August 9, 2021


Chief residents of the NYU Langone Internal Medicine Residency give quick-and-easy, evidence-based answers to interesting questions posed by house staff, both in their clinics and on the wards.

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 A secondary analysis of vitamin B12 and homocysteine levels from the Diabetes Prevention Program (DPP)/DDP Outcomes Study (DDPOS), published in the April of 2016 issue of the Journal of Clinical Endocrinology and Metabolism, showed an increased risk of low vitamin B12 levels with long-term treatment with metformin. Three main theoretical mechanisms of action regarding the contribution of metformin to the lowering of B12, a water-soluble vitamin, have been postulated. A more currently accepted explanation is the interference by metformin on calcium-dependent membrane action responsible for vitamin B12-intrinsic factor (IF) absorption in the terminal ileum. The hydrophobic tail of metformin binds to the hydrocarbon core of the cell membrane, imparting a net positive charge, which in turn repels calcium that is necessary for transporting B12 across the ileal-lumen interface. The second mechanism details the alteration of normal bacterial flora, resulting in bacterial overgrowth and impeded passage of B12-IF into the bloodstream. A third theory describes metformin changing the B12-IF complex by binding to it structurally, decreasing the amount of B12 that passes through the distal ileal wall.

References: Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study
  Metformin, in addition to being the first-line therapy for the treatment of diabetes mellitus 2, also has anti-carcinogenic properties, including direct action on tumor cells by targeting their AMPK pathway (which controls metabolism, angiogenesis, inflammation, and stem cells) and inhibition of cancer growth and proliferation secondary to decreasing insulinemia and glycemia. A recent population-based case-control study was conducted in Iceland involving all 6880 people diagnosed between 2003 and 2017 with first-time basal cell carcinoma, invasive squamous cell carcinoma, and squamous cell carcinoma in situ compared to 69,620 population controls. Data analysis showed that use of metformin was associated with a lower risk of developing basal cell carcinoma, even at low doses: OR 0.71%, 95% confidence interval 0.61-0.83. There was no effect demonstrated with regard to invasive squamous cell carcinoma. Risk of squamous cell carcinoma in situ was mildly elevated in the cohort receiving 501-1500mg daily dose of metformin (OR 1.40; 95% CI 1.00-1.96), although the study did not adjust for ultraviolet exposure, skin type, and other comorbidities. This study suggests that metformin may be a useful agent in preventing basal cell carcinoma in people at high risk of developing this malignancy, but additional studies are needed for confirmation.

References: Metformin is associated with decreased risk of basal cell carcinoma  
  A recent systematic review and meta-analysis of seven studies (n= 342) of glycemic control and five studies (n= 244,439) of risk of incident diabetes examined the impact of proton pump inhibitor as add-on to standard treatment compared to standard treatment alone on hemoglobin A1c or fasting blood glucose levels. Compared with standard treatment alone, addition of a PPI was associated with a significant decrease in hemoglobin A1c (weighted mean difference of -0.36%; 95% CI, -0.68 to -0.05) and fasting blood glucose (weight mean difference of -10.0mg/dL; 95% CI, -19.4 to -0.6 ). However, use of PPI did not reduce the risk of incident diabetes (pooled relative risk, 1.10; 95% CI 0.89-1.34).

References: Effects of Proton Pump Inhibitors on Glycemic Control and Incident Diabetes: A Systematic Review and Meta-Analysis