Treatment of type II diabetes mellitus patients with metformin for prolonged duration and elevated doses were linked with decreased plasma cobalamin and more serious diabetic peripheral neuropathy.

A prospective case-control observational study was carried to explore if long-term utilization of metformin is a risk factor for diabetic peripheral neuropathy.

The study recruited 150 adults with type 2 diabetes mellitus on oral hypoglycemic treatment with clinical proof for diabetic peripheral neuropathy. Participants were segregated into two groups: (i) Metformin treated (Group I, n=75): Subjects were given metformin for the previous six months or more, and (ii) Non-metformin treated (Group II): Subjects who were not given metformin for the previous six months (but given other oral hypoglycemic drugs).

Utilizing the Toronto Clinical Scoring System (TCSS), electrophysiological, and laboratory (methylmalonic acid, cobalamin, and homocysteine) studies, metformin-treated diabetics (MTD) was compared with non-metformin-treated diabetics (NMTD). 

MTD displayed a decline in cobalamin, an increase in homocysteine, and methylmalonic acid, leading to exaggerated diabetic peripheral neuropathy. The median levels of homocysteine and methylmalonic acid in the MTD vs. NMTD group (high statistical significance in MTD), is depicted in the table below:

Compared with NMTD, MTD demonstrated a considerably reduced plasma level of cobalamin. As per Spearman’s correlation, a vital negative correlation was witnessed between cobalamin and elevated dose of metformin, and a vital positive correlation was noted between TCSS and elevated dose of metformin.

The logistic regression analysis demonstrated that MTD had considerably longer metformin use duration, higher metformin dose > 2g, higher TCSS, minimized plasma cobalamin, and considerably higher homocysteine. People on metformin therapy should be monitored regularly for the plasma levels of homocysteine, cobalamin, and methylmalonic acid.

Use of raised doses of metformin for an extended duration can decrease cobalamin and result in more severe diabetic peripheral neuropathy in diabetic patients.