Statins, also known as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely used lipid-lowering drugs with proven effects in both primary and secondary prevention of cardiovascular disease.1 Given the benefit of lowering LDL cholesterol for reduction in risk of cardiovascular morbidity, statin use is highly prevalent with an estimated 25% of adults over age 40 using these lipid-lowering drugs. In adults age 75 and older, 50% are on statin therapy.2 The pleiotropic effects of statins are increasingly being recognized3,4, with benefits beyond lipid-lowering properties and an increasing number of studies demonstrating favorable effects of statins in persons with chronic liver disease and cirrhosis.3 We review the safety of statin use in both the general population and subsequently in persons with cirrhosis, with a specific focus on statin-induced hepatotoxicity and statin-associated muscle symptoms (SAMS). Next, we review available data on efficacy of statins in the clinical management of cirrhosis, including a summary of potential benefits related to reduction in hepatic decompensation and death, effects on portal hypertension, and reduction in risk for HCC. It is important to note that all current evidence on the efficacy of statins in cirrhosis is retrospective, and therefore we will also highlight ongoing prospective studies that we anticipate will increase our understanding of the role of statins in cirrhosis.
POTENTIAL ADVERSE EFFECTS OF STATINS IN THE GENERAL POPULATION
Despite the widespread use of statins, discontinuation of use in the general population is not uncommon, with some studies indicating that up to 10% of patients prescribed statin therapy discontinue therapy due to side effects.5 Statins have been linked to a dose-dependent effect on aminotransferases and risk for SAMS, the latter which is the most common reason for treatment discontinuation.5 We first review our current knowledge on the safety and potential adverse effects of statins in the general population.
Statin-induced hepatotoxicity
In the general population, statins have been linked to a dose-dependent effect on aminotransferases, but in the majority of cases, these transaminase elevations are mild (<3–5 times the upper limit of normal), transient, asymptomatic, and do not require treatment discontinuation.6–9 This effect on aminotransferases can be observed in up to 3% of statin users, and the incidence is similar among all statins indicating an overall class effect.10 Mechanistic pathways for asymptomatic rises in transaminases without histologic changes have not been well elucidated but may result from changes in hepatocyte membrane lipid composition.11 This usually occurs within 90 days after initiation of statin therapy, and a meta-analysis including ∼50,000 patients revealed no significant difference in transaminases between those in treatment and placebo groups after 12 weeks or more of therapy.12 More recent guidelines have indicated that follow-up liver enzyme testing is not uniformly required after statin initiation.13
In contrast, serious hepatotoxicity including jaundice, hepatitis, or acute liver failure is very uncommon with statins.14 A number of studies have evaluated the prevalence of idiosyncratic DILI with statins, which has been reviewed in detail elsewhere.15 In a Swedish registry study, statin use was associated with a very low incidence of severe idiosyncratic DILI (1.2/100,000).10 A population-based study performed in Iceland over a 2-year period identified only 3 cases of clinically significant liver injury from statins.16 Other studies have corroborated these findings and found the rate of statin-induced acute liver failure is 0.2 cases per million in the US.17 Altogether, available data suggests that serious hepatotoxicity related to statins is exceedingly rare. It is important to note that there have been several case reports of autoimmune hepatitis triggered by statins, predominantly several months following statin exposure, and postulated to be secondary to the induction of autoantibodies to biosimilar epitopes.18 This has mainly been reported with atorvastatin and rosuvastatin and responds to immunosuppression similar to other forms of drug-induced autoimmune hepatitis.19–22
Chronic liver disease without cirrhosis and mild elevations in serum transaminases should not be considered a contraindication to statin use. In fact, many patients with mild elevations in liver enzymes likely have concomitant NAFLD, the subset of patients with the most benefit to be gained from initiation and continuation of lipid-lowering therapy. A study leveraging the National Health and Nutrition Examination Survey (NHANES) database and examining trends in statin utilization from 2005 to 2018 revealed that <20% of adults with NAFLD, an independent risk factor for atherosclerotic cardiovascular disease, were receiving statin therapy.23 This is despite a growing body of evidence, predominantly in adults with NAFLD and chronic hepatitis C, which has revealed no difference in risk of hepatocellular injury with statin exposure.6,7,13,24
