Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical,autonomic and cardiac neuropathy in the patient with diabetes

Metformin blocks the absorption of vitamin B12 through a mechanism that has not been established but could be because of interference with the calcium-dependent binding of the intrinsic factor vitamin B12 complex to the cubam receptor in the terminal ileum. The subsequent deficiency of vitamin B12 may cause or accelerate distal symmetrical and autonomic neuropathy in the patient with diabetes. Several observational studies and meta-analyses have reported a significant association between metformin utilization and vitamin B12 deficiency. Prospective studies have shown that not only do metformin utilizers have lower vitamin B12 levels but they also have higher frequencies of distal symmetrical polyneuropathy and autonomic neuropathy (including cardiac denervation, which is associated with increased incidences of cardiac arrhythmias, cardiac events and mortality). Therefore, periodic monitoring of vitamin B12 is recommended in all patients who utilize metformin, particularly if metformin has been used for over 5 years at which stage hepatic stores of vitamin B12 would probably be depleted. Factors that accelerate the loss of hepatic vitamin B12 stores are proton pump inhibitors, bariatric surgery, being elderly and having an increased turnover of red blood cells. If serum vitamin B12 levels are borderline, measurement of methylmalonic acid and homocysteine levels can detect vitamin B12 deficiency at its earliest stage. Therapies include prophylactic calcium and vitamin B12 supplements, metformin withdrawal, replenishing vitamin B12 stores with intramuscular or oral vitamin B12 therapy and regular monitoring of vitamin B12 levels and vitamin B12 supplements if metformin continues to be utilized. With adequate vitamin B12 replacement, while symptoms of neuropathy may or may not improve, objective findings of neuropathy stabilize but do not improve.     

Risk factors of vitamin B(12) deficiency in patients receiving metformin

BACKGROUND: Identification of risk factors for metformin-related vitamin B(12) deficiency has major potential implications regarding the management of diabetes mellitus. METHODS: We conducted a nested case-control study from a database in which the source population consisted of subjects who had levels of both serum vitamin B(12) and hemoglobin A(1c) checked in a central laboratory. We identified 155 cases of diabetes mellitus and vitamin B(12) deficiency secondary to metformin treatment. Another 310 controls were selected from the cohort who did not have vitamin B(12) deficiency while taking metformin. RESULTS: A total of 155 patients with metformin-related vitamin B(12) deficiency (mean +/- SD serum vitamin B(12) concentration, 148.6 +/- 40.4 pg/mL [110 +/- 30 pmol/L]) were compared with 310 matched controls (466.1 +/- 330.4 pg/mL [344 +/- 244 pmol/L]). After adjusting for confounders, we found clinically important and statistically significant association of vitamin B(12) deficiency with dose and duration of metformin use. Each 1-g/d metformin dose increment conferred an odds ratio of 2.88 (95% confidence interval, 2.15-3.87) for developing vitamin B(12) deficiency (P<.001). Among those using metformin for 3 years or more, the adjusted odds ratio was 2.39 (95% confidence interval, 1.46-3.91) (P = .001) compared with those receiving metformin for less than 3 years. After exclusion of 113 subjects with borderline vitamin B(12) concentration, dose of metformin remained the strongest independent predictor of vitamin B(12) deficiency. CONCLUSIONS: Our results indicate an increased risk of vitamin B(12) deficiency associated with current dose and duration of metformin use despite adjustment for many potential confounders. The risk factors identified have implications for planning screening or prevention strategies in metformin-treated patients.     

Vitamin B 12 and folic acid serum levels in diabetics under various therapeutic regimens.

