Are statins ‘IDEAL’ for non-alcoholic fatty liver disease?

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and cause of elevated serum liver enzyme activities in the developed world1. Obesity, diabetes mellitus (DM), and dyslipidaemia, common components of the metabolic syndrome (MetS), are frequently associated with NAFLD; 75–100% of patients with MetS or DM have NAFLD2. NAFLD is characterized by hepatic triglyceride (TG) infiltration in the absence of alcohol abuse or chronic liver disease1. NAFLD includes a spectrum of conditions varying from steatosis to steatosis with inflammation [steatohepatitis (NASH)], necrosis, fibrosis or cirrhosis that rarely progresses to hepatocellular carcinoma3. NAFLD and NASH are the hepatic manifestations of MetS and are associated with increased cardiovascular disease (CVD) risk4. Most NAFLD/NASH patients die from CVD rather than from liver disease4,5. There is no universally accepted treatment for NAFLD1-5.

Keywords::

• Cardiovascular disease
• Clinical benefit
• High dose
• Non-alcoholic fatty liver disease
• Statin treatment
• Transaminases

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and cause of elevated serum liver enzyme activities in the developed world1. Obesity, diabetes mellitus (DM), and dyslipidaemia, common components of metabolic syndrome (MetS), are frequently associated with NAFLD; 75–100% of patients with MetS or DM have NAFLD2. NAFLD is characterized by hepatic triglyceride (TG) infiltration in the absence of alcohol abuse or chronic liver disease1. NAFLD includes a spectrum of conditions varying from steatosis to steatosis with inflammation (non-alcoholic steatohepatitis [NASH]), necrosis, fibrosis or cirrhosis that rarely progresses to hepatocellular carcinoma3. NAFLD and NASH are the hepatic manifestations of MetS and are associated with increased cardiovascular disease (CVD) risk4. Most NAFLD/NASH patients die from CVD rather than from liver disease4,5. There is no universally accepted treatment for NAFLD1–5.

There are common mechanisms between NAFLD/NASH and CVD and an independent contribution of the inflamed liver to the pathogenesis of CVD4,6. Thus, statins have been proposed as treatment for NAFLD/NASH7. Statins treat dyslipidaemia and they also exert an anti-inflammatory pleiotropic effect8. There may be a reluctance to use statins in these patients because elevated aminotransferases are not uncommon in patients where statins are indicated. However, serious liver injury from statins is very rare7.

The Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study was a prospective, randomized, open-label, blinded end-point trial conducted in northern Europe between 1999 and 2005 (median follow-up of 4.8 years); IDEAL enrolled 8888 patients with a history of acute myocardial infarction (MI)9. Participants were randomly assigned to a high dose of atorvastatin (mainly 80 mg/d; n = 4439), or a usual-dose simvastatin (20–40 mg/d; n = 4449). The primary end-point was the occurrence of a major coronary event, defined as coronary death, confirmed non-fatal acute MI or cardiac arrest with resuscitation9. Intensive lowering of low density lipoprotein cholesterol (LDL-C) did not result in a significant reduction in the primary outcome of major coronary events, but reduced the risk of other composite secondary end-points and non-fatal acute MI9.

Recently, a post hoc analysis of IDEAL10 compared intensive vs moderate statin therapy for the prevention of CVD events in patients with a previous MI and normal or elevated baseline serum alanine aminotransferase (ALT) activity10. There were 8863 patients with baseline ALT values, 7782 (87.8%) had an ALT activity < upper limit of normal (ULN), while 1081 (12.2%) had a moderate elevation (<2 × ULN or <3 × ULN for those on a statin at randomization) in ALT activity. At baseline, patients with moderate elevations of ALT activity had a higher body mass index (BMI), diastolic blood pressure, and TG levels, lower high density lipoprotein cholesterol (HDL-C) levels, and a greater prevalence of DM compared with patients with normal baseline ALT activity, thus, MetS was more common among those IDEAL patients with elevated ALT activity at baseline10. In IDEAL, serum ALT activity decreased in the patients with elevated baseline ALT activity, and this group benefited more from intensive statin therapy than from moderate statin therapy in terms of reduction in major CV events1. In participants with elevated baseline ALT activity, major CVD event rates were 11.5% for simvastatin and 6.5% for atorvastatin, indicating a significant risk reduction with intensive statin therapy (hazard ratio [HR], 0.556; 95% confidence interval [CI], 0.367–0.842; p = 0.0056). Heterogeneity of treatment effect was observed but there was a greater benefit for cerebrovascular events and major coronary events with atorvastatin in the elevated ALT activity group than in the normal baseline ALT activity group10. Most patients with moderately elevated baseline ALT levels had ‘atherogenic dyslipidaemia’ or the ‘lipid triad’11,12. These have an increased presence of small, dense LDL (sdLDL) particles, a common finding in insulin resistance and MetS11,12. The reduction of this atherogenic LDL fraction by statin treatment13,14 could have contributed to the greater treatment benefit10. Atorvastatin not only reduces the number of sdLDL particles, but also inhibits, in a dose-dependent manner, lipid oxidation in human LDL particles with a preference in sdLDL13. This could induce a clinical benefit both for the liver and the heart14. The authors concluded that moderate elevations in ALT activity should not be a barrier to prescribing statins in high-risk patients10.

