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   Medscape Medical News from the    
   European Association for the Study of Diabetes (EASD) 2015 Annual Meeting    
   Visit Medscape in Hall B Booth #B13:31    
      
   Metformin Link to Vitamin B12 Deficiency, Neuropathy, in Diabetes    
   Miriam E Tucker    
   September 25, 2015    
        
   STOCKHOLM -- Metformin-related vitamin B12 deficiency might contribute to   
   clinically significant peripheral neuropathy in diabetes patients, new   
   research suggests.    
      
   Guidelines from European Association for the Study of Diabetes (EASD) and the   
   American Diabetes Association do mention vitamin B12 deficiency as a risk of   
   metformin treatment for type 2 diabetes, but they don't make recommendations   
   for screening or    
   supplementation, said Mattijs Out, MD, an internist of vascular medicine at   
   Bethesda Diabetes Research Center, Hoogeveen, the Netherlands, who presented   
   the findings last week at the European Association for the Study of Diabetes   
   2015 Meeting.    
      
   "This is important. The consequences of vitamin B12 deficiency, like   
   neuropathy or mental changes, may be profound. Even more, they may be   
   difficult to diagnose, because they may be ascribed to old age or diabetes   
   itself and may be or become irreversible.   
    On the other hand, vitamin B12 deficiency is relatively easy to diagnose, and   
   treatment is easy, cheap, and effective," Dr Out commented.    
      
   Previous research from Dr Out's group and others has linked metformin use to   
   vitamin B12 deficiency (<150 pmol/L), raising concern that the drug may be   
   contributing to peripheral neuropathy separate from the effect of the diabetes   
   itself.    
      
   In the current study, Dr Out and colleagues examined, for the first time, a   
   very specific biomarker for tissue B12 deficiency, methylmalonic acid (MMA),   
   and examinedthe impact of that on a validated neuropathy score; they found   
   that the overall increase    
   in MMA outweighed the benefit derived from metformin's glucose-lowering effect.   
      
   But during the question-and-answer period, some doctors expressed skepticism,   
   stating that they hadn't seen very high rates of vitamin B12 deficiency in   
   decades of metformin use.    
      
   Session moderator Guntram Schernthaner, MD, professor of medicine at the   
   Medical University of Vienna, Austria, told Medscape Medical News, "I measure   
   only in suspected cases and have almost never found a relationship....The data   
   aren't strong enough in    
   my opinion. I recommend a large database study to investigate how often it's   
   occurring."    
      
   Dr Schernthaner added, "You can measure [vitamin B12] if you suspect   
   [deficiency], but the key question is whether you should have routine   
   screening. But before you recommend this, you have to prove it's a true   
   effect."    
      
   Measuring Metformin's Opposing Effects: HbA1c vs MMA   
      
   Dr Out and colleagues aimed to dissect the two opposite effects of metformin:   
   a reduction in HbA1c, which would be expected to improve neuropathy scores,   
   and an increase in MMA, a marker of B12 depletion leading to worsening of   
   peripheral neuropathy.    
      
   Data were from the Hyperinsulinemia: the Outcomes of its Metabolic Effects   
   (HOME) study of 390 insulin-treated patients with type 2 diabetes from three   
   outpatient clinics in the Netherlands, who were randomized to 850-mg metformin   
   or placebo three times    
   daily for a mean of 4.3 years.    
      
   The original study, published in 2010, found that long-term treatment with   
   metformin increased the risk of vitamin B12 deficiency by 19% (P < .001),   
   which resulted in 5% greater homocysteine concentrations (P = .09).    
      
   The current analysis includes data collected over those 4.3 years from 17   
   visits in which measurements of HbA1c and of the clinically validated Valk   
   Neuropathy Score (Diabet Med. 1992;9:716-721) were collected and six visits in   
   which MMA was measured.    
      
   Using structural equation modeling with adjustment for age and cardiovascular   
   risk factors and accounting for renal clearance of MMA, Dr Out and colleagues   
   determined that after 4.3 years, metformin treatment was associated with a   
   mean increase in MMA of    
   0.039 µmol/L (P = .001).    
      
   Per "gram-year" of metformin (similar to "pack-years" of cigarettes), there   
   was an overall nonsignificant increase in neuropathy score of 0.032 (P = .34).    
      
   This reflects metformin's competing protective effect, Dr Out noted.    
      
   However, with the 0.039-µmol/L increase in MMA factored in, the net effect   
   came to a 0.25-point increase in the Valk neuropathy score, he pointed out.    
      
   Clinical Implications As of Now?    
      
   Dr Out commented, "With over 100 million prescriptions of metformin per year,   
   many patients may be at risk," adding that clinical options include screening   
   for vitamin B12 deficiency after 4 years of metformin use or simply   
   supplementing all patients,    
   possibly with a combination metformin-vitamin B12 pill.    
      
   To Medscape Medical News, he commented, "I think it's always a problem when a   
   side effect is doctor-induced. I think there are enough data to suggest   
   supplementation."    
      
   But Dr Schernthaner disagrees. "I would say this isn't good enough....You need   
   first a large analysis of vitamin B12 to determine the real level [of   
   deficiency]."    
      
   The study was sponsored by Altana, Lifescan, Merck-Lipha, Merck Sharpe &   
   Dohme, and Novo Nordisk. Dr Out and Dr Schernthaner have no relevant financial   
   relationships.    
      
   European Association for the Study of Diabetes 2015 Meeting; Stockholm,   
   Sweden. Abstract 220, presented September 18, 2015.    
      
        
      
      
   http://www.medscape.com/viewarticle/851542   
      
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