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What Are the Current Pharmacological Therapies for Nonalcoholic Fatty Liver Disease?

Published:September 10, 2020DOI:https://doi.org/10.1016/j.jceh.2020.09.001
      Of the currently available drugs tested to treat nonalcoholic fatty liver disease (NAFLD), the most efficacious drugs are pioglitazone (an insulin sensitizer) and vitamin E (an antioxidant). By targeting insulin resistance, the key pathogenic mechanism underlying metabolic syndrome and NAFLD, pioglitazone maybe the preferred drug to treat NAFLD. As we await the results of research trials into multiple new drugs to treat NAFLD, when should we use the currently available patients to treat NAFLD at the present time? To date, no drug has been approved by regulatory agency specifically to treat NAFLD. However, many drugs have been approved to treat other components of metabolic syndrome such as diabetes mellitus and dyslipidemia. Are we underutilizing the currently available drugs to treat NAFLD? Herein, we review the benefits and concerns of the use of these currently available drugs to treat NAFLD and suggest clinical scenarios, wherein the clinician should consider using these drugs.

      Keywords

      The global epidemic of metabolic syndrome, probably secondary to increasing affluence and a more sedentary lifestyle, has led to a rapid increase in nonalcoholic fatty liver disease (NAFLD). The incidence of fatty liver
      • Duseja A.
      • Singh S.P.
      • Saraswat V.A.
      • et al.
      Non-alcoholic fatty liver disease and metabolic syndrome-position paper of the Indian national association for the study of the liver, endocrine society of India, Indian college of cardiology and Indian society of gastroenterology.
      ,
      • Das K.
      • Das K.
      • Mukherjee P.S.
      • et al.
      Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease.
      and of diabetes mellitus
      • Baxi R.
      • Vasan S.K.
      • Hansdak S.
      • et al.
      Parental determinants of metabolic syndrome among adolescent Asian Indians: a cross-sectional analysis of parent-offspring trios.
      is rapidly escalating in India. NAFLD is now increasingly a cause of chronic liver disease in India.
      • Das K.
      • Das K.
      • Mukherjee P.S.
      • et al.
      Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease.
      ,
      • Mukherjee P.S.
      • Vishnubhatla S.
      • Amarapurkar D.N.
      • et al.
      Etiology and mode of presentation of chronic liver diseases in India: a multi centric study.
      The biochemical and histological signatures of metabolic syndrome, as well as NAFLD are often recognised in patients with hepatocellular carcinoma in India.
      • David D.
      • Raghavendran A.
      • Goel A.
      • et al.
      Risk factors for non-alcoholic fatty liver disease are common in patients with non-B non-C hepatocellular carcinoma in India.
      ,
      • Amarapurkar D.N.
      • Dharod M.
      • Gautam S.
      • Patel N.
      Risk of development of hepatocellular carcinoma in patients with NASH-related cirrhosis.
      The most effective intervention to treat NAFLD is weight reduction. The latter is best achieved by dietary modifications and increased physical activity. However, achieving weight reduction is a formidable challenge in many obese patients with NAFLD. In patients with NAFLD progression, the need for pharmacological interventions is a felt need.
      In this review, we discuss the drugs available currently to treat NAFLD – these drugs have mostly targeted different components of the metabolic syndrome.

      Is Any Drug Approved by Regulatory Authorities for Treating NAFLD?

