Review Article - (2014) Volume 3, Issue 3

Pharmacologic Management of Non-Alcoholic Fatty Liver Disease

George Boon-Bee Goh*, Srinivasan Dasarathy and Arthur McCullough
omi_departments of Gastroenterology and Hepatology, Cleveland Clinic Foundation 9500 Euclid Avenue/ A30 Cleveland, OH 44195, USA
*Corresponding Author: George Boon-Bee Goh, Department of Gastroenterology, Cleveland Clinic Foundation 9500 Euclid Avenue/A30 Cleveland, OH 44195, USA, Tel: 1-216-444-6521, Fax: 1-216-445-3889 Email:


Background: Non-alcoholic fatty liver disease (NAFLD) is a common complex chronic liver disease that encompasses a spectrum of disease from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH has the potential to progress to advanced fibrosis and cirrhosis and is associated with increased morbidity and mortality. Currently, there are no definitive universally accepted treatment options available for NASH. Most pharmacological agents that have been investigated are limited by inconsistent efficacy or side effects. We reviewed the current literature on the principle drugs that have been tested for NAFLD in the adult population, with special emphasis on clinical data and safety profiles. Methods: A comprehensive PUBMED/MEDLINE search was conducted to identify principal therapeutic intervention studies for NAFLD, from which a summary of the studies were formulated in this review. Results: A variety of studies, including retrospective, open-label and randomised controlled trials were reviewed in terms of clinical efficacy and side effect profiles. In addition to the most commonly studied therapeutic agents (insulin sensitizers, vitamin E, pentoxifylline, UDCA, PUFA, statins and ezetimibe), emerging pharmacologic agents showing potential efficacy in NAFLD were also explored. Conclusion: Based on risk-benefit profiles, pentoxifylline seems to have the best treatment outcomes currently, with significant improvement in histology while having minimal tolerable side effects. Further clinical research is warranted to understand and improve our repertoire of treatment options, including potential combination therapy, towards this complex disease.


Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, with disease prevalence of approximately 35% [1,2]. It represents a clinico-pathologic disease entity ranging from simple steatosis (SS) , which has a relatively benign course to non-alcoholic steatohepatitis (NASH), where hepatic steatosis is accompanied by significant necroinflammation, hepatocyte injury (ballooning) with or without fibrosis [3]. Patients with NASH are at risk of disease progression and complications; 38% of patients with NASH will have progression of fibrosis in 5 years and 20% will develop cirrhosis over 10 years [4]. In addition, relative to SS or the general population, patients with NASH are at risk of increased mortality, particularly liver related or cardiovascular related mortality [5-7]. Indeed, NAFLD is anticipated to become the leading cause of liver transplantation in the near future [8]. Consequently, there is a pressing need to address this disease in terms of effective and safe treatment options. However, 34 years after the first description by Ludwig et al. [9], NAFLD remains a difficult disease to manage, with no universally accepted pharmacologic treatment options currently available. Lifestyle modification involving diet restriction, weight loss and exercise is often suggested as the first line therapy for NAFLD, but is difficult to maintain on a long term basis. As such, pharmacologic options are then indicated. We reviewed the current literature on the principle drugs that have been tested for NAFLD in the adult population, with special emphasis on clinical efficacy and safety profiles.

Insulin sensitizers

Given that insulin resistance (IR) plays a dominant role in the pathogenesis of NAFLD, insulin sensitizers have been extensively explored as treatment options, the principle agents being metformin and thiazolidinediones (TZD).


Metformin is a biguanide widely used in clinical practice and has been used since the 1950s, but only gained FDA approval in 1994 [10]. It is the first line oral therapy agent for the treatment of type 2 diabetes mellitus (DM), as recommended by American and European diabetes association [11]. Metformin improves insulin sensitivity via inhibition of gluconeogenesis, stimulating glucose uptake in muscles, inhibiting adipose tissue lipolysis and augmenting hepatic fatty acid oxidation [12]. Animal studies first demonstrated the reversal of hepatic steatosis, liver inflammation and ALT abnormalities with metformin [13,14]. Among the first non-randomised clinical trials, Marchesini observed that metformin improved aminotransaminases [15]. Subsequent studies supported the beneficial role of metformin on liver biochemistry and metabolic profiles, but effect of metformin on liver histology remained limited and inconsistent [16]. In particular, metformin did not show improvement of liver histology in randomised trials [16]. As summarised in Table 1, thirteen studies involving metformin in NAFLD have been performed, with variable effects seen in liver enzymes, metabolic parameters and liver histology. Several meta-analyses have also been conducted. Rakoski et al. observed that metformin had no beneficial pooled effects on liver histology, ALT or body mass index (BMI) [17]. In the meta-analysis by Musso et al. involving 671 patients and 11 randomised control trials, metformin did not improve liver histology but significantly reduced body weight, waist circumference and metabolic parameters compared to placebo [18]. Another meta-analysis by Li et al. with 9 studies and 417 patients reported that metformin improved aminotransaminases, IR and BMI, but not liver histology [19]. Current guidelines do not recommend metformin as a treatment for NAFLD [3]. However, it can be used to treat type 2 DM in patients with NAFLD. Metformin is safe and not associated with hepatotoxicity. Furthermore, it does not cause weight gain, an important aspect while managing NAFLD, and is generally well tolerated, with gastrointestinal side effects being most common, but usually not requiring treatment discontinuation. An additional consideration is the potential anti-tumour effect of metformin. With emerging data suggesting the development of hepatocellular carcinoma (HCC) in the context of NAFLD with or without cirrhosis [20, 21], the inverse association seen between HCC risk and long term metformin therapy takes on additional importance [22].

