Metformin Doesn't Play Nice with B12
Abstract & Commentary
By Allan J. Wilke, MD, MA, Professor and Chair, Department of Integrative Medicine, Ross University (Bahamas) Limited, Freeport, Grand Bahama, The Bahamas. Dr. Wilke reports no financial relationship to this field of study.
Synopsis: Vitamin B12 levels fall, and continue to fall, with continued metformin use in patients already receiving insulin.
Source: de Jager J, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: Randomised placebo controlled trial. BMJ 2010;340:c2181; doi: 10.1136/bmj.c2181.
Hyperinsulinaemia: the outcome of its metabolic effects (HOME) is a randomized, placebo-controlled study. These Dutch researchers previously published short-term (16 weeks) results that showed metformin was associated with reduced levels of vitamin B12 (cobalamin) and folate and elevated levels of homocysteine.1 This article extends their follow-up to 52 months.
Briefly, HOME randomized 390 patients already receiving insulin to metformin 850 mg three times daily or matching placebo. Subjects were seen every 3 months for an interval history, physical examination, and laboratory investigations. For this study, blood was drawn at baseline and after 4, 17, 30, 43, and 52 months. All subjects received dietary counseling. Vitamin B12 deficiency and low vitamin B12 level were defined as < 150 pmol/L and 150-219 pmol/L, respectively. At baseline, the patients were almost equally divided between men and women. Patients in the metformin group were older than those in the placebo group (64 vs 59 years). Otherwise, they were evenly matched with an average body mass index (BMI) of 30 kg/m2, average HgbA1c of 7.9, and average blood pressure 160/86 mmHg. They were receiving insulin in doses of 61 IU and 64 IU daily. At the end of the study, 277 subjects were still receiving metformin or placebo. Two patients were lost to follow-up. The data analysis was by intention to treat; per-protocol analysis did not change the results.
Table 1. Select laboratory values from the HOME study.
|
Baseline (metformin/placebo) |
52 months (metformin/placebo) |
%∆ (metformin vs placebo) |
Statistically significant |
|
|
Vitamin B12 (pmol/L) |
378/380 |
288/380 |
-19 |
Yes |
|
Folate (nmol/L) |
18.7/18.7 |
18.9/19.7 |
-5 |
No |
|
Homocysteine (µmol/L) |
14.4/14.6 |
17.7/16.2 |
+5 |
No |
Table 1 (above) demonstrates the laboratory values of interest at baseline and at the end of the study.
When the results were adjusted for age, previous metformin treatment, duration of diabetes, gender, insulin dose, BMI, and smoking, the results did not change.
Table 2. Vitamin B12 deficiency.
|
Vitamin B12 deficiency (< 150 pmol/L) |
Baseline n (%) |
52 months n (%) |
|
Metformin |
3 (1.6) |
19 (9.9) |
|
Placebo |
4 (2.2) |
5 (2.7) |
Table 3. Vitamin B12, low level.
|
Vitamin B12, low-level (150-219 pmol/L) |
Baseline n (%) |
52 months n (%) |
|
Metformin |
14 (7.3) |
35 (18.2) |
|
Placebo |
14 (7.5) |
13 (7.0) |
Tables 2 and 3 display the results of metformin therapy on vitamin B12 deficiency and low levels of vitamin B12 as compared to placebo, using the investigators' definitions.
The hazard ratios for developing vitamin B12 deficiency and low levels of vitamin B12, while on metformin, were 5.5 (95% confidence interval [CI], 1.6-19.1) and 3.0 (95% CI, 1.3-6.6), respectively. When the investigators graphed the average vitamin B12 levels over the entire 52 months of the study, the decline was apparent at the first follow-up visit and continued throughout the study.
