Thiazolidinediones Reduce the Risk of Hepatocellular Carcinoma and Hepatic Events in Diabetic Patients With Chronic Hepatitis B

Terry Cheuk-Fung Yip; Vincent Wai-Sun Wong; Henry Lik-Yuen Chan; Yee-Kit Tse; Vicki Wing-Ki Hui; Lilian Yan Liang; Hye Won Lee; Grace Chung-Yan Lui; Alice Pik-Shan Kong; Grace Lai-Hung Wong


J Viral Hepat. 2020;27(9):904-914. 

In This Article

Abstract and Introduction


Thiazolidinediones (TZDs) improve glycaemic control and ameliorate liver steatosis, inflammation and fibrosis in patients with fatty liver disease. We aimed to study the impact of TZD and glycaemic control on the risk of hepatocellular carcinoma (HCC) and hepatic events in diabetic patients with chronic hepatitis B (CHB). We performed a retrospective cohort study on diabetic patients with CHB in 2000–2017 using a territory-wide electronic healthcare database in Hong Kong. Diabetes mellitus was identified by use of any antidiabetic medication, haemoglobin A1c (HbA1c) ≥6.5%, fasting glucose ≥7 mmol/L in two measurements or ≥11.1 mmol/L in one measurement and/or diagnosis codes. Use of antidiabetic medications was modelled as time-dependent covariates. Of 28 999 diabetic patients with CHB, 3963 (13.7%) developed liver-related events (a composite endpoint of HCC and hepatic events) at a median (interquartile range) follow-up of 7.1 (3.7–11.8) years; 1153 patients received TZD during follow-up. After adjusted for important confounders, TZD use was associated with a reduced risk of liver-related events (adjusted hazard ratio [aHR] 0.46, 95% confidence interval [CI] 0.24–0.88; P = .019). Similar trends were observed in HCC (aHR 0.57) and hepatic events (aHR 0.35) separately. Compared to HbA1c of 6.5% at baseline, patients with HbA1c ≥7% had an increased risk of liver-related events; the risk further increased in 5795 (20.0%) patients with HbA1c ≥9% at baseline (aHR 1.14, 95% CI 1.04–1.26; P = .006). TZD use is associated with a lower risk of liver-related events in diabetic patients with CHB. Liver-related events are more common in patients with high HbA1c levels.


Diabetes mellitus (DM) is a rising global health problem which affects around 422 million people worldwide.[1] DM is linked to insulin resistance and hyperglycaemia, which dysregulates intracellular signalling pathways and promotes carcinogenesis.[2] Previous studies showed that DM is associated with a doubled risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). In contrast, good glycaemic control, careful use of antidiabetic agents, statins as well as angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) may attenuate cancer risk.[3] The glycaemic recommendations of haemoglobin A1c (HbA1c) for adults with DM is 7%;[4] HbA1c ≥7% is considered as suboptimal glycaemic control and has been shown to increase the risk of HCC development among CHB patients.[5]

The impact of some common antidiabetic, lipid-lowering and antiplatelet agents on the risk of HCC in CHB patients has been previously studied. The use of metformin and statins is associated with a reduced risk of HCC among CHB patients in a dose-dependent manner;[6,7] statins use also correlates with a reduced risk of HCC among DM patients.[8] The use of antiplatelet therapy including aspirin and clopidogrel is associated with a reduced HCC risk in CHB patients.[9] The impact of antidiabetic agents including insulin, sulphonylurea and thiazolidinediones (TZDs) on the risk of HCC has also been examined in a meta-analysis.[10] The use of insulin and insulin secretagogues namely sulphonylurea correlates with an elevated risk of HCC. Previous studies showed some evidence on the use of TZD and a reduced risk of HCC. However, the impact of TZD on risk of HCC remains unclear due to a limited number of studies.[10,11] TZD improves glycaemic control by activating peroxisome proliferator-activated receptor gamma (PPARγ) that leads to insulin sensitization and enhanced glucose metabolism. Expression of PPARγ has also been shown to suppress HCC cell growth in mice and in vitro models.[12] Different mechanisms by which TZD induces cell growth arrest, induces apoptosis and prevents cancer cell invasion in cancers in digestive organs have been proposed.[13] On the other hand, the presence of DM or metabolic syndrome increases the risk of cirrhosis in CHB patients.[14] The presence of steatohepatitis, which is highly correlated with DM, also increases the risk of cirrhosis and HCC.[15] TZD has been recommended as a treatment of steatohepatitis to improve liver steatosis, ballooning and necroinflammation.[16] Nonetheless, the impact of TZD on disease progression and development of HCC remains unclear. This study aimed to evaluate the impact of TZD use and glycaemic control on the risk of HCC and hepatic events in a territory-wide cohort of diabetic patients with CHB.