Cholesterol Absorption Inhibitors Linked to Reduced Liver Cancer Risk

Katherine McGlynn, PhD, MPH

Credit: National Cancer Institute

Findings from a recent study are providing clinicians with an overview of the association between nonstatin cholesterol-lowering medications and the risk of liver cancer.^1,2

Leveraging data from the Clinical Practice Research Datalink, the study found a 31% reduced risk of liver cancer with cholesterol absorption inhibitor use and an increased risk of liver cancer with bile acid sequestrant use. However, no associations were observed for fibrates, omega-3 fatty acids, or niacin.^1,2

“To the best of our knowledge, no other population-based studies have evaluated the relations between different types of nonstatin cholesterol-lowering medications and the risk of liver cancer,” Katherine McGlynn, PhD, MPH, a senior investigator in the division of cancer epidemiology and genetics at the National Cancer Institute, and colleagues wrote, acknowledging the lack of research around nonstatins and liver cancer compared to statins’ role in this risk.¹

Worldwide, liver cancer is the sixth most common cancer and the third leading cause of cancer death. Multiple factors have been associated with an increased risk of developing liver cancer, including hepatitis B/C infection, cirrhosis, alcohol use, metabolic dysfunction-associated steatohepatitis, and cigarette smoking.³ Although past research has suggested statin use exhibits a protective effect against liver cancer, nonstatin medications’ association with liver cancer is not well understood.²

To examine the association between nonstatin cholesterol-lowering medications and liver cancer risk, investigators conducted a nested case-control study within the Clinical Practice Research Datalink, a primary care database containing anonymized data on demographic information; medical events; hospital admissions; drug prescriptions; and deaths for approximately 7% of the UK population. The study population was drawn from individuals who were seen from 1988-2019 and included all persons between 10-90 years of age from general practices with up-to-standard data.¹

Cases included patients who had primary liver cancer as a first diagnosis. However, investigators excluded liver cancer cases if there was a diagnosis of a cancer likely to metastasize to the liver in the 5 years before the primary liver cancer diagnosis or if there was a diagnosis of liver metastasis.¹

They then matched control participants to cases in a 4:1 ratio based on age, sex, medical practice, and number of years in the Clinical Practice Research Datalink. For inclusion, controls were required to be free of liver cancer, alive with recorded activity in the Clinical Practice Research Datalink at the time of the matched case's date of diagnosis, and have spent the same number of years in the Clinical Practice Research Datalink as the matched case.¹

In total, the study included 3719 cases and 14,876 matched controls. Among the cohort, the mean age was 69.1 years and 70.1% of participants were male. Investigators pointed out cases were more likely than controls to have ever smoked, have a BMI ≥30 kg/m2, have type 2 diabetes, have chronic HBV and/or HCV infection, have alcohol-related disorders, and have a history of chronic liver disease.¹

Investigators examined 5 classes of nonstatin cholesterol-lowering medications: cholesterol absorption inhibitors; bile acid sequestrants; fibrates; niacin; and omega-3 fatty acids. Additionally, they examined statin use as a comparison for the nonstatin medications.¹

In the overall analysis, ever use of cholesterol absorption inhibitors was associated with a reduced risk of liver cancer (Odds ratio [OR], 0.69; 95% CI, 0.50–0.95). When examined according to recency of use, past use of cholesterol absorption inhibitors was associated with reduced risk (OR, 0.52; 95% CI, 0.33–0.83), but current use was not (OR, 0.92; 95% CI, 0.59–1.42). Further analysis revealed a similar association in participants with (OR, 0.46; 95% CI, 0.22–0.97) and without (OR, 0.89; 95% CI, 0.56–1.42) type 2 diabetes, as well as persons with (OR, 0.53; 95% CI, 0.30–0.96) and without (OR, 0.68; 95% CI, 0.49–0.94) chronic liver disease.¹

Investigators noted ever use of bile acid sequestrants was associated with an increased risk of liver cancer (OR, 5.31; 95% CI, 3.54–7.97), which was most evident for current use (OR, 13.08; 95% CI, 6.98–24.49) and was most pronounced at the lowest cumulative dose (OR, 12.30; 95% CI, 5.42–27.90). Results of analyses based on diabetes and liver disease status were inconsistent, with results suggesting no association with liver cancer among persons with type 2 diabetes (OR, 1.09; 95% CI, 0.24–4.98) but an increased risk among persons without type 2 diabetes (OR, 6.93; 95% CI, 4.24–11.32). Additionally, while there was no association between ever use of bile acid sequestrants and liver cancer among persons with chronic liver disease (OR, 1.14; 95% CI, 0.73–1.80), there was an increased risk among persons without chronic liver disease (OR, 5.52; 95% CI, 3.67–8.32).¹

No associations were observed for the use of fibrates, niacin, or omega-3 fatty acids in adjusted analyses, overall, by recency of use, or by dose. Ever use (OR, 0.65; 95% CI, 0.58–0.74) and current use (OR, 0.61; 95% CI, 0.54–0.69) of statins were associated with a reduced risk of liver cancer, with findings consistent across analyses in type 2 diabetes and chronic liver disease.¹

Investigators outlined multiple limitations to these findings, including the lack of verification of liver cancer diagnoses against cancer registry records; the potential underestimation of asymptomatic viral hepatitis infections; incomplete records of alcohol-related disorders; and the inability to examine race and ethnicity due to these variables not consistently being collected in the Clinical Practice Research Datalink.¹

“As few studies have examined the effects of non-statin cholesterol-lowering drugs on liver cancer risk, the results of our study require replication in other populations. If our findings are confirmed in other studies, however, our results may inform liver cancer prevention research,” McGlynn said in a press release.²

References

1. ^{Shahriar A, Zamani, Barry I. Use of cholesterol-lowering medications in relation to risk of primary liver cancer in the Clinical Practice Research Datalink. CANCER. doi:10.1002/cncr.35436}
2. ^{Wiley. Do non-statin cholesterol-lowering drugs affect liver cancer risk? EurekAlert! July 29, 2024. Accessed July 29, 2024. https://www.eurekalert.org/news-releases/1052211}
3. ^{National Cancer Institute. Liver Cancer Causes, Risk Factors, and Prevention. Liver Cancer. May 15, 2024. Accessed July 29, 2024. https://www.cancer.gov/types/liver/what-is-liver-cancer/causes-risk-factors}