Ld/n, CDE

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 1^7,8).

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 years^6,14) 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 2^19,20).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

Assessment of the mental status of a patient with B12 deficiency may reveal irritability, depressed mood, altered mental functioning, and even psychosis.^28,29

Laboratory Work-up
If findings from the history and physical examination in the patient taking metformin suggest vitamin B12 deficiency, prompt laboratory assessment for the presence of macrocytic anemia, a common consequence of cobalamin deficiency, is needed.^17,30 If this condition is present, further laboratory assessment to differentiate between folic acid and B12 deficiency is critical, as the associated neurologic symptoms can be irreversible without timely treatment.

Assessment for anemias is achieved with the complete blood count (CBC); a mean corpuscular volume (MCV) exceeding 110 fL may be present in patients with macrocytic anemia.^17,31 The serum folate value may be decreased in the presence of vitamin B12 deficiency or folic acid deficiency.¹⁶

Serum concentrations of vitamin B12 should be measured by an optimized assay to evaluate circulating B12 levels. Although laboratory value norms for B12 lack uniformity,^20,32 the lower limit of normal serum B12 has been defined as 150 pmol/L (203 pg/mL) when the patient has clinical signs and symptoms; when two or more readings yield such results; or in conjunction with a total serum homocysteine level exceeding 0.4 mcmol/L.^9,13,20,33

Serum methylmalonic acid (MMA) and total homocysteine (HCY) are more sensitive diagnostic tests that can be used to detect mild or early B12 deficiency. Because these substances depend on B12 as a cofactor in their metabolism, their values will be elevated in the presence of cobalamin deficiency; an elevated MMA concentration is very specific for cobalamin deficiency.^14,34 Patients should also be evaluated for renal disease or dehydration, which are both associated with elevations in MMA levels. Serum HCY levels can be elevated in patients with either folate or B12 vitamin deficiency, but the increase is usually greater in the latter case.^20,35

Intrinsic factor deficiency can also lead to vitamin B12 deficiency. Diagnostic tests to investigate for this condition include intrinsic factor–binding antibody, intrinsic factor–blocking antibody, and parietal cell antibody tests.^15,17,20,36

Treatment/Follow-up
For many years, the standard of treatment for vitamin B12 deficiency in adults has been intramuscular injections of 1,000 mcg/d of cyanocobalamin for one to two weeks, followed by one to two injections weekly for two weeks to one month, then monthly injections thereafter until the deficiency is fully resolved.^13,23,30

In recent years, oral cyanocobalamin has been found to be an effective treatment for the hematologic symptoms associated with macrocytic anemia.³⁷ A daily B12 supplement of 1,000 to 2,000 mcg/d should be taken for one month, followed by a daily maintenance dose of as much as 1,000 mcg/d.^13,28 Cyanocobalamin is also available in a nasal gel.³³

Researchers have also demonstrated that daily use of supplemental calcium can reverse the effects of B12 malabsorption associated with metformin therapy, without interfering with metformin’s therapeutic (hypoglycemic) effects.¹⁰ Alternatively, cessation of the drug has been found to reverse B12 deficiency in a matter of weeks.⁶

Reassessment of laboratory values is recommended every two to three months to evaluate the effectiveness of the chosen treatment plan.²⁹

Patient Education
Patients with metformin-associated vitamin B12 deficiency need dietary counseling, including information about B12–rich food sources (as shown in Table 1). In patients who do not require cyanocobalamin injections, vitamin B12 supplementation will be essential. Patients who do elect intramuscular cyanocobalamin must be taught injection techniques.

If continued use of metformin is deemed necessary, the patient may be advised to take supplemental calcium to help reverse the medication’s effects on B12 levels.¹⁰ Lastly, cessation of metformin has been demonstrated to reverse B12 deficiency quickly.⁶

Patients who continue the metformin regimen may benefit from a referral to a dietitian or pharmacist who is also a diabetes educator. In addition to reinforcing diabetes self-management skills, this clinician can increase the patient’s awareness of the potential effects of metformin along with strategies (appropriate diet and supplementation) to counter the associated adverse effects.

Conclusion
Decreased levels of vitamin B12 have been reported in 10% to 30% of patients who take metformin for treatment of type 2 diabetes, but no consensus exists regarding routine monitoring of B12 levels in these patients. Considering concerns regarding elevated homocysteine concentrations that occur with cobalamin deficiency (ie, the increased risk for cardiovascular disease, particularly in patients with diabetes¹⁶), the call for annual laboratory testing for B12³⁰ appears reasonable. The efficacy of preventive screening to identify “this preventable deficiency”¹⁶ must be demonstrated, however.

Until then, the astute clinician must watch for signs and symptoms of B12 deficiency in diabetic patients who take metformin, with timely diagnosis and appropriate treatment when clinical suspicion is confirmed through laboratory testing.

