Skip to main content

Advertisement

Log in

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

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Dowling RJ, Niraula S, Chang MC et al (2015) Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res 17:32

    Article  PubMed  PubMed Central  Google Scholar 

  2. Libby G, Donnelly LA, Donnan PT et al (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620–1625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bowker SL, Majumdar SR, Veugelers P et al (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29:254–258

    Article  PubMed  Google Scholar 

  4. Dowling RJ, Zakikhani M, Fantus IG et al (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67:10804–10812

    Article  CAS  PubMed  Google Scholar 

  5. Canadian Cancer Trials Group (CCTG). A phase III randomized trial of metformin vs placebo in early stage breast cancer. https://clinicaltrials.gov/ct2/show/NCT01101438?term=a+phase+III+randomized+trial+of+metformin+vs+placebo+in+early+stage+breast+cancer&rank=1

  6. Goodwin PJ, Parulekar WR, Gelmon KA et al (2015) Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst 107:djv006. doi:10.1093/jnci/djv006

    Article  PubMed  PubMed Central  Google Scholar 

  7. Chapman LE, Darling AL, Brown JE (2016) Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab 42(5):316–327

    Article  CAS  PubMed  Google Scholar 

  8. Niafar M, Hai F, Porhomayon J et al (2015) The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med 10:93–102

    Article  PubMed  Google Scholar 

  9. Reinstatler L, Qi YP, Williamson RS et al (2012) Association of biochemical B(1)(2) deficiency with metformin therapy and vitamin B(1)(2) supplements: the National Health and Nutrition Examination Survey, 1999–2006. Diabetes Care 35:327–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. de Jager J, Kooy A, Lehert P et al (2010) Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 340:c2181

    Article  PubMed  PubMed Central  Google Scholar 

  11. Greibe E, Trolle B, Bor MV et al (2013) Metformin lowers serum cobalamin without changing other markers of cobalamin status: a study on women with polycystic ovary syndrome. Nutrients 5:2475–2482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Obeid R (2014) Metformin causing vitamin B12 deficiency: a guilty verdict without sufficient evidence. Diabetes Care 37:22

    Article  Google Scholar 

  13. Greibe E, Miller JW, Foutouhi SH et al (2013) Metformin increases liver accumulation of vitamin B12—an experimental study in rats. Biochimie 95:1062–1065

    Article  CAS  PubMed  Google Scholar 

  14. Stabler SP (2013) Vitamin B12 deficiency. N Engl J Med 368:2041–2042

    Article  CAS  PubMed  Google Scholar 

  15. American Diabetes Association (2017) 8. Pharmacologic approaches to glycemic treatment. Diabetes Care 40:S74

    Google Scholar 

Download references

Acknowledgements

Dr. Lohmann’s work was supported by Hold’Em for Life Translating Discoveries into Breast Cancer Cures (Canada). Dr. Stambolic’s work was supported by the Canadian Institutes of Health Research (CIHR), Canadian Cancer Society Research Institute (CCSRI), and Hold’Em for Life Translating Discoveries into Breast Cancer Cures (Canada). Dr. Goodwin’s work was supported by The Breast Cancer Research Foundation (United States) and Hold’Em for Life Translating Discoveries into Breast Cancer Cures (Canada).

Funding

The MA.32 Study was supported by Canadian Cancer Society Research Institute (CCSRI) (Grant #021039), National Institute of Health (NIH) (Grant #CA180863), Canadian Breast Cancer Foundation (CBCF), Breast Cancer Research Foundation (US), and Apotex (in kind donation of placebo and metformin).

The study sponsors have no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to Pamela Jean Goodwin.

Ethics declarations

Conflict of interest

Drs. Lohmann, Liebman, Brien, Parulekar, Gelmon, Shepherd, Ligibel, Hershman, Rastogi, Hobday, Lemieux, Thompson, Whelan, Mukherjee, Chalchal, Stambolic, Chen, and Goodwin declare no conflict of interest.

Dr. Pritchard reported receiving consulting fees from AstraZeneca, Pfizer, Roche, Amgen, Novartis, GlaxoSmithKline, and Eisai. Dr. Mayer received consulting fees from Novartis and Pfizer. Dr. Bernstein received consulting fees from Bristol-Myers Squibb.

Ethical approval

All procedures performed in the study were in accordance with the ethical standards of the institutional review board of the participating institutions and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

All patients provided written informed consent to participate, including conduct of the correlative analyses reported here.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lohmann, A.E., Liebman, M.F., Brien, W. et al. Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32. Breast Cancer Res Treat 164, 371–378 (2017). https://doi.org/10.1007/s10549-017-4265-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-017-4265-x

Keywords

Navigation