糖尿病嚴重程度與癌症關係研究

Abstract

研究背景： 糖尿病患會併發大小血管併發症，在癌症的發生也比非糖尿病患有較高的機率，包括乳癌、肝癌、胰臟癌、大腸癌等等。過去研究發現高血糖比起正常血糖，呈現更高癌症新發的趨勢；而有嚴重低血糖也比沒有者增加癌症風險；在有腎臟併發症存在的病患也比沒有腎病變者增加癌症風險。透過健保資料庫計算高低血糖和併發症所綜合的糖尿病嚴重指數，納入完整風險因子來分析糖尿病嚴重程度和癌症的關係。 大腸癌是糖尿病最常見的癌症之一, 也是目前發生率最高的癌症. 糖尿病藥物如 Metformin, thiazolidinediones, 非類固醇止痛藥(NSAIDs) 或低劑量阿斯匹林都有研究證實可降低大腸癌發生；然而使用胰島素及Sulfonylureas 則顯示有促癌風險。糖尿病藥物acarbose在基礎和動物實驗中, 可以有效預防大腸癌發生, 可能透過加快大腸蠕動, 減少膽酸及增加短鏈脂肪酸 (byturates)形成有關, 並促進大腸細胞往好的分化, 對大腸癌有減緩發展的好處, 但目前尚未有相關人體研究。本研究納入糖尿病嚴重程度來分析糖尿病用藥acarbose 在糖尿病患是否降低大腸癌的發生率。 研究方法： 藉由台灣1998~2013年健保資料庫，針對糖尿病患四十到六十五歲的糖尿病患者，以世代研究設計方式來探討（一）糖尿病嚴重程度與癌症的關係；（二）糖尿病使用雙醣分解抑制劑 acarbose對新發大腸癌的影響；研究族群如下：

（一）糖尿病嚴重程度與癌症關係： 在1,289,301位糖尿病世代研究族群中，挑選出622,411位40~65歲未有癌症的糖尿病個案，在9年的追縱時間中，從高低血糖急性併發症、和大小血管慢性併發症一一記算每年的糖尿病嚴重程度指標，從糖尿病發病起追縱至癌症發生、死亡、或研究終點。 （二）雙醣分解抑制劑acarbose對糖尿病患新發大腸癌：根據年齡、性別、地域、投保薪資與共病篩選出1,343,484位新發糖尿病個案，以一比一方式配對出199,296 位使用acarbose糖尿病患和相同人數沒有使用acarbose病患族群，從藥物使用起始追縱至大腸癌癌症發生、死亡、或研究終點。 結果： （一）在1998~2013年間篩選過去沒癌症和年齡介於40~60歲間的新發糖尿病患共 622,411位。在糖尿病嚴重程度分成0~5分，嚴重分數愈高者癌症發生率每十萬人年分別為389.2, 453.9, 509.4, 528.9, 537.0, 566.6。最高5分嚴重程度比起最低程度的風險在男性和女性分別為1.08 (95% CI, 1.07-1.09) 和 1.09 (95% CI 1.07-1.10)；校正年齡、地域、投保薪資後的風險為1.05 (95% CI 1.3-1.6) 和 1.07 (95% CI, 1.05-1.08)；額外加上校正共病和三高用藥後的風險為1.03 (95% CI, 1.01-1.04) 和 1.04 (95% CI, 1.02-1.06)。糖尿病嚴重程度從最低增加到最高5分，癌症發生的風險在男性從1.1%增加到28%；在女性從4.5%增加到41%；而糖尿病嚴重度和新發癌症關係在糖尿病發病年紀40~45歲最為明顯，隨著發病年紀增加風險逐漸減少。 （二）在1,487,136人年的追縱中，發生有1,332位新發大腸癌個案，每十萬人發生率為89.6位。使用acarbose治療者降低了27%的新發大腸癌風險 HR 0.73 （95%CI, 0.63-0.83）;而使用acarbose劑量達90~365天和超過365天的病患，降低大腸癌的風險呈現劑量反應效應。（0.69 (95% CI, 0.59-0.82) and 0.46 (95% CI, 0.37-0.58), p for trend <0.001）。 結論： 由研究結果發現糖尿病嚴重程度和新發癌症有很好的相關性，在較年輕發病的糖尿病患，若糖尿病嚴重度升高將有更高癌症風險。運用糖尿病嚴重程度在癌症資料庫研究的例子，以糖尿病用藥acarbose 使用糖尿病嚴重程度作為控制好壞的指標，更明確證實使用acarbose降低大腸癌風險的相關性。

