AJG：降糖药与胰腺癌发病风险的关系尚不明确

图1. Meta分析流程图

胰腺癌是常见的恶性肿瘤。胰腺癌恶性程度高，预后差，5年存活率约5%左右。因胰腺癌诊断时大多已处于晚期，即使可以采用手术方法切除癌肿，但5年存活率仍只有10-20%。引起胰腺癌的原因至今尚不十分清楚，但已明确存在多种危险因素，包括吸烟、饮酒、慢性胰腺炎、肥胖以及具有胰腺癌家族史等，都可增加胰腺癌的患病风险。因目前仍缺乏影响胰腺癌预后及成本效益的相关研究，所以鉴定胰腺癌患病高危影响因素，并对高危患者拟定预防性药物治疗策略可以有效减少胰腺癌造成的负担。数个流行病学调查研究显示胰腺癌患病和糖尿病之间有复杂的联系。

虽然Meta分析及病例对照研究表明2型糖尿病为胰腺癌发病的中度危险因素，但是大量临床证据及流行病学调查研究均显示胰腺癌可引起糖尿病。有多项体内或体外临床前研究表明抗糖尿病药物有降低多种肿瘤发病风险的作用。例如二甲双胍被证实可以通过胰岛素依赖或非胰岛素依赖途径抑制肿瘤形成。噻唑烷二酮类（TZDs）被认为具有抑制细胞生长、促进细胞凋亡，阻止肿瘤细胞侵袭转移的作用。磺脲类药物的降糖机制为刺激胰岛素分泌或增强胰岛素功能，因此具有刺激细胞增殖及肿瘤形成的作用。

流行病学研究也显示糖尿病患者使用二甲双胍或噻唑烷二酮类药物可以降低卵巢癌的发病率及死亡率。但另一方面，胰岛素及促胰岛素分泌激素与肿瘤发病率升高相关。不同的降糖药物对肿瘤发生有着不同的影响，这可能是降低血糖并不能降低肿瘤发病率的原因。在胰腺癌危险因素的研究中，有些显示糖尿病患者服用二甲双胍和噻唑烷二酮类药物有防癌的功效，而另一些研究则显示降糖药物并无此类功效。

为了更好的了解降糖药物是否有预防肿瘤发生的作用，并了解何种药物、何种剂量可以获得更好的效果，美国明尼苏达州罗彻斯特市梅奥诊所胃肠道疾病及肝病科的Siddharth Singh等人对评估常用降糖药物和糖尿病患者发生胰腺癌之间的相关性的观察性研究和随机对照研究进行了系统性综述及Meta分析，结果发现磺脲类药物的使用似乎可以增加糖尿病患者罹患胰腺癌的风险，但因现存研究存在很大的异质性影响了结果的分析，目前还不能确定降糖药使用与糖尿病患者罹患胰腺癌风险之间的相关性。为了明确两者之间的确切关系，需要更深入、设计更优良的前瞻性临床对照研究。该项结果发表在2-13年4月的The American Journal of Gastroenterology上。

Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis.
OBJECTIVES
Several preclinical and observational studies have shown that anti-diabetic medications (ADMs) may modify the risk of pancreatic cancer (PaC). We performed a systematic review and meta-analysis evaluating the effect of metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), and insulin on the risk of PaC in patients with diabetes mellitus (DM).
METHODS
We conducted a systematic search of Medline, EMBASE, and Web of Science, up to June 2012, and published abstracts from major gastroenterology and oncology meetings from 2003 to 2012. Studies were included if they (1) evaluated and clearly defined exposure to metformin, SU, TZDs, and/or insulin, (2) reported PaC outcomes in patients with DM and (3) reported relative risks or odds ratio (OR) or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CIs) were estimated using the random-effects model.
RESULTS
Eleven studies (6 cohort, 3 case-control, and 2 randomized controlled trials (RCTs)) reported 1770 cases of PaC in 730,664 patients with DM. Meta-analysis of observational studies showed no significant association between metformin (n=9 studies; adjusted OR 0.76, 95% CI 0.57-1.03, P=0.073), insulin (n=7 studies; adjusted OR 1.59, 95% CI 0.85-2.96, P=0.144), or TZD (n=4 studies; adjusted OR 1.02, 95% CI 0.81-1.30, P=0.844) use and risk of developing PaC. Use of SU was associated with a 70% increase in the odds of PaC (n=8 studies; adjusted OR 1.70, 95% CI 1.27-2.28, P<0.001). There was considerable inherent heterogeneity between studies not explained by study design, setting, or comparator drug and is likely related to confounding by indication and reverse causality. The pooled analyses of the two RCTs were underpowered and provided non-significant results with wide, non-informative 95% CIs.
CONCLUSIONS
Although SU seems to be associated with increased risk of PaC, meta-analysis of existing studies does not support a protective or harmful association between ADM use and risk of PaC in patients with DM. There was considerable heterogeneity across studies, and future, well-designed, prospective studies would be required to understand this association better.