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 1^7,8).

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 years^6,14) 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 2^19,20).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

Assessment of the mental status of a patient with B12 deficiency may reveal irritability, depressed mood, altered mental functioning, and even psychosis.^28,29

Laboratory Work-up
If findings from the history and physical examination in the patient taking metformin suggest vitamin B12 deficiency, prompt laboratory assessment for the presence of macrocytic anemia, a common consequence of cobalamin deficiency, is needed.^17,30 If this condition is present, further laboratory assessment to differentiate between folic acid and B12 deficiency is critical, as the associated neurologic symptoms can be irreversible without timely treatment.

Assessment for anemias is achieved with the complete blood count (CBC); a mean corpuscular volume (MCV) exceeding 110 fL may be present in patients with macrocytic anemia.^17,31 The serum folate value may be decreased in the presence of vitamin B12 deficiency or folic acid deficiency.¹⁶

Serum concentrations of vitamin B12 should be measured by an optimized assay to evaluate circulating B12 levels. Although laboratory value norms for B12 lack uniformity,^20,32 the lower limit of normal serum B12 has been defined as 150 pmol/L (203 pg/mL) when the patient has clinical signs and symptoms; when two or more readings yield such results; or in conjunction with a total serum homocysteine level exceeding 0.4 mcmol/L.^9,13,20,33

Serum methylmalonic acid (MMA) and total homocysteine (HCY) are more sensitive diagnostic tests that can be used to detect mild or early B12 deficiency. Because these substances depend on B12 as a cofactor in their metabolism, their values will be elevated in the presence of cobalamin deficiency; an elevated MMA concentration is very specific for cobalamin deficiency.^14,34 Patients should also be evaluated for renal disease or dehydration, which are both associated with elevations in MMA levels. Serum HCY levels can be elevated in patients with either folate or B12 vitamin deficiency, but the increase is usually greater in the latter case.^20,35

Intrinsic factor deficiency can also lead to vitamin B12 deficiency. Diagnostic tests to investigate for this condition include intrinsic factor–binding antibody, intrinsic factor–blocking antibody, and parietal cell antibody tests.^15,17,20,36

Treatment/Follow-up
For many years, the standard of treatment for vitamin B12 deficiency in adults has been intramuscular injections of 1,000 mcg/d of cyanocobalamin for one to two weeks, followed by one to two injections weekly for two weeks to one month, then monthly injections thereafter until the deficiency is fully resolved.^13,23,30

In recent years, oral cyanocobalamin has been found to be an effective treatment for the hematologic symptoms associated with macrocytic anemia.³⁷ A daily B12 supplement of 1,000 to 2,000 mcg/d should be taken for one month, followed by a daily maintenance dose of as much as 1,000 mcg/d.^13,28 Cyanocobalamin is also available in a nasal gel.³³

Researchers have also demonstrated that daily use of supplemental calcium can reverse the effects of B12 malabsorption associated with metformin therapy, without interfering with metformin’s therapeutic (hypoglycemic) effects.¹⁰ Alternatively, cessation of the drug has been found to reverse B12 deficiency in a matter of weeks.⁶

Reassessment of laboratory values is recommended every two to three months to evaluate the effectiveness of the chosen treatment plan.²⁹

Patient Education
Patients with metformin-associated vitamin B12 deficiency need dietary counseling, including information about B12–rich food sources (as shown in Table 1). In patients who do not require cyanocobalamin injections, vitamin B12 supplementation will be essential. Patients who do elect intramuscular cyanocobalamin must be taught injection techniques.

If continued use of metformin is deemed necessary, the patient may be advised to take supplemental calcium to help reverse the medication’s effects on B12 levels.¹⁰ Lastly, cessation of metformin has been demonstrated to reverse B12 deficiency quickly.⁶

Patients who continue the metformin regimen may benefit from a referral to a dietitian or pharmacist who is also a diabetes educator. In addition to reinforcing diabetes self-management skills, this clinician can increase the patient’s awareness of the potential effects of metformin along with strategies (appropriate diet and supplementation) to counter the associated adverse effects.

Conclusion
Decreased levels of vitamin B12 have been reported in 10% to 30% of patients who take metformin for treatment of type 2 diabetes, but no consensus exists regarding routine monitoring of B12 levels in these patients. Considering concerns regarding elevated homocysteine concentrations that occur with cobalamin deficiency (ie, the increased risk for cardiovascular disease, particularly in patients with diabetes¹⁶), the call for annual laboratory testing for B12³⁰ appears reasonable. The efficacy of preventive screening to identify “this preventable deficiency”¹⁶ must be demonstrated, however.

Until then, the astute clinician must watch for signs and symptoms of B12 deficiency in diabetic patients who take metformin, with timely diagnosis and appropriate treatment when clinical suspicion is confirmed through laboratory testing.

