*Therapeutic Approach to NAFLD-NASH DOI: http://dx.doi.org/10.5772/intechopen.107487*

**Figure 5.** *Pathway of lipid metabolism and statin action in NAFLD/NASH.*

Several data, demonstrating the beneficial effect of statins come from the posthoc analysis of three perspectives, controlled survival studies. The post-hoc analysis of Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE), included 1600 patients, with coronary heart disease (CHD) and a mean observation time of 3 years. This analysis included 437 patients with NAFLD/NASH. Atorvastatin lowered the levels of serum aminotransferases, normalized the ultrasound imaging of the liver, and decreased cardiovascular events by 64 percent compared to the participants with NAFLD/NASH that did not take statins [17]. Three years later, the researchers of Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) concluded their post-hoc analysis. IDEAL was carried out in four Scandinavian countries and included 8864 patients with cardiovascular disease, of whom 7782 (87.8%) had normal levels of aminotransferases and 1081 (12.2%) elevated levels of ALT, possibly due to NAFLD/NASH. In the patients with elevated ALT, a dose of atorvastatin 80 mg per day, normalized those levels within safety compared to simvastatin 20–40 mg per day. The most important fact was that the patients who received atorvastatin 80 mg per day, suffered half the number of cardiovascular events, strokes and acute coronary events as those who were treated with simvastatin [18]. This shows that the clinical benefit of the treatment with a statin in NAFLD/NASH is a composite special effect and not the result of a class effect of a category of drugs. There was a post-hoc analysis of primary prevention of a multicenter prospective randomized controlled study: Assessing the treatment effect in Metabolic Syndrome Without Perceptible diabetes (ATTEMPT), that included 1123 patients with a mean observation of 4 years that had similar clinical and biochemical benefits with a higher dose of atorvastatin (30 mg per day) in 326 patients who had moderately elevated

levels of hepatic enzymes and ultrasonographic findings of NAFLD. In all the above studies, the patients were included only if the level of aminotransferases were less than three times higher than upper normal levels [19, 20].

Due to the fact that there was no proof of the benefit of the statins in NAFLD/ NASH based on liver biopsy, a pilot study was conducted on 20 subjects to evaluate the effect of 10 mg per day of rosuvastatin in biopsy-proven NASH. A year later, 19 of 20 patients, showed a total remission of NASH in new biopsy findings with subsequent normalization of liver enzyme and ultrasonographic findings. Another study from Italy with 107 patients with biopsy-proven NASH showed benefits from statin therapy, as well as a larger study with participants from Italy and France.

In a study performed on 5400 military personnel in Northern Greece, the NASH and FIB-4 scores were used to identify the ones that had NASH and NAFLD/NASH. Their final number was 613 (541 males and 72 females). These subjects were also confirmed to have NAFLD by ultrasonographic findings. They were subsequently divided into four categories: a control group, a group that received rosuvastatin, a group that received atorvastatin and a group that received pitavastatin. The dose of the statins was treated according to individualized LDL-C goals. The results of this study showed a clear benefit in all statin groups compared to the control group, after one year of treatment, which was manifested in the improvement of NASH and FIB-4 scores as well as of the levels of aminotransferases. It should be stressed that the beneficial results of the use of statins were equally important to the subjects without metabolic syndrome, compared to the ones with metabolic syndrome, proving that the use of statins may have a crucial effect on the management of patients with a genetic disposition to present with NAFLD/NASH, independently of the presence of metabolic syndrome [20].
