Statin-based treatment for cardiovascular risk and non-alcoholic fatty liver disease. Killing two birds with one stone?

Abstract

Cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) share common risk factors and may have a parallel course. Statin treatment alone or in combination with other drugs has a substantially beneficial effect on CVD morbidity and mortality. The question was if these regimens were harmful for the liver. Mounting data suggest that statin monotherapy or statin-based treatments are safe in patients with NAFLD and can improve liver tests and liver ultrasonographic evidence of NAFLD. Recent data suggest that statin-based therapies are beneficial to the liver and at the same time reduce CVD morbidity and mortality in patients with NAFLD more than in subjects without it. These findings suggest that with statins we are able to get two birds with one stone.

Key words::

• Cardiovascular disease
• clinical benefit
• liver enzymes
• non-alcoholic fatty liver disease
• statin

Key messages

• Cardiovascular disease and non-alcoholic fatty liver disease share common risk factors and may have a parallel course; however, statin-based treatments may be beneficial to both diseases.

Non-alcoholic fatty liver disease (NAFLD) is a common condition characterized by triglyceride (TG) occupying more than 5% of the hepatocyte in the absence of excessive alcohol consumption or chronic viral hepatitis (1,2). The term NAFLD incorporates a spectrum of histological findings, varying from steatosis to steatosis with inflammation (steatohepatitis (NASH)), necrosis, fibrosis, or cirrhosis that can progress to hepatocellular carcinoma (2). NAFLD is the most common liver disorder, and its prevalence in the general population ranges from 10% to 39% (3). In the USA, 20% of adults have diagnosed NAFLD, and 2%–3% have NASH (4). Because of the increase in obesity and type 2 diabetes mellitus (T2DM), the prevalence of NAFLD should increase (3). NAFLD may progress to more serious liver disease with associated morbidity and mortality (3,5–9). In addition, NAFLD also increases the risk for cardiovascular disease (CVD) (3,5–9). Common underlying mechanisms between NAFLD and CVD are insulin resistance (IR) (10), low adiponectin levels (11), elevated levels of high-sensitivity C-reactive protein (hsCRP) (which may induce IR) (12), free fatty acid (FFA) accumulation, increased plasma TG levels, oxidative stress, and low high-density lipoprotein cholesterol (HDL-C) levels (13,14).

NAFLD is associated with increased overall mortality (odds ratio (OR) 1.57; 95% confidence interval (CI) 1.18–2.10), resulting from liver- and CVD-related mortality, as well as a 2-fold risk for T2DM (15). NASH results in even higher mortality rates (OR for NASH: 5.7, 95% CI 2.31–14.13; OR for NASH with advanced fibrosis: 10.0, 95% CI 4.35–23.25) (15). CVD and NAFLD share common CVD risk factors such as dyslipidaemia, obesity, T2DM, and hypertension. Effective treatment of these common risk factors might ameliorate both conditions. In this context, statin-based treatment might be beneficial for NAFLD in addition to CVD.

A recent meta-analysis of 26 randomized trials (170,000 patients) showed that statins reduce the incidence of CVD (myocardial infarction, revascularization, and ischaemic stroke) (16). A statin-induced reduction in low-density lipoprotein cholesterol (LDL-C) levels by 2–3 mmol/L decreases CVD risk by about 40%–50% (16). Furthermore, data from the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial (JUPITER) trial (17) suggest a clinical benefit with rosuvastatin in patients with elevated hsCRP but low LDL-C levels (17,18).