      At present no drug is approved by the United States Food and Drug Administration (USFDA) or European Medicines Agency (EMA) to treat NAFLD. Thus, the use of any drug to treat NAFLD currently has to be considered “off-label use” for this indication. However, other diseases associated with metabolic syndrome are often seen in patients with NAFLD. For example, drugs to treat diabetes mellitus or dyslipidemia (which have been approved by these regulatory agencies) are often used in patients with NAFLD who have these disorders.
      Despite the fact that US and European drug regulatory agencies have not approved any drug to be used to treat NAFLD, the overwhelming need for pharmacological therapies in the global epidemic of NAFLD and emerging data of their efficacy to treat NAFLD have translated into recommendations for use of currently available drugs to treat NAFLD in clinical practice guidelines issued by American Association for the Study of Liver Diseases (AASLD),
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      European Association for the Study of the Liver (EASL)
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. European association for the study of the liver (EASL); European association for the study of diabetes (EASD); European association for the study of obesity (EASO).
      and Indian National Association for the Study of the Liver (INASL).
      • Duseja A.
      • Singh S.P.
      • Saraswat V.A.
      • et al.
      Non-alcoholic fatty liver disease and metabolic syndrome-position paper of the Indian national association for the study of the liver, endocrine society of India, Indian college of cardiology and Indian society of gastroenterology.
      (Table 1).
      Table 1List of Current Drugs Used to Treat NAFLD.
      Mechanism of actionSide effectsRecommendation to treat NAFLD
      AASLD
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      EASL
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. European association for the study of the liver (EASL); European association for the study of diabetes (EASD); European association for the study of obesity (EASO).
      PioglitazonePPARγ agonist, decreases insulin resistanceWeight gain, fractures, may precipitate heart failureYes (use in patients with biopsy proven NASH, with/without type 2 diabetes mellitus)Yes (use in patients with NASH, especially in diabetics)
      Vitamin EAntioxidantIncrease in overall mortality, hemorrhagic stroke, prostate cancerYes (use in nondiabetic patients with biopsy proven NASH)Yes (use in nondiabetic, noncirrhotic patients with NASH)
      StatinsHMG CoA reductase inhibitorHepatitis (serious liver injury is rare)No (Can use to treat dsyslipidemia. Avoid in decompensated cirrhosis)No (can use to treat dyslipidemia)
      MetforminDecreases insulin resistanceLactic acidosisNoNo
      Ursodeoxycholic acidDecreases TNF-α,reduces oxidative stress and insulin resistanceHeadache, GI side effectsNoNo
      PPARγ: peroxisome proliferator activated receptor gamma; HMG CoA: 3 hydroxy 3 methyl glutaryl coenzyme A; TNF-α: tumor necrosis factor alpha

      Treating Nonliver Components of Metabolic Syndrome in Patients with NAFLD

      NAFLD maybe considered as a component of the metabolic syndrome. Data now suggest that NAFLD precedes other components of the metabolic syndrome; hence NAFLD can be considered as a precursor of the metabolic syndrome.
      • Lonardo A.
      • Ballestri S.
      • Marchesini G.
      • Angulo P.
      • Loria P.
      Nonalcoholic fatty liver disease: a precursor of the metabolic syndrome.
      There are several unanswered clinical research questions here. What are the risks of using drugs to treat the other components of metabolic syndrome in patients with NAFLD? Does long-term treatment of these nonliver components of the metabolic syndrome favourably influence the natural history of NAFLD? Is there a benefit in choosing one drug over another to treat type 2 diabetes mellitus, in patients with NAFLD? Does treatment of NAFLD alter the natural history of the nonliver components of metabolic syndrome?

      What are the Outcomes Studied in Research Trials Using Currently Available Drugs to Treat NASH?