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 1^7,8).

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 years^6,14) 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 2^19,20).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

Assessment of the mental status of a patient with B12 deficiency may reveal irritability, depressed mood, altered mental functioning, and even psychosis.^28,29

Laboratory Work-up
If findings from the history and physical examination in the patient taking metformin suggest vitamin B12 deficiency, prompt laboratory assessment for the presence of macrocytic anemia, a common consequence of cobalamin deficiency, is needed.^17,30 If this condition is present, further laboratory assessment to differentiate between folic acid and B12 deficiency is critical, as the associated neurologic symptoms can be irreversible without timely treatment.

Assessment for anemias is achieved with the complete blood count (CBC); a mean corpuscular volume (MCV) exceeding 110 fL may be present in patients with macrocytic anemia.^17,31 The serum folate value may be decreased in the presence of vitamin B12 deficiency or folic acid deficiency.¹⁶

Serum concentrations of vitamin B12 should be measured by an optimized assay to evaluate circulating B12 levels. Although laboratory value norms for B12 lack uniformity,^20,32 the lower limit of normal serum B12 has been defined as 150 pmol/L (203 pg/mL) when the patient has clinical signs and symptoms; when two or more readings yield such results; or in conjunction with a total serum homocysteine level exceeding 0.4 mcmol/L.^9,13,20,33

Serum methylmalonic acid (MMA) and total homocysteine (HCY) are more sensitive diagnostic tests that can be used to detect mild or early B12 deficiency. Because these substances depend on B12 as a cofactor in their metabolism, their values will be elevated in the presence of cobalamin deficiency; an elevated MMA concentration is very specific for cobalamin deficiency.^14,34 Patients should also be evaluated for renal disease or dehydration, which are both associated with elevations in MMA levels. Serum HCY levels can be elevated in patients with either folate or B12 vitamin deficiency, but the increase is usually greater in the latter case.^20,35

Intrinsic factor deficiency can also lead to vitamin B12 deficiency. Diagnostic tests to investigate for this condition include intrinsic factor–binding antibody, intrinsic factor–blocking antibody, and parietal cell antibody tests.^15,17,20,36

Treatment/Follow-up
For many years, the standard of treatment for vitamin B12 deficiency in adults has been intramuscular injections of 1,000 mcg/d of cyanocobalamin for one to two weeks, followed by one to two injections weekly for two weeks to one month, then monthly injections thereafter until the deficiency is fully resolved.^13,23,30

In recent years, oral cyanocobalamin has been found to be an effective treatment for the hematologic symptoms associated with macrocytic anemia.³⁷ A daily B12 supplement of 1,000 to 2,000 mcg/d should be taken for one month, followed by a daily maintenance dose of as much as 1,000 mcg/d.^13,28 Cyanocobalamin is also available in a nasal gel.³³

Researchers have also demonstrated that daily use of supplemental calcium can reverse the effects of B12 malabsorption associated with metformin therapy, without interfering with metformin’s therapeutic (hypoglycemic) effects.¹⁰ Alternatively, cessation of the drug has been found to reverse B12 deficiency in a matter of weeks.⁶

Reassessment of laboratory values is recommended every two to three months to evaluate the effectiveness of the chosen treatment plan.²⁹

Patient Education
Patients with metformin-associated vitamin B12 deficiency need dietary counseling, including information about B12–rich food sources (as shown in Table 1). In patients who do not require cyanocobalamin injections, vitamin B12 supplementation will be essential. Patients who do elect intramuscular cyanocobalamin must be taught injection techniques.

If continued use of metformin is deemed necessary, the patient may be advised to take supplemental calcium to help reverse the medication’s effects on B12 levels.¹⁰ Lastly, cessation of metformin has been demonstrated to reverse B12 deficiency quickly.⁶

Patients who continue the metformin regimen may benefit from a referral to a dietitian or pharmacist who is also a diabetes educator. In addition to reinforcing diabetes self-management skills, this clinician can increase the patient’s awareness of the potential effects of metformin along with strategies (appropriate diet and supplementation) to counter the associated adverse effects.

Conclusion
Decreased levels of vitamin B12 have been reported in 10% to 30% of patients who take metformin for treatment of type 2 diabetes, but no consensus exists regarding routine monitoring of B12 levels in these patients. Considering concerns regarding elevated homocysteine concentrations that occur with cobalamin deficiency (ie, the increased risk for cardiovascular disease, particularly in patients with diabetes¹⁶), the call for annual laboratory testing for B12³⁰ appears reasonable. The efficacy of preventive screening to identify “this preventable deficiency”¹⁶ must be demonstrated, however.

Until then, the astute clinician must watch for signs and symptoms of B12 deficiency in diabetic patients who take metformin, with timely diagnosis and appropriate treatment when clinical suspicion is confirmed through laboratory testing.