Risk of Hepatocellular Carcinoma in Diabetic Patients
OBJECTIVES: Using population-based representative insurance claims data, the risk of developing hepatocellular carcinoma (HCC) among diabetes mellitus (DM) patients, as well as whether DM medications alter the risk of developing HCC were investigated.
METHODS: From the Taiwan National Health Insurance Research Database, 19,349 newly diagnosed DM patients 20 years and older and 77,396 comparison subjects without DM were identified from claims from 2000 to 2005. The incidences of HCC at the end of 2008 and the risks associated with hepatitis B and hepatitis C were determined. Whether metformin and thiazolidinediones reduce the risk of developing HCC was also measured.
RESULTS: The incidence of HCC was twice higher in the DM group compared with the non-DM group (21.0 vs. 10.4 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.73 (95% confidence interval (CI)=1.47–2.03) using multivariable Cox proportional hazard regression. Male sex, cirrhosis, hepatitis B, and hepatitis C were significant independent factors that predict HCC, with HRs of 2.32, 8.65, 2.52, and 5.61, respectively. In the stratified analysis, the HR increased to 72.4 (95% CI=42.9–122) among patients with DM, cirrhosis, and hepatitis C. HCC risk reduction was greater for diabetics taking metformin than those taking thiazolidinediones (51 vs. 44% reduction).
CONCLUSIONS: Comorbidity with cirrhosis and/or hepatitis appears to be associated with an extremely increased risk of developing HCC among DM patients. These high-risk patients should be closely monitored for HCC. The use of metformin or thiazolidinediones may reduce the risk of developing HCC.
Hepatitis B and hepatitis C are well-known etiological factors that lead to hepatocellular carcinoma (HCC) in Taiwan. More than 90% of patients with HCC are positive for the hepatitis B surface antigen and/or antibodies against the hepatitis C virus. In addition to viral infections, non-viral causes of HCC have been proposed in studies. Cirrhosis, obesity, diabetes mellitus (DM), fatty liver disease, hereditary hemochromatosis, alcohol, smoking, and other dietary and environmental exposures are also factors that contribute to the development of HCC.
To date, there is accumulating evidence that shows patients with DM are more prone to cancer. A recent American population-based case–control study that consists of 2,061 patients with HCC and 6,183 noncancer controls has shown a significant association between DM and the risk of HCC with an odds ratio of 2.87. A study of site-specific cancer mortality in Asian populations has also reported that DM is associated with higher risk of mortality from liver and pancreatic cancer (1.51 and 1.78, respectively).
HCC has been the most lethal cancer for decades in Taiwan, with a mortality rate of 33.6 per 100,000 persons (n=7759), becoming the second leading cause of cancer deaths after lung cancer in 2009. In Taiwan, epidemiologic studies have found that the prevalence of DM increased from 11.3% in 1987 to 24.9% in 2005; as a result, DM became the fifth leading cause of death in 2009.
Cross-sectional and case–control studies conducted in a southern Taiwanese community with endemic dual hepatitis B and hepatitis C infections have shown that DM is not a risk factor for HCC. On the other hand, another community-based follow-up study in southern Taiwan found that type 2 diabetes is a strong independent predictor of HCC, with a hazard ratio (HR) of 2.7 (95% confidence interval (CI)=1.7–4.3), compared with non-diabetic patients.
Given the significant link of DM with the risk of cancer, lifestyle changes or anti-diabetic drugs that prevent and reverse DM may reduce the risk of cancer. Metformin, a widely used anti-diabetic drug, has recently attracted great attention for lowering cancer risk. It has been found to inhibit cancer cell growth in vitro and in vivo. Epidemiological studies have also shown that metformin therapy is associated with reduced risks of cancer, including breast cancer and HCC. Donadon et al. found that the odds ratio for HCC in diabetic patients treated with metformin dropped to 0.3 compared with those without this therapy. Another case–control study conducted in the United States also showed that treatment with metformin or thiazolidinediones is associated with a 70% reduction in HCC risk among diabetic patients. Both the case–control studies are limited, with small clinical samples of HCC. To the best of our knowledge, only one cohort study, also from Taiwan, has observed the effect of DM medication in reducing the risk of HCC among Asian populations, but only metformin was studied.
To clarify the role of diabetes in the risk of developing HCC, a population-based cohort study, taking advantage of a large-size data set available from the National Health Insurance program in Taiwan, was conducted. The present study investigates further whether the risk of HCC increases with the presence of hepatitis B and/or hepatitis C. Furthermore, it examines whether the HCC risk is reduced with DM therapies, including metformin and thiazolidinediones.
