We read with great interest the recent article titled “Effect of Type 2 Diabetes on Risk for Malignancies Includes Hepatocellular Carcinoma in Chronic Hepatitis C” by Arase et al. published in the March issue of Hepatology. In this Japanese cohort of 4,302 interferon-treated patients with hepatitis C, the authors observed that diabetes mellitus (DM) was associated with a 1.7-fold higher risk of hepatocellular carcinoma (HCC) as compared to patients without DM. Interestingly, they also observed that the risk of HCC was reduced by 44% in diabetics with mean HbA1c <7.0% during follow-up compared with those with mean HbA1c ≥7.0%. The authors concluded that “stringent control of DM is important for protecting against the development of HCC.”
However, before drawing this inference the potential cancer-modifying effect of antidiabetic medications must be considered. In a recent meta-analysis, we have shown that metformin use was associated with a 50% reduction in risk of developing HCC, whereas sulfonylurea or insulin use was associated with a 62% and 161% increase in the risk of HCC, respectively. Metformin may exert its antineoplastic effect by activation of adenosine monophosphate (AMP)-kinase and a consequent inhibition of the mammalian target of rapamycin (mTOR) pathway. On the other hand, sulfonylureas, by increasing insulin secretion, and exogenous insulin itself, can promote carcinogenesis by increasing insulin-like growth factor 1 activity, resulting in abnormal stimulation of multiple cellular proliferation cascades.
Lack of information about antidiabetic medications is a crucial limitation of this study. It is likely that patients with good glycemic control are treated with metformin, whereas patients with poor glycemic control require aggressive polypharmacy and the use of insulin. This selective use of antidiabetic medications driven by glycemic control may explain the apparent lower risk of HCC observed in well-controlled diabetics. Multiple observational studies and meta-analysis have failed to demonstrate an association between intensive glycemic control and risk of cancer, including gastrointestinal cancer.[5-7] The variable effects of different antidiabetic medications on cancer risk modification may explain why intensive glucose lowering with combination therapy is not associated with lower cancer risk.
Siddharth Singh, M.D.1
Preet Paul Singh, M.D.2
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
2Department of Medical Oncology, Mayo Clinic, Rochester, MN