SAMS
Muscle toxicity related to statins is a spectrum of adverse events ranging from myalgias to a more severe phenotype of rhabdomyolysis. SAMS are the most prevalent adverse event with statin therapy, comprising over 70% of all reported adverse events in the general population.25 SAMS usually affects proximal muscles in the lower extremities in a symmetric fashion. The prevalence of SAMS likely differs between statin classes, with the highest risk associated with lipophilic statins given the ability to more freely diffuse into extrahepatic tissues.11 The risk of SAMS is often greatest in the first year of therapy or with a dose increase, and polypharmacy (specifically with the introduction of drugs metabolized by cytochrome P450) may also be a common precipitating event for SAMS development. Additional risk factors include higher statin dose, older age, female sex, frailty, low body mass index, and concomitant alcohol use.26–29
There are also genetic risk factors for SAMS30, including patients with single-nucleotide polymorphisms in a statin membrane transporter (OATP1B1) who are at higher risk of increased exposure.26SLCO1B1 encodes the organic anion-transporting polypeptide (OATP1B1) influx transporter which is expressed on hepatocytes and regulates the uptake of statins, thus influencing their serum levels.31,32 Two common single-nucleotide polymorphism variants of the SLCO1B1 gene (rs2306283 and rs4149056) have been shown to affect OATP1B1 transport function, although these are dependent on their combination in individual haplotypes and on the class of statin used (particularly relevant for lipophilic statins).31,32 The largest effect of rs4149056 is seen with simvastatin, followed by pitavastatin, atorvastatin, pravastatin, and rosuvastatin, with no effect observed for fluvastatin. This difference may be partly explained by varying contributions of other organic anion-transporting polypeptides to hepatic uptake.31 Genome-wide scans have revealed strong associations between simvastatin-associated myopathy and the rs4363656 single-nucleotide polymorphism.26
Other adverse effects
Other adverse effects have been associated with statin use, including new-onset type 2 diabetes mellitus, cataract formation, and renal toxicity, for which mechanistic insights have been reviewed elsewhere.11 There have been studies linking statins with new-onset type 2 diabetes mellitus, but this has predominantly been reported in older recipients with preexisting metabolic comorbidities receiving high-dose statin therapy.33,34 New-onset diabetes has been observed with both lipophilic and hydrophilic statins, and the pathophysiology is not well understood. Renal dysfunction with statin therapy, including mild transient proteinuria, is more controversial and not well established35, as most statins are metabolized by the liver and minimally cleared by the kidney.
SAFETY OF STATINS IN CIRRHOSIS
Safety concerns have been a primary reason cited by providers for less frequent statin use in patients with chronic liver disease.36 As a result, statins are often underprescribed in persons with cirrhosis. For example, a prior study found that among patients with coronary artery disease and cirrhosis undergoing liver transplantation evaluation, only 23% were receiving statin therapy.37 This prevalence of statin use is well below what has been found in routine clinical practice in the US, where studies have revealed that ∼75% of guideline-eligible patients receive statin therapy.38
We do know that pharmacokinetics of statins are altered in persons with cirrhosis due to impairments in synthetic function, with the greatest pharmacokinetic alterations in patients with decompensated disease.39 A recent meta-analysis revealed a trend toward increase in both exposure (AUC) and maximum plasma concentration (Cmax) of statins in adults with Child-Pugh A and B cirrhosis as compared with those without cirrhosis, although data was only available for a subset of statins and the sample size was small.40
Despite altered pharmacokinetics of statins in cirrhosis, several studies have demonstrated low risk of adverse hepatic effects with statin therapy. A population-based cohort study in Taiwan including 37,929 persons with chronic liver disease found very low incidence of hospitalization due to hepatic injury (1.94–2.95/100,000 person days).41 A meta-analysis including 17 clinical studies found no significant difference in DILI or hepatic decompensation (pooled OR = 0.9) in persons with cirrhosis with and without statin exposure.42 Numerous additional studies, both observational and randomized controlled trials, have found no significant hepatotoxicity with statin use in cirrhosis.24,43–46 However, it is worth noting that the proportion of patients included in these studies with more advanced and decompensated cirrhosis (eg, Child-Pugh C) is very limited.
