Review of the role of statins in cirrhosis and portal hypertension.

INTRODUCTION Statins are a group of molecules that inhibit the activity of hydroxymethylglutaryl (HMG-CoA) reductase, lowering cholesterol levels. Besides their lipid-lowering effect, statins have also shown pleiotropic effects such as anti-inflammatory, antioxidative, and antiproliferative1(Fig. 1), thus being a promising therapeutic option for the treatment of many chronic diseases, including chronic liver diseases (CLD). In the last 10 years, once concerns about the safety of statins in patients with impaired liver function have been mostly addressed, several studies have evaluated the use of these drugs in CLD both in experimental models of liver injury and in clinical studies. This manuscript is a brief review on the current status, use, and effects of statins in CLD, mainly focusing on clinical studies assessing the potential therapeutic effect and the safety profile in cirrhotic and pre-cirrhotic conditions and portal hypertension.FIGURE 1: Pleiotropic effects of statins (Adapted from Pose E et al, J Hepatol 2019). The decrease in activation of small GTPases in hepatic stellate cells and liver sinusoidal endothelial cells leads to the activation of the PPARγ molecular pathway that reduces hepatic inflammation. Also, the inhibition of the Rho-kinase molecular pathway leads to the reduction of hepatic fibrogenesis. Finally, the inhibition of the activation of KLF2 leads to a reduced contraction of hepatic stellate cells leading to a reduction of portal pressure.EFFECTS OF STATINS ON PRE-CIRRHOTIC CONDITIONS The first available information in this group of patients derives from large retrospective cohort studies in patients with CLD due to hepatitis B or hepatitis C without cirrhosis. A reduction in the incidence of cirrhosis, development of HCC and mortality was observed in patients that received statin therapy.2,3 In the last few years, studies in patients with pre-cirrhotic conditions have orbited around Metabolic-Associated Fatty Liver Disease, showing a reduction on the risk of progression of fibrosis or the development of incident cirrhosis in retrospective studies of patients that received statins for the treatment of hypercholesterolemia.4 A recent meta-analysis concluded that statins reduce the risk of developing cirrhosis in patients with CLD of different etiologies.5 A summary of studies with statins in patients with pre-cirrhotic conditions is shown in Table 1. TABLE 1 - Cohort studies References Patients source Patients characteristics Study design No. patients Type of statin Follow-up period Endpoint Results Comments Yun, Hepatol Commun, 20226 Republic of Korea’s National Health Insurance Service database Hepatitis B Retrospective cohort study 32.307 statin users vs. 160.473 non-users – 218.472 person-year Diagnosis of cirrhosis Reduced risk of progression to cirrhosis defined at the day of outpatient visit or hospitalization (aHR 0.59) Reduced risk of progression to cirrhosis remained after matching. Dose-dependent protective effect of statins Lee, Am J Gastroenterol, 20217 National Health Information Database of the Republic of Korea NAFLD diagnosed by calculating fatty liver index (FLI) >60 Retrospective cohort study 174.043 statin users vs . 816.093 non-users – 6 years NAFLD development (FLI > 60) Significant liver fibrosis (BARD score ≥2 Reduced risk of NAFLD development (AOR 0.66) Reduced risk of significant liver fibrosis (AOR 0.66) Reduced the risk of NAFLD and liver fibrosis independently from the presence of diabetes mellitus Chang, Hepatology, 20178 Taiwan National Health Insurance Database Hepatitis B, Hepatitis C, and Alcohol-associated cirrhosis Retrospective cohort study 1.174 statin users vs. 6.453 non-users – Approximate median of follow-up of 3 years Decompensation Death HCC development Prevented decompensation aHR 0,39 (0,30-0,50) Decreased mortality aHR 0,46 (0,34-0,0,63) Decreased HCC development aHR 0,52 (0,35-0,76) Lower risk of ascites, variceal bleeding, and hepatic encephalopathy Analysis by etiology in HBV, HCV, and alcohol-associated cirrhosis Dose-dependent relationship Bang, APT, 20179 Danish National Patient Registry Alcohol–associated cirrhosis Retrospective cohort study 