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Statin Use Reduces Hepatocellular Carcinoma Risk in Patients With NAFLD
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BACKGROUND & AIMS
Recent evidence suggests potential clinical benefits of statin in cancer chemoprevention and treatment. Nonalcoholic fatty liver disease (NAFLD) is expected to become the leading cause of hepatocellular carcinoma (HCC). We aimed to investigate the association between statin initiation and the risk of HCC among patients with NAFLD.
In this study using the Optum de-identified Clinformatics database, Cox proportional hazards regression model was performed to determine the risk of HCC in statin initiators versus nonusers. We incorporated inverse probability of treatment weighting (IPTW) to minimize potential confounding.
Among 272,431 adults with NAFLD diagnosis, IPTW model shows that statin initiators had 53% less risk of developing HCC compared with nonusers (hazard ratio [HR], 0.47; 95% confidence interval, 0.36-0.60). In the subcohort with fibrosis-4 index data available, statin initiation was associated with 56% hazard reduction of developing HCC in NAFLD after adjusting for fibrosis-4 index score (HR, 0.44; 0.30-0.65). The association between statin initiation and lower risk of HCC development was observed for both lipophilic statin (HR, 0.49; 0.37-0.65) and hydrophilic statin (HR, 0.40; 0.21-0.76). Moreover, we observed greater hazards reduction as the dose and duration of statin use increased. NAFLD patients with more than 600 cumulative defined daily doses of statin had 70% reduction in hazards of developing HCC (HR, 0.30; 0.20-0.43).
Our study provides strong evidence for the association between statin initiation and reduced risk of HCC development in NAFLD patients. These findings imply that statin can be used as a protective medication for NAFLD patients to reduce the risk of HCC.
Disclosure statements are available on the authors' profiles:
Statin Use and Reduced Hepatocellular Carcinoma Risk in Patients With Nonalcoholic Fatty Liver DiseaseClin. Gastroenterol. Hepatol. 2023 Feb 01;21(2)435-444.e6, B Zou, MC Odden, MH Nguyen
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The incidence of hepatocellular carcinoma (HCC) is rising worldwide, which also coincides with the increasing prevalence of NAFLD.1 Although cirrhosis is the strongest risk factor for HCC, there is a growing body of literature demonstrating that patients with non-cirrhotic NAFLD remain at increased risk for HCC. The study by Zou et al recognizes the potential chemopreventive benefits of a frequently prescribed medication such as a statin in a population of patients with NAFLD. By leveraging a large database from Optum with almost 300,000 patients, the authors provide compelling evidence that statins may decrease the incidence of HCC. They use inverse probability of treatment weighting to avoid potential confounding of common variables, including aspirin and metformin use, and found that statin use was associated with a 53% reduction in the hazard of developing HCC. Furthermore, the authors discovered a dose-dependent relationship, with higher cumulative statin doses conferring a greater risk reduction in HCC. The study was well-designed with multiple sensitivity analyses. Although there were limitations as expected in a large database study with missing variables and unverifiable medication use, the authors demonstrated a consistent reduction in HCC incidence with statin use across analyses.
Although the exact antineoplastic mechanism is unknown, statins regulate cholesterol production and uptake by interfering with the mevalonate pathway, which can have downstream effects such as apoptosis and cell cycle disruption. As such, statins have demonstrated chemopreventive properties in multiple cancers, including HCC.2 This study adds to the existing literature of the potential benefits of statins in HCC reduction among patients with chronic viral hepatitis. Additionally, patients with NAFLD may already have an indication for statin and the study by Zou et al highlights yet another potential use for the medication. In a time when there are no medications to treat NAFLD, employing a medication like statin that is commonly prescribed may mitigate the risk of HCC in this patient population.
Fatty liver cancer prevention
Fatty liver progresses from fat accumulation to inflammation to fibrosis to cirrhosis to cancer. Previous studies have shown a protective association between statins and hepatocellular carcinoma (HCC) for inflammatory conditions of the liver. This study evaluated insurance records to determine whether there is a similar protective effect for non-alcoholic fatty liver disease (NAFLD).
Of the 272,431 subjects with non-alcoholic fatty liver disease, 73,385 were on a statin and 199,046 were not. Of those on a statin, there was a 53% reduction in the incidence rate of HCC. This effect was greater with longer use. Although previous studies found a benefit for only fat soluble statins, this study found benefit for both fat and water (eg, rosuvastatin) soluble statins.
How do statins reduce HCC risk?
This is unknown but ideas include reducing inflammation, modulating cholesterol metabolism pathways, and downregulation of hepatic oncogenes. Although this remains allusive, our familiarity with this class of drugs combined with these promising findings support statins as a useful tool in preventing the last and most severe result of fatty liver.
The most effective therapy
It is frustrating when I read in journal articles that we currently do not have an FDA-approved drug for NAFLD. What we need to be messaging is that we already have a cure for this condition, and it does not require a drug.
Fatty liver is part of the process of metabolic dysfunction that results from excess sugar intake, weight gain, and inactivity. Like prediabetes and early type II diabetes, it can be reversed and even cured with lifestyle modifications.
If glucose rises in the bloodstream and is not utilized in the muscle for energy, the liver makes triglycerides (TG) to store the unused sugar. The TG then accumulate in the liver triggering inflammation. Elevated TG also promote pancreatitis worsening the risk of diabetes, resulting in all sorts of downstream consequences that require us to add one drug after another.
Treatment of NAFLD is not about drugs. However, if this is ignored, statins appear to be helpful in preventing liver cancer.