      The outcomes of drug trials to treat NAFLD may be classified as liver-related outcomes, outcomes related to cardiovascular events and overall survival.
      Liver-related outcomes studied in non alcoholic steatohepatitis (NASH) drug trials include biochemical, histological and clinical parameters. Normalisation of raised liver enzymes (serum alanine aminotransferase (ALT)) is easily studied; however changes in liver enzymes maybe nonspecific. The need for serial liver biopsies before and after treatment is a challenge in the studies of histological outcomes. Most studies of liver histology used the NAFLD Activity Score (NAS) comprising hepatocellular ballooning, lobular inflammation and macrovesicular steatosis as the main histological outcome studied.
      • Brunt E.M.
      • Kleiner D.E.
      • Wilson L.A.
      Belt P, Neuschwander-Tetri BA; NASH Clinical Research Network (CRN). Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings.
      However, it is now recognized that fibrosis on liver biopsy correlates best with long-term clinical outcomes.
      • Angulo P.
      • Kleiner D.E.
      • Dam-Larsen S.
      • et al.
      Liver fibrosis, but No other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
      The NAS score does not include liver fibrosis.
      Noninvasive markers of liver fat and liver fibrosis have also been used to assess efficacy of drugs to treat NAFLD.
      Reduction in the incidence of new onset hepatic decompensation and reduction in the incidence of hepatocellular carcinoma with drugs to treat NAFLD are relevant clinical outcomes to be studied. Cardiovascular events are commoner cause of death in patients with NAFLD than liver-related complications.
      • Adams L.A.
      • Lymp J.F.
      • St Sauver J.
      • et al.
      The natural history of nonalcoholic fatty liver disease: a population-based cohort study.
      Hence, reduction in incidence of cardiovascular events and improved overall survival are important clinical outcomes to be studied in NAFLD drug trials.

      Duration of Drug Trials to Treat NAFLD

      Similar to other components of the metabolic syndrome such as diabetes mellitus and dyslipidemia, NAFLD is a lifelong disorder. The trials of drugs to treat NAFLD studied patients who were given these medicines for finite time periods (Table 2) a period of 6–36 months (pioglitazone) and 6–24 months (vitamin E). Complications of longer term treatment and benefits derived from long-term treatment in NAFLD are not known at present. Thus, at the present time, the clinician has to factor in this duration of the drug used in these studies and apply this information in the judicious use of these drugs to treat patients with NAFLD.
      Table 2Results of Meta-analysis: Effects of Insulin Sensitisers and Vitamin E to Treat NAFLD.
      • Said A.
      • Akhter A.
      Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis.
      ,
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      PioglitazoneMetforminVitamin E
      Duration of treatment6–24 months6–12 months6–24 months
      Liver biochemistry
      serum ALTImprovedImprovedImproved
      Liver histology
      BallooningImprovedWorseImproved
      Lobular inflammationImprovedNot improvedImproved
      SteatosisImprovedNot improvedImproved
      FibrosisMay improveNot improvedNot improved
      Body mass indexIncreasedNo changeDecreased
      Metabolic parameters
      HOMA I.R.BetterBetterNot tested
      Fasting blood sugarBetterBetter
      Total cholesterolBetterBetter
      NAFLD: nonalcoholic fatty liver disease.; ALT: alanine aminotransfe
      • Banini B.A.
      • Cazanave S.C.
      • Yates K.P.
      • et al.
      Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)
      Haptoglobin 2 allele is associated with histologic response to vitamin E in subjects with nonalcoholic steatohepatitis.
      rase; HOMA I.R.: homeostatic model assessment insulin resistance.