A pilot study showed that atorvastatin (10– 80 mg/daily depending on serum cholesterol levels) is both safe and effective in patients with NAFLD and hyperlipidaemia (19). Both serum aminotransferase activity and lipid levels were reduced significantly during atorvastatin treatment (19). In another study, after treatment with 10 mg of atorvastatin daily for 24 months, 23 patients (74%) with NAFLD achieved normal transaminase activity (20). Adiponectin levels increased, whereas tumour necrosis factor-α levels decreased. The concentration of long-chain fatty acids also decreased. Liver steatosis and NAFLD activity score improved (20). The NASH-related metabolic parameters improved with treatment, as did liver fibrosis in some patients. However, 4 of 17 patients had progression of fibrosis over the 2-year period. It is unclear whether this divergent response represents sampling error, heterogeneity of the population, or untreated postprandial hypertriglyceridaemia (20). In this context, statin-fibrate combination treatment might be beneficial. Indeed, we compared atorvastatin (20 mg/day), micronized fenofibrate (200 mg/day), and their combination in a prospective, open-label, randomized study in 186 patients with NAFLD and the metabolic syndrome (MetS) (21). At the end of treatment (follow-up 54 weeks), 67% of patients on atorvastatin, 42% on fenofibrate, and 70% on combination treatment no longer had biochemical or ultrasonographic evidence of NAFLD (P < 0.05 versus base-line). The atorvastatin–fenofibrate combination and atorvastatin monotherapy were more effective than fenofibrate alone in reducing both biochemical and ultrasonographic evidence of NAFLD. Since NAFLD and atherosclerotic disease may progress in parallel within MetS or T2DM (21), the treatment options described above may benefit both the heart and liver (21). Indeed, it was shown in patients with T2DM (22) or MetS without T2DM (23) that a target-driven and intensified intervention aimed at multiple risk factors improves risk factors for both NAFLD and CVD and reduces the estimated CVD risk (22,23). Again, the atorvastatin–fenofibrate combination had the most beneficial effect on all lipid parameters and on estimated CVD risk.

Improvement of NAFLD has also been reported with other hypolipidaemic agents. A decline in transaminase activity and normalization of ultrasonographic evidence of fatty liver were observed when omega-3 fatty acids were administered to patients with hypertriglyceridaemia (24,25).

In patients with T2DM, treatment with a fixed-dose combination of atorvastatin 10 mg + metformin SR 500 mg reduced body mass index, HbA_1c (by 23.1%), total cholesterol (by 31.2%), LDL-C (by 35.4%), and very-low-density lipoprotein cholesterol (by 19.6%) levels (26). A 9.5% increase in HDL-C levels was also observed (26). Moreover, pretreatment with atorvastatin augments the beneficial effects of metformin in patients with polycystic ovary syndrome, a condition that may include IR (27).

In another study in patients with T2DM, an atorvastatin 10 mg + metformin 850 mg/day combination prevented the glucose loading-induced elevation in levels of glucose and inflammatory markers more than metformin 850 mg/day monotherapy (28). The combination of insulin and atorvastatin also improved glycaemic control and lipid profile, and decreased circulating hsCRP levels and liver inflammatory and oxidative stress markers in animal models (13). In another study involving an animal model of T2DM, a high-fat diet increased CVD risk, whereas the combined use of atorvastatin and insulin improved CVD risk markers (29).

Thiazolidinediones (TZDs) improve liver histology in patients with NASH (30,31). Recent studies questioned the long-term safety of TZDs (especially rosiglitazone) (32), and the majority of patients with NASH who were included in TZDs studies were non-diabetic. It is therefore unclear whether TZDs are effective in diabetic patients with NASH. In fact, T2DM was associated with a less favourable response to rosiglitazone (33). An on-going study (PIVENS; NCT00063622) should provide more information on their safety and efficacy (30). TZDs have not been evaluated in combination with statins in NAFLD.

Statins have been combined with ursodeoxycholic acid (UDCA) in patients with NASH (34). This combination appears to be both safe and effective, but more evidence is required (34). Another study evaluated a multifactorial intervention in NASH (35). Atorvastatin and losartan combination improved both biochemical parameters and steatosis/ necroinflammation. Pentoxifylline showed similar efficacy in normotensive/non-dyslipidaemic patients, while UDCA did not improve the histological score but improved biochemical parameters (35).

