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The use of lipophilic – but non-hydrophilic statins – predicts a significantly lower risk of hepatocellular carcinoma (HCC) and death in patients with chronic viral hepatitis, suggests a study nationwide. and proportional to more than 16,000 patients.
In the analyzes in particular, the benefits of lipophilic statins were related to dose and duration. The greatest reduction in the risk of HCC occurred after at least 600 defined daily doses cumulative – the equivalent of taking a statin at moderate dose for approximately 2 years.
"Now that we have remedies for hepatitis C, it's important to focus on preventing long-term adverse effects, such as HCC, in high-risk patients or those already suffering from fibrosis," he said. Tracey G. Simon, MD, MPH, Massachusetts General Hospital and Harvard Medical School, Boston, stated theheart.org | Medscape Cardiology.
"What I find great is that prevention is an issue that is of great concern to our patients and that is attracting more and more attention from hepatologists," said Simon, lead author of the I & # 39; study, published online on 19 August in Annals of Internal Medicine.
Previous data have linked statins to improved survival and reduced risk of HCC in chronic liver diseases. However, the role of the type and dose of statin remains uncertain. Retrospective data from the United States and, recently, from large cohort studies in Southeast Asia, have largely demonstrated the consistent benefits of lipophilic statins, including atorvastatin, simvastatin, fluvastatin, and and lovastatin.
One of the main reasons for this study is inconsistent results or a nil association with the prevention of liver cancer when populations have primarily used hydrophilic statins, such as pravastatin or rosuvastatin, she said .
Swedish register data
The present study is based on data collected prospectively in Swedish national registers concerning 63,279 adults with confirmed hepatitis B or hepatitis C who started statin therapy from 2005 to 2013. Among them, 16,668 adults of which 6554 users of lipophilic statins and 1780 users of hydrophilic statins were matched. to 8334 non users.
The use of statins has been defined as comprising at least 30 defined daily cumulative doses (CDD) of prescriptions filled with statins. The median follow-up was about 8 years old. There were 616 cases of HCC and 1803 deaths, 462 of which were liver related.
Compared with non-users, users of lipophilic statins had a newly adjusted adjusted risk of newly discovered HCC of 44%. [HR]0.56; 95% CI, 0.41-0.79) and an absolute risk difference of -4.8% (8.1% vs. 3.3%).
In contrast, no significant associations were found between the use of hydrophilic statins and the risk of HCC (HR, 0.95%; 95% CI, 0.86 – 1.08; absolute difference , 8.0% vs 6.8%).
Relative to non-users, the 10-year mortality was significantly lower among users of lipophilic statins (15.2% vs. 7.3%, HRa, 0.62, 95% CI, 0.45-0, 91) and hydrophilic statins (16.0% vs. 11.5%, HRa, 0.88, 95% CI, 0.80-0.97).
Despite relatively few liver-related deaths, these events were significantly lower with lipophilic statins (aHR, 0.76, 95% CI, 0.50 to 0.92) but not with hydrophilic statins (aHR, 0, 98, 95% CI, 0.72 to 1.46).
The results were similar in all subgroups, including those with and without antiviral treatment and cirrhosis, and in several sensitivity analyzes, the authors reported.
With respect to the dose and duration of statins, there was a significant dose-dependent inverse association between a higher lipophilic statin CDD and a 10-year lower adjusted HCC risk (absolute difference of -3.4% for the 30-year period). at 299 cDD, -4.6% for 300 to 599 cDD, and -5.9% for 600 cDDD or more; P for the trend <0.001).
A similar association was present for all-cause mortality risk (-7.1%, -7.2% and -9.6%, respectively); P for trend = 0.001).
No such association has been found between increasing the number of CDDD hydrophilic statins and the results of adjusted or repeat analyzes in the unpaired population of statin users. In addition, the benefits of lipophilic statins were similar in all subgroups, including those with and without use of cirrhosis or antiviral treatment, and in several sensitivity analyzes, the authors reported.
"Seeing this risk gradient in all our different analyzes suggests that this could be a real cause-and-effect relationship," Simon said.
Biologically plausible
There are several possible biological bases for the results. First, preclinical studies suggest that lipophilic statins prevent viral replication, potentiate antiviral treatment, and stimulate anti-tumor immunity more effectively than hydrophilic statins. Second, lipophilic statins are passively absorbed into cells across cell membranes, whereas hydrophilic statins require transporter mediated transport, which is reduced in patients with severe hepatic fibrosis to enter hepatocytes. -she explains.
In addition, lipophilic statins, but not hydrophilic statins, exert consistent antitumor effects, including the induction of G0 / G1 cell cycle arrest, the inhibition of Ras / Raf signaling. Med / ERK and the triggering of apoptosis.
"So, in addition to entering hepatocytes more easily, it could be that lipophilic statins alter the expression of genes or alter downstream signaling cascades that play a role in inflammation and apoptosis, "Simon said.
The limitations of the study are possible residual confusion and lack of monitoring data for lipids, fibrosis and HCC. The study was also conducted in a predominantly white cohort, although it is widely acknowledged that the epidemiology of HCC is very different in European whites from that, for example, in Asian patients.
Simon said it was too early to change practice based on this study and that the results should be validated in other prospective cohorts, particularly those with diverse populations.
"In addition, we need well-designed randomized trials on statins for the prevention of HCC, which compare the types of individual statins and evaluate the optimal timing of statin initiation for effective reduction." risk, "she said.
Studies evaluating the role of different types of statins, their dosages and their duration of use are also warranted in patients with other types of liver disease, Simon said. "When we think of statins, the biggest concern for people's minds is the growing population of patients with non-alcoholic fatty liver disease because of all the cardiovascular risk factors observed in these patients. very attractive preventative drug in this population, in some ways we are working on one stone on two birds, so to speak. "
Simon has benefited from a North American training grant from the American College of Gastroenterology. Information on grants and co-authors and conflicts of interest are listed in this article.
Ann Intern Med. Posted online 19 August 2019. Summary
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