The prevalence of SAMS in persons with cirrhosis on statin therapy appears to be comparable to prevalence in the general population, but ultimately more data is needed and particularly in those patients with more advanced disease. A meta-analysis including 17 clinical studies found no statistically significant difference in myalgia events (pooled OR = 1.45) in persons with cirrhosis with and without statin exposure.42 A single-center retrospective case-control study that included 1099 adults with decompensated cirrhosis listed for liver transplantation compared safety (defined by side effects, discontinuation, change in Model for End-stage Liver Disease Score, nontransplant hospitalization, and mortality) between those who took statins for at least 90 days before liver transplantation. There was no significant increase in these adverse events in statin users, and specifically, only 1 statin user developed myalgias but this did not require statin discontinuation.47 However, in one of the largest randomized trials to date evaluating statin use (simvastatin 40 mg daily) in persons with decompensated cirrhosis, 2/69 (3%) patients experienced rhabdomyolysis.48 This effect may be precipitated by the fact that simvastatin is extensively metabolized by the liver with a first-pass effect and is highly protein bound. Notably, lower doses of simvastatin (20 mg daily) were not associated with a significantly higher risk of rhabdomyolysis, but the study sample size was small and ultimately more safety data are needed. These data suggest that providers should have high vigilance for SAMS and rhabdomyolysis in patients with cirrhosis receiving statin therapy, particularly those with decompensated cirrhosis.
In summary, statins have excellent safety profile in persons with compensated cirrhosis and serious hepatotoxicity is rare. High vigilance for SAMS in all persons with cirrhosis on statin therapy is warranted. It is possible that there is a subset of patients with cirrhosis that are too ill for statin therapy as evidence on statin safety is lacking in persons with decompensated cirrhosis. Given limited data in this patient population, we suggest caution from use in advanced cirrhosis (Child-Pugh≥9), in which it is crucial to weigh the risks and benefits, as well as avoidance of high-dose simvastatin (40 mg daily) until further prospective evidence is available.
STATIN CHOICE IN PERSONS WITH CIRRHOSIS
The choice of statin therapy, as well as the dosing intensity, incorporates consideration of both efficacy and risk of adverse effects. Statin formulations differ in solubility (hydrophilic vs. lipophilic) and metabolism (whether metabolized by the cytochrome P450 system or not).49 Hydrophilic statins, including pravastatin and rosuvastatin, have liver-mediated mechanisms required for uptake, which results in greater hepatoselectivity. Lipophilic formulations, such as simvastatin and atorvastatin, can become more widely distributed in different tissues. Hydrophilic statins are excreted unchanged, whereas lipophilic statins generally undergo oxidative biotransformation before excretion.49
It is worth noting that studies to date have shown that there are no significant differences in efficacy related to coronary artery disease outcomes between hydrophilic and lipophilic statins. A meta-analysis that included 11,697 patients enrolled in 11 randomized controlled trials revealed similar risk reduction for major adverse cardiac events and all-cause mortality. Notably, SAMS did not differ between statin formulations either.50 A multicenter prospective study including 508 patients with acute myocardial infarction evaluating secondary prevention found no significant difference in secondary cardiovascular outcomes between type of statin during a follow-up period of 2 years.51 However, transient alanine aminotransferase elevation was higher (OR = 2.7) in lipophilic rather than hydrophilic-treated patients in adults prescribed statin therapy for cardiovascular risk reduction.50
There is paucity of data related to statin choice, particularly hydrophilic versus lipophilic statins, in persons with cirrhosis and clinical studies have been limited to use of simvastatin, atorvastatin, and pravastatin.52 Data is also limited in adults with noncirrhotic chronic liver disease. Prior studies have found that atorvastatin and fluvastatin were associated with the most potent antifibrotic effects in a cohort of adults with noncirrhotic chronic hepatitis C.53 Lipophilic statins, as compared with hydrophilic statins, were more associated with reduced incidence of HCC and mortality in a nationwide viral hepatitis cohort.54
Data on hepatic dose adjustment related to pharmacokinetics in cirrhosis is also lacking. One study identified that atorvastatin was associated with the greatest increase in AUC, particularly in those with decompensated cirrhosis, whereas pharmacokinetics of rosuvastatin were not significantly altered in persons with cirrhosis.40 Other studies have yielded conflicting results and have shown that the maximum plasma concentrations of rosuvastatin, as well as fluvastatin, are increased by almost 2-fold in cirrhosis.55 A more recent meta-analysis aimed to address the pharmacokinetics of statins in cirrhosis, with rosuvastatin and pitavastatin showing minimal changes in pharmacokinetic profiles in Child-Pugh A cirrhosis, but atorvastatin leading to pronounced pharmacokinetic shifts.52 No pharmacokinetic data were available on simvastatin in cirrhosis, despite the fact that this statin has been utilized in a number of clinical trials, which are reviewed later.52
Altogether, there is currently insufficient evidence to recommend one statin over another in persons with cirrhosis. Future studies are needed to examine pharmacokinetics and safety of statin formulation and dosage in cirrhosis. We eagerly await data randomized data with larger sample sizes, which are detailed later.
