Persons living with diabetes face numerous challenges—balancing lifestyle changes, monitoring blood sugars, and maintaining their medication regimen. Metformin, an oral blood glucose–lowering agent belonging to the drug class known as biguanides, has been found effective in regulating blood glucose without increasing insulin secretion or triggering weight gain.1,2 Based on a 2009 consensus algorithm jointly issued by the American Diabetes Association and the European Association for the Study of Diabetes,3 metformin is recommended as first-line therapy at the time of diagnosis of type 2 diabetes.
Currently, metformin is the most commonly prescribed generic oral medication for persons with type 2 diabetes.4 A review of the literature dating back almost 40 years reveals a reduction in vitamin B12 levels in 10% to 30% of metformin users.3,5,6 Vitamin B12 (cobalamin) is a water-soluble nutrient that is essential for DNA synthesis, red blood cell formation, and nerve cell maintenance. The recommended dietary allowance for the nonpregnant, nonlactacting adult is 2.4 mcg/d.7,8 Animal products are a good source of this vitamin (see Table 17,8).
The incidence of vitamin B12 deficiency in the general population, as reported in the literature, varies somewhat9 (see “Laboratory Work-Up,” below). A deficiency of cobalamin can occur anywhere along its complex metabolic pathway, with potential effects on multiple body systems.
Although the exact mechanism for metformin-associated cobalamin deficiency has not been identified, researchers have suggested that metformin may block calcium absorption, a process that is integral to B12 metabolism.10 Others have reported that bacterial flora changes may induce food-cobalamin malabsorption.11-13 Duration of metformin use (eg, 4 to 9 years6,14) and dosing levels appear to be relevant factors in the development of B12 deficiency.6,15 The risk for this deficiency nearly triples with each 1.0–g/d increment in metformin dosage, according to a recent report.15
In the patient with metformin-associated cobalamin deficiency, hematologic, gastrointestinal (GI), neuropsychiatric, and cardiovascular symptoms are all possible. Of note, the elevated homocysteine levels associated with this deficiency are a known risk factor for cardiovascular disease (including the risk for atheromatosis in patients with diabetes) and thus an important consideration.14,16-18
Most signs and symptoms of vitamin B12 deficiency can be reversed through treatment. Therefore, it is essential for the primary care clinician to be attentive to patients’ risk factors for this deficiency and to facilitate early diagnosis, when appropriate, by conducting a thorough history and physical and ordering appropriate laboratory testing.
Presentation and Patient History
Because of the multisystem effects of diabetes, the patient who is taking metformin may experience a variety of symptoms. Whether these symptoms are attributable to cobalamin malabsorption or the direct result of diabetes disease mechanisms must be determined. Of note, patients with diabetes who present with the symptoms discussed here must be carefully assessed for several other conditions associated with vitamin B12 deficiency (see Table 219,20).Certain components of the patient history require particular attention, including the history of present illness, a complete past medical history, and the review of systems.
A full examination of all currently used medications, with their dosages, should be performed; antacids, H2-receptor antagonists, and proton pump inhibitors, for example, have been shown to interfere with cobalamin absorption.21 Certain chemotherapy agents (eg, methotrexate22) and excessive use of nitrous oxide can also impede cobalamin absorption.23,24 The dietary history should include supplements and explore sources of vitamin B12 intake.
When conducting the review of systems, the clinician should focus on the hematologic, GI, and nervous systems. Characteristic hematologic symptoms associated primarily with anemia include fatigue and lightheadedness.17
GI-related consequences of B12 deficiency often involve malabsorption issues. These patients may present with symptoms of a sore or burning tongue—one of the earliest signs of cobalamin deficiency.25 Patients often report weight loss, poor appetite, diarrhea or constipation, and abdominal discomfort.6,7,26,27
Investigating symptoms that affect the neuropsychiatric system is imperative, as irreversible neurologic damage can occur if treatment is not initiated early. Neuropsychiatric symptoms, such as peripheral neuropathies that can mimic diabetic neuropathy (numbness, tingling, burning),11 are common complaints in patients with vitamin B12 deficiency.28 They may report weakness and an unsteady gait in the lower extremities, followed by weakness in the upper extremities.26,28 Others may report symptoms of depressed mood, forgetfulness, paranoia, or even cognitive impairment.26,29
Physical Exam
During the thorough examination of a patient in whom B12 deficiency is suspected, the clinician should look for pallor of the skin and sclera, and a smooth, shiny, beefy-colored tongue.25 Signs of a severe deficiency include a tachycardic heart rate and a systolic flow murmur on auscultation of the chest.28 The neurologic examination should include assessment of extremity reflexes; patients with vitamin B12 deficiency may be hyporeflexive or hyperreflexive.28 Such a patient may respond abnormally to the Romberg test (ie, loss of balance when the patient’s eyes are closed) and/or exhibit Babinski’s sign (on testing of the plantar reflex, abnormal dorsiflexion of the large toe and fanning of the other toes). Vibration and proprioceptive senses may be diminished.28