Metformin (Glucophage, Bristol-Myers Squibb) is a commonly utilized biguanide agent for the treatment of diabetes. Increasingly, it appears that metformin may paradoxically increase the risk of neuropathy in the patient with diabetes. Therefore, when you see a patient with diabetes who is taking metformin, greater surveillance may be necessary for the presence of sensory, autonomic and motor neuropathy.
Wile and colleagues noted that metformin increases homocysteine levels as well as methylmalonic acid levels, both contributing factors to neuropathy.1 The study noted the increased frequency and severity of diabetic neuropathy in patients taking metformin, as well as reduced levels of B12.
In a recent issue of Diabetes Care, Palomba and co-workers also affirmed that metformin raises serum homocysteine levels with resultant endothelial dysfuction.2 They suggested that folate supplementation may be helpful in reducing this effect.
The suggestion that metformin may act to raise homocysteine levels is not new as others have suggested that more than six months of exposure to metformin results in rising homocysteine levels.3,4
Studies have previously suggested that elevated levels of homocysteine to be operative may play a role in the evolution of diabetic neuropathy.5
Metformin interferes with the absorption of vitamin Band, as a result, the chronic use of metformin may act to reduce vitamin B levels in the patient with diabetes. Vitamin B compounds are critical for normal nerve health and function. Accordingly, a reduction in the level of vitamin B may result in an increased incidence of neuropathy in those taking metformin.6
In addition, L-methyl folate (Metanx, Pamlab), the active form of folic acid, directly stimulates nitric oxide production, increasing blood flow to neural tissue and reversing endothelial dysfunction. L-methyl folate, pyridoxine and cobalamin are essential for the reduction of homocysteine. Homocysteine, a non-essential amino acid, increases the incidence of neuropathy by reducing blood flow to neural tissue (and wounds) by inducing vascular thrombosis and reducing levels of nitric oxide available for vasodilation.
Additionally, the kidneys clear homocysteine from the system and in the patient with decreasing renal mass, increased levels of homocysteine may also occur.
Epidermal nerve fiber density testing in the patient taking metformin frequently demonstrates significant evolving loss of nerve fiber density, even in the patient without neuropathy associated complaints or concerns. Supplementation with L-methyl folate, vitamin B6 and B12 may reverse the progression of this pathology in some patients. Remember that many individuals cannot convert OTC folic acid to the necessary active form. Therefore, these patients may derive little or no benefit from OTC vitamin B preparations.
One should carefully evaluate any patient taking metformin for longer than six months for occult and unappreciated sensory, motor or autonomic neuropathy. Recognition and quantification with epidermal nerve fiber density testing allows assessment of the extent of disease as well as the response to management. Neuropathy is a major risk factor for ulceration and amputation. Early interdiction of the progress of neuropathy may result in a lower risk of amputation.
Editor’s note: Dr. Jacobs is a lecturer for Pamlab.
1. Wile DJ, Toth C. Scientific sessions, American Academy of Neurology. April 29, 2009.
2. Palombas. S, Falbo A, Giallauria F, et al. Effects of metformin with or without supplementation with folate on homocysteine levels and vascular endothelium of women with polycystic ovary syndrome. Diabetes Care 2010; 33(2):246-51. 2010
3. Omrani GHR, Lari OB, Mehdizadeh AR, et al. Comparison of serum homocysteine level in metformin versus glibenclamide treated type 2 dm patients. Iranian J . Diab and Lipid Dis 2004; 4 (2):95. 2005
4. Hermann LS, Nilsson B, Wettre S. Vitamin B12 status of patients treated with metformin: a cross-sectional cohort study. Br J Diabetes Vasc Dis 2004; 4(6):401–6.
5. Ambrosch A, Dierkes J, Lobmann R, et al. Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med 2001 Mar;18(3):185-92.
6. Braza M, Hanley J, Bhatia A, Martinez M. Prevalence of vitamin B12 deficiency in Hispanic patients with type 2 diabetes mellitus (DM) on long-term metformin — is it associated with peripheral neuropathy? Presented at American Diabetes Association 69th Annual Scientific Sessions, New Orleans, June 5-9, 2009.