Abstract and Introduction
Abstract
OBJECTIVES: Using population-based representative insurance claims data, the risk of developing hepatocellular carcinoma (HCC) among diabetes mellitus (DM) patients, as well as whether DM medications alter the risk of developing HCC were investigated.
METHODS: From the Taiwan National Health Insurance Research Database, 19,349 newly diagnosed DM patients 20 years and older and 77,396 comparison subjects without DM were identified from claims from 2000 to 2005. The incidences of HCC at the end of 2008 and the risks associated with hepatitis B and hepatitis C were determined. Whether metformin and thiazolidinediones reduce the risk of developing HCC was also measured.
RESULTS: The incidence of HCC was twice higher in the DM group compared with the non-DM group (21.0 vs. 10.4 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.73 (95% confidence interval (CI)=1.47–2.03) using multivariable Cox proportional hazard regression. Male sex, cirrhosis, hepatitis B, and hepatitis C were significant independent factors that predict HCC, with HRs of 2.32, 8.65, 2.52, and 5.61, respectively. In the stratified analysis, the HR increased to 72.4 (95% CI=42.9–122) among patients with DM, cirrhosis, and hepatitis C. HCC risk reduction was greater for diabetics taking metformin than those taking thiazolidinediones (51 vs. 44% reduction).
CONCLUSIONS: Comorbidity with cirrhosis and/or hepatitis appears to be associated with an extremely increased risk of developing HCC among DM patients. These high-risk patients should be closely monitored for HCC. The use of metformin or thiazolidinediones may reduce the risk of developing HCC.
Introduction
Hepatitis B and hepatitis C are well-known etiological factors that lead to hepatocellular carcinoma (HCC) in Taiwan. More than 90% of patients with HCC are positive for the hepatitis B surface antigen and/or antibodies against the hepatitis C virus. In addition to viral infections, non-viral causes of HCC have been proposed in studies. Cirrhosis, obesity, diabetes mellitus (DM), fatty liver disease, hereditary hemochromatosis, alcohol, smoking, and other dietary and environmental exposures are also factors that contribute to the development of HCC.
To date, there is accumulating evidence that shows patients with DM are more prone to cancer. A recent American population-based case–control study that consists of 2,061 patients with HCC and 6,183 noncancer controls has shown a significant association between DM and the risk of HCC with an odds ratio of 2.87. A study of site-specific cancer mortality in Asian populations has also reported that DM is associated with higher risk of mortality from liver and pancreatic cancer (1.51 and 1.78, respectively).
HCC has been the most lethal cancer for decades in Taiwan, with a mortality rate of 33.6 per 100,000 persons (n=7759), becoming the second leading cause of cancer deaths after lung cancer in 2009. In Taiwan, epidemiologic studies have found that the prevalence of DM increased from 11.3% in 1987 to 24.9% in 2005; as a result, DM became the fifth leading cause of death in 2009.
Cross-sectional and case–control studies conducted in a southern Taiwanese community with endemic dual hepatitis B and hepatitis C infections have shown that DM is not a risk factor for HCC. On the other hand, another community-based follow-up study in southern Taiwan found that type 2 diabetes is a strong independent predictor of HCC, with a hazard ratio (HR) of 2.7 (95% confidence interval (CI)=1.7–4.3), compared with non-diabetic patients.
Given the significant link of DM with the risk of cancer, lifestyle changes or anti-diabetic drugs that prevent and reverse DM may reduce the risk of cancer. Metformin, a widely used anti-diabetic drug, has recently attracted great attention for lowering cancer risk. It has been found to inhibit cancer cell growth in vitro and in vivo. Epidemiological studies have also shown that metformin therapy is associated with reduced risks of cancer, including breast cancer and HCC. Donadon et al. found that the odds ratio for HCC in diabetic patients treated with metformin dropped to 0.3 compared with those without this therapy. Another case–control study conducted in the United States also showed that treatment with metformin or thiazolidinediones is associated with a 70% reduction in HCC risk among diabetic patients. Both the case–control studies are limited, with small clinical samples of HCC. To the best of our knowledge, only one cohort study, also from Taiwan, has observed the effect of DM medication in reducing the risk of HCC among Asian populations, but only metformin was studied.
To clarify the role of diabetes in the risk of developing HCC, a population-based cohort study, taking advantage of a large-size data set available from the National Health Insurance program in Taiwan, was conducted. The present study investigates further whether the risk of HCC increases with the presence of hepatitis B and/or hepatitis C. Furthermore, it examines whether the HCC risk is reduced with DM therapies, including metformin and thiazolidinediones.
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