Statins in NAFLD: Taking a Closer Look at Benefits

LONDON – Substantial reductions in liver fat and fibrosis can be achieved with statin therapy, according to research presented at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.

Statins are thought to have multiple beneficial actions in people with fatty liver disease, but there has been little insight into how they may be exerting such effects.

Now, data from the Rotterdam Study and others suggest that statins may be reducing the formation of lipid droplets as well as influencing the expression of important inflammatory genes.

The results “require further confirmation,” the team behind the work said, which was done at Erasmus Medical Center in Rotterdam, the Netherlands, in collaboration with researchers at The First Affiliated Hospital of Wenzhou (China) Medical University.

“Statins are inversely associated with multiple components of the NAFLD [nonalcoholic fatty liver disease] spectrum,” said Ibrahim Ayada, a PhD student in the department of gastroenterology and hepatology at Erasmus MC.

“Statins can inhibit lipid synthesis in organoids and statins also exhibit healthy inflammatory effects, which might contribute to the hepatoprotective effects that we observe in our population studies,” Ayada said.

A Rising Problem That Needs Addressing

Together NAFLD and NASH constitute a significant and increasing health burden, Ayada observed, noting that there were an estimated 64 million people in the United States and 52 million people in Europe, at least, with the rise mirroring the obesity pandemic.

“The number of patients visiting outpatient clinics has nearly doubled within a study period of 5 years,” he said.

“There is no pharmacologic therapy,” he reminded his audience, observing that fatty liver disease was a major indication for liver transplantation.

Statins are a long-standing staple of cardiovascular disease management and are known to have pleiotropic effects, Ayada explained. Their use in NAFLD and non-alcoholic steatohepatitis (NASH) has been purported but is supported by inconclusive evidence.

Indeed, a prior Cochrane review performed in 2013 found only two studies that were eligible for analysis and had “high risk of bias and a small numbers of participants,” according to the review’s authors.

Examining the Connection

To look at the possible benefits of statins in people with NASH and examine how these effects might be occurring, Ayada and collaborators first took data from the Rotterdam Study, a large population-based prospective cohort that has been collecting data on its participants since the early 90s.

Data on over 4,500 participants were examined and of these, just over 1,000 had NAFLD. Statin versus no statin use was found to be associated with around a 30% reduction in fatty liver disease, with an odds ratio or 0.72 for NAFLD.

Then, looking only at a subset of patients with biopsy-proven NAFLD, statin use was associated with a 45% reduction in NASH (OR, 0.55) and a 24% reduction in fibrosis, although only the NASH reduction was significant (P = .031). The purpose of this cohort is to look at potential biomarkers and all participants had donated blood, urine, and stool samples; all were of Chinese descent, Ayada said.

“We then pooled our results with existing evidence in a meta-analysis,” said Ayada, including 16 studies. While results showed an overall inverse association, only the findings for a reduction in NAFLD and fibrosis were significant; the relationship between statins and NASH was not significant.

Investigating Mechanistic Effects

Then, for the second part of their work, Ayada and associates looked at potential mechanistic effects of statins.

“We did part two because we knew part one was going to be cross-sectional and we could only show the association and not causality, so we tried to shed some light on possible pathways,” he said.

To do this they used a novel model of liver organoids developed to study fatty liver disease and test potential therapeutics. In this model human liver organoids are exposed to sodium lactate, sodium pyruvate, and octanoic acid, which induce the formation of lipid droplets. Exposing the organoids to statins – simvastatin and lovastatin were used in the experiments – resulted in a reduced number of the induced lipid droplets.

“Although all concentrations of statins significantly inhibited the lipid size versus the control, the major effect was quite modest,” observed Ayada. The effect was most noticeable at the highest dose used (10 micromolar), and what they think might be happening is that the statins are clearing the smaller droplets first, leaving the larger ones behind.

Next, they looked at the effect of statin treatment on inflammatory gene expression in liver-derived monocytes. These will turn into macrophages and play a key role in chronic inflammation, Ayada explained. Initial results suggest that several proinflammatory cytokines such as interleukin-1 beta, IL-6, and IL-8 may be downplayed by statin therapy.

An anti-inflammatory effect of statins was also reported in unrelated poster presentations at the congress. While researchers Seul Ki Han and associated from South Korea showed an anti-inflammatory effect of a combination of simvastatin and ezetimibe (SAT083), a Dutch team found that atorvastatin reduced the infiltration of hepatic macrophages, neutrophils, and monocytes, as well as lowering levels of proinflammatory cytokines (SAT033).

Statins for NASH – A Missed Opportunity?

“As far as I am aware there is no robust evidence from large, randomized trials to suggest statins lessen chances of NAFLD, or improve its surrogate markers such as ALT or GGT [gamma-glutamyltransferase] levels,” Naveed Sattar, PhD, FRCP, FRCPath, FRSE, FMedSci, commented in an interview.

“The Rotterdam study is merely cross-sectional and cannot answer the question of causality,” added Sattar, who is professor of metabolic medicine and Honorary Consultant in Cardiovascular & Medical Science at the University of Glasgow. “It may be people who have less NAFLD are more likely to be prescribed statins, perhaps because doctors are wary of prescribing statins to those with slightly deranged liver tests,” he qualified.

Moreover, said Sattar, “prior evidence shows statins are underused in people with heart disease but who have NAFLD, which represents a missed opportunity to prevent heart disease.

“If statins had positive effects for preventing conversion of NAFLD to NASH or lessening fibrosis, I believe we would have known that by now.”

As for use of statins in future treatments of fatty liver disease, Sattar said: “I would not pin my hopes on statins to improve liver health, but doctors need to remember statins are safe in people with NAFLD or NASH and they should not be withheld in those who have existing cardiovascular disease or at elevated risk.”

The study received no commercial funding. Ayada and Sattar had no relevant conflicts of interest.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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