The aim of the present study was to reconsider the problem of the haematological consequences of biguanide treatment by evaluating serum vitamin B 12 and folic acid levels as well as classical haematological parameters in 30 diabetics treated by metformin. For purpose of comparison, similar evaluations were done in diabetics treated with insulin (27 patients) or sulfonylureas (13 patients). Results indicated that mean serum levels of vitamin B 12 were significantly lower in patients receiving metformin than in both other groups. In the metformin-treated group, five patients had serum levels of vitamin B 12 below 270 pg/ml and five had borderline values. No difference was found in the mean serum folic acid levels between the three groups. Similarly, there were no differences in the red blood cell counts, volumes or haemoglogin concentrations nor in the mean values of serum iron and lacticodeshydrogenase levels between the three groups. Since the haematologic and neurologic complications of vitamin B 12 deficiency may only appear after the deficiency had existed for 10-15 years, the lack of haematological alteration may be explained by the fact that the vitamin B 12 deficiency was not present for a sufficient period of time. We conclude that it may be wise to monitor the haematological values as well as vitamin B 12 levels at regular intervals in diabetic patients treated with metformin so that B 12 hypovitaminosis and its complications can be prevented.     

Metformin-related vitamin B12 deficiency

Metformin is an invaluable hypoglycaemic agent. We report two cases who had symptomatic vitamin B12 deficiency related to metformin use; the mechanisms are discussed. The clinician must be aware of the possibility of metformin-associated B12 deficiency in users who suffer cognitive impairment, peripheral neuropathy, subacute combined degeneration of the cord or anaemia.     

Association Between Vitamin B12 Levels and Mortality in Hospitalized Older Adults

OBJECTIVES: To investigate the effect of various medications on vitamin B12 status and the association between vitamin B12 levels and mortality. DESIGN: Retrospective cross‐sectional study. SETTING: Four internal medicine departments and the geriatrics department at Kaplan Medical Center (KMC), Rehovot and Harzfeld Geriatrics Hospital, Gedera, Israel. PARTICIPANTS: One thousand five hundred seventy patients aged 65 and older hospitalized at the KMC and Hartzfeld Hospital in 2007. MEASUREMENTS: Blood vitamin B12 levels and demographic, clinical, and laboratory data obtained from electronic medical records. RESULTS: Vitamin B12 deficiency (≤200 pmol/L) was found in 15% of older hospitalized patients. Fifty percent of the patients had high vitamin B12 levels (≥350 pmol/L), 68.2% of whom were aged 80 and older. Metformin use was clearly associated with lower vitamin B12 levels. In patients aged 65 and older, an inverse correlation was found between vitamin B12 levels and albumin, metformin, and angiotensin‐converting enzyme (ACE) inhibitor use. Age, number of medications, and mortality were linearly correlated with vitamin B12 levels. CONCLUSION: Higher vitamin B12 levels were associated with greater mortality, but it is unclear whether vitamin B12 is a marker or a surrogate marker or even a substance that directly causes death. Further investigation is needed to clarify.     

Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial

OBJECTIVE: Metformin is a key treatment option in type 2 diabetes. However, metformin may decrease vitamin B12 levels and increase levels of homocysteine, a cardiovascular risk factor. We investigated whether 16 weeks of treatment with metformin affects serum concentrations of homocysteine, folate and vitamin B12 in subjects with type 2 diabetes treated with insulin. DESIGN: Placebo-controlled, randomized trial. Measurements: at baseline and 16 weeks later. SETTING: This trial was conducted in the outpatient clinics of three general hospitals in The Netherlands. SUBJECTS: A total of 745 patients with type 2 diabetes, treated with insulin and not known with a contraindication for the use of metformin, were approached; 390 gave informed consent and entered the study. Thirty-seven subjects dropped out (12 placebo and 25 metformin users). INTERVENTION: Addition of metformin or placebo to insulin therapy. PRIMARY OUTCOME PARAMETERS: Serum homocysteine, folate, vitamin B12, indices of glycaemic control and body weight. RESULTS: Amongst those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with an increase in homocysteine of 4% (0.2 to 8; P=0.039) and with decreases in folate [-7% (-1.4 to -13); P=0.024] and vitamin B12 [-14% (-4.2 to -24); P<0.0001]. In addition, the increase in homocysteine could be explained by the decreases in folate and vitamin B12. CONCLUSION: In patients with type 2 diabetes, 16 weeks of treatment with metformin reduces levels of folate and vitamin B12, which results in a modest increase in homocysteine. The clinical significance of these findings remains to be investigated.     

