Metformin With Either Histamine H2-Receptor Antagonists or Proton Pump Inhibitors: A Polypharmacy Recipe for Neuropathy via Vitamin B12 Depletion

According to the most recent data from the Centers for Disease Control and Prevention, 25.8 million people in the United States (8.3% of the population) have diabetes (1). Type 2 diabetes accounts for 90–95% of diabetes diagnoses, and >85% of people with type 2 diabetes are overweight or obese (1). Increased BMI, which is common in the type 2 diabetes population, has a well-established association with symptoms of gastroesophageal reflux disease (GERD) (2,3). Central adiposity is an important risk factor in the development of reflux and, subsequently, erosive esophagitis, Barrett’s esophagus, esophageal adenocarcinoma, and gastric cardia adenocarcinoma (2,3). Increased BMI is not the only risk factor for the development of GERD, particularly among people with diabetes. Among those with type 2 diabetes, peripheral neuropathy is an independent risk factor for erosive esophagitis (4). In this population, there is a greater incidence of erosive esophagitis among individuals with neuropathy than among those without neuropathy, although those with and without neuropathy experience similar GERD symptoms (4). Approximately 60–70% of people with diabetes have mild to severe forms of nervous system damage, which may partly explain why low-grade esophageal dysplasia is twice as likely in individuals with than in those without diabetes (1,5). Additionally, both asymptomatic and symptomatic reflux is more prevalent in individuals with diabetes than in those without diabetes (6,7). Likewise, type 2 diabetes has been demonstrated to be a risk factor for symptomatic GERD (8). Among individuals with diabetes, 40.7% experience symptomatic GERD, and 70% of those use oral antidiabetic medications. Thus, it is likely that millions of individuals are managing blood glucose and GERD concomitantly with oral medications (1,7) Therefore, it is important to assess the drug interactions and clinical sequelae that may occur with this particular polypharmacy scenario. This article addresses the potential for vitamin B12 depletion induced by concomitant use of metformin and acid-suppressing medications to contribute to neuropathy among individuals with diabetes.