CLINICAL USE SETTINGS FOR STATINS IN CIRRHOSIS
In addition to their lipid-lowering properties, statins exhibit multiple pleiotropic effects such as antioxidative, antiproliferative, and anti-inflammatory properties, as well as the capacity to improve endothelial function and to stimulate neoangiogenesis. Preclinical evidence suggests a number of proposed mechanisms which underscore potential clinical benefit in cirrhosis including: (1) decreased oxidative stress and inflammation in part related to effects on mesenchymal stem cell differentiation56–58, (2) improvement in endothelial function and hepatic vascular tone through nitric oxide synthesis and increase in endothelial progenitors59–62, (3) decreased stellate cell turnover63, and (4) protection from lipopolysaccharide-mediated damage and ischemia-reperfusion injury.64,65 A summary of preclinical evidence regarding the proposed mechanisms by which statins may influence liver disease progression is shown in Figure 1.
;)
Figure 1: Overview of preclinical evidence for proposed mechanisms by which statins may influence the natural history of chronic liver disease, including the following states: hepatic inflammation, advanced fibrosis/cirrhosis, cirrhosis with portal hypertension, and HCC. Abbreviations: LPS, lipopolysaccharide; NO, nitric oxide.
A number of studies have shown benefit of statins in precirrhotic liver disease, including prevention and retardation of fibrosis progression, but these have recently been reviewed elsewhere.66,67 Here, we focus on the potential role of statins in cirrhosis, specifically as it relates to risk of hepatic decompensation and mortality. We also review data on the effects of statin on portal hypertension and risk for HCC. A summary of the evidence to date regarding the association of statin use on the natural history of cirrhosis is shown in Figure 2.
Figure 2: Summary of clinical evidence on the effect of statins on the natural history of cirrhosis. Most clinical evidence has been obtained from retrospective studies.
Reduction in disease progression: risk of hepatic decompensation and mortality
Progression to decompensation in cirrhosis portends a significant change in clinical status and prognosis, and therefore prevention of initial hepatic decompensation is important. An increasing number of observational studies have yielded data suggesting benefit from statins in reducing the risk of hepatic decompensation and mortality in cirrhosis. We have summarized these studies and their primary findings in Table 1.
Table 1 -
Summary of studies to date with data on the association between statin therapy and risk of hepatic decompensation and mortality in cirrhosis
| Referencesa |
Etiologies of cirrhosis |
Patient population |
Primary study finding |
| Motzkus-Feagans et al.73 |
HCV and alcohol |
Adult US veterans with cirrhosis but without decompensation (n = 19,739) |
Statin use associated with less hospitalizations for infections (HR = 0.67) |
| Kumar et al.68 |
NAFLD, alcohol, and viral hepatitis |
Adults with biopsy-proven cirrhosis (n = 243) |
Statin use associated with lower mortality (HR = 0.53) |
| Mohanty et al.71 |
HCV |
Adult US veterans with compensated cirrhosis (n = 40,512) |
Statin use associated with lower risk of decompensation (HR = 0.55) and mortality (HR = 0.56) |
| Bang et al.70 |
Alcohol |
Adults with cirrhosis enrolled in Danish registry (n = 24,748) |
Statin use associated with lower risk of mortality (HR = 0.57) |
| Chang et al.69 |
HCV and HBV and alcohol |
Adults with cirrhosis and Taiwan National Health Insurance (n = 1350) |
Statin use associated with lower risk of decompensation in HBV (HR = 0.39) and HCV cirrhosis (HR = 0.51), but not significant in alcohol-related cirrhosis |
| Kaplan et al.72 |
HCV, alcohol, NASH |
Adult US veterans with new diagnosis of cirrhosis (n = 74,984) |
Each year of statin exposure among new initiators was associated with reduced mortality (HR = 0.92) |
| Mahmud et al.74 |
HCV, alcohol, and NASH |
Adult US veterans with cirrhosis (n = 84,963) |
Statin use associated with lower risk of acute-on-chronic liver failure (HR=0.75) |
aAll studies included are retrospective cohort studies and enrolled patients with established cirrhosis.