It has been proposed that ALT activity might be used as a surrogate marker for NAFLD in addition to metabolic disease markers15,16. The ALT cut-off values for NAFLD diagnosis were estimated at 25 U/L for males and 17 U/L for females15. Thus, it is likely that most of IDEAL patients with moderate elevations of ALT activity had NAFLD, the most common cause for elevated serum liver enzyme activities1. Besides, most IDEAL patients with a high baseline ALT value had MetS10. Thus, in this post-hoc analysis of the IDEAL trial, the administration of a high atorvastatin dose was safe (minor ALT elevations were observed in 1% of participants), including the 1081 patients with mild to moderately elevated serum ALT activity at baseline. Moreover, these 1081 IDEAL patients had a significantly greater statin-induced benefit (coronary death, non-fatal acute MI, resuscitated cardiac arrest or stroke) than in 7782 patients with normal serum ALT activity at baseline10.

Three years ago a post-hoc analysis17 of the prospective, randomized, controlled, target based, open-label Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study18 demonstrated a significant CVD benefit with statin therapy in coronary heart disease (CHD) patients with elevated ALT activity (<3 × ULN) at baseline17. In this subgroup analysis, the 1600 GREACE patients randomized to receive statin treatment or usual care over a 3 year follow-up period were stratified by baseline ALT activity into those with moderately elevated ALT activity and those with normal ALT activity at baseline. In the elevated baseline ALT activity group, CVD events occurred in 9.7% of statin-treated patients (n = 227) and in 30.0% of usual-care patients (n = 210). The 68% reduction in relative risk for CVD events was significantly greater than the 39% relative risk reduction achieved by statin therapy vs usual care in patients with normal ALT activity at baseline (CVD event rate: 13.8 vs 22.9%, respectively)17. We concluded that it was likely that elevated ALT activity and fatty liver on ultrasound were indicators of NAFLD and that the lipid lowering and pleiotropic effects of statin therapy prevented the progression of NAFLD thus contributing to the reduction of CVD events17.

To exclude the possibility that this effect of statins only occurs in secondary prevention high risk patients, we tested this hypothesis in MetS patients with NAFLD but without CVD or DM, first in a small study (n = 186)19 and then in a survival study, the Assessing The Treatment Effect in Metabolic Syndrome Without Perceptible diabeTes (ATTEMPT)20. ATTEMPT was a prospective, randomized, open-label study that included 1123 MetS patients (aged 45–65 years), followed up for 42 months20. Patients received intensive lifestyle intervention and drug therapy with atorvastatin in all patients (LDL-C targets <100 mg/dl [group A] or <130 mg/dl [group B]), inhibitors of the renin–angiotensin–aldosterone axis for hypertension, metformin for dysglycaemia and orlistat for obesity. Attaining the treatment target of LDL-C <100 mg/dl within multifactorial treatment of MetS, is achievable and beneficial even in patients without DM or known CVD. In a post hoc analysis of the ATTEMPT study, we assessed the long-term effects of the multifactorial intervention mentioned above on liver tests and their association with CVD events in patients with MetS, without DM or CVD21. In the two groups of this analysis all treatments were exactly the same except the dose of the statin (atorvastatin 34 mg/day in the first and 24 mg/day in the second group) aiming to achieve an LDL-C target of <100 mg/dl in the first and <130 mg/dl in the second21. The results showed that attaining multiple treatment targets is safe and beneficial in primary prevention patients with MetS and NAFLD (defined by liver tests and ultrasound). Lipid levels and ALT, AST, alkaline phosphatase, gamma glutamate transferase activities normalized, liver ultrasound findings associated with NAFLD resolved and no CVD events occurred in patients with the high atorvastatin dose (vs 5 events in the low dose atorvastatin group).

These effects are probably shared by other statins since in a preliminary report that included six patients with biopsy proven NASH, rosuvastatin (10 mg/day) improved (by the third month) liver enzyme activities which returned to normal. There was also a complete resolution of NASH in the post-treatment biopsy in five of the six patients22.

In conclusion, NAFLD, NASH and CVD share common risk factors. Statins can improve some of these risk factors and thus might prevent or treat NAFLD/NASH. Furthermore, statins improve symptom-free survival from CVD in patients with NAFLD to a greater extent than in those with ‘normal’ livers. Such a dual clinical benefit may lead physicians to consider statin treatment for NAFLD patients with elevated ALT activity (<3 × ULN)23.

Transparency

Declaration of funding

This editorial was written independently. The authors did not receive financial or professional help with the preparation of the manuscript.

Declaration of financial/other relationships

NK has given talks and attended conferences sponsored by Novartis, Pfizer, MSD and AstraZeneca. AK has given talks and attended conferences sponsored by Menarini, AstraZeneca, Novartis and Pfizer. DPM has given talks and attended conferences sponsored by Genzyme, MSD.