Risk of Hepatocellular Carcinoma in Diabetic Patients and Risk Reduction Associated With Anti-diabetic Therapy
A Population-based Cohort Study
Shih-Wei Lai MD; Pei-Chun Chen PhD; MSPH; Kuan-Fu Liao MD; MS; Chih-Hsin Muo MS; Cheng-Chieh Lin MD; PhD; Fung-Chang Sung PhD; MPH
Posted: 04/24/2012; The American Journal of Gastroenterology. 2012;107(1):46-52. © 2012 Nature Publishing Group
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HCC is usually secondary to either cirrhosis or a viral infection such as hepatitis B or hepatitis C.[23] The present study demonstrates the role of DM in HCC risk. Diabetic patients have an incidence of HCC twice higher than non-diabetics, indicating that approximately 11 additional cases of HCC develop annually per 10,000 diabetic patients. The incidence of HCC is higher in patients with DM regardless of sex, age, or follow-up period.
The adjusted HR for developing HCC in diabetics in the current study is 1.73, which is lower than the risk found in other studies. In the systematic review by El-Serag et al.,[24] DM was associated with an increased risk of developing HCC (risk ratio=2.5, 95% CI=1.9–3.2) independent of alcohol use or viral hepatitis. Another systematic review showed that patients with DM are 3.64 times (95% CI=2.61–5.07) more likely to develop HCC compared with non-diabetics.[25] The risk of developing HCC varies with DM duration and other comorbidities.[24-27]
Previous literature has consistently reported the association of HCC with other comorbidities, particularly for DM patients with cirrhosis, hepatitis B, and/or hepatitis C[1-3,26,27] In line with these findings, the present study observed a synergistic effect between DM and liver comorbidities regarding the development of HCC. Furthermore, the prevalence rates of cirrhosis, hepatitis B, and hepatitis C were higher in the DM group than in the non-DM group. The HCC risk was strongly associated with these three comorbidities, particularly cirrhosis (HR=8.65). Patients with hepatitis C are at twice higher HCC risk than those with hepatitis B (HR=5.61 vs. HR=2.52). A new and significant finding is that HCC increased markedly to an HR of 72.4 for diabetics with cirrhosis and hepatitis C compared with patients without those disorders. A Netherlands study found that, in patients with chronic hepatitis C and advanced cirrhosis, DM is also independently associated with HCC development, with an HR of 3.28 (95% CI=1.35–7.97).[27] Beasley et al.[28] found that in Taiwan, the incidence of primary HCC among carriers of the hepatitis B surface antigen is 223 times higher than that among non-carriers. However, hepatitis C is more important than hepatitis B in the present study.
Several studies have assessed the association between anti-diabetic drugs and the risk of developing HCC; all found reduced risk associated with metformin treatment.[19-21] The results of the present study confirm the effect of metformin. Furthermore, we found that thiazolidinedione treatment is also significantly associated with a reduced incidence of HCC. To our knowledge, only one hospital-based case–control study in the United States[20] has shown that thiazolidinediones may reduce the risk of HCC, which is consistent with our observation. Evidence from in vivo studies has shown that thiazolidinediones inhibited tumor formation in the liver,[29] providing a plausible biological basis for our observations.
Previous case–control studies have shown that sulfonylurea users have an increased risk of developing HCC compared with non-users.[19,20] In contrast, the present study shows a 25% risk reduction in patients using sulfonylureas, but the association was not statistically significant. We found that 92.5% of sulfonylurea users have switched to other anti-diabetic drugs, which might, to some extent, offset the unfavorable effect of sulfonylurea on risk of HCC. Further prospective studies may be helpful for clarifying the association of sulfonylureas with HCC.
A hospital-based case–control study in the United States found that patients that have had diabetes for >10 years have a 2.2-fold increased risk of developing HCC (95% CI=1.2–4.8) compared with those that have had diabetes for 2 to 5 years.[20] Thus, the risk may increase with the increasing duration of DM. In the present study, the risk of developing HCC associated with diabetes was the highest in patients 2–3 years after diagnosis of DM, without considering medications. We further assessed the risk of developing HCC in terms of the duration of taking anti-diabetic drugs. The risk of developing HCC decreased as the duration of taking the medications increased. The trend is most obvious for patients who have been taking metformin for at least 1 year. The HR was 0.49 (95% CI=0.31–0.78) after taking metformin for 12–23 months, which decreased to 0.26 (95% CI=0.18–0.39) after taking it for ≥24 months compared with non-users of metformin (data not shown). This trend was less pronounced among patients taking α-glucosidase inhibitors. The risk fluctuated among patients taking other medications.
The strength of the present study is its large sample size. The results are likely to illustrate the direction of HCC prevention in patients with DM. Although the concept is not novel, the population-based data set with a large sample size allows the demonstration of risk factors for HCC with a minimal tendency for selection bias in Taiwan. It likewise increased the statistical power and precision of risk estimation.
However, the present study has a number of limitations that originated from using insurance data. First, a number of suspected risk factors for HCC were not available, such as cigarette smoking, aflatoxin exposure, and body mass index. The inability to account for these factors may result in certain degrees of bias from confounding. Second, the claims' data do not contain laboratory test results. Thus, the extent of DM control among the study subjects was not accounted for because hemoglobin A1c values are not available. Third, this observational study does not explore the mechanism by which DM is related to HCC. Finally, misclassification and measurement errors in drug exposure might have occurred if the patients failed to take the prescribed drugs. Non-compliance is likely to cause underestimation of the drug effect.
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