One of the earliest studies to demonstrate the association between statins and risk of hepatic decompensation included 81 statin users (defined by 3 consecutive months or more of therapy) and 162 matched controls (matched to age, sex, and Child-Pugh class) with biopsy-proven cirrhosis (all etiologies eligible for inclusion). Statin users had a 47% lower risk of mortality compared with nonusers.68 A population-based and propensity-matched retrospective study including 1350 adults in Taiwan with cirrhosis (etiologies included chronic hepatitis B and C and alcohol-related) revealed a dose-dependent lower risk of decompensation among statin users in those with HBV and HCV cirrhosis (adjusted HR = 0.39 and 0.51, respectively). The primary benefit was seen in reduction of ascites-related complications. However, there was not a statistically significant reduction in risk of hepatic decompensation in those with alcohol-related cirrhosis, which was postulated to be potentially related to medication adherence although ultimately unclear.69 A subsequent retrospective population-based Danish registry study which included 24,748 individuals with alcohol-related cirrhosis, among which 15% were statin users, noted an ∼40% reduction in all-cause mortality in those with statin exposure.70
Several studies utilizing the United States Veterans Health Administration data have found similar associations between statin use and reduction in risk for hepatic decompensation and mortality. Mohanty et al.71 performed a retrospective cohort including 40,512 veterans with compensated cirrhosis secondary to HCV and found an ∼40% lower risk of hepatic decompensation and death. Kaplan et al.72 reported that among both existing and new initiation statin users with Child-Pugh A and B cirrhosis, each cumulative year of statin exposure was associated with an 8% decrease in mortality. Among US veterans with cirrhosis (n = 19,379) followed for hospitalizations with infections, statin users experienced a 33% reduction in rate of infection.73 In addition, a recent study stratified 84,963 US veterans with cirrhosis into 3 groups based on statin exposure (statin naive, existing statin user, and new statin initiator) and noted that statin use was associated with an ∼40% reduction in acute-on-chronic liver failure.74 This finding is corroborated by findings from a randomized controlled trial (LIVERHOPE) examining simvastatin in cirrhosis, which identified a serum metabolomic signature of acute-on-chronic liver failure comprised of 32 metabolites, of which 18 were affected by statin treatment.75
Several meta-analyses have examined the association between statin use and the risk of hepatic decompensation and mortality. A meta-analysis including 121,058 persons from 13 studies reported that statin use in cirrhosis was associated with a 46% lower risk of hepatic decompensation.76 In a subgroup analysis of a subsequent meta-analysis which included 10 studies (1 randomized, 9 observational) with 259,453 subjects, a pooled HR of 0.54 for hepatic decompensation and 0.67 for mortality was noted, but the quality of evidence was deemed low.
It is important to note the limitations of the current data examining the effect of statins on risk for hepatic decompensation and mortality in persons with cirrhosis. All studies to date are retrospective cohort studies. Although the sample size was large in many of these studies, including several population-based studies, there is likely residual confounding on liver disease progression, including factors such as concomitant nonselective beta-blocker use, alcohol use, as well as diabetes and other comorbidities. Moreover, statin dose and duration are likely not precisely measured based on a retrospective study design. It is plausible that those patients with more compensated cirrhosis are the patients more likely to be receiving statin therapy, thus overestimating the benefit of statins in cirrhosis. Furthermore, most data have been derived from cohorts with cirrhosis secondary to viral hepatitis [chronic hepatitis B (HBV) and chronic hepatitis C (HCV)], so generalizability to diverse etiologies of cirrhosis is less clear. Ultimately, prospective randomized data is needed before the recommendation for use of statins in cirrhosis to prevent decompensation and reduce the risk of all-cause mortality.