Reference Intervention Sample size Duration Liver enzymes Histology Other endpoints
Marchesini [15] Met 20 4 mths ↓ALT NA ↓IR, ↓ Liver Volume
Nair [96] Met 15 12 mths Transient ↓ALT,AST Improved  
Uygun [97] Met vs Diet 36 6 mths ↓ALT, AST Not improved ↓IR
Bugianesi [98] Met vs Diet 110 12 mths Not improved Improved ↓IR, ↑% of normal ALT
Duseja [99] Met vs Diet 50 6 mths ↓ALT NA  
De Oliveria [100] Met + NAC 20 6 mths ↓ALT Improved ↓IR
Idilman [101] Met vs Diet/Ex 74 12 mths Not improved Not improved ↓IR, ↓BMI
Loomba [102] Met 28 12 mths ↓ALT Improved ↓IR ,↓ weight
Haukeland [103] Met Vsplac 48 6 mths Not improved Not improved ↓weight, ↓lipids
Garinis [104] Met vs Diet 50 6 mths Not improved NA ↓IR, ↓BMI, ↑adiponectin
Shields [105] Met vs LM 19 12 mths Not improved Not improved  
Shargorodsky [106] Met vsplac 63 12 mths Not improved NA ↓ arterial stiffness, ↑adiponectin
Sofer [107] Met vsplac 63 4 mths Not improved NA ↓Vascular stiffness

Met: Metformin, Vit E: Vitamin E, NAC: N Acetylcysteine, Ex: Exercise, Plac: Placebo, LM: Lifestyle Modification, mths: Months, NA: Not Assessed, IR: Insulin Resistance, BMI: Body Mass Index.

Table 1: Studies of Metformin in adult NAFLD patients.


Thiazolidinediones (TZDs) are agonists to peroxisomal proliferatoractivated receptor (PPAR) γ, which decrease hepatic lipogenesis, improve insulin sensitivity both centrally and peripherally, and stimulate hepatic fatty acid oxidation while augmenting adiponectin levels [23]. They include troglitazone (which has since been removed due to hepatotoxicity potential), rosiglitazone and pioglitazone. Rosiglitazone was associated with decreased liver aminotransferases, improved steatosis, ballooning and inflammation but had no effect on fibrosis [24]. The FLIRT trial confirmed the effect of rosiglitazone on liver aminotransferase and steatosis, but also did not demonstrate improvement on fibrosis [25]. Furthermore, extension of treatment with rosiglitazone did not improve liver histology [26]. Other studies have focused on pioglitazones, which also reported efficacy in improving aminotransaminases but variable effects on liver histology [27,28]. In the landmark PIVENs trial with the largest number of NAFLD patients in a treatment trial, pioglitazone was associated with decreased aminotransaminases, reduction of hepatic steatosis and lobular inflammation, but not fibrosis. However, the histological improvements did not attain the prespecified level of significance for primary histological outcome [29]. The principal trials of TZDs in NAFLD are illustrated in Table 2. Meta-analysis of studies evaluating TZDs in NAFLD show consistently that TZDs improved steatosis, ballooning and inflammation [17,18,30,31], while only one metaanalysis showed improvement in fibrosis [31]. Improvement in fibrosis was also seen in another meta-analysis when trials focusing specifically on pioglitazones were analysed [30]. However, the drawbacks of TZD therapy are also considerable. The beneficial effects of TZDs are not maintained with discontinuation of therapy, suggesting the need for continued long term therapy [32]. In addition, the safety of sustained TZD use has also been questioned. Increased risk of edema [33] and heart failure [34] have been reported with TZD usage. An increased risk of cardiovascular events was seen with rosiglitazone [35] but not with pioglitazone [36] leading to restrictions on the usage of rosiglitazone in clinical practice. Other pertinent considerations include weight gain [average weight gain of 4.4 kg [31], bone loss with increased risk of fractures [37] and increased risk of bladder cancers [38]. Consequently, there are reservations in recommending TZDs as a major therapeutic option.

Reference Intervention Sample size Duration Liver enzymes Histology Other endpoints
Caldwell [108] Troglitazone 10 6 mths ↓ALT Not improved -
Neuschwander [24] Rosiglitazone 30 48 wks ↓ALT, AST Improvement ↓IR, ↑BMI
Promrat [109] Pioglitazone 18 48 wks ↓ALT Improvement ↓hepatic fat, wt gain
Sanyal [110] Pioglitazone+Vit E vsVit E 20 6 mths No improvement Improvement ↓IR, ↓FFA
Belfort [111] Pioglitazone vsplac 55 6 mths ↓ALT, AST Improvement ↓IR, ↓hepatic fat
Aithal [112] Pioglitazone vsplac 74 12 mths ↓ALT, AST Improvement ↓IR, ↓GGT, ↓Ferritin, wt gain
Idilman [101] Rosiglitazone vs Diet/Ex 74 48 wks No improvement Not improved ↓IR
Ratziu [25] Rosiglitazone vsplac 63 12 mths ↓ALT Improvement ↓IR, ↑adiponectin, wt gain
Sanyal [29] Pioglitazone vsplac 274 24 mths ↓ALT, AST Improvement ↓IR, wt gain

Vit E: vitamin E, plac: placebo, Ex: exercise, mths: months, IR: insulin resistance, BMI: body mass index, wt: weight, FFA: free fatty acid

Table 2: Studies of thiazolidinediones [TZDs] in adult NAFLD patients.

Antioxidants & cytoprotective agents

Antioxidants: Oxidative stress and accompanying proinflammatory cytokines have been recognised as an important aspect of NASH pathogenesis. Hence, several studies of antioxidants have been conducted in NAFLD, with the most commonly studied antioxidant agent being vitamin E. Multiple studies of vitamin E either alone or in combination with other agents have been performed with generally beneficial results Table 3. The largest trial was the PIVENS trial with 247 non-diabetic NASH patients, which showed that 800 IU of vitamin E improved aminotransaminases, hepatic steatosis and inflammation, but had no effect on fibrosis [29]. A separate randomised controlled study demonstrated that a combination of vitamin E and C improved histological fibrosis scores but not histological inflammation or ALT [39]. Of concern, however, high dose vitamin E (400 iu or more) has been implicated in increased all-cause mortality in one meta-analysis [40], which was not observed in other meta-analysis [41,42]. Furthermore, a separate meta-analysis observed that vitamin E might be associated with increased risk for hemorrhagic stroke [43], while the SELECT trial suggested an increased incidence of prostate cancer in healthy men taking 400 iu of vitamin E daily over 7 years [44]. Accordingly, the enthusiasm for vitamin E has been tampered by concerns over safety with long term use of vitamin E. Nevertheless, vitamin E can still be considered as a treatment option in non-diabetic patients with NASH, as suggested by the guidelines of the American Association for the Study of Liver Diseases (3).