Evidence is emerging that diabetes is associated with an increased risk of cancer compared with non-diabetes. However, little is known about the risk of cancer associated with the severity of diabetes exclusively in patients with diabetes. We created adapted diabetic complication severity index (aDCSI) as proxy of diabetic severity. There were two objectives to this research; (1) to investigate the associations of aDCSI and risk of cancer from any cause; (2) apply the aDCSI as a variable for proxy of diabetic control in the study of use of an acarbose and risk of colorectal cancer in patients with diabetes. Methods: We conducted two population-based cohort studies base on the National Health Insurance Research Database (NHIRD). (1) The diabetic cohort of the Taiwan NHIRD from 1998 through 2013, comprising 1,289,301 newly diagnosed diabetic patients, was enrolled. The time-varying covariates of the aDCSI were created from 0 to 5+, by collecting all vascular and metabolic complications annually. Study follow-up continued from onset of diabetes until the first of the following events occurred: incident cancer, death or end of study. (2) In the use of an acarbose on the risk of colorectal cancer: Newly diagnosed persons with diabetes (n=1,343,484) were enrolled between 1998 and 2010. One non-acarbose control was randomly selected for each acarbose-using subject after matching for age, gender, diabetes onset and comorbidities. Cox proportional hazards regression with a competing risk analysis was used to calculate the hazard ratios and 95% confidence interval for the association between acarbose use and incident colorectal cancer for each eligible case and control pair (n=199,296 pairs). Results: (1) The 622,411 diabetic patients who were enrolled had a mean age of 53 years and average follow-up duration of 9.3 years. In the adjusted Cox analysis, the overall hazard ratios of cancer from any cause were 1.03 (1.02-1.03) and 1.05 (1.03-1.06), with a substantial increase from 1.0% to 12% and from 3.0% to 24% for the top versus bottom quartiles of aDCSI in men and women, respectively. Among patients with diabetes onset age at 40-45 years, the risk of incident cancer was 1.63 (1.31-2.02) to 1.88 (1.38-2.56) for the top versus bottom quartiles of aDCSI in men and women. However, among patients with diabetes onset age at 60-65 years, the risk of incident cancer was 0.99 (0.97-1.01) and 1.18 (1.03-1.36) for the top versus bottom quartiles of aDCSI in men and women. (2) There were 1,332 incident cases of colorectal cancer in the diabetic cohort during the follow-up period of 1,487,136 person-years. The overall incidence rate was 89.6 cases per 100,000 person-years. Patients treated with acarbose had a 27% reduction in the risk of colorectal cancer compared with controls. The adjusted HRs were 0.73 (95% CI, 0.63-0.83), 0.69 (95% CI, 0.59-0.82) and 0.46 (95% CI, 0.37-0.58) for patients using >0 to 90, 90 to 365 and more than 365 cumulative defined daily doses (DDDs) of acarbose, respectively, compared with subjects who did not use acarbose (P for trend <0.001). Conclusion: This study confirmed that among patients with diabetes, higher severity of complications of diabetes increased the risk of cancer compared with the lowest severity of complications of diabetes, and the risk was more prominent in those with younger diabetes onset age. Acarbose use reduced the risk of incident colorectal cancer in patients with diabetes in a dose-dependent manner, after adjustment for confounding factors, including the diabetic complication severity index.