Diabetes medications and risk of HCC

Abstract

Type 2 diabetes mellitus is a recognized risk factor for HCC in patients with liver disease, independent from the etiology of their liver disease. Hence, prevention and treatment of type 2 diabetes mellitus and its underlying cause, insulin resistance, should be considered a treatment target for patients with liver disease. The drug armamentarium for diabetes is wide and consists of agents with insulin‐sensitizing activity, agents that stimulate insulin secretion, insulin itself, and agents that reduce gastrointestinal and urinary glucose absorption. From an endocrinology perspective, the main goal of treatment is the achievement of euglycemia; however, in patients at risk of, or with known underlying liver disease, the choice of diabetic medication as it relates to potential hepatic carcinogenesis remains complex and should be carefully considered. In the last decade, increasing evidence has suggested that metformin may reduce the risk of HCC, whereas evidence for other classes of diabetic medications, particularly some of the newer agents including the sodium glucose cotransporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists, is fewer and often inconsistent. In this review, we aim to summarize the current evidence on the potential effects of the most widely used diabetic agents on liver cancer tumorigenesis.

Development and prognosis of hepatocellular carcinoma in patients with diabetes

“…(83) Similarly, increasing evidence has suggested the potential hepatoprotective effects of some antidiabetic drugs. (84,85) Metformin is a biguanide compound that improves insulin resistance by targeting the enzyme AMP-activated protein kinase, which induces the muscle uptake of glucose from the blood. In 2005, it was first reported that the use of metformin in patients with T2DM may reduce their risk of cancer.…”

“…(87, 91) Singh et al also conducted a post hoc analysis of randomized controlled trials, and their results did not reveal any significant association between antidiabetic medication use and the risk of HCC (90). Thus, further validation based on evidence from randomized clinical trials is warranted.Insulin is a potent mitogen associated with the upregulation of various growth factors that stimulate several signaling pathways related to cell proliferation and apoptosis inhibition (84). HCC in patients with diabetes 16 Epidemiologic evidence indicates that the insulin secretion rate influences cancer risk or prognosis, and patients with diabetes treated with insulin have a higher risk of HCC.…”

Hepatocellular Carcinoma Chemoprevention with Generic Agents

“…glitazones), suppress oncogenic molecular pathways in multiple cancer types, including HCC, likely with their pleiotropic effects besides insulin sensitization and adenosine monophosphate-activated protein kinase (AMPK) activation. 49…”

“…54 In contrast, other commonly used anti-diabetics, i.e., sulfonylureas, a-glucosidase inhibitor, and insulin when combined with other drugs, likely increase HCC risk according to retrospective and prospective clinical studies. 49,53,54 Clinical evidence is still lacking, but new classes of anti-diabetic agents such as sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP1) receptor agonists have shown to elicit anti-HCC effect in cell culture systems and rodent models of NAFLD-driven HCC, 49 suggesting their role in HCC chemoprevention to be determined in future studies.…”

Iron-Induced Hepatocarcinogenesis—Preventive Effects of Nutrients

“…Additionally, retinoids significantly ameliorated hyperglycemia, insulin resistance, and hepatic steatosis in a mouse model of NAFLD ( 74 , 75 ). Hyperglycemia and hyperinsulinemia, which are frequently complicated with NAFLD, are also risk factors for HCC ( 76 ). Thus, from dual aspects, retinoid supplementation would be an efficient strategy to prevent HCC development in patients with NAFLD.…”