Effects on portal hypertension
There is increasing interest in the use of statins to reduce HVPG and thus ameliorate portal hypertension in persons with cirrhosis. Preclinical evidence has demonstrated that simvastatin decreases sinusoidal pressure by increasing hepatic nitric oxide production77, and these vasoprotective effects may be mediated by the upregulation of Kruppel-like factor 2.78 The use of statins to alleviate portal hypertension would be synergistic with nonselective beta-blockade, the effects of which are mediated by reducing portal blood flow.79 In a proof-of-concept study, 23 consecutive patients with cirrhosis were randomized to propranolol alone versus propranolol with atorvastatin and HPVG was estimated at baseline and after 30 days. A greater decrease in HVPG was seen in those receiving atorvastatin, but long-term clinical outcomes did not differ between groups.80 The lack of effect on clinical outcomes could be related to the study’s small sample size and short treatment duration.
Several subsequent randomized controlled trials have examined the effect of statins on portal hypertension. Pollo-Flores and colleagues randomized 34 patients with cirrhosis and portal hypertension to simvastatin or placebo for 3 months and examined for a decrease in HVPG of at least 20% from baseline or to ≤12 mm Hg after the treatment. Most patients were Child-Pugh Class A or B and about two thirds were receiving nonselective beta-blocker therapy. Overall, 55% of the simvastatin group had a clinically relevant decrease in HVPG, compared with none in the placebo group.45 A subsequent randomized double-blind trial included 59 patients with cirrhosis and portal hypertension randomized to simvastatin versus placebo for 1 month and found that simvastatin decreased HVPG by ∼8%.48 The BLEPS (Bleeding Prevention with Simvastatin) trial is the largest trial to date examining statins and portal hypertension and included 158 adults with cirrhosis at the time of initial variceal hemorrhage and thus requiring secondary prophylaxis. Patients were randomized at 14 clinical centers to either simvastatin (20 mg/d for 2 wk followed by 40 mg/d) or placebo and followed for up to 24 months. The primary endpoint was a composite rebleeding and death. Simvastatin had no effect on rebleeding but was associated with survival benefit in those with Child-Pugh A and B cirrhosis (HR = 0.39).48 Strict inclusion criteria may affect generalizability to patients presenting with variceal bleeding, given those patients with more advanced hepatic dysfunction were excluded from study enrollment.
Reduction in HCC risk
HCC incidence is increasing and is a major contributor to cancer burden both in the US and worldwide.81 Mechanisms by which statins may reduce the risk of HCC have been recently reviewed elsewhere and include effects on inflammation and angiogenesis, viral replication (in persons with viral hepatitis), and inhibition of mevalonate synthesis.82 One of the earliest studies to demonstrate an association between statin use and reduction in HCC incidence was a matched case-control study including adults with diabetes. Statin use was associated with a 25% reduction in risk for HCC in adjusted analyses.83 Several retrospective cohort studies, predominantly in viral hepatitis cohorts and with the use of lipophilic statins, have found a lower incidence of HCC with statin exposure.76,84–89 Among these studies, only a few have predominantly included patients with advanced fibrosis and cirrhosis.89
A prior meta-analysis reported that statin users were 37% less likely to develop HCC than nonusers, although there were heterogeneous results, risk factors for HCC varied widely, and the benefit was predominantly driven by studies including Asian populations.90 More recently, a meta-analysis that included data from 25 studies with 1,925,964 patients reported a 25% reduction in HCC incidence in statin users, as compared with nonusers, in adjusted analyses.91 The effect of statins on reduced HCC incidence was dose-dependent, more pronounced with lipophilic statins, and greatest in those with viral hepatitis (specifically chronic hepatitis B). Limitations of both meta-analyses include inconsistencies in adjusting for HCC risk factors and heterogeneity among studies. Moreover, there was a lack of granular data on statin dosage as well as the exposure duration in most studies.
There is emerging data regarding statin use following the diagnosis of HCC. Statin use has been associated with decreased HCC recurrence in liver transplant recipients92 and following curative primary resection93,94, although statin use has not been demonstrated to influence overall survival in these populations. Thrift et al.95 utilized the Veterans Administration Central Cancer Registry and found that statin use after diagnosis of HCC was recorded for 15% of patients and associated with a decreased risk of cancer-specific death (adjusted HR = 0.85) and all-cause mortality (adjusted HR = 0.89). However, another study found that the addition of pravastatin to sorafenib in those with advanced HCC did not improve overall survival compared with sorafenib alone.43
Altogether, evidence to date suggests that statin therapy is associated with reduced incidence of HCC and may yield benefits following diagnosis of HCC, but prospective randomized data is needed, particularly in those patients with established cirrhosis.
