糖尿病病人阿斯匹林化學預防的成效分析研究

Abstract

研究背景與目的 糖尿病會增加多種癌症的發生，特別是大腸直腸癌與肝癌。低劑量aspirin目前是癌症熱門的化學預防藥物之一，但還沒有足夠的證據顯示低劑量aspirin可以降低癌症發生的危險。目前還沒有研究專門探討在糖尿病族群使用低劑量aspirin與大腸直腸癌與肝癌發生的相關研究。探討低劑量aspirin 預防癌症的同時，是否因腸胃道潰瘍與出血的副作用，而抵銷低劑量aspirin使用的效用? 所以本研究的目的是應用台灣健保資料庫之回溯性與前瞻性世代研究，來探討糖尿病病人使用低劑量aspirin與大腸直腸癌、肝癌與腸胃道出血發生之相關。 研究材料與方法 本研究的資料來源為台灣健保資料庫2005年百萬抽樣歸人檔，2000–2009年的就醫資料，選取30歲以上曾使用降血糖藥物的「糖尿病世代」，為研究對象。以曾使用低劑量aspirin為治療組，不曾使用低劑量aspirin為對照組。追蹤期間從2005.1.1–2009.12.31。利用傾向性分數校正方式調整干擾因子，並利用time-varying Cox regression model 調整immortal time 來評估使用低劑量aspirin與大腸直腸癌、肝癌與腸胃道出血的關係。 結果 在糖尿病大腸直腸癌研究世代，結果顯示低劑量aspirin使用頻率>5次/週（高頻率），且使用期間4–5年（中等期間）與>5年（長期間），可以分別降低大腸直腸癌47%與58%發生的危險（Harzad ratio (HR): 0.53, 95% CI: 0.30–0.96；HR: 0.42, 95% CI: 0.27–0.65）。但使用頻率≤5次/週（低、中等頻率）且使用期間≤5年（短、中等期間），無法降低大腸直腸癌發生的危險。 在糖尿病肝癌研究世代，結果顯示低劑量aspirin使用期間>5年，使用頻率≤2、3–5與>5次/週，可以分別降低肝癌41%、53%與65%發生的危險（HR: 0.59, 95% CI: 0.40–0.89；HR: 0.47, 95% CI: 0.31–0.72；HR: 0.35, 95% CI: 0.23–0.54）。使用頻率>5次/週，且使用期間4–5年，可以降低肝癌41%發生的危險（HR: 0.59, 95% CI: 0.37–0.96）。但使用頻率≤5 次/週，且使用期間≤5年，則無法降低肝癌發生的危險。 在糖尿病腸胃道出血研究世代，低劑量aspirin使用頻率≤5次/週，且使用期間≤5年，都會增加腸胃道出血發生的危險。若使用頻率>5 次/週，且使用期間>5年，反而減少腸胃道出血發生的危險（HR:0.58, 95% CI:0.48–0.71）。 結論 研究結果顯示糖尿病病人在高頻率（>5次/週）且長時間（>5年）的使用低劑量aspirin，可以降低大腸直腸癌發生的危險。在長時間使用低劑量aspirin，無論多少頻率，可以降低肝癌發生的危險，且有「頻率效應」。但在「低、中等頻率」（≤5次/週）且「短、中等期間」（≤5年）下，則無法降低大腸直腸癌與與肝癌發生的危險。糖尿病病人使用低劑量aspirin會增加腸胃道出血發生的危險。但若可以長時間（>5年）且高頻率（>5次/週）使用低劑量aspirin，腸胃道出血發生的危險反而降低。至於糖尿病病人需要使用「多少頻率」與「多久時間」的低劑量aspirin，才能有效預防癌症的發生，且不增加嚴重腸胃道出血的機會，應是未來優先探討的問題。

Background and objective Diabetes increases the risk of the incidence of many types of cancer. Aspirin has been proposed as a potentially effective chemopreventive agent for cancer for many years. Some studies have suggested that aspirin use can reduce the risk of colorectal cancer. Most of the previous studies have focused on the general population, and none have focused specifically on patients with diabetes. The purpose of this study was to evaluate whether low-dose aspirin can reduce the risk of colorectal cancer and hepatocellular carcinoma and increase the risk of gastrointestinal bleeding in people with diabetes using a population-based reimbursement database. Material and methods We studied ≥ 30-year-old patients with diabetes included in the Longitudinal Health Insurance Database 2005 in Taiwan, who were treated with hypoglycaemic drugs during 2000 to 2009. We used a time-varying Cox regression model to adjust for immortal time bias and to estimate the adjusted hazard ratio (HR) and 95% CI for the association between low-dose aspirin use and colorectal cancer, hepatocellular carcinoma and gastrointestinal bleeding occurrence. Results In the diabetes and colorectal cancer cohort, low-dose aspirin use >5 times/week (high frequency) for 4–5 years (moderate duration) and >5 years (long duration) was found to reduce the risk of colorectal cancer by 47% and 58% respectively (HR: 0.53, 95% CI: 0.30–0.96；HR: 0.42, 95% CI: 0.27–0.65). Low and moderate frequency (≤2 and 3–5 times/week) and short and moderate duration (≤3 and 4–5 years) of low-dose aspirin use did not reduce the risk of colorectal cancer. In the diabetes and hepatocellular carcinoma cohort, low-dose aspirin use ≤2, 3–5 and >5 times/week for >5 years was found to reduce the risk of hepatocellular carcinoma by 41%, 53% and 65%, respectively (HR: 0.59, 95% CI: 0.40–0.89; HR: 0.47, 95% CI: 0.31–0.72; HR: 0.35, 95% CI: 0.23–0.54). Low-dose aspirin use >5 times/week for 4–5 years reduced the risk of hepatocellular carcinoma by 41% (HR: 0.59, 95% CI: 0.37–0.96). Low and moderate frequency and short and moderate duration of low-dose aspirin use did not reduce the risk of hepatocellular carcinoma. In the diabetes and gastrointestinal bleeding cohort, low-dose aspirin use ≤5 times/week for ≤5 years was found to increase the risk of gastrointestinal bleeding. Low-dose aspirin use >5 times/week for >5 years reduced the risk of gastrointestinal bleeding (HR:0.58, 95% CI:0.48–0.71). Conclusions Low-dose aspirin use with high frequency (> 5 times/week) and long duration (> 5 years) reduced the risk of colorectal cancer. Low-dose aspirin use for long duration reduced the risk of hepatocellular carcinoma in patients with diabetes in a frequency-dependent manner, whereas low and moderate frequency and short and moderate duration of low-dose aspirin use did not. Low-dose aspirin use will increase the risk of gastrointestinal bleeding in patients with diabetes. Further studies should evaluate the frequency and duration of low-dose aspirin use that are sufficient to prevent the incidence of colorectal cancer and hepatocellular carcinoma and not increase the risk of gastrointestinal bleeding in patients with diabetes.