1. Treatments to Rule Them All
Lifestyle intervention, with modifications in diet and physical activity, has become the first line treatment for patients with NAFLD. A greater extent of weight loss, induced by lifestyle changes, is associated with the level of improvement in histologic features of NASH. The highest rates of NAS reduction, NASH resolution and fibrosis regression occurred in patients with weight losses of 10% or more 
. Furthermore, age, sex, T2DM and genes impact on the effect of diet in weight loss and NASH resolution 
. These factors are integrated in the so called ‘nutritional geometry’, which considers the relevance of nutrition, science and the environment to understand how food components interact to regulate the properties of diets 
. Stratifying patients according to the geometry of nutrition could improve the rate of response 
Regarding weight loss, therapies such as bariatric surgery and metabolic endoscopic techniques can be useful alternatives as only 10% of participants achieved enough body weight reduction through lifestyle interventions 
. Bariatric surgery has also been shown to improve obesity, its metabolic consequences and NASH 
. However, given the surgical risk, it cannot be considered a first-line therapy, especially in those patients with decompensated cirrhosis or portal hypertension. In this context, endoscopic bariatric techniques have emerged as a potential treatment option as they can reproduce those benefits in a minimally invasive manner 
. However, this kind of intervention might be eligible only in obese patients.
On the other hand, a recent expert meeting has gathered strong evidence that regular physical activity plays an important role in preventing NAFLD and improving intermediate clinical outcomes 
. Various studies have demonstrated an improvement in NAFLD with personalized physical exercise programs 
, even in the absence of significant weight loss 
, and a reduction of the hepatic venous pressure gradient in cirrhotic patients 
The prescription of an appropriate diet and the indication of physical exercise in proportion to the disease and the characteristics of the patients is the main curative option for all NAFLD patients, including lean NAFLD 
. A randomized controlled trial from Asia demonstrates using MR spectroscopy that almost half of non-obese individuals achieved NAFLD remission with 3–5% weight loss 
Thus, an innovative therapeutic strategy in this setting would be the constitution of multidisciplinary units integrating clinicians (hepatologists, endocrinologists, cardiologists, internists), physiotherapists, nutritionists, nurses, social educators and, of course, patients, where a health-promoting diet, avoidance of tobacco, alcohol and other toxins, and sustainable, inclusive and adapted physical activity is prescribed considering the needs of each patient. Furthermore, such multidisciplinary units allow the integration of adequate assessments for the risk of both significant liver and vascular disease, macro and/or microvascular complications of T2DM, the risk of hepatic and extrahepatic neoplasms and other potential comorbidities.
2. Targeted Therapy
Thanks to the continuous research on NAFLD pathogenesis, several druggable targets have been identified and thus targeted therapies for NAFLD treatment have entered clinical trials, which have been recently and extensively reviewed by Santos-Laso et al. 
. However, limited impact has been achieved for now, probably due to the extensive placebo effect in NAFLD 
, the complexity of the pathological pathways involved 
, the short follow-up time for the expected outcomes to be evaluated and the limited characterization of NAFLD patients before inclusion in clinical trials 
2.1. Targeting Lipid Metabolism
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which include PPARα, PPARγ and PPARβ/δ. The pan-PPAR agonist lanifibranor acts through the activation of all PPAR isoforms, reducing TG levels and increasing insulin sensitization, glucose metabolism and fatty acid metabolism. Lanifibranor has successfully completed a 24-week phase IIb trial, meeting its primary endpoint of a reduction of two points or more in the SAF (steatosis, activity and fibrosis) score, with no increase in fibrosis, and the secondary endpoint of reducing fibrosis by at least one stage without worsening NASH. Lanifibranor is well tolerated, although side effects include mild weight gain. Thus, a phase III study is underway 
Statins have been demonstrated to reduce steatosis in those with NASH and it prevents liver events in patients with metabolic syndrome with advanced NASH. Furthermore, a possible protective role of statin treatment against NAFLD progression to HCC was also demonstrated in observational studies. Interestingly, it has been shown that statins reduce CVR more in NAFLD vs. non-NAFLD high-risk individuals 
Oltipraz is a synthetic dithiolethione that functions as an anti-steatogenic agent against NAFLD by inhibiting LXR-α activity, which decreases the expression of SREBP-1c within the liver, reducing the synthesis of fatty acids but enhancing lipid oxidation 
. Although two phase III clinical trials have been completed, no data are available yet. However, the results from the phase II trial showed that oltipraz decreased liver fat content and BMI while absolute changes in insulin resistance, liver enzymes, lipids and cytokines were not significant 
Resmetirom is a liver-directed, orally active, selective thyroid hormone receptor-β agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. In phase II clinical trials, Resmetirom treatment resulted in significant reductions in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH, while the adverse events were transient mild diarrhea and nausea 
It could be hypothesized that obese patients, those with genetic predisposition to lipid accumulation or increased circulating levels of TG due to metabolic syndrome, might benefit from therapies targeting lipid metabolism.