The combination of angiotensin enzyme inhibitors (ACE-I) with atorvastatin and/or fenofibrate appears to improve NAFLD (21–23). Losartan, an angiotensin receptor blocker (ARB), was also beneficial in these patients (35). In another study, postprandial hypertriglyceridaemia and hyperglycaemia induced endothelial dysfunction and exerted pro-inflammatory effects, whereas combination treatment with atorvastatin and irbesartan (an ARB) prevented these adverse effects more than either agent alone (36). In this context, we previously reported that a statin + ACE-I combination reduces CVD events more than a statin alone and considerably more than an ACE-I alone (37). Thus, statins, in monotherapy or in combination with other agents, appear to be the corner-stone of treatment of both NAFLD and CVD (38). This was also suggested in a recent post-hoc analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) study (39). GREACE was a prospective, intention-to-treat study that randomly assigned 1,600 patients with coronary heart disease either to ‘usual care’ or ‘structured care’ (with atorvastatin) aiming to reach the LDL-C goal of <100 mg/dL (2.6 mmol/L) (40). The primary outcome of this post-hoc analysis was risk reduction for the first recurrent CVD event in patients treated with a statin who had moderately abnormal liver tests (defined as serum alanine aminotransferase or aspartate aminotransferase concentrations of <3-fold the upper limit of normal (ULN)) and ultrasonographic evidence of NAFLD, compared with patients with abnormal liver tests who did not receive a statin (39). This risk reduction was also compared with that observed in patients treated (or not) with a statin and normal liver tests (39). At base-line, 437 patients had moderately abnormal liver tests and ultrasonographic evidence of NAFLD. From those, the 227 patients who were treated with a statin (mainly atorvastatin ∼24 mg/day) showed a substantial improvement in liver tests (P < 0.0001) and liver ultrasound, whereas the 210 patients who were not treated with a statin had further increases in liver enzyme activities (39). CVD events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3.2 events/100 patient-years) and in 63 (30%) of 210 patients with abnormal liver tests who did not receive statin (10.0 events/100 patient-years; 68% relative risk reduction (RRR); P < 0.0001). This CVD risk reduction was greater (P = 0.007) than in patients with normal liver tests (90 (14%) events in 653 patients receiving a statin (4.6 events/100 patient-years) versus 117 (23%) in 510 patients not receiving a statin (7.6 events/100 patient-years); 39% RRR; P < 0.0001). Seven of 880 participants (<1%) of the entire GREACE study who received a statin discontinued this treatment because of liver-related adverse effects (transaminase activity >3-fold the ULN). These results suggest that CVD patients with NAFLD have a greater risk for recurrent CVD events than those without NAFLD and that statin treatment improves liver function and at the same time protects from recurrent CVD events (39).

Ezetimibe is an inhibitor of intestinal cholesterol absorption commonly prescribed in combination with statins (41). There is evidence that ezetimibe exerts beneficial effects on NAFLD including biochemical and histological improvement (41–44). The mechanisms involved may include the presence of Niemann-Pick C1-like 1 (NPC1L1), a protein involved in cholesterol transport in the liver as well as in the intestine (44). Ezetimibe treatment may also improve NASH (45). There is an urgent need for more extensive and appropriately designed trials of ezetimibe monotherapy as well as in combination with statins in patients with NAFLD or NASH.

The relationship between statins (and other drugs) and NAFLD may be even more complex than outlined above. For example, there is evidence that statins may increase the risk of new-onset diabetes (NOD), but despite that statins are thought to be beneficial (46,47). Although this evidence has limitations, we need to consider that there may be specific vulnerable populations (e.g. those with metabolic syndrome or taking diabetogenic drugs (such as thiazides and beta-blockers) as well as the elderly and obese) (46,47). Counterbalancing this potential increased risk of NOD there are life-style measures and drugs that ‘protect’ patients from NOD (47,48). In line with this argument any statin-related improvement in NAFLD may also protect from NOD. These possibilities need to be investigated in appropriately designed trials.

In conclusion, the burden of CVD and NAFLD is enormous (49,50), and statin treatment alone or in combination with some drugs appears to be safe in patients with NAFLD and can improve liver tests and liver ultrasonographic evidence of NAFLD. At the same time statins reduce CVD morbidity and mortality (16,51). These findings suggest that with statins we are able to kill two birds with one stone. However, if we also take into consideration that some statins have a protective effect on renal function (52–57), then we might get three birds with one stone!

Declaration of interest: This editorial was written independently. The authors did not receive financial or professional help with the preparation of the manuscript. The authors have given talks, attended conferences, and participated in advisory boards and trials sponsored by various pharmaceutical companies.