For our next #GUTBlog, Professor El-Omar has invited Professor Jaime Bosch, Dr Juan Abraldes, and Dr Jordi Gracia-Sancho, from the Department of Biomedical Research (Hepatology), Inselspital, University of Bern, Switzerland, to write about their paper “Cirrhosis as new indication for statins” published in Gut in May 2020.
“The inspiration to use statins for the treatment of cirrhosis came from a paper by Bill Sessa, back in 2001. The paper described how simvastatin enhanced eNOS activity through AKT-dependent phosphorylation of eNOS. At that time at the lab we were actively looking at increasing NO delivery at the intrahepatic circulation to overcome the liver sinusoidal endothelial dysfunction that contributes to portal hypertension by enhancing the hepatic vascular tone. We knew this was not due to a decreased expression of eNOS, but to a decreased eNOS activity, as previously shown by Drs Shah, Garcia-Cardena, Sessa and Groszmann at Yale University. I had the privilege of interacting with them through my visits and collaboration with Dr Groszmann, who has been my life-long mentor. This paper (and my profound respect to the work of Bill Sessa and Roberto Groszmann) inspired me for starting a series of clinical and traslational studies to explore whether administration of statins could be a good strategy for the treatment of portal hypertension in cirrhosis. All subsequent work in Barcelona deeply involved my co-workers, Drs Juan G.Abraldes and Jordi Gracia-Sancho, and many PhD students and post-doctoral fellows.
From the beginning we focused on using simvastatin for two reasons; first, as a lipophilic statin it had a good potential for being concentrated in the liver; second, and more important, being a generic drug, its repurposing for cirrhosis and portal hypertension will result in a cheap and easily accessible therapy worldwide. Our first studies clearly showed that there was an avenue for the use of statins, as shown in cirrhotic rat models by increased eNOS phosphorylation, enhanced NO availability, reversal of endothelial dysfunction, and decreased portal resistance and portal pressure. In patients with cirrhosis we observed reduced portal pressure response to postprandial splanchnic hyperemia, decreased estimated vascular resistance and increase NOx in hepatic venous blood. This encouraged a phase II double-blind cooperative randomized clinical trial (RCT) in patients with cirrhosis and portal hypertension that showed that 4-week simvastatin administration, but not placebo, significantly decreased portal pressure (measured by the hepatic vein pressure gradient, HVPG) without changing hepatic blood flow or systemic hemodynamics. This was accompanied by improved liver clearance and intrinsic clearance of ICG, demonstrating ameliorated liver function. These findings supported that simvastatin could impact the natural history of cirrhosis, not only by decreasing portal pressure, but also by improving liver function. At that time, Dr Garcia-Cardena (now in Boston at the Brigham’s) was working on the role of the transcription factor KLF2 mediating the effects of statins in vascular biology, and we started a fruitful cooperation that began by a postdoctoral stage of Dr Gracia-Sancho at his lab and that continued for years afterwards. These studies shed light on the molecular mechanisms of the beneficial effects of statins in cirrhosis, including the mechanism of its antifibrotic and liver protection effects in front of ischemia reperfusion injury, LPS administration, and during liver preservation, gastrointestinal bleeding and acute-on-chronic liver failure (ACLF), among others.
These studies provided further background evidence to promote the clinical use of simvastatin in patients with advanced cirrhosis. With the help of colleagues from other hospitals in Spain, we could get grants from the Spain’s Ministry of Health to fund a double-blind, multicenter RCT examining whether addition of simvastatin or placebo to standard of care could reduce rebleeding (primary outcome) and death (main secondary outcome) in patients with cirrhosis and portal hypertension surviving an episode of variceal bleeding (the BLEPS study). Standard of care was the combination of endoscopic band ligation and non-selective beta-blockers. This trial showed that albeit addition of simvastatin did not decrease rebleeding, it did improve survival, mainly by decreasing deaths from rebleeding and from bacterial infections. Since our preclinical studies demonstrated that simvastatin protected liver function from ischemia-reperfusion injury and during hypovolemic shock, and prevented liver deterioration and death after LPS injection and ACLF, we proposed that our findings were mechanistically linked to the favorable effects of statins on liver biology. Moreover, we found that simvastatin (40 mg/day) was safe for most patients with cirrhosis and relatively low degrees of liver failure, but that it could cause excessive muscle toxicity in patients with Child-C cirrhosis, since we had two cases of self-limited rhabdomyolysis among them. Later studies confirmed this finding and showed that Child-C patients should not receive over 20 mg of simvastatin per day.
The same year the BLEPS study was published a series of observational studies did found that statin exposure was statistically associated with a lower rate of progression to cirrhosis, clinical decompensation and death in several liver diseases (chronic viral hepatitis, alcoholic liver disease and non-alcoholic steato-hepatitis, among other). Although the transportability of the results of observational studies is low, and many are not confirmed in prospective clinical trials, we hope that this will not be the case in the scenario of statin administration in the treatment of cirrhosis, due to the results of our clinical trials and by the mechanistic evidence from preclinical studies supporting its use. Altogether we foresee an increased use and proven efficacy of statins in patients with cirrhosis, with the greater beneficial effects being anticipated in early and intermediate stages of cirrhosis.”
Jaume Bosch (@jaumebosch9), Jordi Gracia-Sancho (@JSGracia) and Juan G Abraldes (@JuanAbraldes)