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LONG TERM USE OF METFORMIN – A RISK FOR VITAMIN B12 DEFICIENCY

My Daddy has diabetes and has been taking Metformin for years. Recently I read that long-term use of Metformin could lead to Vitamin B12 deficiency. Kindly throw more light on this issue. This was an enquiry from a reader. Metformin is a first line agent for the treatment of type 2 diabetes. Metformin is a first line drug therapy in the management of type ll diabetes mellitus (T2DM). It reduces blood sugar (glucose) mainly by inhibiting hepatic glucose production and increasing peripheral glucose uptake. It has a side effect of diarrhea, abdominal cramps, lactic acidosis (rare) and vitamin B12 deficiency.

A multicentre randomised controlled trial of 390 patients with diabetes mellitus showed that those taking 850 mg of metformin three times per day had an increased risk of vitamin B12 deficiency and low vitamin B12 levels. This effect increased with duration of therapy, and patients had an unclear prophylactic supplementation response.

A case-control study that compared 25,956 patients who had vitamin B12 deficiency with 184,199 control patients found a significantly increased risk of vitamin B12 deficiency in patients who had taken proton pump inhibitors (e.g. Esomeprazole, Omeprazole, etc) or histamine H2 blockers (e.g. Ranitidine, Cimetidine, etc) for at least two years. In light of these findings, long-term use of these medications should be periodically reassessed, particularly in patients with other risk factors for vitamin B12 deficiency (Mulla et al. Metformin Use And Vitamin B12 Deficiency. Endocrine Abstracts (2018) 59 P092 | DOI: 10.1530/endoabs.59.P092).

Vitamin B12 (cobalamin) deficiency is a common cause of macrocytic anaemia and has been implicated in a spectrum of neuropsychiatric disorders.  Diagnosis of vitamin B12 deficiency is typically based on measurement of serum vitamin B12 levels, however, about 50 per cent of patients with subclinical disease have normal B12 levels. A more sensitive method of screening for vitamin B12 deficiency is measurement of serum methylmalonic acid and homocysteine levels, which are increased early in vitamin B12 deficiency.

Vitamin B12 (cobalamin) plays an important role in DNA synthesis and neurologic function. Vitamin B12 (cobalamin) is a water-soluble vitamin obtained through the ingestion of fish, meat, and dairy products, as well as fortified cereals and supplements. It is coabsorbed with intrinsic factor, a product of the stomach’s parietal cells, in the terminal ileum after being extracted by gastric acid. Vitamin B12 is crucial for neurologic function, red blood cell production, and DNA synthesis, and is a cofactor for three major reactions: the conversion of methylmalonic acid to succinyl coenzyme A; the conversion of homocysteine to methionine; and the conversion of 5-methyltetrahydrofolate to tetrahydrofolate.

In the United States and the United Kingdom, the prevalence of vitamin B12 deficiency is approximately 6% in persons younger than 60 years, and nearly 20% in those older than 60 years. Latin American countries have a clinical or subclinical deficiency rate of approximately 40%. The prevalence is 70% in Kenyan school children, 80% in East Indian preschool-aged children and 70% in East Indian adults. Certain risk factors increase the prevalence of vitamin B12 deficiency. Dietary insufficiency, pernicious anaemia (i.e., an autoimmune process that reduces available intrinsic factor and subsequent absorption of vitamin B12), and long-term use of metformin or acid-suppressing medications (proton pump inhibitors, H2 receptor antagonists) have been implicated in B12 deficiency.

Deficiency can lead to a wide spectrum of hematologic and neuropsychiatric disorders that can often be reversed by early diagnosis and prompt treatment.Screening average-risk adults for vitamin B12 deficiency is not recommended. Screening may however be necessary in patients with one or more risk factors, such as persons with gastric or small intestine resections. The use of metformin for more than four months, use of proton pump inhibitors or histamine H2 blockers for more than 12 months, vegans or strict vegetarians, and adults older than 75 years may also require screening. Initial laboratory assessment should include a complete blood count and serum vitamin B12 level. Measurement of serum methylmalonic acid should be used to confirm deficiency in asymptomatic high-risk patients with low-normal levels of vitamin B12.

Oral administration of high-dose vitamin B12 (1 to 2 mg daily) is as effective as intramuscular administration for correcting anaemia and neurologic symptoms. Intramuscular therapy leads to more rapid improvement and should be considered in patients with severe deficiency or severe neurologic symptoms. Absorption rates improve with supplementation, therefore, patients older than 50 years and vegans or strict vegetarians should consume foods fortified with vitamin B12 or take vitamin B12 supplements. Patients who have had bariatric surgery should receive 1 mg of oral vitamin B12 per day indefinitely. Use of vitamin B12 in patients with elevated serum homocysteine levels and cardiovascular disease does not reduce the risk of myocardial infarction or stroke, or alter cognitive decline.

Vitamin B12 deficiency affects multiple systems, and sequelae vary in severity from mild fatigue to severe neurologic impairment. The substantial hepatic storage of vitamin B12 can delay clinical manifestations for up to 10 years after the onset of deficiency. Bone marrow suppression is common and potentially affects all cell lines, with megaloblastic anaemia being most common. The resultant abnormal erythropoiesis can trigger other notable abnormal laboratory findings, such as decreased haptoglobin levels, high lactate dehydrogenase levels, and elevated reticulocyte count. Symptoms typically include being easily fatigued with exertion, palpitations, and skin pallor. Skin hyperpigmentation, glossitis, and infertility have also been reported.

Neurologic manifestations are caused by progressive demyelination and can include peripheral neuropathy, areflexia, and the loss of proprioception and vibratory sense. Areflexia can be permanent if neuronal death occurs in the posterior and lateral spinal cord tracts. Dementia-like disease, including episodes of psychosis, is possible with more severe and chronic deficiency. Clinical evaluation seems to show an inverse relationship between the severity of megaloblastic anaemia and the degree of neurologic impairment.

Maternal vitamin B12 deficiency during pregnancy or while breastfeeding may lead to neural tube defects, developmental delay, failure to thrive, hypotonia, ataxia, and anaemia. Women at high risk or with known deficiency should supplement with vitamin B12 during pregnancy or while breastfeeding.

In general, patients with an irreversible cause should be treated indefinitely, whereas those with a reversible cause should be treated until the deficiency is corrected and symptoms resolved. If vitamin B12 deficiency coexists with folate deficiency, vitamin B12 should be replaced first to prevent subacute combined degeneration of the spinal cord.

A 2005 Cochrane review involving 108 patients with vitamin B12 deficiency found that high-dose oral replacement (1 mg to 2 mg per day) was as effective as parenteral administration for correcting anaemia and neurologic symptoms.

Because of potential interactions from prolonged medication use, health care providers should consider screening patients for vitamin B12 deficiency if they have been taking proton pump inhibitors or H2 blockers for more than 12 months, or metformin for more than four months.

EDWARD O. AMPORFUL

CHIEF PHARMACIST

COCOA CLINIC

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