Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: A nationwide nested case‐control study

Abstract

Relationship on new statin use and the risk of hepatocellular carcinoma (HCC) in patients with incident type 2 diabetes mellitus (T2DM), who might be at the risk of developing HCC, is uncertained. A nationwide population-based nested case-control study was conducted within the National Health Insurance Service National Sample Cohort 2002-2013 in Korea. Newly prescribed statin after newly diagnosed T2DM was defined as statin use. Controls were matched to case patients on age, sex, follow-up time, and the date of diabetes diagnosis at a five-to-one ratio. Odds ratios (ORs) for associations of statin use with HCC were calculated using conditional logistic regression. After at least a 5-year HCC-free period, there were 229 incident HCC cases and 1,145 matched controls from 47,738 patients with incident diabetes. Of these 229 incident HCC cases, 27 (11.8%) were statin users, whereas 378 (33.0%) were statin users among 1,145 controls. Statin use was associated with a reduced risk of HCC development (adjusted OR [AOR]= 0.36, 95% confidence interval [CI] 0.22-0.60) after adjustment for chronic viral hepatitis, liver cirrhosis, alcoholic liver disease, previous cancer, aspirin use, insulin use, sulfonylurea use, metformin use, thiazolidinedione use, history of chronic obstructive pulmonary disease, Charlson comorbidity score, household income level, and residential area. Risk reduction was accentuated with an increase of cumulative defined daily doses (cDDD) compared with non-users (AORs 0.53, 0.36, 0.32, and 0.26 in ≤60, 60-180, 181-365, and >365cDDD, respectively; P for trend <0.0001). The risk reduction was apparent in the presence of liver disease (AOR = 0.27, 95% CI 0.14-0.50), including heterogeneous groups of clinical diagnosis of liver disease, but not significant in the absence of liver disease (AOR = 0.64, 95% CI 0.32-1.29). Among patients with new onset T2DM, statin use before HCC diagnosis may have a beneficial inhibitory effect on HCC development in a dose-dependent manner, especially in individuals with liver disease.

Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study

“…Previously, using a data source of 229 HCC case patients and 1,145 control cases, from patients with type 2 DM, statin initiation was reported to reduce the risk of incident HCC with an AOR of 0.36 (95% CI 0.22-0.60). 24 In the present study, we included the general population and examined the effect of statin use for HCC from the whole general population. In the DMmatched analysis, consistent with the previous results, the beneficial effect of statin use on HCC was greater in patients with DM, compared to subjects without DM, although DM alone was an increasing risk factor of HCC.…”

Prevention of Hepatocellular Carcinoma by Statins: Clinical Evidence and Plausible Mechanisms

“…Several studies reported that higher dosage and longer duration of statin use was associated with greater protective effects on the development of HCC. 104,107,[112][113][114] In contrast, Chiu et al showed that there was no significant doseresponse relationship in statin use and HCC development. 103 In vivo studies showed a dose-dependent effect of statin on angiogenesis, presenting a proangiogenic effect at low doses and an antiangiogenic effect at high doses of statin use.…”

“…Several studies have demonstrated that the use of statins is inversely associated with the risk of incident HCC (►Table 2). [101][102][103][104][105][106][107][108][109][110][111][112][113][114] Using the Korean National Health Insurance Service Physical Health Examination Cohort from 2002 to 2013, 1,642 HCC cases were matched to 8,210 control individuals. 113 In this longitudinal nationwide nested casecontrol study, statin users had a 56% lower risk of HCC than nonusers.…”

Breaking the matching in nested case–control data offered several advantages for risk estimation

“…While a research study is designed to answer a specific research question, it is common for investigators to conduct subsequent analyses of subgroups in order to investigate associations in more detail. Some recent examples for the nested case-control design are the studies conducted by Devore et al, 61 Kim et al, 62 Boursi et al 63 and Liu et al 64 There is an abundant literature on subgroup analyses for randomised clinical trials. [65][66][67][68][69][70] The general advice, however, is to restrict subgroup analyses as much as possible, as the main issue is their overuse and over interpretation, in addition to the underuse of appropriate statistical tests for interaction.…”

“…As subgroup analyses are regularly performed in nested case-control studies [61][62][63][64] and as it remains unclear if these analyses can provide valid estimates, simulation studies were performed, which aimed to answer the following specific questions:…”