Reference Intervention Sample size Duration Liver enzymes Histology Other endpoints
Yakaryilmaz [113] Vit E 9 24 wks ↓ALT, AST Improvement ↓IR
Bugianesi [98] Vit E vs Diet 110 12 mths Not improved NA  
Sanyal [29] Vit E vsPlac 274 24 mths ↓ALT, AST Improvement  
Pietu [62] Vit E+UDCA 101 4 years ↓ALT, AST Improvement  
Dufour [61] Vit E+UDCA vsplac 48 24 mths ↓ALT, AST Improvement  
Harrison [39] Vit E+C vsplac 49 6 mths Not improved Improvement  
Foster [114] Vit E/Vit C/Atorvastatin vsplac 1005 4 years NA NA Reduced steatosis on CT
Satapathy [115] Pentoxifylline 18 6 mths ↓ALT, AST NA ↓IR, ↓TNF α, ↓fatigue
Satapathy [116] Pentoxifylline 9 12 mths ↓ALT, AST Improvement  
Lee [45] Pentoxifyllinevsplac 11 3 mths ↓AST NA  
Van Wagner [46] Pentoxifyllinevsplac 30 12 mths Not improved Not improved  
Zein [47] Pentoxifyllinevsplac 55 12 mths ↓ALT Improvement  

Vit E: vitamin E, plac: placebo, UDCA: ursodeoxycholic acid, wks: weeks, mths: months, NA: not assessed, IR: insulin resistance, TNFα: tumor necrosis factor α

Table 3: Studies of Vitamin E and Pentoxifylline in adult NAFLD patients.

Pentoxifylline: Pentoxifylline is a non-selective phosphodiesterase inhibitor with anti-inflammatory properties via TNF-α inhibition. Few randomised, placebo controlled trials on patients with NASH have been conducted, most with favourable results Table 3. In a small pilot study, Lee et al. found that while aminotransaminases improved with pentoxifylline, there was no effect on the inflammatory markers -TNF-α and IL-6. However, this study was limited by a small sample size and short duration of treatment [45]. A separate trial found no significant benefit of pentoxifylline on aminotransaminases or liver histology [46]. In contrast, Zein et al. found that pentoxifylline improved NAFLD activity scores, steatosis, inflammation and fibrosis, but not ballooning [47]. A recent meta-analysis of 5 randomised trials found that pentoxifylline reduced aminotransaminases, steatosis, inflammation and fibrosis [48]. In terms of safety profile, only minor side effects were reported with pentoxifylline. These include nausea, emesis, headaches and abdominal cramps, which did not usually require treatment discontinuation [46,47].

Polyunsaturated fatty acids: N-3 polyunsaturated fatty acids (PUFA) are essential fatty acids that can only be derived from exogenous sources. Some data suggest that a low dietary intake of PUFA may have a role in NAFLD pathogenesis [49]. In addition, PUFA has been shown to improve hypertension, dyslipidemia and cardiovascular disease [50], diseases closely related to NAFLD [51]. PUFA act by regulating gene transcription factors involved in hepatic lipid metabolism [52] which have down-stream effects of increased insulin sensitivity, inhibition of hepatic lipogenesis, increased fatty acid oxidation and reduction of pro-inflammatory cytokines [53]. Various studies using a range of PUFA dosages, composition of the PUFA and duration of treatment have not found consistent results in the context of NAFLD Table 4 [53]. More importantly, most of the studies did not evaluate histological endpoints of treatment. Among the first trials, Capanni et al. found that PUFA improved liver aminotransaminases, metabolic profiles and hepatic steatosis on imaging [54]. Other studies have provided collaborative observations [53]. A meta-analysis of 9 trials and 355 patients found that there were beneficial changes in hepatic steatosis but less convincing evidence of improvement in aminotransaminases with PUFA therapy [55]. Two recent randomised controlled trials which provided histological outcome measures did not demonstrate improved liver histology, but in fact suggested worsening of insulin resistance with PUFA therapy in one trial [56,57]. More studies are required before PUFA can be recommended as a treatment option in NAFLD.

Reference Intervention Sample size Duration Liver enzymes Histology Other endpoints
Capanni [54] n-3 PUFA 56 12 mths ↓ALT, AST NA ↓TG, ↓FG, improved LET and DPI
Spadaro [117] n-3 PUFA + diet vs diet 40 6 mths ↓ALT NA ↓TG, ↓TNF α, ↓IR, ↓liver fat on US
Zhu [118] n-3 PUFA vsplac 144 24 wks ↓ALT NA ↓TG, ↓LDL, ↓liver fat on US
Tanaka [119] EPA 23 12 mths ↓ALT, AST Improved ↓TChol, ↓liver fat on US
Sofi [120] n-3 PUFA + diet vs diet 11 12 mths ↓ALT, AST NA ↓TG, ↑HDL, ↑adiponectin
Vega [121] n-3 PUFA 22 8 wks NA NA ↓TG
Cussons [122] n-3 PUFA vsplac 25 8 wks Not improved NA ↓TG, ↓BP, ↓liver fat on MRS
Dasarathy [56] n-3 PUFA vsplac 37 48 wks Not improved Not improved ↑IR
Sanyal [57] EPA vsplac 243 12 mths Not improved Not improved ↓TG
Mendez-S [123] UDCA vsplac 27 6 wks Not improved NA  
Lindor [59] UDCA vsplac 166 2 years Not improved Not improved  
Leuschner [124] UDCA vsplac 185 18 mths Not improved Not improved ↓GGT
Ratziu [60] UDCA vsplac 126 12 mths ↓ALT, AST NA ↓GGT, ↓IR, ↓FibroTest

Plac: Placebo, Mths: Months, Wks: Weeks, NA: Not Assessed, TG: Triglyceride, FG: Fasting Glucose, LET: Liver Echo Texture, DPI: Doppler Perfusion Index, TNF α: Tumor Necrosis Factorα, IR: Insulin Resistance, US: Ultrasound, HDL: High Density Lipoprotein, BP: Blood Pressure, MRS: Magnetic Resonance Spectroscopy, GGT: Gamma Glutamyl Transferase.