Prevalence of intrinsic factor antibodies and vitamin B12 malabsorption in older patients admitted to a rehabilitation hospital

It is possible that the commonly measured serum level of vitamin B12 may miss some cases when used to detect vitamin B12 malabsorption and deficiency in older persons. Serum levels of vitamin B12 and intrinsic factor antibody (IFAB) were determined on 250 consecutive patients over the age of 70 admitted to a rehabilitation hospital. Patients with abnormal results on either test were given the standard Schilling test when possible. Eight patients had documented B12 malabsorption. Of these, five had a low serum B12 level alone and one had a low serum B12 level and a positive IFAB level; however, two patients had positive IFAB and normal serum B12 levels. Serum IFAB level may serve as a useful adjunct to serum B12 level in detecting vitamin B12 malabsorption in older patients.     

Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency

Metformin treatment is a known pharmacological cause of vitamin B12 (Cbl) deficiency with controversial responsible mechanisms. A possible diagnosis of this deficiency is based mainly on the combination of patient's medical history (usually long-term metformin use), clinical examination (possible neuropsychiatric symptoms and signs), laboratory studies which confirm a Cbl deficiency (haematological abnormalities, low serum Cbl levels, elevated serum total homocysteine and methylmalonic acid levels), and exclusion other causes of Cbl deficiency (as pernicious anaemia, food-cobalamin malabsorption syndrome, other drugs, etc.). In our review, recommendations for diagnosis and management of metformin-induced Cbl deficiency (MICD) in diabetic patients based on medical bibliography are presented and discussed.     

Vitamin B12 and folate deficiency in later life

OBJECTIVES: to examine the prevalence of vitamin B12 deficiency and folate deficiency in later life in representative samples of the elderly population in the United Kingdom. DESIGN: a population-based cross-sectional analysis of 3,511 people aged 65 years or older from three studies was used to estimate the age-specific prevalence of vitamin B12 deficiency and of folate deficiency. Vitamin B12 deficiency is conventionally diagnosed if serum vitamin B12 < 150 pmol/l ('low vitamin B12'). We defined 'metabolically significant vitamin B12 deficiency' as vitamin B12 < 200 pmol/l and blood total homocysteine >20 micro mol/l. Folate deficiency, which usually refers to serum folate <5 nmol/l, was defined as 'metabolically significant' if serum folate was <7 nmol/l and homocysteine >20 micro mol/l. RESULTS: the prevalence of vitamin B12 deficiency, whether defined as low vitamin B12 or metabolically significant vitamin B12 deficiency increased with age in all three studies, from about 1 in 20 among people aged 65-74 years to 1 in 10 or even greater among people aged 75 years or greater. The prevalence of folate deficiency also increased with age, and was similar to that for vitamin B12 deficiencies, but only about 10% of people with low vitamin B12 levels also had low folate levels. CONCLUSION: the high prevalence of vitamin B12 and folate deficiency observed in older people indicates a particular need for vigilance for deficiency of these vitamins. Reliable detection and treatment of vitamin deficiency could reduce the risk of deficiency-related disability in old age.     

Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post hoc analysis of a randomized controlled 4.3 year trial

Aims

Metformin treatment is associated with a decrease of serum vitamin B12, but whether this reflects tissue B12 deficiency is controversial. We studied the effects of metformin on serum levels of methylmalonic acid (MMA), a biomarker for tissue B12 deficiency, and on onset or progression of neuropathy.

Vitamin B 12 deficiency in the elderly

Vitamin B 12 deficiency is usually a disease of older persons, and much controversy has surrounded the significance of the deficiency of this vitamin in these patients. This article explores the mechanism of action of vitamin B 12, the clinical and laboratory features of vitamin B 12 deficiency, and a rational treatment plan. Once vitamin B 12 deficiency is recognized and diagnosed, it can be easily treated, usually with gratifying results.     

Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus

OBJECTIVES: Metformin is widely used in patients with type 2 diabetes but may decrease vitamin B(12) levels and increase levels of homocysteine (Hcy), a cardiovascular risk factor. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, may reduce markers of inflammation. We investigated whether 6 weeks' treatment with metformin or rosiglitazone affects serum concentrations of Hcy, folate, or vitamin B(12) in subjects with newly diagnosed type 2 diabetes compared with controls. METHODS: We examined 165 patients with type 2 diabetes. Fasting blood samples, a physical examination, and a complete medical history were performed at the beginning and at the end of the treatment. All blood samples were obtained after a 12-h fast. RESULTS: After treatment, metformin use was associated with an increase in levels of Hcy by 2.36 micromol/l and decreases in folate and vitamin B(12) concentrations by -1.04 ng/ml and -20.17 pg/ml. During rosiglitazone treatment, Hcy levels decreased by -0.92 micromol/l; folate and vitamin B(12) levels remained unchanged. Metformin and rosiglitazone significantly decreased levels of triglyceride (TG), low-density lipoprotein (LDL), total cholesterol (total-C), HbA1c, insulin, and homeostasis model assessment (HOMA). Metformin also significantly decreased body weight. In controls, there was no change in Hcy, folic acid, vitamin B(12), TG, LDL, total-C, HbA1c, insulin, or HOMA levels. Homocysteine change did not correlate with insulin, folate, or vitamin B(12) changes in the metformin and rosiglitazone groups. CONCLUSIONS: In patients with type 2 diabetes, metformin reduces levels of folate and vitamin B(12) and increases Hcy. Conversely, rosiglitazone decreases Hcy levels in this time period. The clinical significance of these findings remains to be investigated.     

Metformin: a review of its pharmacological properties and therapeutic use.

In a survey, the pharmacological and clinical documentation of metformin is presented and discussed, and the present state of knowledge relating to metformin-associated lactic acidosis is reviewed. The use of metformin in the treatment of diabetes is based on clinical experience over twenty years. It has been well documented that metformin is effective in maturity-onset diabetes both as monotherapy and in combination with a sulphonylurea. An advantage of metformin treatment is the tendency to weight reduction and the absence of significant hypoglycaemia; blood glucose levels are reduced only to normal. The disadvantages are the gastro-intestinal side effects and the potential risk of vitamin B 12 and folic acid deficiency during long-term use. Metformin-associated lactic acidosis is a very rare complication, which has mainly occured in patients with serious renal insufficiency or other contra-indications to the use of metformin. The association between phenformin and lactic acidosis has led to withdrawal of this biguanide in several countries. Metformin differs from phenformin in certain important respects, and the normal use of metformin does not involve the risk of side effects disproportionate to the intended effect. Further experimental studies are required to substantiate pharmacokinetics and metabolic effects of metformin in man.     

Vitamin B12 deficiency in the aged: a population-based study

BACKGROUND: vitamin B12 deficiency is common in the aged, but it is controversial whether only some risk groups should be investigated instead of screening the entire aged population. OBJECTIVES: to describe the prevalence of vitamin B12 deficiency in the Finnish aged, and to find out if the subjects especially prone to vitamin B12 deficiency could be identified by the risk factors or clinical correlates. DESIGN: a cross-sectional, population-based study of 1048 aged subjects (age 65-100 years) was carried out. Data on lifestyle factors and clinical conditions were collected, physical examinations were conducted and laboratory variables related to vitamin B12 were measured. RESULTS: vitamin B12 deficiency had been previously diagnosed in 27 (2.6%) subjects, and a laboratory diagnosis (total vitamin B12 <150 pmol/l, or total vitamin B12 150-250 pmol/l and holotranscobalamin < or =37 pmol/l and homocysteine > or =15 micromol/l) was made for 97 (9.5%) subjects. Low serum total vitamin B12 (<150 pmol/l) was observed in 6.1% and borderline total vitamin B12 (150-250 pmol/l) in 32% of the subjects. Male gender (OR 1.9, 95% CI 1.2-2.9), age > or =75 (OR 2.2, 95% CI 1.4-3.4) and refraining from milk products (OR 2.3, 95% CI 1.2-4.4) increased the probability for vitamin B12 deficiency. Anaemia (OR 1.3, 95% CI 0.7-2.3) or macrocytosis (OR 1.2, 95% CI 0.6-2.7) did not predict vitamin B12 deficiency. CONCLUSION: undiagnosed vitamin B12 deficiency is remarkably common in the aged, but no specific risk group for screening can be identified. Thus, biochemical screening of unselected aged population is justified. General practitioners play a key role in diagnosing early vitamin B12 deficiency.     

