Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes

Abstract

Introduction: Type 2 diabetes (T2DM), which is more prevalent (more than 90% of all diabetes cases) and the main driver of the diabetes epidemic, now affects 5.9% of the world’s adult population, with almost 80% of the total in developing countries. At present, 537 million adults (20–79 years) are living with diabetes—1 in 10. This number is predicted to rise to 643 million by 2030 and 783 million by 2045. In India, reports show that 69.2 million people are living with diabetes (8.7%) as per 2015 data. Long-term metformin treatment is a known pharmacological cause of vitamin B12 (Vit B12) deficiency, as was evident within the first 10–12 years after it started to be used. Methods: This was a cross-sectional study conducted in the Postgraduate Department of Medicine in one of the tertiary hospitals in Kashmir. A total of 1600 consecutive patients with T2DM were taken for the study. Out of which 700 patients met the inclusion criteria. These 700 patients were divided into two groups: those taking metformin, and those who were not on metformin. Cumulative metformin doses were recorded in patients taking metformin, using history of dose and duration of treatment. Serum Vit B12 levels were taken for all patients. Based on the results of Vit B12 levels, patients were classified into normal levels (20 pmol/L), possible B12 deficiency (150–220 pmol/l), and definite deficiency (<150 pmol/L). Results: Our results depicted that patients on prolonged metformin therapy showed an increase in Vit B12 deficiency by 11.16%. The prevalence of clinical neuropathy in the metformin-exposed group was 45%, whereas, a prevalence of 31.8% was found in the non-metformin group. The mean age of patients with neuropathy was higher than those without neuropathy (59.01 ± 7.14 vs. 49.95 ± 7.47) (p-value < 0.514, statistically insignificant). Conclusions: In our study, we found that metformin use is associated with Vit B12 deficiency, which is dependent upon the cumulative dose of metformin. Importantly, prolonged metformin use is also associated with an increase in the prevalence of clinical neuropathy.

Correlation between long-term use of metformin and incidence of NAFLD among patients with type 2 diabetes mellitus: A real-world cohort study

“…Several studies demonstrated that vitamin B12 deficiency occurred when patients taken metformin for more than 2-4 years (45,47). Metformin use is associated with vitamin B12 deficiency, which is dependent upon the cumulative dose of metformin (48). Due to the clinical benefits of metformin use, its associated side effects such as vitamin B12 deficiency is often overlooked in T2DM patients.…”

“…Metformin use is associated with vitamin B12 deficiency, which is dependent upon the cumulative dose of metformin ( 48 ). Due to the clinical benefits of metformin use, its associated side effects such as vitamin B12 deficiency is often overlooked in T2DM patients.…”

Peripheral Neuropathy: A review of mechanism-based treatments with a focus on metformin as a possible choice

“…However, the outcomes of studies, using Metformin as symptomatic treatment of diabetic neuropathy, is not consistent with pre-clinical studies. Many studies have mentioned that vitamin B12 deficiency caused by Metformin use in diabetic patients can cause and even worsen diabetic neuropathy and should be carefully noticed in diabetic population [49][50][51][52][53][54].…”

“…However, there are concerns about using Metformin as an adjuvant for the treatment of PN. To date, many clinical studies suggested that long-term use of Metformin, especially over 5 years and higher cumulative dose of Metformin is associated with vitamin B12 deficiency, which can cause progression of central and peripheral neuropathy [49][50][51][52][53][54]. Contrary to initial disappointing results, Russo et al mentioned that in type 2 DM patients who received Metformin for at least 6 months, vitamin B12 deficiency was just mild and didn't have a relationship with developing diabetic neuropathy [76].…”

Vitamin B12 deficiency linked to metformin usage in Pakistan

“…Furthermore, a recent study in a tertiary hospital in Kashmir concluded that long-term metformin use led to an appreciable rise in vitamin B12 deficiency among treated patients. This deficiency could cause the rise in clinical neuropathy observed in metformin patients in Pakistan [7] . This adverse relation between metformin and vitamin B12 has further been augmented by the most extensive multicentre cross-sectional to date held at Baqai Institute of Diabetology and Endocrinology (BIDE), Baqai Medical University (BMU), Karachi, Pakistan.…”