      Current Pharmacological Therapies

      The currently available drugs to treat NAFLD which have been tested in clinical trials, their mechanisms of action, side effects and recommendation by professional societies are mentioned in Table 1. Insights into the mechanisms of disease pathogenesis have enabled therapeutic targets to be identified in NAFLD. Most of these drugs are aimed at different aspects of the metabolic syndrome seen in patients with NAFLD. Insulin resistance and oxidative stress are the two important phenomena which have been targeted by currently available drugs to treat NAFLD.
      Randomised controlled trials have tested two insulin-sensitizing drugs (pioglitazone
      • Aithal G.P.
      • Thomas J.A.
      • Kaye P.V.
      • et al.
      Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.
      • Belfort R.
      • Harrison S.A.
      • Brown K.
      • et al.
      A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • Nash C.R.N.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
       metformin
      • Haukeland J.W.
      • Konopski Z.
      • Eggesbø H.B.
      • et al.
      Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial.
      • Idilman R.
      • Mizrak D.
      • Corapcioglu D.
      • et al.
      Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis.
      • Shields W.W.
      • Thompson K.E.
      • Grice G.A.
      • Harrison S.A.
      • Coyle W.J.
      The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial.
      ) and vitamin E
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • Nash C.R.N.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Dufour J.F.
      • Oneta C.M.
      • Gonvers J.J.
      • et al.
      Swiss Association for the Study of the Liver. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis.
      ,
      • Harrison S.A.
      • Torgerson S.
      • Hayashi P.
      • Ward J.
      • Schenker S.
      Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis.
      to treat NAFLD. Meta-analysis of the effects of these 3 drugs in patients with NAFLD have been performed.
      • Said A.
      • Akhter A.
      Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis.
      ,
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      It is not known if combining pioglitazone with vitamin E will have a synergistic beneficial effect in patients with NAFLD.
      The main side effects of these drugs are weight gain, increased incidence of congestive heart failure (pioglitazone), lactic acidosis (metformin) and increased risk of prostate cancer (vitamin E).
      Ursodeoxycholic acid may improve serum transaminases in patients with NAFLD. Relative safety of this drug means it is easy to administer. However, the low quality of evidence in randomised trials of its efficacy has meant that ursodeoxycholic acid is not recommended by AASLD and EASL (Table 1).

      Efficacy of Pioglitazone, Metformin and Vitamin E to Treat NAFLD: Results of Meta-analyses
      • Said A.
      • Akhter A.
      Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis.
      ,
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.

      On meta-analysing the data from 4 randomised controlled trials of Thiazolidinediones pioglitazone – 3 trials, rosiglitazone – 1 trial) to treat NASH, use of Thiazolidinediones was associated with improvement in ballooning degeneration (combined odds ratio: 2.11 (95% CI: 1.33–3.36), improvement in lobular inflammation (combined odds ratio (OR): 2.58 (95% confidence interval (CI): 1.68–3.97) and improvement in steatosis (combined OR: 3.39 (95% CI: 2.19–5.25) compared with placebo. In some patients, pioglitazone may improve liver fibrosis. When the use of pioglitazone alone (137 patients) was compared to placebo (134 patients), pioglitazone use was associated with improvement in liver fibrosis (combined OR: 1.68 (95% CI: 1.02–2.77).
      • Boettcher E.
      • Csako G.
      • Pucino F.
      • Wesley R.
      • Loomba R.
      Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis.
      Metformin therapy for NASH, on meta-analysis, was associated with worsening of lobular inflammation (weighted mean increase: 0.21 (95% CI: 0.11–0.31, P < 0.0001), whereas there was no significant improvement in steatosis, ballooning degeneration and fibrosis on liver biopsy.
      • Said A.
      • Akhter A.
      Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis.
      Vitamin E therapy for NASH, on meta-analysis, was associated with significant improvement in steatosis (weighted mean decrease: – 0.6 (95% CI: – 0.85 to – 0.35, P < 0.0001), lobular inflammation (weighted mean decrease: – 0.4 (95% CI: – 0.61 to – 0.2, P = 0.0001), and ballooning (weighted mean decrease: −0.3, 95% CI: – 0.54 to – 0.07, P = 0.01) compared with placebo. However, fibrosis did not improve significantly on liver biopsy.
      • Said A.
      • Akhter A.
      Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis.
      Thus, these two meta-analyses of drugs to treat NASH demonstrate improved liver histological scores with pioglitazone and vitamin E. However, metformin does not improve the NAS liver histological score. Liver fibrosis improved only with pioglitazone (when analysed from trials which used pioglitazone alone, ie. excluding trial using rosiglitazone). Of the three drugs, use of pioglitazone and metformin was associated with improvement in insulin resistance.

      Which is the Preferred Drug to Treat Diabetes Mellitus in Patients with NAFLD?