Table 4: Studies of PUFA and UDCA in adult NAFLD patients.

Ursodeoxycholic acid (UDCA): UDCA is a naturally occurring hydrophilic bile acid originally approved for treatment of primary biliary cirrhosis. It acts through alteration of the bile acid pool, immune modulation and reduction of oxidative stress [58]. Several studies exploring effects of UDCA monotherapy or in combination with other agents have reported improvement in aminotransaminases predominantly, with less convincing efficacy in histology Table 4 [49]. Initial UDCA monotherapy at a dose of 13-15 mg/kg did not show any efficacy on aminotransaminases or liver histology [59] while higher dose UDCA monotherapy (28-35 kg/mg) improved aminotransaminases and serum markers of fibrosis (Fibrotest), but no histologic endpoints were evaluated [60]. In combination with vitamin E, UDCA also showed mainly improvement of aminotransaminases [61,62]. In a recent meta-analysis of 3 studies involving 385 subjects, UDCA did not demonstrate any biochemical benefits in NASH. In addition, while there was improvement of lobular inflammation, there was also a suggestion that fibrosis may increase with UDCA [63]. While UDCA is generally well tolerated, with only minor gastrointestinal side effects observed, based on the limited evidence of drug efficacy, UDCA is generally not recommended in NAFLD [27,64].

Lipid lowering agents

Lipotoxicity, which is the hepatic accumulation of lipid molecules that lead to inflammatory damage of hepatocytes, has emerged as an important mechanism in the pathogenesis of hepatic steatosis, steatohepatitis and fibrosis [65]. Therefore, lipid lowering therapy may improve liver disease by improving lipid profile and lowering lipotoxicity [66].

Statins: Statins are potent lipid lowering agents via their inhibition of hydroxymethylglutaryl-coenzyme A reductase. Besides lowering cardiovascular risk, statins also have immunomodulatory, antioxidative, anti-thrombotic and anti-inflammatory properties [67,68]. Traditionally, the concerns that statins can induce aminotransaminase elevations had limited the use of statins in liver disease. However, several studies have demonstrated the safety of statin use in NAFLD [69,70]. Moreover, several studies reported improvement in liver aminotransaminases or hepatic steatosis on imaging Table 5 [71]. In the only randomised placebo controlled trial with post treatment histology, Nelson et al. found that simvastatin did not improve aminotransaminases or histological features of NASH [72]. On the other hand, fibrosis was less frequently seen in patients taking statins in another study that explored changes in liver histology over time [73]. In addition, data from the post hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study provide a compelling argument to use statins in NAFLD; statins were well tolerated, improved aminotransaminases and reduced risk of cardiovascular events [74]. As such, statins can be recommended for treatment of dyslipidemia in NAFLD patients, but not as a specific treatment of NAFLD.

Reference Intervention Sample size Duration Liver enzymes Histology Other endpoints
Nelson [72] Simvastatin vsplac 16 6 mths ↓ALT Not improved  
Abel [125] Simvastatin + Ezevs simvastatin 45 6 mths ↓ALT,AST NA  
Rallidis [126] Pravastatin 5 6 mths ↓ALT Improved ↓TChol
Lewis [127] Pravastatin vsplac 291 36 wks ↓ALT NA ↓TChol, ↓LDL, ↓TG
Hyogo [128] Atorvastatin 31 24 mths ↓ALT,AST Improved ↓TChol, ↓LDL, ↓TG, ↑HDL
Gomez-D [129] Atorvastatin 25 12 mths ↓ALT,AST NA ↓TChol
Athyros [74] Atorvastatin vs no statin 437 36 mths ↓ALT,AST NA ↓cardiovascular events
Kimura [130] Atorvastatin 43 12 mths ↓ALT,AST Improved Improved lipids, ↓AGEs
Antonopoulos [131] Rosuvastatin 23 8 mths ↓ALT,AST NA ↓GGT, Improved lipids
Nakahara [132] Rosuvastatin 19 24 mths Not improved Improved ↓TChol, ↓LDL
Ekstedt [73] Variable statins vs no statins 68 10-16yrs Not improved Improved ↑frequency of DM

Eze: Ezetimibe, Plac: Placebo, Mths: Months, Wks: Weeks, Yrs: Years, NA: Not Assessed, TChol: Total Cholesterol, LDL: Low Density Lipoprotein, TG: Triglyceride, HDL: High Density Lipoprotein, AGE: Advanced Elycation Endproducts, GGT: Gamma Glutamyl Transferase, DM: Diabetes Mellitus

Table 5: Statins in adult NAFLD patients.

Ezetimibe: Ezetimibe inhibits dietary cholesterol absorption from the intestinal lumen via inhibition of the sterol transporter, Niemann-Pick C1-like 1 (NPC1L1) protein, conse quently leading to reduced serum cholesterol levels [75]. Studies have explored ezetimbe monotherapy or in combination with other agents such as statins and acarbose, which in general, showed improvement in aminotransaminases and lipid profile Table 6 [75]. Two pilot open labelled trials demonstrated that ezetimibe improved insulin resistance, lipid profile, aminotransaminases and inflammatory markers, while also extending benefits to steatosis, necroinflammation, ballooning and NAS on histology. However, there was no significant effect on fibrosis [76,77]. A subsequent and only RCT to date that evaluated ezetimibe in NAFLD with post treatment histology reported significant improvement in histological ballooning and fibrosis from baseline, but there were no significant histological differences compared to placebo. In addition, ezetimibe worsen HbA1c levels [78]. Further studies are warranted to evaluate ezetimibe in NAFLD.

