Background and Summary

Therapy with metformin can be useful in helping people manage complications of type 2 diabetes. The drug also has side effects, some of which need to be considered by HIV+ users. One such side effect is reduced absorption of vitamin B₁₂. For people living with HIV/AIDS such a side effect can be particularly serious because a number of studies have documented reduced absorption of vitamin B₁₂ in these people. Moreover, some diabetics develop nerve damage in their hands/feet - a condition called diabetic PN (peripheral neuropathy). The symtoms of this form of nerve damage are similar to vitamin B₁₂ deficiency.

In order to absorb vitamin B₁₂, cells in the intestine need the mineral calcium. Metform appears to push calcium away from the surface of some intestinal cells. Molecules that depend on calcium, such as receptors for vitamin B₁₂ cannot work properly without calcium. Therefore, metformin can indirectly reduce the absorption of vitamin B₁₂ by interferring with calcium in the intestine. To find out if supplements of calcium 1.2 grams/day could improve absorption of vitamin B₁₂, researchers in New York conducted a small study.

Study Details

Researchers enrolled 21 subjects with type 2 diabetes into this study. Most had this condition for an average of 6 years. None were supposed to have abused alcohol or other drugs. As well, no subject had liver disease or vitamin B₁₂ deficiency. To manage their diabetes, subjects were using oral sulfonylureas (DiaBeta, Glucotrol) before they entered the study. Researchers switched 14 subjects from sulfonylurea to metformin, up to 800 mg three times daily, for four months. The remaining seven subjects continued to use sulfonylurea and served as a comparison group. After three months subjects taking metformin also received calcium carbonate 1.2 grams/day for one month.

Results - Vitamin B₁₂ levels

At the start of the study levels of vitamin B₁₂ in the two groups were as follows:

• Metformin - 400 pg/ml
  
• Control - 335 pg/ml

This difference was not statistically significant. After three months the average levels of vitamin B₁₂ were as follows:

• Metformin - 282 pg/ml
  
• Control - 364 pg/ml

This decrease in vitamin B₁₂ levels in the metformin group was statistically significant; that is, not likely due to chance alone. Vitamin B₁₂ levels in the control group did not change significantly during the study.

Results - more than vitamin B₁₂ levels

Researchers also measured levels of a protein called holoTCII (holotranscobalamin II or B₁₂-TCII). This protein represents the useable or bioavailable form of vitamin B₁₂ in the body. Among metformin users, changes in holoTCII levels over the course of the study were as follows:

• At the start of the study - 175 pg/ml
• Three months later - 111 pg/ml

This decrease was statistically significant.

Results - Effect of calcium supplements

Taking 1.2 g/day of calcium "partially reversed" the low holoTCII levels, according to the study researchers. Indeed, levels of this protein rose by 15% - a significant increase - after a month of calcium supplementation. Readers should note that the test that measures vitamin B₁₂ levels did not detect any changes after subjects took calcium for a month.

Results - Side Effects

No subject developed serious side effects associated with use of metformin such as lactic acidosis.

Reflections on measuring vitamin B₁₂

At one time researchers thought that measuring the total level of vitamin B₁₂ in the blood was sensitive enough to help them detect and diagnose vitamin B₁₂ deficiency. In the past 10 years, however, researchers have found that some groups of people - such as the elderly and PHAs - can have apparently normal levels of vitamin B₁₂ and yet still have symptoms of vitamin B₁₂ deficiency. This situation arises, in part, because tests to measure vitamin B₁₂ directly, also detect a number of closely related compounds.

The holoTCII test measures the vitamin B₁₂ that is available in the blood for use by cells. Holo TCII levels often fall before vitamin B₁₂ levels do so. The results of this study on metformin and vitamin B₁₂ are important for PHAs, particularly those who are using or considering use of metformin. As well, we remind PHAs about the pitfalls of relying on some of the long-standing tests for vitamin B₁₂ such as the "Schilling test."

REFERENCES

1. Herbert V, Fong W, Gulle V and Stopler T. Low holotranscobalamin II is the earliest serum marker for subnormal vitamin B₁₂ (cobalamin) absorption in patients with AIDS. Am J Hematol 1990 Jun;34(2):132-9.

2. Bauman WA, Shaw S, Jayatilleke E, et al. Increased intake of calcium reverses vitamin B₁₂ malabsorption induced by metformin. Diabetes Care 2000 Sep;23(9):1227-31.

3. Klee GG. Cobalamin and folate evaluation: measurement of methylmalonic acid and homocysteine versus vitamin B₁₂ and folate. Clin Chem 2000 Aug;46(8 Pt 2):1277-83.

4. Snow CF. Laboratory diagnosis of vitamin B₁₂ and folate deficiency: a guide for the primary care physician. Arch Intern Med 1999 Jun 28;159(12):1289-98.

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