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

Abstract

Background Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates 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<181pmol/L were considered deficient, 181 to 221pmol/L borderline and ≥ 222pmol/L sufficient. Methylmalonic acid(MMA) and homocysteine (HC) were assayed in those with VitB12 levels<222pmol/L. Statistical analyses used Spearman’s ranked correlation coefficients and the Wilcoxon signed rank test for continuous variables and Chi-square test for categorical variables. Results 237 patients received metformin and 255, 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 six 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<181pmol/L; at 6 months, 18 patients (15 metformin and 3 placebo) (p=0.004). Median hemoglobin was similar at baseline, metformin, 130g/L (124-137), and placebo arms, 131g/L (124-137), (p=0.38) and at 6 months, metformin, 131g/L (91-162), and 131g/L (106-169) in placebo group, (p=0.11). Of the 74 subjects with vitamin B12<222pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and 2 had elevated HC (>15umol/L). At 6 months, 1 patient (metformin) had MMA >0.4umol/L and 3 (2 metformin, 1 placebo) had HC>15umol/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, 6 and 60 months.

Relationship between metformin use and vitamin B12 status in patients with type 2 diabetes in Japan

“…Homocysteine, which is converted to methionine in the presence of VB12, is a marker for the activity of the vitamin. Some studies have found that the serum level of homocysteine was unaltered, whereas that of VB12 was reduced in patients treated with metformin, suggesting that the depletion of the vitamin was not sufficient to affect its biological actions in the body. The relationship between metformin use and both VB12 deficiency and the risk of associated health problems thus remains unclear.…”

An Investigation on Vitamin B12 Serum Levels among Type 2 Diabetic Patients Treated with Metformin Compared to Normal Levels

“…However, according to former studies, it was more than proposed durations for onset of metformin effectiveness on serum level of Vitamin B12. In the study of Lohmann [23], the level of Vitamin B12 significantly decreased following to metformin intake compared to placebo. In contrast, in our results no relationship was seen between metformin use duration and Vitamin B12.…”

Effect of metformin on serum vitamin B12 and red blood cell indices in North Indian subjects with diabetes mellitus

“…17,18 Some studies have found unchanged blood homocysteine even with decreased vitamin B12 in individuals on metformin therapy. [18][19][20] On the contrary, many studies demonstrated homocysteine rise despite the metformin-induced vitamin B12 diminution. 16,21 The discrepancy among these studies indicates that additional factors like age, nutritional status, food habits, metformin dosage are accountable for metformin-induced vitamin B12 reduction.…”