Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial
Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial
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DOI：
10.1016/s1470-2045(15)00565-3
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发表时间：
2016-04-01
期刊：
影响因子：
51.1
通讯作者：
Nakajima, Atsushi
中科院分区：
文献类型：
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作者：
Higurashi, Takuma;Hosono, Kunihiro;Nakajima, Atsushi
结直肠癌的发病率和死亡率在全球范围内不断增加，需要新的预防策略来减轻这种疾病的负担。口服糖尿病药物二甲双胍可能对癌症有化学预防作用，包括结肠直肠癌。然而，目前还没有二甲双胍用于结直肠癌化学预防的临床试验数据。因此，我们设计了一项为期1年的临床试验，以评估二甲双胍对散发性结直肠癌的安全性和化学预防作用（通过腺瘤和息肉复发评估）在腺瘤复发的高风险患者中。来自日本五家医院的既往有单个或多个结直肠腺瘤或息肉经内镜切除的非糖尿病成人患者入组研究。通过分层的基于计算机的随机化方法，将符合条件的患者随机分配（1：1）接受口服二甲双胍（每日250 mg）或相同的安慰剂片剂，并按机构、年龄、性别和体重指数分层。所有患者、内镜医师、医生和研究者均对药物分配保持盲态，直至试验结束。二甲双胍或安慰剂给药1年后，进行结肠镜检查以评估共同主要终点：腺瘤或息肉的数量和患病率。我们的分析包括所有根据意向治疗原则进行随机分配的参与者。该试验在大学医院医学信息网络（UMIN）注册，编号为UMIN 000006254。结果在2011年9月1日至2014年12月30日期间，498例通过内窥镜切除单个或多个结直肠腺瘤的患者入选研究。排除不合格后，151例患者接受随机分组：79例分配至二甲双胍组，72例分配至安慰剂组。二甲双胍组71例患者和安慰剂组62例患者接受了1年随访结肠镜检查。总息肉的患病率二甲双胍组中增生性息肉加腺瘤的发生率和腺瘤的发生率显著低于安慰剂组（总息肉：二甲双胍组71例患者中27例[38.0%; 95% CI 26.7-49.3]，安慰剂组62例患者中35例[56.5%; 95% CI 44.1-68.8]; p=0.034，风险比[RR] 0.67 [95% CI 0.47-0.97];腺瘤：二甲双胍组22例[30.6%; 95% CI 19.9-41.2]/71例患者，安慰剂组32例[51.6%; 95% CI 39.2 -64.1]/62例患者; p=0.016，RR 0.60 [95% CI 0.39-0.92]）。二甲双胍组息肉的中位数为0（IQR 0-1），安慰剂组为1（0-1）（p=0.041）。二甲双胍组腺瘤的中位数量为0（0-1），安慰剂组为0（0-1）（p=0.037）。15例（11%）患者发生不良事件，均为1级。在为期1年的试验中，我们没有记录到严重的不良事件。解释低剂量二甲双胍给药1年，无糖尿病患者是安全的。低剂量二甲双胍可降低息肉切除术后异时性腺瘤或息肉的患病率和数量。美托洛尔在结直肠癌的化学预防中具有潜在的作用。然而，还需要进一步的大型、长期试验才能提供明确的结论。
Background The prevalence of, and mortality from, colorectal cancer is increasing worldwide, and new strategies for prevention are needed to reduce the burden of this disease. The oral diabetes medicine metformin might have chemopreventive effects against cancer, including colorectal cancer. However, no clinical trial data exist for the use of metformin for colorectal cancer chemoprevention. Therefore, we devised a 1-year clinical trial to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence.Methods This trial was a multicentre, double-blind, placebo-controlled, randomised phase 3 trial. Non-diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled into the study from five hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive oral metformin (250 mg daily) or identical placebo tablets by a stratified computer-based randomisation method, with stratification by institute, age, sex, and body-mass index. All patients, endoscopists, doctors, and investigators were masked to drug allocation until the end of the trial. After 1 year of administration of metformin or placebo, colonoscopies were done to assess the co-primary endpoints: the number and prevalence of adenomas or polyps. Our analysis included all participants who underwent random allocation, according to the intention-to-treat principle. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000006254.Findings Between Sept 1, 2011, and Dec 30, 2014, 498 patients who had had single or multiple colorectal adenomas resected by endoscopy were enrolled into the study. After exclusions for ineligibility, 151 patients underwent randomisation: 79 were assigned to the metformin group and 72 to the placebo group. 71 patients in the metformin group and 62 in the placebo group underwent 1-year follow-up colonoscopy. The prevalence of total polyps (hyperplastic polyps plus adenomas) and of adenomas in the metformin group was significantly lower than that in the placebo group (total polyps: metformin group 27 [38.0%; 95% CI 26.7-49.3] of 71 patients, placebo group 35 [56.5%; 95% CI 44.1-68.8] of 62; p=0.034, risk ratio [RR] 0.67 [95% CI 0.47-0.97]; adenomas: metformin group 22 [30.6%; 95% CI 19.9-41.2] of 71 patients, placebo group 32 [51.6%; 95% CI 39,2-64.1] of 62; p=0.016, RR 0.60 [95% CI 0.39-0.92]). The median number of polyps was zero (IQR 0-1) in the metformin group and one (0-1) in the placebo group (p=0.041). The median number of adenomas was zero (0-1) in the metformin group and zero (0-1) in the placebo group (p=0.037). 15 (11%) of patients had adverse events, all of which were grade 1. We recorded no serious adverse events during the 1-year trial.Interpretation The administration of low-dose metformin for 1 year to patients without diabetes was safe. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of colorectal cancer. However, further large, long-term trials are needed to provide definitive conclusions.