FUTURE RESEARCH AND CONCLUSIONS
There are several randomized controlled trials underway to examine efficacy of statins in cirrhosis. We have included a summary of these clinical trials in Table 2. There are several challenges related to trial design, including appropriate patient selection criteria as well as determination of statin formulation, dosage, and duration of treatment, which is reflected by the diversity in these criteria in active trials. Another challenge is the lack of consensus definitions for clinically significant endpoints in cirrhosis clinical trials.96 Furthermore, the clinical event rate for hepatic decompensation is much lower in prospective studies that makes it difficult to power the trial on clinical events. There are no data to replace these clinical events with noninvasive methods such as elastography (including vibration-controlled transient elastography or magnetic resonance elastography) as a clinically significant reduction in liver stiffness is uncertain in patients with cirrhosis. There are data regarding an increase in liver stiffness with both vibration-controlled transient elastography and magnetic resonance elastography to be associated with an increased risk of hepatic decompensation (Table 3).97–100 Until further data trials are utilizing elastography-assessed changes in liver stiffness to examine the efficacy of statin therapy in the prevention of hepatic decompensation in patients with cirrhosis. Nevertheless, we expect these studies will bolster existing cohort data and yield data not only on the clinical benefit of statins in cirrhosis, but also data on dosing, duration of therapy, and pharmacokinetics in the cirrhotic population.
Table 2 -
Prospective randomized controlled trials examining the efficacy of statin therapy in cirrhosis
| Clinical trial (NCT) |
Patient population |
Statin choice and duration |
Clinical endpoints |
| SACRED Trial (NCT03654053) |
Adults with compensated cirrhosis and clinically significant portal hypertension
Recruited from 11 Veterans Affairs medical centers |
Simvastatin 40 mg/d vs. placebo for 24 mo |
Primary:
Hepatic decompensation (variceal hemorrhage, ascites, encephalopathy)
Secondary:
HCC
Liver-related death
Death from any cause
Complications of statin therapy |
| STATLiver Trial (NCT04072601) |
Adults with cirrhosis and clinically significant portal hypertension |
Atorvastatin 10–20 mg/d vs. placebo for 18 mo |
Primary:
Composite endpoint of numbers of death or liver transplantation
Number of hospitalizations with liver-related complications
Secondary:
Patient survival
Number of adverse events
Number of patients developing decompensation
Additional secondary endpoints can be reviewed at clinicaltrials.gov |
| Liver Cirrhosis Network (LCN) |
A National Institutes of Health (NIH) initiative which will include a multicenter randomized controlled trial examining statins in adults with cirrhosis. Details regarding study design are not publicly available |
Table 3 -
Liver stiffness–based endpoints in cirrhosis trials
| Clinically significant change in liver stiffness |
| VCTEa |
Increase/change in LSM≥20% or ≥5 kPa |
| MREb |
Increase/change in LSM≥20% or ≥1 kPa
Change in liver stiffness category from<5 kPa to 5–8 kPa or ≥8 kPa |
aVCTE data: Loomba et al.
98, Petta et al.
100.
bMRE data: Ajmera et al.
97, Gidener et al.
99.
Abbreviations: LSM, liver stiffness measurement; MRE, magnetic resonance elastography; VCTE, vibration-controlled transient elastography.
In summary, statins have an acceptable safety profile in cirrhosis, although we advise caution in use in those with Child-Pugh C cirrhosis given the potential for adverse effects (specifically rhabdomyolysis) and lack of robust data in this population. There is promising data on the benefits of statins in cirrhosis, specifically related to the risk of hepatic decompensation and mortality, reduction in HVPG, and as chemoprevention for HCC. However, given the predominantly retrospective nature of current data, it is likely premature to recommend empiric statin use in cirrhosis in the absence of a cardiovascular indication.
CONFLICTS OF INTEREST
Rohit Loomba serves as a consultant for Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Inipharm, Intercept, Ionis, Janssen Inc., Madrigal, Metacrine Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sagimet, 89 bio, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer, and Siemens. Rohit Loomba is also co-founder of Liponexus Inc. Suzanne R. Sharpton has no conflicts to report.
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