Helicobacter pylori--is it a novel causative agent in Vitamin B12 deficiency?

BACKGROUND: Evidence for vitamin B12 deficiency usually involves combinations of low serum vitamin B12 levels, clinical and metabolic abnormalities, and therapeutic response. Identification of the underlying cause is important in the diagnosis of vitamin B12 deficiency that is usually attributed to malabsorption. Helicobacter pylori is one of the most common causes of peptic ulcer disease worldwide and a major cause of chronic superficial gastritis leading to atrophy of gastric glands. It is suggested that there may be a casual relationship between H. pylori and food-cobalamin malabsorption. OBJECTIVES: To evaluate the H. pylori incidence in patients with vitamin B12 deficiency prospectively and to assess whether treatment for H pylori infection could correct this deficiency over time. PATIENTS AND METHODS: We performed a prospective cohort study involving 138 patients who had anemia and vitamin B12 deficiency. An upper gastrointestinal endoscopy was performed to assess the severity of atrophic gastritis and biopsy specimens for Campylobacter-like organisms tests and histological examination for H pylori were obtained at the time of diagnosis. The diagnosis of H. pylori prompted a combination treatment. RESULTS: Helicobacter pylori was detected in 77 (56%) of 138 patients with vitamin B12 deficiency and eradication of H pylori infection successfully improved anemia and serum vitamin B12 levels in 31 (40 %) of 77 infected patients. CONCLUSIONS: Helicobacter pylori seems to be a causative agent in the development of adult vitamin B12 deficiency. Eradication of H. pylori infection alone may correct vitamin B12 levels and improve anemia in this subgroup of patients.     

Deoxyuridine suppression: biochemical basis and diagnostic applications

The deoxyuridine (dU) suppression test evolved out of investigations into the biochemical basis of the megaloblastic changes seen in vitamin B12 and folate deficiency. Although the abnormality in dU suppression which occurs in vitamin B12- or folate-deficient states is assumed to reflect impaired methylation of deoxyuridylate, there is still no direct demonstration that this is so. Furthermore, there is evidence that reactions other than the methylation of deoxyuridylate are involved in the phenomenon of dU suppression. Nevertheless, in clinical practice abnormal dU suppression serves as a sensitive index of the presence of megaloblastosis due to vitamin B12 or folate deficiency. dU suppression is also abnormal in a number of conditions other than vitamin B12 or folate deficiency, but its overall specificity in detecting tissue dysfunction due to these two deficiency states is considerably higher than that of the serum vitamin B12 or red cell folate levels. Consequently, the test enables us simply and rapidly to define those patients in whom macrocytosis is unrelated to a deficiency of vitamin B12 or folate. For these reasons, the dU suppression test has been adopted by several laboratories across the world for investigating patients with (a) possible vitamin B12 or folate deficiency, (b) macrocytosis, and (c) megaloblastic erythropoiesis. Since the dU suppression test is abnormal in transcobalamin II deficiency and in some congenital disorders of vitamin B12 and folate metabolism, it is very useful in the investigation of obscure anaemias in infancy and childhood. In addition, it has contributed to our understanding of the mechanisms underlying the myelotoxicity of certain drugs, and particularly of nitrous oxide.     

