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

Abstract

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.

Diabetes-Induced Cardiac Autonomic Neuropathy: Impact on Heart Function and Prognosis

“…It is important to increase water consumption and the number of small meals and avoid abrupt changes in body posture. The resting tachycardia characteristic of the worsened stage of vagal dysfunction in CAN may be treated with cardioselective (i.e., beta-1) beta-adrenergic antagonists to improve vagal function [ 19 , 29 , 30 , 41 ]. As CAN progresses, reduced sympathetic response occurs and provokes orthostatic hypotension [ 20 ], which is treated with approved drugs targeted at primary or neurogenic orthostatic hypotension, such as droxidopa, midodrine, clonidine, pyridostigmine, and fludrocortisone.…”

“…However, long-term therapy with metformin, an insulin sensitizer, was recently associated with CAN aggravation due to its interference in vitamin B12 absorption in diabetic patients. Vitamin supplementation is recommended for diabetic patients in biguanide therapy for over 5 years or with additional risk factors (advanced age, bariatric surgery, or anti-ulcer therapy) and may be combined with calcium supplementation [ 41 ].…”

Association of Elevated Serum Uric Acid with Nerve Conduction Function and Peripheral Neuropathy Stratified by Gender and Age in Type 2 Diabetes Patients

“…We also did not collect information on hypoglycemic agents for diabetes. Metformin may influence the level of SUA and increase the risk of neuropathy [ 46 ]. Thirdly, the nerve conduction testing in our study could only reflect the functional status of large fibrous nerves of peripheral nerves but could not detect the small fibrous nerves.…”

Prevalence of Vitamin B12 Deficiency in Type 2 Diabetes Mellitus Patients on Metformin Therapy

“…Metformin inhibits calcium-dependent channels in the ileum, hence preventing the absorption of vitamin B12 in the ileum. Several studies have shown that extended use of metformin causes vitamin B12 insufficiency through this mechanism [11][12][13][14][15][16]. A severe deficit may cause significant neurological problems [17].…”