Reference Intervention Sample size Duration Liver enzymes Histology Other endpoints
Yoneda [77] Ezetimibe 10 6 mths ↓ALT,AST Improved ↓LDL, ↓ CRP, ↓type IV collagen 7S
Chan [133] Ezetimibe + diet vs diet 10 16 wks Not improved NA ↓IHTG, Improved lipids, ↓CRP,↓IL-6
Park [76] Ezetimibe 45 24 mths ↓ALT Improved ↓IR, ↓CRP, Improved lipids
Takeshita [78] Ezetimibevsplac 32 6 mths Not improved Improved ↓TChol, ↑ HbA1C

NA: Not Assessed, LDL: Low Density Lipoprotein, CRP: High Sensitivity C-reactive Protein, IHTG: Intrahepatic Triglyceride, IL-6: Interleukin-6, IR: Insulin Resistance, TChol: Total Cholesterol

Table 6: Ezetimibe in adult NAFLD patients.

Emerging Drug Therapies

A variety of new therapeutic agents targeting various aspects of pathogenesis in NAFLD are currently emerging. Novel antidiabetic agents target the Glucagon-like peptide-1 (GLP-1) incretin pathway which regulate blood glucose by stimulation of insulin release, improve hepatic fatty acid oxidation and insulin sensitivity [79]. They include GLP-1 analogues (exenatide, liraglutide) and dipeptidyl peptidase (DPP) IV inhibitors (sitagliptin, vildagliptin, saxagliptin) which prevent the rapid degradation of GLP-1 [28]. A small open labelled case series found that exenatide improved grade of ballooning and fibrosis score in 4 out of 8 diabetic patients with NASH, accompanied by significant improvement in weight loss, diabetic profile and aminotransaminase [80]. A separate study found that liraglutide improved BMI, aminotransferases and APRI (AST to platelet ratio index) score, a surrogate non-invasive marker of hepatic fibrosis [81] Two other studies investigated the use of sitagliptin, demonstrating beneficial effects ranging from reduction in BMI, aminotransferases, ballooning and NASH scores [82,83]. Another agent of increasing interest in NAFLD is the Farnesoid X receptor (FXR) agonist. Obeticholic acid (OCA) is a semisynthetic FXR agonist which can modulate hepatic lipogenesis, steatosis and insulin resistance, in addition to inhibiting inflammatory and fibrogenic responses [84]. A pilot study demonstrated that OCA was well tolerated, improved insulin sensitivity, aminotransaminases and markers of inflammation/ fibrosis in diabetic subjects with NASH [85]. The Farnesoid X Receptor Ligand Obeticholic Acid in NASH treatment (FLINT) trial conducted by the NASH clinical research network investigating the use of OCA in NASH patients had recently ended and published results are currently being eagerly awaited. Another exciting agent in development is the lysyl oxidase-like-2 (LOXL-2) inhibitor monoclonal antibody, simtuzumab, which is an anti-fibrotic agent currently being investigated in NASH patients with advanced fibrosis/cirrhosis [49,86]. There have been a number of many other pharmacological agents with potential benefits in NAFLD. However, there are extremely limited data on the efficacy of these agents that prevent a reliable review or recommendation for their clinical use. These would include probiotics [87-89], S-Adenosylmethionine (SAMe) supplements [90,91], α-lipoic acid [92,93] and milk thistle/silybin [94,95]. Other investigatory agents can also be found at the national institute of heath website: http://


NAFLD is an increasingly prevalent disease with potentially severe outcomes, yet current treatment approaches remain much to be desired. At present, no drug has universally been accepted for the treatment of NAFLD, as evidenced by the myriad of approaches explored. Most therapeutic agents do not show clear consistent efficacy or are limited by side effect profiles. Balancing these two aspects, pentoxifylline seems to have the best treatment outcomes with significant improvement in histology while having minimal tolerable side effects. Further clinical research is warranted to understand and improve our repertoire of treatment options towards this complex disease.


