背景和目標 癌症於已開發國家名列死亡原因首位，於開發中國家名列第二位，糖尿病 則名列第九位。在台灣，從2008 年起，糖尿病和癌症分別列居十大死因的第一和 第五位。隨著世界人口持續的增加，糖尿病患也隨著增多，台灣糖尿病患有年輕 化的趨勢，愈來愈多40 歲以下的患者出現。大量證據顯示糖尿病與會增加的罹癌 風險相關，流行病學研究也顯示metformin 用於第二型糖尿病患者能夠降低罹癌風 險，然而，大多數研究metformin 和癌症之間關係的文獻中，大部份是對白種人 的研究，且僅有少數提供了metformin 使用劑量的詳細資料與降低罹癌風險的關聯 性，因此本研究致力於探討metformin 與降低罹癌風險之間的劑量相關性。 研究方法 本研究採回溯性全國人群 (population-based) 研究方法，分析資料取自台灣 國民健康保險資料庫，於承保抽樣歸人檔 (Longitudinal Health Insurance Database, LHID) 擷取1997-2002 年的病患資料，並運用ICD-9-CM 國際診斷碼250.XX 篩選 出1998 年1 月1 日至2002 年12 月31 日間新診斷出糖尿病的病患，納入之病患 須至少經過三次確診為糖尿病，且排除1998年1月1日前已診斷出糖尿病的病患。 研究納入之服用糖尿病藥物及未服用任何糖尿病藥物的糖尿病患者，追蹤其六年 之門診資料，再以ICD-9-CM 國際診斷碼140.XX-208.XX、209.XX-239.XX 篩選 出罹患癌症的病患。對照組則取自2002 年之病患資料，每一位糖尿病患則依年齡 與性別，用SAS 軟體隨機選取兩位未罹患癌症之非糖尿病患之資料。在研究組 (糖 尿病患者) 中再分成四組：第一組：未服用任何糖尿病藥物；第二組：僅服用 metformin；第三組：服用除metformin 之外之其他糖尿病藥物；第四組：服用 metformin 及其他糖尿病藥物。 研究結果 相較於未服用任何糖尿病藥物的糖尿病病患，單只服用metformin 的病患罹 癌率odd ratio 為0.87 (95% CI=0.74-1.02)，校正後odds ratio 為0.99 (95% CI=0.85-1.16)，並沒有顯著降低。然而，進一步分析服用metformin 之劑量時，發 現服用metformin 劑量大於360 每日界定劑量 (defined daily doses, DDD) 的病患 罹癌風險降低，服用metformin 360-720 DDD、720-1080 DDD 及 >1080 DDD 的病 患，校正後odds ratio 分別為0.37 (95% CI=0.21-0.64)、0.34 (95% CI=0.16-0.71)及 0.25 (95% CI=0.08-0.82)。在併服metformin 和其他糖尿病藥物的病患身上，亦發 現降低更大幅度的odds ratio，odds ratio 於服用metformin 小於90 DDD 之後就有 下降現象。劑量相關性也與癌症發生時間的早晚相關，罹癌時間在併服metformin 與其他糖尿病藥物的病患群中，更是有明顯延長的現象。 結論 糖尿病會增加第二型糖尿病病患的罹癌風險。不論是單獨使用metformin 或是併用其他糖尿病藥物，降低罹癌的效果皆隨著metformin 劑量的增加而更為顯 著，metformin 副作用較少且相對安全，因此可考慮用作預防癌症的化學預防藥物(chemoprevention)。
Background and Objective Worldwide cancer is the number one killer in developed countries and the second leading killer in developing countries while diabetes is ranked number nine. In Taiwan, cancer and diabetes are among the top ten leading causes of death, since 2008,these two conditions occupy the first and the fifth position on the top-ten list of causes of death respectively. As the world population continues to develop there is an increase in diabetes mellitus incidence, and in Taiwan diabetes patients are becoming younger,as more and more diabetic patient who are below the age of 40 years emerge. There is a body of evidence that now links diabetes mellitus with an increased risk of developing cancer. Epidemiologic evidence also associates the use of metformin (one of the drugsused in the management of type 2 diabetes mellitus) with a reduction in cancer risk in type 2 diabetes patients. Most of the studies on the association between metformin and cancer, however, have been done in Caucasian populations and have very little details on the actual doses used by the subjects in the study as a result there was a lack of knowledge on the effect of metformin dose on the cancer risk reduction effect in type 2 diabetes patients. Thus this study aimed at determining the effects of metformin on cancer risk reduction in type 2 diabetic patients. Methods This was a retrospective nationwide population-based study that used data from the Taiwan National Health Insurance Research Dataset. The longitudinal health insurance database (LHID) 2008 records for the years 1997–2002 were used. Study subjects were identified as patients with a principal diagnosis of diabetics (ICD-9-CM codes 250.XX) between January 1, 1998 and December 31, 2002. Only patients who had at least consensus three diagnosed episodes of diabetes were included in the study sample. Patients who were diagnosed with diabetes before January 1, 1998 were excluded. The study sample included diabetic patients who had received anti-diabetic drugs and those who did not receive any anti-diabetic drugs treatment during the follow-up period. Each patient was individually tracked for six years from their index outpatient visit to identify all who developed cancer (ICD-9-CM codes140.XX-208.XX, 209.XX-239.XX). A control group was identified from the remaining subjects in the 2002 administrative data, by identifying two non-diabetes mellitus patients without a previous cancer diagnosis and matching them with one patient in the study sample for age and gender. The non-diabetes mellitus subjects were chosen randomly using a SAS program. The study sample (diabetes mellitus patients) was further divided into four groups: Group 1 consisted of patients not taking any anti-diabetic drug; group 2 those on metformin monotherapy; group 3 had those on other anti-diabetic drugs except metformin; group 4 had patients on metformin in addition to other anti-diabetic drugs. Results The results showed no decrease in odds ratios for cancer in diabetic patients who received metformin monotherapy compared with diabetic patients who did not receive any anti-diabetic drugs. The odds ratio and adjusted odd ratio were 0.87 (95% CI=0.74-1.02) and 0.99 (95% CI=0.85-1.16). However, a dose-response analysis found cancer risk reduction effects in patients on metformin monotherapy who received >360 defined daily doses (DDD) of metformin, the adjust odds ratio were 0.37 (95% CI=0.21-0.64), 0.34 (95% CI=0.16-0.71) and 0.25 (95% CI=0.08-0.82) for patients who received metformin at 360-720 DDD, 720-1080 DDD and > 1080 DDD respectively (1 DDD = 2000 mg of metformin). Greater reduction in odds ratio were found in diabetic patients who received metformin and other anti-diabetic drugs with decrease in odds ratio showing after <90 DDD of metformin. There was also a dose-dependent increase in cancer onset times with the most significant increases observed in the group who received metformin in combination with other anti-diabetic drugs. Conclusion Diabetes increases the risk of cancer in type 2 diabetes patients. The cancer risk reducing effects of metformin used in type 2 diabetes patients increases with cumulative increase in dose of metformin, regardless of whether metformin is used as monotherapy or in combination with other anti-diabetic drugs. Metformin is a relatively safe drug which produces few side effects. Hence it is good candidate for cancer chemoprevention.