Background
Metformin stands as the first-line pharmacological treatment for type 2 diabetes mellitus worldwide, prescribed to millions of patients due to its efficacy, safety profile, and cost-effectiveness. However, long-term metformin use has been consistently associated with vitamin B12 deficiency, a complication that can lead to serious neurological manifestations including peripheral neuropathy, cognitive impairment, and megaloblastic anemia. Previous research has identified clinical risk factors such as duration of metformin therapy, dosage, and baseline B12 levels, yet the underlying genetic predisposition to this adverse effect remained poorly understood.
The clinical burden of metformin-induced B12 deficiency is substantial. Studies suggest that approximately 10-30% of patients on long-term metformin therapy develop biochemical B12 deficiency, with many experiencing subclinical depletion that may progress to symptomatic disease. The variability in individual susceptibility has long puzzled clinicians, with some patients developing deficiency within a few years of treatment while others remain replete despite decades of use. This heterogeneity has led researchers to hypothesize that genetic factors may play a significant role in determining individual vulnerability to metformin’s effect on B12 absorption.