  1. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, et al. (2011) Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. ClinGastroenterolHepatol 9: 524-530.
  2. Vernon G, Baranova A, Younossi ZM (2011) Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment PharmacolTher 34: 274-285.
  3. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, et al. (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55:2005-2023.
  4. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH (2009) Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 51: 371-379.
  5. Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, et al. (2006) Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44: 865-873.
  6. Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, et al. (2011) Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 53: 1874-1882.
  7. Söderberg C, Stål P, Askling J, Glaumann H, Lindberg G, et al. (2010) Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 51: 595-602.
  8. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, et al. (2011) Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 141: 1249-1253.
  9. Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980) Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo ClinProc 55: 434-438.
  10. Woods YL, Petrie JR, Sutherland C (2009) Dissecting insulin signaling pathways: individualised therapeutic targets for diagnosis and treatment of insulin resistant states. EndocrMetab Immune Disord Drug Targets 9: 187-198.
  11. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, et al. (2012) Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 35:1364-1379.
  12. Barbero-Becerra VJ, Santiago-Hernandez JJ, Villegas-Lopez FA, Mendez-Sanchez N, Uribe M, et al. (2012) Mechanisms involved in the protective effects of metformin against nonalcoholic fatty liver disease. Curr Med Chem 19: 2918-2923.
  13. Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, et al. (2000) Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 6: 998-1003.
  14. Kita Y, Takamura T, Misu H, Ota T, Kurita S, et al. (2012) Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis. PLoS One 7: e43056.
  15. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, et al. (2001) Metformin in non-alcoholic steatohepatitis. Lancet 358: 893-894.
  16. Rouabhia S, Milic N, Abenavoli L (2014) Metformin in the treatment of non-alcoholic fatty liver disease: safety, efficacy and mechanism. Expert Rev GastroenterolHepatol 8: 343-349.
  17. Rakoski MO, Singal AG, Rogers MA, Conjeevaram H (2010) Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment PharmacolTher 32: 1211-1221.
  18. Musso G, Cassader M, Rosina F, Gambino R (2012) Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 55: 885-904.
  19. Li Y, Liu L, Wang B, Wang J, Chen D (2013) Metformin in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Biomed Rep 1: 57-64.
  20. Baffy G, Brunt EM, Caldwell SH (2012) Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 56: 1384-1391.
  21. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W (2013) Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol 108: 881-891.
  22. Yki-Järvinen H (2004) Thiazolidinediones. N Engl J Med 351: 1106-1118.
  23. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR (2003) Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38: 1008-1017.
  24. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, et al. (2008) Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135: 100-110.
  25. Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, et al. (2010) Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51: 445-453.
  26. Younossi ZM, Reyes MJ, Mishra A, Mehta R, Henry L (2014) Systematic review with meta-analysis: non-alcoholic steatohepatitis - a case for personalised treatment based on pathogenic targets. Aliment PharmacolTher 39: 3-14.
  27. Ozturk ZA, Kadayifci A (2014) Insulin sensitizers for the treatment of non-alcoholic fatty liver disease. World J Hepatol 6: 199-206.
  28. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, et al. (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362: 1675-1685.
  29. Boettcher E, Csako G, Pucino F, Wesley R, Loomba R (2012) Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment PharmacolTher 35: 66-75.
  30. Mahady SE, Webster AC, Walker S, Sanyal A, George J (2011) The role of thiazolidinediones in non-alcoholic steatohepatitis - a systematic review and meta analysis. J Hepatol 55: 1383-1390.
  31. Lutchman G, Modi A, Kleiner DE, Promrat K, Heller T, et al. (2007) The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology 46: 424-429.
  32. Berlie HD, Kalus JS, Jaber LA (2007) Thiazolidinediones and the risk of edema: a meta-analysis. Diabetes Res ClinPract 76: 279-289.
  33. Hernandez AV, Usmani A, Rajamanickam A, Moheet A (2011) Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis and meta-regression analysis of placebo-controlled randomized clinical trials. Am J Cardiovasc Drugs 11: 115-128.
  34. Singh S, Loke YK, Furberg CD (2007) Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 298: 1189-1195.
  35. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE (2007) Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298: 1180-1188.
  36. Murphy CE, Rodgers PT (2007) Effects of thiazolidinediones on bone loss and fracture. Ann Pharmacother 41: 2014-2018.
  37. Turner RM, Kwok CS, Chen-Turner C, Maduakor CA, Singh S, et al. (2013) Thiazolidinediones and associated risk of Bladder Cancer: a Systematic Review and Meta-analysis. Br J ClinPharmacol .
  38. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S (2003) Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 98: 2485-2490.
  39. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, et al. (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142: 37-46.
  40. Gerss J, Köpcke W (2009) The questionable association of vitamin E supplementation and mortality--inconsistent results of different meta-analytic approaches. Cell MolBiol (Noisy-le-grand) 55 Suppl: OL1111-1120.
  41. Berry D, Wathen JK, Newell M (2009) Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality. Clin Trials 6: 28-41.
  42. Schürks M, Glynn RJ, Rist PM, Tzourio C, Kurth T (2010) Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ 341: c5702.
  43. Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, et al. (2011) Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306: 1549-1556.
  44. Lee YM, Sutedja DS, Wai CT, Dan YY, Aung MO, et al. (2008) A randomized controlled pilot study of Pentoxifylline in patients with non-alcoholic steatohepatitis (NASH). HepatolInt 2: 196-201.
  45. Van Wagner LB, Koppe SW, Brunt EM, Gottstein J, Gardikiotes K, et al. (2011) Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol 10: 277-286.
  46. Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, et al. (2011) Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 54: 1610-1619.
  47. Zeng T, Zhang CL, Zhao XL, Xie KQ (2014) Pentoxifylline for the treatment of nonalcoholic fatty liver disease: a meta-analysis of randomized double-blind, placebo-controlled studies. Eur J GastroenterolHepatol 26: 646-653.
  48. Mazzella N, Ricciardi LM, Mazzotti A, Marchesini G (2014) The role of medications for the management of patients with NAFLD. Clin Liver Dis 18: 73-89.
