Metformin – hidden problems

Metformin, a drug which is now universally accepted as the first line pharmacological treatment for Type 2 diabetes does have a recognised list of side effects and cautions. These include gastrointestinal symptoms and guidance regarding renal function. Indeed, NICE advise a dose reduction in patients whose eGFR falls to between 35-40 and to discontinue when eGFR falls below 30 (although there is evidence to suggest that it is safe in patients with lower values). However, there are other less well known issues which are often not recognised. Lactic acidosis, myalgia and taste disturbance are not uncommon.  However, despite being recognised in 1969, the impact of Metformin on Vitamin B12 levels is often poorly recognised or ignored. Vitamin B12 is a water-soluble vitamin that plays a very fundamental role in DNA synthesis, optimal haemopoesis and neurological function. As a result, vitamin B12 deficiency presents with features of haematological and neuro-cognitive dysfunction. Decrease in vitamin B12 absorption and levels following Metformin use typically starts as early as the 4th month. Clinically overt features of vitamin B12 deficiency manifest by 5–10 years owing to the large body stores in the liver mainly that are not quickly depleted. The proposed mechanisms to explain Metformin induced vitamin B12 deficiency among patients with T2DM include: alterations in small bowel motility which stimulates bacterial overgrowth and consequential vitamin B12 deficiency, competitive inhibition or inactivation of vitamin B12 absorption and alterations in intrinsic factor (IF) levels. Metformin has also been shown to inhibit the calcium dependent absorption of the vitamin B12-IF complex at the terminal ileum. This inhibitory effect is reversed with calcium supplementation. Recent evidence regarding the impact of Metformin on B12 comes from paper in a recent issue of JCEM. The study reviewed patients previously enrolled in the diabetes prevention programme where the Metformin arm received 850mg bd. After 5 years of the study, low B12 levels affected 4.3% of the Metformin group and 2.3% of the placebo group. Those taking Metformin were more likely to have anaemia, regardless of their B12 status whilst those patients with low B12 were more likely to have a peripheral neuropathy. Given the link between Metformin and B12 deficiency and its clinical impact, patients should have their B12 intermittently measured and replaced if found to be low.

Dr Mark Freeman