Original research: Vitamin B12 levels in type 2 diabetes patients taking metformin
Vitamin B12 deficiency is a known effect of treatment with metformin in patients with type 2 diabetes, and is implicated in the development of complications of diabetes. However, there are no guidelines on whether or not patients on metformin should be screened. To ascertain the prevalence in her own practice, the author carried out an observational study. Approximately 25% of patients had low B12 levels, enabling appropriate treatment to be prescribed.
INTRODUCTION
B12 is one of eight B vitamins, a group of cobalt containing compounds (Figure 1). The recommended dietary intake is 2 to 3 ug/day and it occurs in eggs, meat and poultry. B12 is bound to proteins and separated by protease and HCL; it combines with intrinsic factor in the stomach and uses calcium to facilitate absorption. Excess B12 can be stored in the liver for years but is also excreted in urine.
Vitamin B12 has an important role to play in the body including the formation of blood, the functioning of the brain and central nervous system, metabolism, the release of energy from food, the processing of folic acid and the synthesis of DNA.1
There are several known causes of low B12 levels including pernicious anaemia, autoimmune disease, parietal cell destruction leading to lack of intrinsic factor (for example in patients who undergo gastric surgery). Alcohol in excess can reduce B12 absorption and so can nicotine. Bacteria can bind to B12 in the gut preventing absorption. Patients taking a proton pump inhibitor (PPI) or histamine H2 receptor antagonist can be at increased risk as gastric acid is needed to release B12 from protein for absorption.2 There are certain other higher risk groups for B12 deficiency, including patients on anti-convulsants and those with Crohn's disease, and risk rises with age.3,4
Metformin is a biguanide and the corner stone of management for patients with type 2 diabetes, largely because there is long-term data showing improved cardiovascular outcomes for patients on this treatment.5,6 The fact that it does not cause weight gain or hypoglycaemia are other major benefits. However, metformin is thought to affect the calcium dependent membrane action during intrinsic factor uptake by the ileal surface receptors, and it may also reduce serum folic acid.
Low B12 levels can lead to an increase in serum homocysteine, which is a risk factor for vascular disease,2 peripheral neuropathy, mania and psychosis, depression and poor memory. Patients with type 2 diabetes are at increased risk of cardio vascular disease, neuropathy and depression.7 Neuropathy is a debilitating complication of diabetes and in the absence of routine screening, B12 deficiency may present with irreversible neurone damage.8
METHOD
This was an observational study carried out in a UK GP Surgery over a period of 9 months. B12 levels were checked along with routine blood tests for this group as they became due. No patient was subjected to an additional procedure as the B12 request was included in their routine biochemistry. For the purpose of this study, data was also collected regarding gender, age, duration of diabetes, length of time on metformin and whether the patient was taking a proton pump inhibitor or H2 antagonist. The aim of the study was to identify patients with low B12 and collect additional data to indicate whether there are factors which might appear to raise the likelihood of low B12 in this group. Low B12 was classified as less than 180 pg/ml (Normal range 180 to 914 pg/ml).
RESULTS
The surgery had 127 patients with type 2 diabetes and who were prescribed metformin. The patients in the study ranged in age from 36 to 91 years, 77 were male and 50 female. Duration of diabetes ranged from 1 to 25 years and duration of metformin therapy ranged from 1 to 19 years, 21 patients were taking a proton pump inhibitor and one was taking an H2 receptor antagonist (ranitidine). Body mass index (BMI) ranged from 21 to 47. The lowest B12 level found was < 50 pg/ml in a 78 year-old woman who had had diabetes for 18 years and been on metformin for 17 years.
Of the patients screened, 32 (25.19%) were found to have a low B12. (Tables 3 - 6)
DISCUSSION
The author was prompted to carry out this study after reading an article regarding low B12 levels in patients taking metformin.8,9 This information led to a wish to investigate if there were a proportion of patients at the authors practice taking metformin who had undiagnosed low B12 levels. B12 deficiency is known to rise with age but the levels found in this study exceed those to be expected in the elderly.3
B12 deficiency related to metformin can occur in the absence of raised mean corpuscular volume (MCV), so the full blood count is not an adequate screening test.10
This was a very small observational study and therefore results can only be interpreted with caution. However, the percentage of patients found to have a low B12 result (25.19%) correlates with a previous cross sectional study of 203 patients with diabetes.11 It is not possible to establish cause and effect from a study of this nature due to the high likelihood of confounding factors. It has been suggested, however, that observational evidence does have a role to play in medicine, despite the need to interpret results with caution.12
Results appear to show more females than males having a low B12 level and an increase after 10 years diagnosis and 10 years on metformin. There were also a higher percentage of low B12 results in patients on a PPI, which finding supports the results of another trial.13
Low B12 was more prevalent in the over-65s. Other studies have also found a rising prevalence of vitamin B12 deficiency in patients over 65 in the absence of diabetes, with results ranging between 10 and 14% .3,4 Prior case reports and small studies have been carried out regarding Vitamin B12 deficiency in patients with type 2 diabetes taking metformin and in addition a randomised controlled trial of 390 patients in the Netherlands of patients on insulin plus metformin or placebo.9,14,15 The increased incidence of low B12 in this group is therefore recognised, but there are no official guidelines regarding screening or treatment, although some endocrinologists have suggested patients in this group are tested annually or given an annual 1mg hydroxocabalamin injection upon commencing metformin.8
Patients found to have low B12 levels may be offered hydroxocabalamin injection of varying schedules or oral vitamin B12.