794 statin users vs. 4.623 non-users Simvastatin 79% Atorvastatin 8% Rosuvastatin 6% Approximate median of follow-up of 4 years Decompensation Death Prevented decompensation HR 0,29 (0,24-0,34) Decreased mortality HR 0,57 (0,45-0,71) Adjusted for adhesion to treatment but not for liver function scores. HE was not recorded as a decompensation Mohanty, Gastroenterology, 201610 US Veterans Health Administration Hepatitis C-related compensated cirrhosis Retrospective cohort study 1.323 statins users vs. 12.522 non-users Simvastatin 85% Lovastatin 10% Pravastatin 3% Rosuvastatin 1% Fluvastatin 1% Median of 2,5 years for statin users, 1,5 years for non-users Decompensation Death Prevented decompensation aHR 0,55 (0,39-0,77) Decreased mortality aHR 0,56 (0,46-0,69) Adjusted for analytical values and liver function scores. Also found a lower risk of ascites and variceal hemorrhage Dongiovanni, J Hepatol, 20154 Multicenter European cohort Patients with metabolic risk factors who underwent liver biopsy Cross-sectional cohort study 107 statins users vs. 1.094 nonusers Simvastatin 49% Rosuvastatin 27% Atorvastatin 17% Pravastatin 4% Fluvastatin 2% No follow-up period, cross-sectional study Liver fibrosis Steatohepatitis Associated with protection from liver fibrosis stage F2-F4 (OR 0.42)Associated with protection from steatohepatitis (OR 0.25) Matched cohort of 100 statins users vs. nonusers adjusted for gender, age, and genetic variants. Kumar, Dig Dis Sci, 201411 Partners Research Patient Data Registry NAFLD, Alcohol, Hepatitis C, and Hepatitis B-related cirrhosis Retrospective cohort study 81 statin users vs. 162 nonstatin users Simvastatin 49% Atorvastatin 30% 3 years for statin users, 2,5 years for non-users Decompensation Death Prevented decompensation HR 0,58 (0,34-0,98) Decreased mortality HR 0,66 (0,33-0,86) Low number of patients included, risk of selection and reporting biases Biopsy proven cirrhosis C. Motzkus-Feagans, APT, 201312 US Veterans Health Administration Hepatitis C and alcohol-associated compensated cirrhosis Retrospective cohort study 2.468 statins users vs. 16.408 nonstatin users Simvastatin 90% Lovastatin 9.4% 3,3 years Infections Prevented infections aHR 0,67 (0,47-0,95) Adjusted for age and comorbidities No data on liver function tests Not clear if patients with decompensated cirrhosis are included Note: Cohort studies of statins in patients with Chronic Liver Diseases.Abbreviations: aHR indicates adjusted HR; FLI indicates Fatty Liver Index; NAFLD, non-alcoholic fatty liver disease; BARD; AOR, adjusted odds ratio; OR, odds ratio; aHR, adjusted hazard ratio; HR, hazard ratio; HCC, hepatocellular carcinoma; HBV, hepatiits B virus; HCV, hepatitis C virus; HE, hepatic encephalopathy. Taken together, these studies suggest that statins may have beneficial effects by decreasing the progression of CLD. Nonetheless, these studies have some limitations as they are retrospective in nature and information might be incomplete or subject to biases. Currently, there are several ongoing randomized control trials (RCTs) assessing the efficacy of statins on liver fibrosis in CLD that will hopefully clarify if statins are beneficial in this scenario.13 EFFECTS OF STATINS ON CIRRHOSIS To date, several studies have shown the beneficial effects of statins in patients with cirrhosis, decreasing the rates of decompensation and mortality.8,9 A recent study has also demonstrated the effect of statins in preventing the development of acute-on-chronic liver failure.14 Nevertheless, a notable part of this evidence comes from retrospective cohorts, and results must be interpreted with caution. Patients in these studies had mixed etiologies of cirrhosis, mainly viral hepatitis and alcohol-associated liver disease. The characteristics and results of these studies are summarized in Table 1. The only RCT with hard clinical endpoints to date showed an increase in survival in patients with cirrhosis and portal hypertension treated with simvastatin after an episode of variceal bleeding, although the study was negative for the primary endpoint that was a combined endpoint of rebleeding and death.15 As a result of the evidence and studies developed to date, EASL guidelines recognize the beneficial effects