  49. Kromhout D, Yasuda S, Geleijnse JM, Shimokawa H (2012) Fish oil and omega-3 fatty acids in cardiovascular disease: do they really work? Eur Heart J 33: 436-443.
  50. Targher G, Day CP, Bonora E (2010) Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 363: 1341-1350.
  51. Jump DB (2008) N-3 polyunsaturated fatty acid regulation of hepatic gene transcription. CurrOpinLipidol 19: 242-247.
  52. Di Minno MN, Russolillo A, Lupoli R, Ambrosino P, Di Minno A, et al. (2012) Omega-3 fatty acids for the treatment of non-alcoholic fatty liver disease. World J Gastroenterol 18: 5839-5847.
  53. Capanni M, Calella F, Biagini MR, Genise S, Raimondi L, et al. (2006) Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment PharmacolTher 23: 1143-1151.
  54. Parker HM, Johnson NA, Burdon CA, Cohn JS, O'Connor HT, et al. (2012) Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 56: 944-951.
  55. Dasarathy S, Dasarathy J, Khiyami A, Yerian L, Hawkins C, et al. (2014) Double-blind Randomized Placebo-controlled Clinical Trial of Omega 3 Fatty Acids for the Treatment of Diabetic Patients With Nonalcoholic Steatohepatitis. J ClinGastroenterol
  56. Sanyal AJ, Abdelmalek M, Suzuki A, Cummings W, Chojkier M, et al. (2014) No Significant Effects of Ethyl-eicosapentanoic Acid on Histologic Features of Nonalcoholic Steatohepatitis in a Phase 2 Trial. Gastroenterology.
  57. Lazaridis KN, Gores GJ, Lindor KD (2001) Ursodeoxycholic acid 'mechanisms of action and clinical use in hepatobiliary disorders'. J Hepatol 35: 134-146.
  58. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, et al. (2004) Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39: 770-778.
  59. Ratziu V, de Ledinghen V, Oberti F, Mathurin P, Wartelle-Bladou C, et al. (2011) A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 54: 1011-1019.
  60. Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, et al. (2006) Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. ClinGastroenterolHepatol 4: 1537-1543.
  61. Pietu F, Guillaud O, Walter T, Vallin M, Hervieu V, et al. (2012) Ursodeoxycholic acid with vitamin E in patients with nonalcoholic steatohepatitis: long-term results. Clin Res HepatolGastroenterol 36: 146-155.
  62. Wu SD, Li L, Wang JY (2012) Ursodeoxycholic acid for nonalcoholic steatohepatitis. Eur J GastroenterolHepatol 24: 1247-1253.
  63. Malinowski SS, Byrd JS, Bell AM, Wofford MR, Riche DM (2013) Pharmacologic therapy for nonalcoholic fatty liver disease in adults. Pharmacotherapy 33: 223-242.
  64. Cusi K (2012) Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142: 711-725.
  65. Farrell G (2014) Should we lower lipids in nonalcoholic fatty liver disease? ClinGastroenterolHepatol 12: 152-155.
  66. Weitz-Schmidt G (2002) Statins as anti-inflammatory agents. Trends PharmacolSci 23: 482-486.
  67. Nseir W, Mahamid M (2013) Statins in nonalcoholic fatty liver disease and steatohepatitis: updated review. CurrAtheroscler Rep 15: 305.
  68. Browning JD (2006) Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology 44: 466-471.
  69. Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel (2006) An assessment of statin safety by hepatologists. Am J Cardiol 97: 77C-81C.
  70. Lomonaco R, Sunny NE, Bril F, Cusi K (2013) Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs 73: 1-14.
  71. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA (2009) A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: A randomized placebo-controlled trial. J ClinGastroenterol 43: 990-994.
  72. Ekstedt M, Franzén LE, Mathiesen UL, Holmqvist M, Bodemar G, et al. (2007) Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J Hepatol 47: 135-141.
  73. Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, et al. (2010) Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 376: 1916-1922.
  74. Filippatos TD, Elisaf MS (2011) Role of ezetimibe in non-alcoholic fatty liver disease. World J Hepatol 3: 265-267.
  75. Park H, Shima T, Yamaguchi K, Mitsuyoshi H, Minami M, et al. (2011) Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol 46: 101-107.
  76. Yoneda M, Fujita K, Nozaki Y, Endo H, Takahashi H, et al. (2010) Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis: An open-label, pilot study. Hepatol Res 40: 566-573.
  77. Takeshita Y, Takamura T, Honda M, Kita Y, Zen Y, et al. (2014) The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial. Diabetologia 57: 878-890.
  78. Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S, et al. (2011) Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. LivInt 31:1285-1297.
  79. Kenny PR, Brady DE, Torres DM, Ragozzino L, Chalasani N, et al. (2010) Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol 105: 2707-2709.
  80. Ohki T, Isogawa A, Iwamoto M, Ohsugi M, Yoshida H, et al. (2012) The effectiveness of liraglutide in nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and pioglitazone. ScientificWorldJournal 2012: 496453.
  81. Yilmaz Y, Yonal O, Deyneli O, Celikel CA, Kalayci C, et al. (2012) Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis. ActaGastroenterolBelg 75: 240-244.
  82. Iwasaki T, Yoneda M, Inamori M, Shirakawa J, Higurashi T, et al. (2011) Sitagliptin as a novel treatment agent for non-alcoholic Fatty liver disease patients with type 2 diabetes mellitus. Hepatogastroenterology 58: 2103-2105.
  83. Adorini L, Pruzanski M, Shapiro D (2012) Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 17: 988-997.
  84. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, et al. (2013) Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145: 574-582.
  85. Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, et al. (2010) Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 16: 1009-1017.
  86. Ma YY, Li L, Yu CH, Shen Z, Chen LH, et al. (2013) Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol 19: 6911-6918.
  87. Wong VW, Won GL, Chim AM, Chu WC, Yeung DK, et al. (2013) Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol 12: 256-262.
  88. Li Z, Yang S, Lin H, Huang J, Watkins PA, et al. (2003) Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37: 343-350.
  89. Abdelmalek MF, Sanderson SO, Angulo P, Soldevila-Pico C, Liu C, et al. (2009) Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology 50: 1818-1826.
  90. Nakano H, Yamaguchi M, Kaneshiro Y, Yoshida K, Kigawa G, et al. (1998) S-adenosyl-L-methionine attenuates ischemia-reperfusion injury of steatotic livers. Transplant Proc 30: 3735-3736.
  91. Jung TS, Kim SK, Shin HJ, Jeon BT, Hahm JR, et al. (2012) α-lipoic acid prevents non-alcoholic fatty liver disease in OLETF rats. Liver Int 32: 1565-1573.
  92. Min AK, Kim MK, Kim HS, Seo HY, Lee KU, et al. (2012) Alpha-lipoic acid attenuates methionine choline deficient diet-induced steatohepatitis in C57BL/6 mice. Life Sci 90: 200-205.
  93. Abenavoli L, Bellentani S (2013) Milk thistle to treat non-alcoholic fatty liver disease: dream or reality? Expert Rev GastroenterolHepatol 7: 677-679.
  94. Aghazadeh S, Amini R, Yazdanparast R, Ghaffari SH (2011) Anti-apoptotic and anti-inflammatory effects of Silybummarianum in treatment of experimental steatohepatitis. ExpToxicolPathol 63: 569-574.
