CCTG MA.32 中非糖尿病乳腺癌患者二甲双胍与安慰剂对维生素 B12 代谢的影响。
Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32.
机构信息
Department of Medicine, Division of Medical Oncology and Hematology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, 1284-600 University Ave, Toronto, ON, M5G 1X5, Canada.
Department of Medicine, Division of Clinical Epidemiology, University of Toronto, Toronto, ON, Canada.
出版信息
Breast Cancer Res Treat. 2017 Jul;164(2):371-378. doi: 10.1007/s10549-017-4265-x. Epub 2017 Apr 26.
BACKGROUND
Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples.
METHODS
VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels <181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels <222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables.
RESULTS
237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 <181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 <222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (>15μmol/L). At 6 months, one patient (metformin) had MMA >0.4μmol/L and 3 (2 metformin, 1 placebo) had HC > 15μmol/L.
CONCLUSIONS
There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.
背景
在糖尿病患者中，二甲双胍与维生素 B12（VitB12）水平降低有关。CCTG/MA.32 试验研究了二甲双胍与安慰剂对非糖尿病高危乳腺癌患者的乳腺癌（BC）结局的影响。我们分析了前 492 名患者配对血样的基线和 6 个月的二甲双胍（与安慰剂相比）时的 VitB12 水平。
方法
VitB12 在基线和 6 个月的空腹血浆中进行中心分析。水平<181pmol/L 被认为是缺乏的，181-221pmol/L 为边缘，≥222pmol/L 为充足。在 VitB12 水平<222pmol/L 的患者中检测甲基丙二酸（MMA）和同型半胱氨酸（HC）。使用 Spearman 秩相关系数和 Wilcoxon 符号秩检验进行连续变量的统计分析，使用卡方检验进行分类变量的统计分析。
结果
237 名患者接受二甲双胍治疗，255 名患者接受安慰剂治疗；二甲双胍和安慰剂组的中位（四分位间距）基线 VitB12 水平分别为 390（290，552）和 370（290，552）pmol/L（p=0.97）。6 个月时，二甲双胍组中位数为 320（244，419）pmol/L，安慰剂组为 380（286，546）pmol/L（p=0.0001）。基线时，15 名患者（11 名服用二甲双胍，4 名服用安慰剂）VitB12<181pmol/L，6 个月时，18 名患者（15 名服用二甲双胍，3 名服用安慰剂）（p=0.004）。基线、二甲双胍组和安慰剂组的中位血红蛋白相似，分别为 130g/L（124-137）和 131g/L（124-137）（p=0.38），6 个月时，分别为 131g/L（91-162）和 131g/L（106-169）（p=0.11）。在任何时间点（45 名服用二甲双胍，29 名服用安慰剂）有 74 名 VitB12<222pmol/L 的受试者中，基线时 MMA 正常，且所有患者的 HC 均升高（>15μmol/L）。6 个月时，一名患者（服用二甲双胍）MMA>0.4μmol/L，3 名患者（2 名服用二甲双胍，1 名服用安慰剂）HC>15μmol/L。
结论
服用二甲双胍 6 个月后 VitB12 生化缺乏的发生率增加；这与贫血无关。进一步的研究将在基线和 6 个月及 60 个月时检查所有受试者的 VitB12 水平。
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