症的化學預防藥物 (chemoprevention agents)。
Background and objectives
In 2012, cancer is the number one killer while diabetes mellitus (DM) ranked number five. For the past few years, epidemiology studies worldwide and from Taiwan showed that there were increase incidence and prevalence in cancer and DM. There are an abundance of evidence revealing that DM confers significant risk for many forms of cancer and may increase patients’ cancer risk. Thiazolidinediones (TZDs) are selective ligands of the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) that are used to treat DM. Studies showed that TZDs may have tumor suppressor activity because it can mediate cell cycle arrest, induction of apoptosis, and inhibition of cell invasion. Due to the insufficient clinical data regarding the TZDs effects on cancer risk, especially among Asian populations, I conducted a retrospective study in Taiwan to assess the risk of development of all kinds of cancer among DM patients treated with TZDs relative to those treated with other anti-DM drugs and those not prescribed any anti-DM drugs.
Methods
The study included 32,891 patients identified from the Longitudinal Health Insurance Database, with at least three consecutive episodes of diagnosed type 2 DM between January 1, 1998 and December 31, 2002. Only patients who had not been diagnosed with DM or cancer before January 1, 1998 were included to ensure that only newly identified cases were included. I classified the type 2 DM patients into the following groups: patients who were prescribed pioglitazone or rosiglitazone; patients who were prescribed other anti-DM drugs besides TZDs, these drugs included metformin, sulfonylureas, acarbose, insulin analogues and others; patients who were not prescribed any anti-DM drugs. The non-DM control group: for each study group patient, four non-DM and non-cancer control patients were randomly selected from the remaining population, resulting in 131,564 matched controls.
Results
The adjusted HRs for those prescribed TZDs were 0.74 (95%CI 0.43-1.26, p=0.27), 0.39 (95%CI 0.33-0.45, p<0.001) and 0.49 (95%CI 0.27-0.89, p=0.02) respectively, relative to Non-DM patients, DM patients prescribed other anti-DM drugs besides TZDs and DM patients not prescribed any anti-DM drugs. In the subsequent analysis, I analyzed TZDs’ dose effect on cancer risk and found that the effects of TZDs were significantly dose-dependent (p for trend <0.001). I analyzed the association between TZDs and cancer types. Results showed that the risk of breast, brain, colorectal, ear-nose-throat, kidney, liver, lung, prostate, stomach, uterus cancer were significantly lower in those prescribed TZDs.
Conclusions
The findings indicate that TZDs may lower the risk of overall cancer with a significant dose-related effect. The risk of many kinds of cancer may be lessened by the use of TZDs. Further studies are warranted to determine if this association is causal and whether TZDs have the potential to be used clinically as cancer chemoprevention agents. |
