Many clinicians are missing opportunities to prevent neuropathy by failing to check vitamin B12 levels in their diabetic patients on metformin.
That’s the conclusion of a massive scoping review of evidence from databases across the globe, undertaken by Ian Parsonage and colleagues at the School of Health Sciences at the University of Bath, UK.
The review, published in April by the British Medical Journal, indicates that fewer than 20% of diabetic patients on long-term metformin therapy and at increased risk for neuropathy, had their B12 levels checked.
Some of the studies included in the review showed that the number of patients who’d had their B12 tested was as low as 2-4%. In many cases, physicians only tested if patients showed symptoms of neuropathy. It seems that proactive, ongoing screening is the exception, not the rule.
Gaps in Implementation
This general pattern is true world-wide, say the authors. And it is happening despite the fact that most physicians who prescribe metformin are aware of the potential for drug-induced B12 deficiency and its consequent neuropathy. But knowledge of this general fact largely fails to translate into practice patterns that would improve identification and correction of B12 deficiency.
Metformin interferes with calcium-dependent absorption of B12—aka cobalamin–in the terminal ileum, which can lead not only to neuropathy but to megaloblastic anemia.
In one study they reviewed, 94% of physicians recognized B12 deficiency as a potential consequence of metformin use, but more than half failed to identify the correct laboratory threshold for deficiency.
Given that neuropathy is a common consequence of diabetes itself, it can be a challenge—without careful testing–to untangle whether a given case is due to the disease process itself, or to the metformin treatment. But it’s an important distinction to make because neuropathy that develops secondary to B12 deficiency can be reversed—or at least mitigated—by targeted supplementation.
According to functional medicine physician Jacob Teitelbaum, MD, an estimated 2.2 million cases of neuropathy in the US may be directly attributable to metformin use, rather than to diabetes itself. Many of these cases could be prevented or at least improved simply by giving metformin users a multivitamin containing vitamin B12.
“Sadly, physicians are not addressing this easily preventable problem,” says Teitelbaum, who specializes in chronic pain and neurological problems including neuropathy.
“Simple measures could prevent much of the toxicity caused by diabetes. It is highly recommended that people on metformin take a multivitamin containing at least 100 micrograms of vitamin B12.”
–Jacob Teitelbaum, MD
Several major medical organizations—including the American Diabetes Association—have issued guidelines that recommend periodic testing of vitamin B12 levels in diabetic people taking metformin. But these guidelines are short on specific, detailed recommendations. This owes, in part, to a lack of consensus on the optimal way to measure B12 and determine deficiency.
An Old Problem
Researchers have long recognized the potential for metformin to cause B12 decreases in B12 levels, leading to secondary neuropathy. Clinical case reports from the 1970s pointed to this association, bolstered by several observational studies suggesting a connection. But until the 2000s there were no serious, well-powered, large-scale studies of the phenomenon. And it was not until 2022—at which point metformin us was nearly ubiquitous– that medical organizations and government agencies began issuing guidance.
Metformin interferes with calcium-dependent absorption of B12—aka cobalamin–in the terminal ileum, which can lead not only to neuropathy but to megaloblastic anemia.
Each additional year of metformin use was associated with 5% increased likelihood of deficiency. And those taking this drug for four or more years, had a 41% increase in odds of developing B12 deficiency.
Prevalence estimates for metformin-induced B12 deficiency vary widely—anywhere from 4% to 30%– depending on the thresholds used in the various studies. One of the largest epidemiological studies looking at this question indicated that diabetics on metformin have a roughly 5% increased risk of developing clinically-significant deficiency compared with non-users.
The risk increased with duration of metformin use. Each additional year of metformin use was associated with 5% increased likelihood of deficiency (P < .05). And those taking this drug for four or more years, had a 41% increase in odds of developing B12 deficiency, compared with those taking it for less than four years.
How frequently does the drug-induced vitamin deficiency result in neuropathy?
Again, statistics vary widely across the published studies. One large-scale analysis of nearly 50,000 patients by researchers at the Peking University Health Science Center, Beijing, showed that metformin-treated patients had a neuropathy incidence of 7.12 per 1,000 versus 3.91 per 1,000 in those not on the drug. They estimated that metformin conferred an 84% increased risk of neuropathy.
A smaller single-center study from researchers in Srinagar, India, showed neuropathy in 45% of metformin-treated patients versus 32% of those not taking the drug.
A Clear Pattern
The specific statistics can be debated, but the general pattern seems clear: prolonged metformin use can lead to B12 deficiency, which in turn leads to secondary neuropathy in some cases.
The American Diabetes Association’s most recent standards of care guidelines from 2023 do acknowledge the problem of metformin-induced B12 deficiency. But they offer only a broad-stroke monitoring suggestion rather than specific guidance.
ADA states that “a person who has been on metformin for more than 4 years or is at risk for vitamin B12 deficiency should be monitored for vitamin B12 deficiency annually.” But the guidelines do not define specific thresholds for deficiency, nor do they mention strategies for reversing deficiency or preventing neuropathy.
In 2021, a committee of Italian researchers headed by Marco Infante at the Saint Camillus International University of Health Sciences, Rome, published a comprehensive “field of vision” paper which proposed “criteria for a cost-effective vitamin B12 deficiency screening in metformin-treated patients, which could serve as a practical guide for identifying individuals at high risk for this condition.”
Infante and colleagues contend that both vitamin B12 screening and supplementation are inexpensive, and that wide implementation of testing and treatment would be highly cost-effective in diabetic populations taking metformin. They make a good case for this, but so far, the framework they outlined has not yet been adopted by any of the major national or international public health agencies.
Need for System Changes
The review paper just published by Parsonage and colleagues was based on analysis of 23 studies looking at practice patterns regarding B12 monitoring in metformin users. The signals are very clear: routine testing is uncommon, and when doctors do test, it’s usually after almost 3 years of continuous treatment.
They note that, “many clinicians recognized the association between metformin and B12 deficiency, but a substantial proportion of clinicians underestimated the severity or failed to recall critical diagnostic thresholds.”
“A person who has been on metformin for more than 4 years or is at risk for vitamin B12 deficiency should be monitored for vitamin B12 deficiency annually.”
–American Diabetes Association 2023 Standards of Care Guidelines
Most troubling is that the patients who are at the highest risk for developing B12 deficiency and secondary neuropathy—the elderly, those on high metformin doses, vegans, those on proton pump inhibitors—are the least likely to be tested.
In some of the studies Parsonage and colleagues reviewed, physicians cited reasons for the gap in testing: lack of institutional prompts, concerns about additional testing costs, competing clinical priorities.
The University of Bath team stresses that simply raising awareness will not solve the problem in the absence of structural and systemic changes. Echoing other authors, they suggest “introduction of electronic prompts, updated clinical guidelines, educational workshops and routine inclusion of B12 monitoring in diabetes management checklists.”
But healthcare system change is an arduous process and it seldom happens fast. In the mean time, Dr. Teitelbaum urges clinicians to be proactive about this issue.
He stressed that roughly 17 million Americans are on metformin, and estimated that metformin-induced B12 deficiency could be responsible for well over 2.2 million cases of neuropathy.
“Simple measures could prevent much of the toxicity caused by diabetes. It is highly recommended that people on metformin take a multivitamin containing at least 100 micrograms of vitamin B12. This multivitamin could also prevent numerous other toxicities from the diabetes.”
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