Journal Article

Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32

Chalchal, Haji I., Chen, Bingshu E., Brien, William, Lemieux, Julie, Thompson, Alastair Mark, Pritchard, Kathleen I., Parulekar, Wendy R., Gelmon, Karen A., Mukherjee, Som D., Lohmann, Ana Elisa, Goodwin, Pamela Jean, Bernstein, Vanessa, Stambolic, Vuk, Shepherd, Lois E., Ligibel, Jennifer A., Hobday, Timothy J., Mayer, Ingrid A., Whelan, Timothy Joseph, Liebman, Mira F., Hershman, Dawn L., Rastogi, Priya

2017

Overview

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.

• Publisher: Springer US,Springer,Springer Nature B.V
• Subject: Adult / Analysis / Anemia / Antidiabetics / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - therapeutic use / Breast cancer / Breast Neoplasms - blood / Breast Neoplasms - drug therapy / Breast Neoplasms - metabolism / Cancer patients / Cancer research / Clinical Trial / Diabetes / Diabetes mellitus / Diabetics / Diet therapy / Fasting / Female / Hemoglobin / Hemoglobins / Homocysteine / Homocysteine - blood / Humans / Laboratory testing / Medicine / Medicine & Public Health / Metformin / Metformin - administration & dosage / Metformin - therapeutic use / Methylmalonic Acid - blood / Middle Aged / Oncology / Physiological aspects / Rankings / Treatment Outcome / Vitamin B 12 - blood / Vitamin B12 / Vitamin deficiency / Vitamins