of statins in cirrhosis but also claim that further clinical research is needed in this field.16 In this regard, several RCTs with hard endpoints are currently ongoing to confirm these potential beneficial effects of statins in compensated and decompensated cirrhosis (NCT04072601, NCT03654053, NCT01282398, and NCT03654053). To note most of these trials are being conducted with simvastatin, which is the one that has accumulated the most evidence for this indication. A summary of the trials with statins in cirrhosis is shown in Table 2. TABLE 2 - Clinical trials References Patients source Patients characteristics Study Design Number of patients Type of statin Follow-up period Endpoint Results Comments Muñoz, Dig Dis Sci, 202117 Tertiary Hospital in Argentina Compensated and decompensated cirrhosis Prospective, open, uncontrolled trial 30 patients Simvastatin 1 year Simvastatin safety assessed by liver and muscle toxicity No cases of liver injury. Dose reduction in 23% of patients due to muscle toxicity Muscle toxicity in patients with MELD score >12 points and Child-Pugh C cirrhosis Vijayaraghavan, Am J Gastroenterol, 202018 Tertiary Hospital in India Cirrhosis and portal hypertension (HVPG≥12mm Hg) Unicenter open-label RCT 110 patients on simvastatin plus carvedilol vs. 110 patients on carvedilol in incremental dose Simvastatin 3 months Change in HVPG Proportion of patients achieving hemodynamic response at the end of 3 months: 32.7% in each group Two patients in each group presented an episode of portal hypertensive bleeding. One patient died in the carvedilol plus simvastatin group vs. 3 in the car+vedilol group Pose, Lancet Gastroenterol Hepatol, 202019 9 European Academic Centers Decompensated cirrhosis and Child-Pugh score7-12 points Multicenter RCT 16 patients on simvastatin 40 mg/day plus rifaximin 1200 mg/day, 14 patients on simvastatin 20 mg/day plus rifaximin mg/day, 14 patients on placebo Simvastatin 3 months Simvastatin safety assessed by liver and muscle toxicity Significant increase in the levels of transaminases and creatin kinase in the simvastatin 40 mg plus rifaximin group. Three cases of rhabdomyolysis in this group. No significant increase in transaminase levels or muscle toxicity in the simvastatin 20 mg group. Bishnu, Eur J Gastroenterol Hepatol, 201820 Tertiary Hospital in India Cirrhosis and portal hypertension (HVPG≥12mm Hg) Unicenter randomized single-blind, open-labeled Trial 11 patients on atorvastatin 20 mg daily with propranolol in incremental dose Atorvastatin 1 month Change in HVPG Decrease in HVPG 2.82 vs. 2.58 mm Hg in atorvastatin vs. no-atorvastatin group Assessment of clinical outcomes after 1-year follow-up, no differences in the incidence of decompensations or death Abraldes, Gastroenterology, 201615 14 Spanish Academic Centers Cirrhosis and variceal bleeding 5-10 days before inclusion Multicenter RCT 69 patients on statin treatment vs. 78 patients on placebo Simvastatin 2 years Rebleeding or death (composite) Death No significant decrease in risk of rebleeding or death Decreased mortality HR 0,39(0,15-0,98) Decrease in liver-related death No significant decrease in the primary endpoint or in specific complications of cirrhosis P. Pollo-Flores, Digestive and Liver Disease, 201521 1 Universitary Hospital Cirrhosis and portal hypertension (HVPG≥5 mm Hg) Unicenter RCT 14 patients on statin treatment vs. 20 patients on placebo Simvastatin 3 months Change in HVPG Reduced HVPG in patients under statin treatment compared with placebo: -2 vs. 0 mm Hg, P=0,02 Previous variceal bleeding independent variable associated with clinically significant response to simvastatin Nonsevere adverse events related to medication Abraldes, Gastroenterology, 200922 3 Universitary Hospitals Cirrhosis and portal hypertension (HVPG≥12 mm Hg) Multicenter RCT 27 patients on statin treatment vs. 28 patients on placebo Simvastatin 1 month Change in HVPG Decreased HVPG from 18,5 to 17,1 mmHg (P=0,003), no decrease in the placebo group Simvastatin administration improved quantitative tests of liver function (indiocyanine green clearance) non-severe adverse events related to medication Note: Clinical Trials with statins in patients with cirrhosis.Abbreviations: HVPG, hepatic venous