Commentary
I usually avoid reviewing articles that report secondary outcomes (e.g., changes in laboratory values), rather than patient-oriented outcomes, but I made an exception in this case, because this group had already published patient-oriented outcomes2 and because vitamin B12 deficiency is known to have adverse clinical effects. They did not report any clinical manifestations of these low levels in their patients; however, there is no reason to suspect that metformin protects patients from vitamin B12 deficiency, and, indeed, now there is a report of neuropathy secondary to metformin therapy.3 Its author notes that it takes 12-15 years to exhaust vitamin B12 stores, and that metformin has been available in the United States for 12 years. Although elevated homocysteine levels are associated with coronary heart disease and stroke, I am going to ignore the homocysteine results, because several large trials of homocysteine-lowering therapy with B vitamins have shown no clinical benefit.4,5 The strength of this study is its long follow-up, 4.3 years. The main reasons to accept its findings cautiously are that the study population was already on insulin and their lack of symptoms. Most of our patients taking metformin are not on insulin, and we don't know if the findings apply to them. As the editorialists write, "... we have no robust research underpinning the assumption that people with vitamin B-12 concentrations of 150 pmol/L or less are indeed vitamin B-12 deficient. Although they may be at higher risk for vitamin B-12 deficiency related effects, these risks are not clearly quantified or always directly related to vitamin B-12 concentrations."6 They conclude, "Patients taking metformin (not just those also treated with insulin) should be randomised to systematic serum vitamin B-12 screening or routine care, with patient oriented outcomes and costs included in the outcomes. Otherwise, we risk increasing the burden on patients and the costs of care by treating biochemical outcomes rather than outcomes that matter to patients."
As I was researching the literature on this topic, I was surprised to find out how long we have known the relationship between use of metformin and vitamin B12 deficiency. The earliest articles were published in 1971 and 1972.7-9 The mechanism of action apparently is metformin affecting calcium-dependent membrane channels, causing malabsorption of the vitamin B12/intrinsic factor complex in the ileum. Increasing calcium intake can reverse this malabsorption.10
Metformin is the pharmacologic bulwark of our treatment of type 2 diabetes; it is first-line therapy.11 Many patients are already taking it, and many more will be started. As a clinician, bearing in mind the editorialists caveats, how should you act on the results of this study?
Before you initiate metformin therapy, consider checking your patient's vitamin B12 level. If your patient develops a neuropathy, you will be hard pressed to prove it wasn't your treatment.
Periodically, consider checking your patient's vitamin B12 level. I am not aware of any recommendations about how often "periodically" is, but because it takes years for vitamin B12 stores to become exhausted, every 3-5 years seems reasonable.
Unless your patient has a contraindication to the use of supplemental calcium, start it. Calcium is cheap and has other beneficial effects.
Consider initiating oral vitamin B12 therapy simultaneously with metformin. It is cheap and relatively innocuous.
Do not wait for vitamin B12 symptoms to appear to start supplementation. The neurological symptoms are often improved with therapy, but sometimes incompletely.12
Do not wait for the hematologic manifestations of vitamin B12 deficiency to appear to initiate treatment; the neuropsychiatric symptoms can appear before any change in the red blood cell indices.13
If your diabetic patient who is taking metformin develops a neuropathy, don't automatically assume that it is diabetic neuropathy. Diabetic neuropathy and vitamin B12 deficiency neuropathy manifest differently.
References
1. Wulffelé MG, et al. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus. J Intern Med 2003;254:455-463.
2. Kooy A, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009;169:616-625.
3. Bell DS. Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy. South Med J 2010;103:265-267.
4. Ebbing M, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography trial. JAMA 2008;300:795-804.
5. Lonn E, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567-1577.
6. Vidal-Alaball J, Butler CC. Reduced serum vitamin B-12 in patients taking metformin. BMJ 2010;340:c2198.
7. Berchtold P, et al. Effects of a biguanide (Metformin) on vitamin B 12 and folic acid absorption and intestinal enzyme activities. Scand J Gastroenterol 1971;6:751-754.
8. Tomkin GH, et al. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J 1971;2:685-687.
9. Herbert V. Metformin and B-12 malabsorption. Ann Intern Med 1972;76:140-141.
10. Bauman WA, et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 2000;23:1227-1231.
11. Rodbard HW, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007;13(Suppl 1):1-68.
12. Healton EB, et al. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore) 1991;70:229-245.
13. Lindenbaum J, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720-1728.
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