Chak Amitabh, Buttar Navtej S, Foster Nathan R, Seisler Drew K, Marcon Norman E, Schoen Robert, Cruz-Correa Marcia R, Falk Gary W, Sharma Prateek, Hur Chin, Katzka David A, Rodriguez Luz M, Richmond Ellen, Sharma Anamay N, Smyrk Thomas C, Mandrekar Sumithra J, Limburg Paul J
Department of Gastroenterology and Hepatology, University Hospitals Case Medical Center, Cleveland, Ohio.
Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
Clin Gastroenterol Hepatol. 2015 Apr;13(4):665-72.e1-4. doi: 10.1016/j.cgh.2014.08.040. Epub 2014 Sep 15.
BACKGROUND & AIMS: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation.
Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n = 38) or placebo (n = 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point.
The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P = .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P = .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P = .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3).
In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.
肥胖与肿瘤形成相关，可能是通过影响细胞增殖的胰岛素介导细胞途径。有人提出二甲双胍可通过降低血清胰岛素水平来预防与肥胖相关的癌症。我们对巴雷特食管（BE）患者进行了一项随机、双盲、安慰剂对照的2期研究，以评估二甲双胍对胰岛素途径激活生物标志物磷酸化S6激酶（pS6K1）的影响。
通过癌症预防网络的8个参与机构招募了74名BE患者（平均年龄58.7岁；58名男性[78%]；52名BE长度>2 cm[70%]）。参与者被随机分为两组，一组每天服用二甲双胍（第4周时增至2000 mg/天，n = 38），另一组服用安慰剂（n = 36），为期12周。在基线和第12周时通过食管胃十二指肠镜检查收集活检标本。我们计算并比较了服用二甲双胍与安慰剂的受试者之间pS6K1中位数水平的变化百分比，将其作为主要终点。
两组之间pS6K1中位数水平的变化百分比无显著差异（服用二甲双胍的受试者中为1.4%，服用安慰剂的受试者中为-14.7%；单侧P = 0.80）。二甲双胍与血清胰岛素水平几乎显著降低相关（服用二甲双胍的受试者中位数降低4.7%，服用安慰剂的受试者中升高23.6%，P = 0.08），以及胰岛素抵抗的稳态模型评估指标也降低（服用二甲双胍的受试者中位数降低7.2%，服用安慰剂的受试者中升高38%，P = 0.06）。二甲双胍对细胞增殖（基于KI67检测）或细胞凋亡（基于半胱天冬酶3水平）无影响。
在一项BE患者的化学预防试验中，与安慰剂相比，每天服用二甲双胍12周并未使食管组织中pS6K1水平大幅降低。尽管二甲双胍降低了血清胰岛素水平和胰岛素抵抗，但它并未明显改变食管组织中的上皮细胞增殖或凋亡。这些发现不支持将二甲双胍作为预防BE相关癌变的化学预防药物。临床试验注册号，NCT01447927。