A new 13C breath test to detect vitamin B12 deficiency: a prevalent and poorly diagnosed health problem

Vitamin B12 deficiency is emerging as a growing public health problem. The most commonly used diagnostic tests are limited in accuracy, sensitivity, and are non-specific for B12 deficiency. The aim of this study was to develop a simple B12 breath test (BBT) to more accurately evaluate vitamin B12 status as an alternative to the most common diagnostic test, serum B12 levels. The breath test is based on the metabolism of sodium 1-(13)C-propionate to (13)CO(2) which requires B12 as a cofactor. We initially compared the BBT to current B12 diagnostic methods in 58 subjects. Subjects also received a second BBT 1-3 days after initial testing to evaluate reproducibility of results. Propionate dosage, fasting times, and collection periods were compared, respectively. The dose of sodium 1-(13)C-propionate (10-50 mg) gave equivalent results while an 8 h fast was essential. Statistical analysis revealed that breath collection times could be reduced to just a baseline and 10 and 20 min following propionate dosing. We also measured the incidence of B12 deficiency with the BBT in 119 patients with chronic pancreatitis, Crohn's disease, small intestinal bacterial overgrowth, and subjects over 65 years of age. The BBT results agreed with previous publications showing a higher incidence of B12 deficiency in these patients. The BBT may provide clinicians with a non-invasive, accurate, reliable, and reproducible diagnostic test to detect vitamin B12 deficiency.     

The effect of recombinant human intrinsic factor on the uptake of vitamin B12 in patients with evident vitamin B12 deficiency

We report on the use of recombinant human intrinsic factor (rhIF) in a new vitamin B12 absorption test. Holotranscobalamin (holoTC) was measured before and 24 hours after intake of three 9-mg doses of vitamin B12 (B12) and again 24 hours after intake of the same dose of B12 together with rhIF (rhIF-B12). Nine patients with evident vitamin B12 deficiency had a significantly higher increase in holoTC after intake of rhIF-B12 than after intake of B12. Twenty-eight patients with suspected vitamin B12 deficiency showed no additional increase in holoTC after intake of rhIF-B12. We conclude that rhIF promotes B12 absorption among patients with evident vitamin B12 deficiency.     

Independent effect of vitamin B12 deficiency on hematological status in older Chinese vegetarian women

We have examined the independent effect of vitamin B(12) deficiency on hematological indices in older Chinese vegetarian women using a cross-sectional study design: 119 women older than 55 years who had been vegetarian for more than 3 years were studied. Fasting blood samples were taken for complete blood count, serum iron, total serum iron binding capacity, serum iron saturation, serum vitamin B(12), serum folate, serum methylmalonic acid levels (MMA), and renal function test. Subjects with iron deficiency (iron saturation <15%) and those with serum creatinine >150 mmol/L were excluded. The prevalence of definite vitamin B(12) deficiency (vitamin B(12) level < 150 pmol/L and MMA >or= 0.4 micromol/L) was 42%. Another 32.8% had possible vitamin B(12) deficiency (either criterion). The prevalence of iron deficiency was 10%. After exclusions, 96 subjects were further analyzed. Vitamin B(12) deficiency defined by serum vitamin B(12) and MMA was associated with a decrease in hemoglobin concentrations by up to 0.9 g/dL, but it was not associated with an increase in mean corpuscular volume (MCV). Serum MMA but not vitamin B(12) levels correlated inversely with hemoglobin and platelet counts and positively with MCV, after adjustment of confounding factors. However, the percentage of subjects with anemia did not increase significantly until serum MMA became >1.0 micromol/L. In conclusion, vitamin B(12) deficiency was associated with a significant decrease in hemoglobin concentration. However, anemia associated with vitamin B(12) deficiency was seldom macrocytic. We recommend that older vegetarians should be given vitamin B(12) supplements routinely.