2.2. Targeting Glucose Metabolism
Pioglitazone is a PPARγ agonist used in the treatment of T2DM due to its properties as an insulin sensitizer 
. Moreover, results have been published regarding pioglitazone evaluation in non-diabetic NAFLD patients in comparison to vitamin E supplementation 
. There was no benefit of pioglitazone compared to placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes such as steatohepatitis resolution, decrease in mean AST and ALT levels and improvement in insulin resistance 
GLP-1 receptor agonists (GLP-1RA) are widely used in the treatment of T2DM. Studies have found that GLP-1R has multiple biological effects, such as neuroinflammation reduction, nerve growth promotion, heart function improvement, appetite suppression, gastric emptying delay, blood lipid metabolism regulation and fat deposition reduction. Thus, effects of GLP-1RA include neuroprotection, cardiovascular protection and metabolic regulation 
. Semaglutide has completed a phase II trial showing resolution of NASH with no worsening of fibrosis. Although it was unable to achieve its secondary outcome of improvement of fibrosis with no worsening of NASH, the drug induces a significant weight loss and most common adverse events were gastrointestinal 
. Encouraging pilot results of the evaluation of exenatide, another GLP-1RA, for the treatment of NAFLD have been released 
. Moreover, cotadutide, a dual GLP-1RA and glucagon receptor agonist, has been evaluated in a phase IIb clinical trial showing improved glycemic control and weight loss, along with improvements in hepatic parameters such as reduction in ALT, AST and gamma-glutamyltransferase (GGT) levels, as well as improvements in NFS and FIB-4 index 
Dipeptidyl peptidase 4 (DPP-4) inhibitors work by blocking the enzymatic inactivation of endogenous incretin hormones, resulting in glucose-dependent insulin release and a decrease in glucagon secretion 
. Early results evaluating DPP-4 inhibitor vildagliptin in NAFLD patients with T2DM have shown significant improvement in blood sugar regulation, BMI, ALT, liver fibrosis and steatosis indices 
SGLT-2 inhibitors promote urinary excretion of glucose by inhibiting its renal proximal tubular reabsorption 
. Dapagliflozin and empagliflozin are SGLT-2 inhibitors undergoing phase III clinical trials for the treatment of NASH. To date, it has been demonstrated that dapagliflozin can markedly reduce hepatic enzymes and metabolic indicators and improve body composition 
These drugs are prescribed in the treatment of T2DM. Thus, clinical guidelines have already included the preferential use of drugs with effects on the liver in the management of T2DM patients with NAFLD 
2.3. Targeting Bile Acid Metabolism
Obeticholic acid (OCA) is a potent FXR agonist evaluated for the treatment of NASH-mediated fibrosis thanks to its ability to reduce liver fat and fibrosis in animal models of NAFLD. Currently being tested in phase III clinical trials 
, phase II studies demonstrated that OCA treatment improved multiple histological NASH features 
Aramchol is a fatty acid–BA conjugate that has demonstrated an ability to reduce liver fat and inflammation in NAFLD patients. Results from the phase IIb trial showed that aramchol was safe and well tolerated 
. Although the primary end point of a reduction in liver fat did not meet the pre-specified significance level, the observed safety and changes in liver histology and enzymes encouraged the initiation of phase III trials 
, whose interim analysis revealed that the open-label part met its objectives.
These treatments may be especially useful in the management of lean NAFLD as these patients have shown specific alterations of BA metabolism 
2.4. Targeting Oxidative Stress, Inflammation and Fibrosis
N-acetylcysteine is frequently used where intracellular oxidant–antioxidant balance is concerned and it has protective effects against liver injury 
. Its potential as antioxidant treatment in NAFLD has been demonstrated in animal models 
, whereas information in NAFLD patients is scarce but promising 
. Thus, a phase III clinical trial evaluating the effect of N-acetylcysteine on markers of oxidative stress and insulin resistance in patients with NAFLD is currently recruiting participants.
Pentoxifylline is a methylxanthine derivative with a variety of physiological effects at the cellular level, which include decreases in TNF-α gene transcription, affecting multiple steps in the cytokine/chemokine pathway that has been implicated in NAFLD pathogenesis. Thus, it has been evaluated in several clinical trials mostly showing beneficial effects in weight loss, improved liver function and histological changes in patients with NAFLD/NASH 
. However, other studies have failed in demonstrating pentoxifylline’s effectiveness in reducing transaminases compared to placebos, and it did not positively affect any of the metabolic markers postulated to contribute to NASH 
Secukinumab is a monoclonal antibody against IL-17 used in the treatment of psoriasis. It has been shown to have neutral effects on fasting plasma glucose, lipid parameters and liver enzymes, while reducing levels of CRP, a marker for systemic inflammation, and markers of oxidative stress. Secukinumab produced improvements in arterial elasticity, coronary artery function and myocardial deformation indices, thus protecting from CVR 
. However, publication of phase III clinical trial results evaluating liver function is pending.
Finally, lubiprostone is a laxative drug that improves intestinal permeability. It was reported to ameliorate increases in intestinal permeability induced by a high-fat and high-cholesterol diet in an atherosclerosis mouse model, while in humans it improved the increased intestinal permeability induced by non-steroidal anti-inflammatory drugs. Thus, lubiprostone might prevent the excessive inflammation and fibrosis induced by gut-derived endotoxin in NAFLD patients 
. Results from the phase IIa study have shown that lubiprostone was well tolerated and reduced the levels of liver enzymes in patients with NAFLD and constipation 
. Therefore, recruitment for the phase III clinical trial is already open.
Treatments targeting inflammation and fibrosis might be eligible for patients with more advanced disease or those with enhanced inflammation due to co-morbidities such as IMIDs, whereas targeting intestinal permeability could be indicated for those with dysbiosis or IBD.