Is Metformin the Best Choice for Type 2 Diabetes Patients?

Metformin has been associated with a higher incidence of peripheral neuropathy.

Hyperglycemia has been associated with numerous clinical complications. Having high sugar levels in the blood can cause severe damage to the kidneys, eyes, and nervous system, as well as cardiovascular complications, Peripheral neuropathy is the most widely recognized complication in patients with diabetes and is characterized by nerve damage that leads to numbness, loss of sensation, and can cause pain in the extremities. According to studies, about 60%-70% of patients with diabetes will develop peripheral neuropathy if they don’t control their blood glucose. Some common risk factors of diabetic peripheral neuropathy include the duration of diabetes, age, HbA1C, and diabetic retinopathy. Diabetes peripheral neuropathy can have serious complications that can lead to amputation or even death. These reasons represent why it is essential to understand the possible risk factors and make adjustments to decrease the risk. There are some treatments available that can slow the progression of the disease.  

Metformin is the first-line treatment for patients with type 2 diabetes mellitus. In previous studies, metformin has been associated with low levels of cobalamin and high levels of homocysteine. Cobalamin, a reduced molecule of cyanocobalamin (Vitamin B12), can help keep the body’s nerve and blood cells healthy, and having low levels of this component can lead to anemia, nerve damage, memory or thinking problems. On the other hand, homocysteine is an amino acid that contains sulfur. Elevated homocysteine is associated with heart and blood vessel diseases. Examples of these complications include increased blood coagulation, oxidative stress, and cardiomyocyte impairments. Some studies have shown that high levels of homocysteine can cause various neurological conditions like peripheral neuropathy. Some studies found a correlation between the duration of treatment with metformin and vitamin B12 deficiency.  

A recent case-control, prospective, analytical, observational study studied 150 patients with type 2 diabetes with diabetic peripheral neuropathy to determine if metformin is a risk factor for developing the condition. They observed metformin-treated diabetes patients versus non-metformin diabetes patients for 1.5 years and looked for cobalamin, methylmalonic acid, and homocysteine levels. These patients must have been treated with metformin for at least six months to participate in the study. They also utilized the Toronto Clinical Scoring System (TCSS) to assess the severity of diabetic peripheral neuropathy. Researchers looked for symptoms of diabetic peripheral neuropathy, family history of this condition, duration of diabetes mellitus, and current medications. They assessed nerve conductivity and some laboratories (complete blood count, electrolytes, renal and hepatic functions, thyroid-stimulating hormone, rheumatoid factors, serum folate, HbA1C, and serum cobalamin levels).  Statistical tests used include Chi-square tests, Mann-Whitney U test, correlation coefficient, Spearman’s correlation coefficient, and logistic regression analysis to evaluate their results.  

While evaluating the results, they found that metformin-treated diabetes patients had a higher moderate to severe diabetic peripheral neuropathy and higher scores for the TCSS than the patients non-treated with metformin (10 versus 5; p<0.001). Also, they found lower serum cobalamin in the metformin-treated patients versus patients not treated with metformin (222 versus 471; p<.001). In terms of homocysteine and methylmalonic acid levels, they found that metformin patients have higher levels than those not taking metformin (p<0.05). Moreover, they found that patients taking metformin had slower conductivity than the other group (p<0.05). Researchers also evaluated the correlation of severity of diabetic peripheral neuropathy with cobalamin (r:-0.81; p<0.05), methylmalonic acid (r:0.71; p<0.05), and homocysteine (r=0.73; p<0.05).  

Some limitations observed were that this research was a single-site study, and generalizability cannot take place. Also, the sample size was limited, and they did not monitor glycemic control. They also did not look for long-term effects of risk factors concerning the development of diabetic peripheral neuropathy.  

Generally, this study confirmed that the long-term use of metformin could lead to low levels of cobalamin, can increase methylmalonic acid and homocysteine levels, which can cause severe diabetic peripheral neuropathy. Clinicians need to assess vitamin B12 in patients with type 2 diabetes who are treated with metformin.  

Practice Pearls: 

• Metformin, which is the first-line treatment for patients with type 2 diabetes, decreases cobalamin levels, and increases homocysteine levels.
• Low levels of cobalamin and high levels of methylmalonic acid and homocysteine are associated with diabetic peripheral neuropathy or the deterioration of the condition. 
• Levels of cobalamin, methylmalonic acid, and homocysteine should be monitored regularly in patients with type 2 diabetes.

Hashem, M, et al. The relationship between exacerbated diabetic peripheral neuropathy and metformin treatment in type 2 diabetes mellitus. Nature Research (2021). 11:1940. doi:10.1038/s41598-021-1631-8.  

Laura Martínez López, PharmD. Candidate 2021, Lake Erie College of Osteopathic Medicine, College of Pharmacy 

College of Pharmacy