Fat-Soluble Statins May Alter Liver Ca Risk in Chronic Hepatitis

Patrice Wendling

August 20, 2019

Use of lipophilic — but not hydrophilic — statins predict significantly lower risks for hepatocellular carcinoma (HCC) and death in patients with chronic viral hepatitis, suggests a nationwide, propensity-matched study of more than 16,000 patients.

Notably in the analyses, the benefits of lipophilic statins were dose- and duration-dependent. The greatest reduction in HCC risk occurred after at least 600 cumulative defined daily doses — the equivalent of taking a moderate-dose statin for about 2 years.

"Now that we have cures for hepatitis C, it's important now to focus on preventing long-term adverse outcomes, like HCC, in patients who are high risk or who already have fibrosis," Tracey G. Simon, MD, MPH, Massachusetts General Hospital and Harvard Medical School, Boston, told theheart.org | Medscape Cardiology.

"What I think is great is that prevention is something that our patients are asking a lot about and is something that is gaining more and more attention with hepatologists," said Simon, lead author of the study, published online August 19 in Annals of Internal Medicine.

Prior data have linked statins with improved survival and reduced HCC risk in chronic liver disease, however, the role of statin type and dose remains unclear. Retrospective data from the United States and recently from large cohort studies in Southeast Asia have largely shown consistent benefits with lipophilic statins, which include atorvastatin, simvastatin, fluvastatin, and lovastatin.

One of the primary reasons for this study is inconsistent results or a null association with liver cancer prevention when populations have been primarily users of hydrophilic statins, such as pravastatin or rosuvastatin, she said.

Swedish Registry Data

The present study drew upon data prospectively collected in Swedish national registries from 63,279 adults with confirmed hepatitis B or hepatitis C who started statin therapy from 2005 to 2013. Among these, 16,668 adults, including 6554 lipophilic statin users and 1780 hydrophilic statin users, were matched to 8334 nonusers.

Statin use was defined as at least 30 cumulative defined daily doses (cDDD) of filled statin prescriptions. Median follow-up was about 8 years. There were 616 incident HCC cases and 1803 deaths, of which 462 were liver-related deaths.

Compared with nonusers, lipophilic statin users had a 44% lower adjusted relative risk of new-onset HCC (hazard ratio [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 association was found between hydrophilic statin use and HCC risk (HR, 0.95%; 95% CI, 0.86 - 1.08; absolute difference, 8.0% vs 6.8%).

Compared with nonusers, 10-year mortality was significantly lower among both lipophilic statin users (15.2% vs 7.3%; aHR, 0.62; 95% CI, 0.45 - 0.91) and hydrophilic statin users (16.0% vs 11.5%; aHR, 0.88; 95% CI, 0.80 - 0.97).

Despite relatively few liver-related deaths, such events were significantly lower with lipophilic statins (aHR, 0.76; 95% CI, 0.50 - 0.92) but not with hydrophilic statins (aHR, 0.98; 95% CI, 0.72 - 1.46).

The findings were similar across all subgroups, including those with and without cirrhosis or antiviral therapy use, and across several sensitivity analyses, the authors reported.

As for statin dose and duration, there was a significant dose-dependent inverse association between higher lipophilic statin cDDD and lower 10-year adjusted HCC risk (–3.4% absolute difference for 30 to 299 cDDDs, –4.6% for 300 to 599 cDDDs, and –5.9% for 600 or more cDDDs; P for trend < .001).

A similar association was present for all-cause mortality risk (–7.1%, –7.2%, and –9.6%, respectively; P for trend = .001).

No such associations were found between increasing hydrophilic statin cDDD and either outcome in adjusted analyses or when repeated in the unmatched population of statin users. In addition, the benefits with lipophilic statins were similar across all subgroups, including those with and without cirrhosis or antiviral therapy use, and across several sensitivity analyses, the authors reported.

"To see that gradient of risk in all of our different analyses suggests this may be a true causal relationship," Simon said.

Biologically Plausible

There are several possible biological underpinnings for the findings. First, preclinical studies suggesting that lipophilic statins prevent viral replication, potentiate antiviral therapy, 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 carrier-mediated transports, which are reduced in patients with severe liver fibrosis, to enter hepatocytes, she explained.

Also, lipophilic statins, but not hydrophilic statins, exert consistent antitumor effects, including induction of G0/G1 cell cycle arrest, inhibition of Ras/Raf/Med/ERK signaling, and triggering apoptosis.

"So in addition to entering hepatocytes more easily, it might be that lipophilic statins are modifying gene expression or changing downstream signaling cascades that play a role in inflammation and apoptosis," Simon said.

Limitations of the study are possible residual confounding and the lack of lipid, fibrosis, and HCC surveillance data. The study was also conducted in a primarily white cohort, although it is widely known that the epidemiology of HCC is vastly different in white Europeans than, for example, Asian patients.

Simon said it's too early to change practice based on this study and that the findings would need to be validated in additional prospective cohorts, in particular those with diverse populations.

"Additionally, what's needed are well-designed randomized trials of statins for HCC prevention that compare individual statin types, and which assess the optimal timing of statin initiation for effective risk reduction," she said.

Studies assessing the role of individual statin types, doses, and durations of use are also warranted in patients with other kinds of liver disease, Simon said. "When we think about statins, what looms large in people's minds is the growing population of patients with nonalcoholic fatty liver disease because of all the cardiovascular risk factors found in these patients. Statins are a very appealing preventative medication in that population because it feels like, in some ways, we're working on two birds with one stone, so to speak."

Simon was supported by a North American training grant from the American College of Gastroenterology. Co-author grant support and conflict of interest information are listed in the article.

Ann Intern Med. Published online August 19, 2019. Abstract

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