clinical topic updates

Metformin, Vitamin B12 Status, and the Risk of Diabetic Peripheral Neuropathy

by Marie E. McDonnell, MD

Overview

Both elevated blood glucose and low vitamin B12 levels are associated with peripheral neuropathy. Since long-term metformin use may predispose individuals with type 2 diabetes to vitamin B12 deficiency, screening for vitamin deficiency in this group of patients may be especially high yield.

Expert Commentary

Marie E. McDonnell, MD

Chief, Diabetes Section
Division of Endocrinology, Diabetes and Hypertension
Director, Diabetes Program
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA

“Given the evidence, I would suggest that we should be screening for vitamin B12 deficiency every year in patients who have been on metformin for 5 years or longer.”

Marie E. McDonnell, MD

It is challenging to know the extent to which metformin might be contributing to the neuropathy that we see in patients with type 2 diabetes for a number of reasons, including the fact that metformin is so commonly prescribed and the variable manifestations of diabetic neuropathy. For instance, the most common form of diabetic neuropathy, distal symmetric polyneuropathy, is already present to some degree in at least 10% to 15% of patients newly diagnosed with type 2 diabetes. Further, the rates of diabetic neuropathy vary considerably depending on the test used (eg, nerve conduction studies will identify neuropathy in many more patients than we can detect clinically).

If we accept the assumption that neuropathy is primarily caused by high blood sugar, which is supported by the Diabetes Control and Complications Trial, then a key question becomes: Could metformin be responsible for accelerating the progression of diabetic neuropathy? Based on the available evidence, the most likely mechanism involves vitamin B12 and perhaps even folic acid, since the absorption of both seems to be impaired with metformin. We do see more vitamin B12 deficiency in long-term metformin users in the Diabetes Prevention Program Outcomes Study cohort. At 5 years, a low/borderline low vitamin B12 levels were more common in the metformin group than in the placebo group (19.1% vs 9.5%), with the likelihood of low vitamin B12 increasing over time. 

Vitamin B12 deficiency is associated with peripheral neuropathy and loss of sensation in peripheral nerves. Such deficiency may cause damage to specific nerves in the nerve bundle that are also commonly involved in neuropathy due to high blood sugar (ie, large-fiber nerves). Patients with neuropathy from vitamin B12 deficiency may have symptoms of imbalance, which are also common in diabetic neuropathy.

Given the evidence, I would suggest that we should be screening for vitamin B12 deficiency every year in patients who have been on metformin for 5 years or longer. The test is relatively inexpensive, and vitamin B12 deficiency is associated with many conditions that overlap with diabetic neuropathy, including pain, risk of falls, ulcerations, and amputations. I suspect that our guidelines will likely evolve to include additional language regarding the need for such screening and the best methods for detection, although the inherent challenges in such recommendations include consensus on the best screening test(s) to use (eg, vitamin level alone or with methylmalonic acid). Many patients ask if they should avoid using metformin given the risk of vitamin deficiency, especially since metformin does not have the major impact on cardiovascular outcomes that is observed with some of the other agents in our toolbox. But since glucose control is primary in the prevention of diabetic neuropathy and metformin overall has an acceptable side-effect profile, if a patient is achieving glycemic targets while on metformin, I would emphasize detection and treatment of the vitamin deficiency rather than switching to another medication. Also important to consider is that since vitamin B12 deficiency is relatively common, especially in the older adult, metformin is not always the clear culprit. There are many other potential causes that should be explored when deficiency is diagnosed. However, if patients raise concerns regarding metformin, I support them in treating their diabetes with non-metformin options, as long as they can do so and maintain good glycemic control.

References

Alvarez M, Sierra OR, Saavedra G, Moreno S. Vitamin B12 deficiency and diabetic neuropathy in patients taking metformin: a cross-sectional study. Endocr Connect. 2019;8(10):1324-1329. doi:10.1530/EC-19-0382

Aroda VR, Edelstein SL, Goldberg RB, et al; Diabetes Prevention Program Research Group. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes study. J Clin Endocrinol Metab. 2016;101(4):1754-1761. doi:10.1210/jc.2015-3754

Hicks CW, Selvin E. Epidemiology of peripheral neuropathy and lower extremity disease in diabetes. Curr Diab Rep. 2019;19(10):86. doi:10.1007/s11892-019-1212-8

Monnier VM, Bautista O, Kenny D, et al. Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial. Diabetes. 1999;48(4):870-880. doi:10.2337/diabetes.48.4.870

Leishear K, Boudreau RM, Studenski SA, et al; Health, Aging, and Body Composition Study. Relationship between vitamin B12 and sensory and motor peripheral nerve function in older adults. J Am Geriatr Soc. 2012;60(6):1057-1063. doi:10.1111/j.1532-5415.2012.03998.x

Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154. doi:10.2337/dc16-2042

Wakeman M, Archer DT. Metformin and micronutrient status in type 2 diabetes: does polypharmacy involving acid-suppressing medications affect vitamin B12 levels? Diabetes Metab Syndr Obes. 2020;13:2093-2108. doi:10.2147/DMSO.S237454

Wolffenbuttel BHR, Wouters HJCM, Heiner-Fokkema MR, van der Klauw MM. The many faces of cobalamin (vitamin B12) deficiency. Mayo Clin Proc Innov Qual Outcomes. 2019;3(2):200-214. doi:10.1016/j.mayocpiqo.2019.03.002

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