  95. Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP (2004) Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment PharmacolTher 20: 23-28.
  96. Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, et al. (2004) Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment PharmacolTher 19: 537-544.
  97. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, et al. (2005) A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 100: 1082-1090.
  98. Duseja A, Das A, Dhiman RK, Chawla YK, Thumburu KT, et al. (2007) Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. Ann Hepatol 6: 222-226.
  99. de Oliveira CP, Stefano JT, de Siqueira ER, Silva LS, de Campos Mazo DF, et al. (2008) Combination of N-acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non-alcoholic steatohepatitis. Hepatol Res 38: 159-165.
  100. Idilman R, Mizrak D, Corapcioglu D, Bektas M, Doganay B, et al. (2008) Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment PharmacolTher 28: 200-208.
  101. Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, et al. (2009) Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment PharmacolTher 29: 172-182.
  102. Haukeland JW, Konopski Z, Eggesbø HB, von Volkmann HL, Raschpichler G, et al. (2009) Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 44: 853-860.
  103. Garinis GA, Fruci B, Mazza A, De Siena M, Abenavoli S, et al. (2010) Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study. Int J Obes (Lond) 34: 1255-1264.
  104. Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ (2009) The Effect of Metformin and Standard Therapy versus Standard Therapy alone in Nondiabetic Patients with Insulin Resistance and Nonalcoholic Steatohepatitis (NASH): A Pilot Trial. TherapAdvGastroenterol 2: 157-163.
  105. Shargorodsky M, Omelchenko E, Matas Z, Boaz M, Gavish D (2012) Relation between augmentation index and adiponectin during one-year metformin treatment for nonalcoholic steatohepatosis: effects beyond glucose lowering? CardiovascDiabetol 11: 61.
  106. Sofer E, Boaz M, Matas Z, Mashavi M, Shargorodsky M (2011) Treatment with insulin sensitizer metformin improves arterial properties, metabolic parameters, and liver function in patients with nonalcoholic fatty liver disease: a randomized, placebo-controlled trial. Metabolism: clinical and experimental 60: 1278-84.
  107. Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, et al. (2001) A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol 96: 519-525.
  108. Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, et al. (2004) A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39: 188-196.
  109. Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, et al. (2004) A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. ClinGastroenterolHepatol 2: 1107-1115.
  110. Belfort R, Harrison SA, Brown K, Darland C, Finch J, et al. (2006) A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355: 2297-2307.
  111. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, et al. (2008) Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135: 1176-1184.
  112. Yakaryilmaz F, Guliter S, Savas B, Erdem O, Ersoy R, et al. (2007) Effects of vitamin E treatment on peroxisome proliferator-activated receptor-alpha expression and insulin resistance in patients with non-alcoholic steatohepatitis: results of a pilot study. Intern Med J 37: 229-235.
  113. Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, et al. (2011) Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol 106: 71-77.
  114. Satapathy SK, Garg S, Chauhan R, Sakhuja P, Malhotra V, et al. (2004) Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol 99: 1946-1952.
  115. Satapathy SK, Sakhuja P, Malhotra V, Sharma BC, Sarin SK (2007) Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis. J GastroenterolHepatol 22: 634-638.
  116. Spadaro L, Magliocco O, Spampinato D, Piro S, Oliveri C, et al. (2008) Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig Liver Dis 40: 194-199.
  117. Zhu FS, Liu S, Chen XM, Huang ZG, Zhang DW (2008) Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol 14: 6395-6400.
  118. Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, et al. (2008) Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J ClinGastroenterol 42: 413-418.
  119. Sofi F, Giangrandi I, Cesari F, Corsani I, Abbate R, et al. (2010) Effects of a 1-year dietary intervention with n-3 polyunsaturated fatty acid-enriched olive oil on non-alcoholic fatty liver disease patients: a preliminary study. Int J Food SciNutr 61: 792-802.
  120. Vega GL, Chandalia M, Szczepaniak LS, Grundy SM (2008) Effects of N-3 fatty acids on hepatic triglyceride content in humans. J Investig Med 56: 780-785.
  121. Cussons AJ, Watts GF, Mori TA, Stuckey BG (2009) Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy. J ClinEndocrinolMetab 94: 3842-3848.
  122. Méndez-Sánchez N, González V, Chávez-Tapia N, Ramos MH, Uribe M (2004) Weight reduction and ursodeoxycholic acid in subjects with nonalcoholic fatty liver disease. A double-blind, placebo-controlled trial. Ann Hepatol 3: 108-112.
  123. Leuschner UF, Lindenthal B, Herrmann G, Arnold JC, Rössle M, et al. (2010) High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 52: 472-479.
  124. Abel T, Fehér J, Dinya E, Eldin MG, Kovács A (2009) Safety and efficacy of combined ezetimibe/simvastatin treatment and simvastatin monotherapy in patients with non-alcoholic fatty liver disease. Med SciMonit 15: MS6-11.
  125. Rallidis LS, Drakoulis CK, Parasi AS (2004) Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 174: 193-196.
  126. Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, et al. (2007) Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 46: 1453-1463.
  127. Hyogo H, Ikegami T, Tokushige K, Hashimoto E, Inui K, et al. (2011) Efficacy of pitavastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: An open-label, pilot study. Hepatol Res 41: 1057-1065.
  128. Gómez-Domínguez E1, Gisbert JP, Moreno-Monteagudo JA, García-Buey L, Moreno-Otero R (2006) A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment PharmacolTher 23: 1643-1647.
  129. Kimura Y, Hyogo H, Yamagishi S, Takeuchi M, Ishitobi T, et al. (2010) Atorvastatin decreases serum levels of advanced glycationendproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH. J Gastroenterol 45: 750-757.
  130. Antonopoulos S, Mikros S, Mylonopoulou M, Kokkoris S, Giannoulis G (2006) Rosuvastatin as a novel treatment of non-alcoholic fatty liver disease in hyperlipidemic patients. Atherosclerosis 184: 233-234.
  131. Nakahara T, Hyogo H, Kimura Y, Ishitobi T, Arihiro K, et al. (2012) Efficacy of rosuvastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: An open-label, pilot study. Hepatol Res 42: 1065-1072.
  132. Chan DC , Watts GF, Gan SK, Ooi EM, Barrett PH (2010) Effect of ezetimibe on hepatic fat, inflammatory markers, and apolipoprotein B-100 kinetics in insulin-resistant obese subjects on a weight loss diet. Diabetes Care 33: 1134-1139.
Citation: Goh GBB, Dasarathy S, McCullough A (2014) Pharmacologic Management of Non-Alcoholic Fatty Liver Disease. Adv Pharmacoepidemiol Drug Saf 3:157.

Copyright: © 2014 Goh GBB, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.