Use of metformin is a cause of vitamin [B.sub.12] deficiency - Letter to the Editor

American Family Physician,  Jan 15, 2004  

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TO THE EDITOR: I read with great interest the superb review of vitamin [B.sub.12] deficiency by Drs. Oh and Brown, (1) and I believe it is one of the most clinically useful papers written about this topic. However, I noticed that among the etiologies of food-cobalamin malabsorption, no mention was made of metformin use, which is an unfamiliar, yet increasingly common, cause of cobalamin deficiency in adults.

Small studies and case reports have shown that 10 to 30 percent of patients who are prescribed metformin show signs of reduced vitamin [B.sub.12] absorption leading to clinically significant abnormalities in about 30 percent of cases.

A recent cohort study (2) conducted at the University Hospital of Strasbourg, France, examined patients with a diagnosis of metformin-associated cobalamin deficiency and concluded that metformin causes at least 6 percent of the incidence of vitamin [B.sub.12] deficiency and that resulting hematologic abnormalities and peripheral neuropathy are quite common.

Different mechanisms have been proposed, including alterations in intestinal mobility, bacterial overgrowth, and interactions with a complex of intrinsic-factor/vitamin [B.sub.12] and cubilin, an endocytic receptor involved in the absorption of cobalamin. [B.sub.12]-intrinsic factor complex uptake by ileal cell surface, a calcium-dependent process, also is affected by metformin because of impaired calcium availability. (3-5) During the past five years, the increasing knowledge of the role of insulin resistance in type 2 diabetes has led to a linear widespread use of biguanides for the treatment of this condition and other conditions associated with insulin resistance, such as metabolic syndrome, nonalcoholic fatty liver disease, and polycystic ovary syndrome; therefore, in patients with vitamin [B.sub.12] deficiency or evidence of peripheral neuropathy or macrocytosis, the use of metformin always should be considered within the differential diagnosis of food-bound [B.sub.12] malabsorption. The clinical significance of metformin-induced low levels of serum vitamin [B.sub.12] associated with an increase in serum homocysteine levels as a risk factor for vascular disease is still controversial. Calcium supplementation appears to be an effective treatment5 as well as intramuscular or oral crystalline cyanocobalamin. Discontinuation of metformin also should be considered in refractory cases.

DAVID R. BUVAT, M.D.

Department of Internal Medicine

St. John's Mercy Medical Group

608 Bus Rt. 66

St. Robert, MO 65584

REFERENCES

(1.) Oh R, Brown DL. Vitamin [B.sub.12] deficiency. Am Fam Physician 2003;67:979-86.

(2.) Andres E, Noel E, Goichot B. Metformin-associated vitamin [B.sub.12] deficiency. Arch Intern Med 2002;162: 2251-2.

(3.) Gilligan MA. Metformin and vitamin [B.sub.12] deficiency. Arch Intern Med 2002;162:484-5.

(4.) Andres E, Goichot B, Schlienger JL. Food cobalamin malabsorption: a usual cause of vitamin [B.sub.12] deficiency. Arch Intern Med 2000;160:2061-2.

(5.) Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin [B.sub.12] malabsorption induced by metformin. Diabetes Care 2000;23:1227-31.

IN REPLY: We greatly appreciate Dr. Buvat's comments regarding the association of metformin and vitamin [B.sub.12] malabsorption. At the time we submitted our article, (1) the articles that Dr. Buvat mentions in his letter were not available for review. Because an association between metformin and impaired vitamin [B.sub.12] absorption has been described in the literature since 1971 (2) and the numbers of prescriptions for metformin are on the rise, physicians should be aware of the potential for vitamin [B.sub.12] malabsorption with prolonged use of metformin.

Using the new diagnostic markers to determine vitamin [B.sub.12] deficiency, as many as 6 percent of cases of vitamin [B.sub.12] deficiency may be associated with metformin use. (3) Physicians should be aware that metformin-associated [B.sub.12] malabsorption may be dose-related and that [B.sub.12] deficiency may not be apparent for at least five to 10 years after chronic metformin use. (3,4)

Dr. Buvat also recommends calcium supplementation for patients on long-term metformin. We would recommend caution, because study results have shown that calcium supplementation, while decreasing malabsorption, did not increase serum vitamin [B.sub.12] levels. (5) It is currently unknown if calcium supplementation will reverse [B.sub.12] malabsorption to a degree necessary to prevent deficiency. Calcium supplementation should not be prescribed for the prevention or treatment of metformin-induced vitamin [B.sub.12] deficiency until further elucidated. We recommend that oral vitamin [B.sub.12] be the treatment of choice in the majority of patients with vitamin [B.sub.12] deficiency.

ROBERT C. OH, CPT, MC, USA

DAVID L. BROWN, MAJ, MC, USA

Department of Family Practice

Madigan Army Medical Center

Fort Lewis, WA 98431

REFERENCES