Research on repurposing statins, beta-blockers and G-CSF as disease-modifying agents to decompensated cirrhosis

Decompensated cirrhosis is often characterized by a dramatic shortening of life expectancy unless liver transplantation is performed.1 With about 5% to 7% of compensated cirrhosis patients developing decompensated cirrhosis each year, only targeted therapies aiming at specific complications are used to manage decompensated cirrhosis patients.1 The absence of an effective meditation that could treat the disease from the root has hastened the research and development of corresponding drugs.

To address the decompensated cirrhosis by dealing with the course, disease-modifying agents should be adopted.1  Several studies have shown that disease-modifying agents have the potential effectiveness to influence the tumultuous course of decompensated cirrhosis. Disease-modifying agents should be defined as being able to modify the course of decompensated cirrhosis, having the positive impacts on the global burden of the disease and cost-effectiveness, also showing clinical benefits in randomized controlled trial with hard primary endpoints, improving the quality-of-life and safety.2  Elisa Pose, a researcher of Clinic Barcelona and her colleagues, thereby, reviewed the previous researches and evaluated whether the three old drugs, namely statins, beta-blockers, and granulocyte colony stimulating factor (G-CSF), could meet those requirements and becoming a potential disease-modifying agent.2

Regarding the performance of statins, evidence showed that it did not only reduce portal hypertension effectively, but also significantly reduced the hepatic and systemic inflammations, which constituted the key complications of liver cirrhosis.2  In a previous randomized controlled trial, simvastatin demonstrated survival benefits when added to the standard treatment for Child-Pugh class A or B cirrhosis.3 However, it was also found to be positively associated with the risk of rhabdomyolysis.3  The research team then conducted a multicentre, double-blind, placebo-controlled phase 2 trial to evaluate the safety of simvastatin plus rifaximin in patients with Child-Pugh class B or C cirrhosis.4  Recruited patients were randomized at 1:1:1 ratio to receive simvastatin 20mg per day plus rifaximin 1,200mg per day (n=16); simvastatin 40mg per day plus rifaximin 1,200mg per day (n=18); or placebo of both drugs (n=16).4  Development of liver or muscle toxicity was defined as the primary endpoint, which was indicated by changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and creatine kinase.4  Patient receiving simvastatin 40mg per day plus rifaximin had significantly higher mean of AST (62IU/L; 95% CI: 7-116 vs. 191IU/L; 95% CI: 138-245; p=0.0009), ALT (35IU/L 95% CI: 6-64 vs. 96IU/L 95% CI: 68-123; p=0·0025), and creatine kinase (152IU/L 95% CI: -426-729 vs. 1,160IU/L 95% CI: 596-1,725; p=0.014).4 Also, three rhabdomyolysis cases (19%) were reported in the group with simvastatin 40mg per day plus rifaximin.4  On the other hand, no significant differences in AST, ALT or creatine kinase between the simvastatin 20mg per day plus rifaximin group and placebo were observed (all p>0.05).4

The above data indicated a positive association of simvastatin 40mg per day and toxicity in patients with decompensated cirrhosis. Considering the above results, the research team concluded that more randomized clinical trials with low and safe doses of simvastatin are needed to assess the role of statins as a disease modifier in decompensated cirrhosis.4

Beta-blockers have shown clinical benefits in patients with compensated cirrhosis and portal hypertension, preventing decompensation cirrhosis.2 Evidence has indicated that long term treatment of beta-blockers could increase the decompensation-free survival in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH), mainly by reducing the incidence of ascites.5 However, the researcher highlighted that there was in fact little evidence on the potential beneficial effects of beta-blockers in decompensated cirrhosis.2 Although evidence showed that carvedilol had negative association with mortality in patients with acute-on-chronic liver failure (ACLF), more studies and researches have to be conducted in order to examine the efficacy and safety of beta-blockers as a disease-modifying agent in decompensated cirrhosis.6

Regarding G-CSF, heterogeneous results have been shown in different studies.7 A randomized clinical trial reported the potential efficacy of G-CSF in decompensated cirrhosis. It was proved that the addition of G-CSF to the standard medical treatment could increase hematopoietic stem cells in patients with decompensated cirrhosis, as well as increase the survival of patients.8 While a report from a meta-analysis of randomized controlled trials of G-CSF for patients with decompensated cirrhosis, ACLF or alcoholic hepatitis showed heterogeneity between Asian and European studies.7 G-CSF was significantly associated with mortality reduction of more than 70% at 3 months, while this favorable effect was only seen in Asian studies, survival of patients treated with G-CSF seemed to be even worse than the untreated.7 The researcher, therefore, concluded that more evidence is needed to define the role of G-CSF, especially its performance on Asian and European patients.2

Repurposing the above-mentioned three old drugs has provided new candidates for the treatment of decompensated cirrhosis. Upon reviewing the three drugs, the researcher concluded that while the investigation process of statins was in an advanced stage, more evidence is needed for indicating the role of beta-blockers and G-CSF.2 “The proposal or discovery of disease modifiers in cirrhosis is an exciting field research and an unmet need of the current hepatology”, the researher remarked when highlighting the need of further researches on disease modifiers.2


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