Editorial for ‘Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis’

Authors


Primary biliary cirrhosis (PBC) is a progressive liver disease with orphan status primarily affecting women at a rather low prevalence [1-4]. Ursodeoxycholic acid (UDCA) is currently the only approved therapy for PBC [2, 5]. The treatment response is assessed by the effects on serum alkaline phosphatase (AP), as patients with an incomplete biochemical response to UDCA (e.g. AP >1.5 × ULN after 1 year) remain at increased risk for progression to cirrhosis and liver-related death [6, 7].

PBC is often associated with changes in lipoprotein metabolism. Early-stage PBC shows mildly elevated low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein cholesterol (VLDL-C) and markedly increased high-density lipoprotein cholesterol (HDL-C) while patients with advanced PBC stage have markedly elevated LDL-C and decreased HDL-C [3]. Hypercholesterolaemia is an established cardiovascular risk factor and lipid-lowering drugs such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are well established in effectively lowering LDL-C [8, 9], showing benefits also in individuals at low risk of major cardiovascular events [10]. However, the relationship of PBC to atherosclerotic risk is still a matter of debate [3].

In this issue, Cash et al. [11] have investigated the effects of statins in PBC on endothelial function, antioxidant status and vascular compliance. Twenty-one PBC patients were randomized to receive simvastatin 20 mg or placebo for 12 months but only 7 and 6 patients, respectively, completed the study. The main finding was that statin therapy in PBC patients appears safe and effective in reducing total cholesterol and LDL-C by 21% and 40%, respectively, which is in accordance with previous studies on the use of statins in PBC [12-16].

Statins can be distinguished by their lipophilicity and subdivided into hydrophilic (such as pravastatin or rosuvastatin) and lipophilic statins (such as simvastatin and atorvastatin). By interacting with hydrophobic phospholipids acyl chains, lipophilic statins have different metabolism and antioxidant effects. It may be reassuring that all statins used were safe despite different lipophilicity and hence membrane interactions (simvastatin, atorvastatin, pravastatin), metabolism via sulfation (pravastatin) [13] or oxidation (CYP3A4, atorvastatin or simvastatin) [11, 15, 16] and despite rather diverse patient populations with early [15] or more advanced PBC stages [11].

During atherosclerosis development, oxidative stress modifies LDL leading to appearance of oxidized LDL (oxLDL) particles which in turn favours foam cells formation and plaque development [17]. Therefore, antioxidant effects of statins may play an important role. Atorvastatin lowered oxLDL in PBC [15], providing a plausible explanation for improved vascular function in these patients. Unfortunately Cash et al. did not measure this parameter, although lowered LDL-C levels would suggest a similar reduction in oxLDL in late-stage disease patients. Interestingly, antioxidants such as vitamin C and carotene were not changed significantly although showing a trend for increased levels in simvastatin-treated PBC patients. If such a trend might be considered as desirable, it is also important to keep in mind that antioxidant supplementation blocked the response of HDL to simvastatin/niacin therapy in patients [18, 19]. In contrast to atorvastatin, simvastatin does not generate active metabolites [20], when atorvastatin metabolites inhibit LDL oxidation even at nanomolar concentrations [20]. Therefore, it is tempting to speculate that atorvastatin rather than simvastatin may provide a direct antioxidant protection without disturbing endogenous vitamin levels, thus maximizing anti-atherosclerotic effects in PBC. This hypothesis still needs to be verified in larger cohorts of patients carefully monitored for their food intake and vitamin supplementation.

So far, there are only limited data on subclinical atherosclerosis and vascular status in PBC patients [15, 21, 22]. To characterize endothelial function Cash et al. [11] measured serum markers of inflammation and vascular compliance, assessed by pulse wave analysis (PWA) and pulse wave velocity (PWV). After 12 months of treatment levels of high sensitivity C-reactive protein (hsCRP), soluble intracellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) did not differ between both treatment groups and vascular compliance was also not affected. However, in a former study from the same investigators, 51 PBC patients had significantly higher concentrations of hsCRP, sICAM-1 and sVCAM–1 and lower PWV compared to 34 controls [22]. Moreover, another long-term trial using low-dose atorvastatin in patients with early-stage PBC only showed beneficial effects in sVCAM–1 (but not in sICAM–1) and improved vascular function [15]. These discrepancies could be explained by the use of different statins not equally efficient in ameliorating inflammation and vascular status in PBC patients. Moreover, in advanced stage PBC patients, statins may no longer be able to counteract the deterioration of endothelial functions and inflammation. The effectiveness of statins could also differ between biochemical responders and non-responders to UDCA.

This study suggests that statin therapy seems to be safe in PBC patients as no deterioration of liver enzymes was observed which is in agreement with previous studies [23]. However, similar to previous studies with atorvastatin but contrasting previous reports with simvastatin [12, 14-16], simvastatin did not improve serum markers of cholestasis emphasizing the need for more effective therapies e.g. with peroxisome proliferator-activated receptors or farnesoid X receptor agonists, especially in PBC patients not responding to UDCA.

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