Folic acid supplement must not be given unless B12 is normal as it can mask symptoms while neurological damage may be occurring, eventually leading to symptoms of weakness, memory problems, irreversible neuropathy, tingling and mouth problems.8
CONCLUSION
The number of low B12 results found in this small group is consistent with previous findings, and suggests it may be beneficial to screen for this deficiency in patients with diabetes taking metformin, as part of routine management. In the elderly population, studies have found low B12 rates of 10 to 14%, 3,4 but in this study across an age range of 36 to 91 years the prevalence of low B12 was 25.19%. There are, of course, cost implications in carrying out the B12 tests, but if all patients on metformin were offered B12 supplementation instead of screening, there would be both cost and ethical considerations, since some patients would be taking a medication they did not need.
Low B12 in this group is a modifiable risk factor for reducing the risk of diabetes complications and should therefore be considered in as part of a structured programme of care.
Neuropathy is a common complication of diabetes but by early detection or prevention of B12 deficiency, neuropathy may be prevented or delayed. Diabetes complications are costly to the NHS in terms of medications and care and this would have to be taken into account in deciding the cost effectiveness of screening or treatment.
The author has been unable to find official national guidance on screening or management of low B12 in this patient group and has submitted the topic to NICE for future consideration.
REFERENCES
1. Holman R. Metformin as first choice in oral diabetes treatment. The UKPDS experience. Journ Annu Diabetol Hotel Dieu 2007: 13-20
2. Type 2 diabetes. National clinical guideline for management in primary and secondary care. Royal College of Physicians; London: 2008
3. Gavard J, Lustman PJ, Clouse R. Prevalence of depression in adults with diabetes: an epidemiological evaluation. 1993. Diabetes Care 1993; 16:1167-1178.
4. Bell SH. Vitamin B12 deficiency: A chronic complication of metformin therapy that can cause irreversible neurone damage. Southern Medical Journal 2010 101097/SMJ. Ob13e3181ce0e4d
5. Pflipsen MC, Oh RC, Saguil A et al. The prevention of vitamin B12 deficiency in patients with type 2 diabetes: A cross sectional study. J Am Board Fam Med 2009;22: 528-34
6. Holt T. Evidence-based medicine. Part 5: Observational evidence. Diabetes and Primary Care 2011;13: 289
7. Varighese G, Scarpello J. Metformin and vitamin B12 deficiency: the role of H2 receptor antagonists and proton pump inhibitors. Oxford Journal Age and Ageing 2007;36:1:110-111
8. Pennypicker LC, Allen RD, Kelly JP et al. High prevalence of cobalin deficiency in elderly out patients. J Am Geriat Soc 1993;41(8):891-2.
9. Clark R, Grimley Evans J, Nexo G et al. Vitamin B12 and folate deficiency in later life. 2004 Oxford Journal Age and Ageing. Vol 33 (1) 34-41
10. de Jager J, Kooy A, Lehert P et al Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B12 deficiency: randomised placebo controlled trial. BMJ 2010;340:c2181 doi:10.1136/bmj.c2181
11. Wettre S. Vitamin B12 status of patients treated with metformin: a cross sectional cohort study. 2004 British Journal of Diabetes and Vascular Disease 2004;4(6):401-406
12. Lui KW, Dai LK, Woo J. Metformin related B12 deficiency 2006. Oxford Journal Age and Ageing 2006;35:200-201.
13. NHS Choices. B Vitamins and Minerals. B vitamins and folic acid. http://www.nhsuk/conditions/vitaminsandminerals/Pages/vitamin-B.aspx
14. Alfthan G, Aro A, Gem KF. Plasma Homocystein and ischaemic heart disease. 1998. Arch Int Med 1998:158: 862-7
15. Ousterhuis WP, Neissen RW, Bossoyut PM, Sturk A. Diagnostic value of the mean corpuscular volume in detection of B12 deficiency. Scand J Lab Invest 2000;60(1):9-18