pressure gradient; MELD, Model for End-Stage Liver Disease; mg, milligrams; mmHg, millimeters of mercury; RCT, randomized controlled trial.. EFFECTS OF STATINS ON PORTAL HYPERTENSION The effect of statins on portal hypertension has been studied in 4 RCTs through the measurement of HVPG in patients receiving statin therapy versus placebo, at baseline and at 1 or 3 months depending on the study.18,20,22,23 Except for 1 study that was conducted with atorvastatin, all the studies used simvastatin. Three RCTs showed a significant decrease in portal pressure in patients treated with statins.20,22,23 All 3 trials included a different proportion of patients treated with propranolol, ranging from 50% to 100%. Notably, statins decreased portal pressure independently of the use in combination with propranolol. Only 1 trial failed to show a significant reduction in portal pressure; in this trial simvastatin was prescribed in combination with carvedilol instead of propranolol.18 The use of carvedilol as bleeding prophylaxis in this trial could have affected the negative results, but further controlled studies are needed to assess the potential effect of this combination. Although a recent study showed positive results on the reduction of portal pressure with simvastatin and carvedilol, it was a noncontrolled study, and thus, conclusions should be taken with caution.24 A summary of the trials with statins for portal hypertension is shown in Table 2. As a result of the previous evidence, Baveno VII guidelines encourage the use of statins in patients with cirrhosis that already have an approved indication for their use, given that they may also decrease portal pressure (scientific grade of recommendation A1) and improve overall survival (scientific grade of recommendation B1) in this patient population.25 Similar recommendations are given by the EASL Guidelines for the management of patients with decompensated cirrhosis. In these guidelines, the potential benefit of the treatment with statins in patients with cirrhosis is acknowledged, but the recommendations are that further evidence is needed to confirm their safety and potential benefits in decompensated patients.16 SAFETY OF STATINS IN CIRRHOSIS Two side effects of statin therapy may be of particular concern in patients with cirrhosis, which are liver and muscle toxicity. Liver toxicity associated with statins is frequently consistent with transient elevations of transaminase levels, and severe DILI is extremely rare.26 Muscle toxicity severity ranges from myalgia to the most severe form, rhabdomyolysis. The risk of severe muscle toxicity seems to be related to statin systemic exposure, which is increased in patients with liver cirrhosis and impaired liver function, probably due to the reduced metabolism of the drugs.27 In patients with compensated cirrhosis, (Child A) treatment with simvastatin at high doses (40 mg per day) was not associated with an increased risk of muscle toxicity.18,20,22,23 However, in the 2 clinical trials developed to date, including patients with decompensated cirrhosis and impaired liver function, a higher risk of muscle toxicity has been shown.15,19 In contrast, no muscle toxicity has been described with low doses of simvastatin (20 mg per day) in this population.19 Nevertheless, it should be noted that most of the evidence on the safety of statins in patients with cirrhosis comes from studies with simvastatin or atorvastatin, which are lipophilic compounds. In the general population, hydrophilic statins, such as pravastatin and rosuvastatin, have shown a better safety profile and have been associated with a lower risk of muscle toxicity; moreover, these drugs undergo minimal hepatic metabolization.28 Studies with these statins in patients with cirrhosis are needed to explore their potential beneficial effects and their safety profile. With the current evidence, it seems reasonable to use statins with caution in the population of patients with decompensated cirrhosis and only at low doses of 20 mg/day. In this regard, Baveno VII consensus recommends using low doses of simvastatin (max. 20 mg) in patients with decompensated cirrhosis, being more restrictive for their use in Child-Pugh C cirrhosis (D.1 level of recommendation).