      When one considers insulin resistance as the driver of metabolic syndrome and of NAFLD, it appears logical to use drugs which counter insulin resistance to treat diabetes mellitus in patients with NAFLD and diabetes mellitus. In practice, it is common for us to see patients with type 2 diabetes mellitus and fatty liver being treated with noninsulin-sensitising drugs such as insulin or other oral hypoglycemic agents for control of blood sugars. Using only insulin to treat type 2 diabetes mellitus will probably not favourably impact fatty liver disease.
      In a cross-sectional study of 346 patients with type 2 diabetes mellitus and (liver biopsy proven) fatty liver reported that 24% of patients were on insulin. Patients on insulin were more likely to have NASH or significant liver fibrosis. In this study, the use of antidiabetic drugs which increase insulin levels (eg. sulfonylureas) or use of exogenous insulin were independently associated with increased risk of NASH or liver fibrosis. The use of sulfonylureas was associated with a 2-fold increase in risk of significant fibrosis and the use of insulin with a 2-fold increase in risk of NASH.
      • Nascimbeni F.
      • Aron-Wisnewsky J.
      • Pais R.
      • et al.
      LIDO study Group. Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease.

      Why was Pioglitazone Tested to Treat NAFLD in Nondiabetic Patients?

      The drug regulatory authorities such as USFDA and EMA approve drugs for use for a specific indication based on evidence of safety and efficacy of these drugs to treat patients with that disease demonstrated in clinical trials. It appears that in the pioneering research reported in the landmarks trials to treat NAFLD with pioglitazone, the investigators strategically chose to test the drug in patients with fatty liver, without diabetes. This strategy was probably chosen to test if pioglitazone is (or is not) effective to treat fatty liver disease.
      • Aithal G.P.
      • Thomas J.A.
      • Kaye P.V.
      • et al.
      Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.
      If the authors had chosen patients with fatty liver and diabetes mellitus, it could be argued that the benefit (if any) of pioglitazone to treat fatty liver was due to the antidiabetic effect of the drug. This strategic planning by the authors seems to have borne fruit – we now have incontrovertible evidence that pioglitazone improves biochemical and histological parameters in patients with fatty liver (without diabetes).
      • Aithal G.P.
      • Thomas J.A.
      • Kaye P.V.
      • et al.
      Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.
      Although the guidelines issued by the AASLD
      • Chalasani N.
      • Younossi Z.
      • Lavine J.E.
      • et al.
      The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
      and EASL
      EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. European association for the study of the liver (EASL); European association for the study of diabetes (EASD); European association for the study of obesity (EASO).
      recommend the use of pioglitazone in patients with fatty liver in nondiabetics, the clinician can use pioglitazone as a drug to treat diabetes, in patients with fatty liver and diabetes.

      What is the Reluctance to Use of Pioglitazone to Treat NAFLD?

      A recent retrospective study of 1008 patients with liver biopsy–proven NAFLD (NASH 63%, advanced fibrosis 17%) from 8 countries in the Asia Pacific region reported that only 4% of these patients were treated with vitamin E and 2% were treated with pioglitazone.
      • Chan W.K.
      • Treeprasertsuk S.
      • Imajo K.
      • et al.
      Clinical features and treatment of non alcoholic fatty liver disease across the Asia Pacific region-the GO ASIA initiative.
      Pioglitazone was approved by the USFDA in the year 1999 for the treatment of type 2 diabetes mellitus. The side effects of pioglitazone are weight gain, osteoporosis, fractures and congestive cardiac failure. It is important to screen for cardiac issues and carry out echocardiogram to rule out diastolic dysfunction or any other abnormality. The concern about increased risk of urinary bladder cancer has turned out to be unfounded. Current data suggest that the objection to use pioglitazone citing increased urinary bladder risk is more “legalistic” rather than evidence based.
      • Davidson M.B.
      Pioglitazone (Actos) and bladder cancer: legal system triumphs over the evidence.
      Thiazolidinediones are peroxisome proliferator activated receptor gamma (PPAR-γ) agonists which decrease insulin resistance. However, in this class of drugs, two drugs have been withdrawn from market due to safety concerns. Troglitazone was withdrawn due to hepatotoxicity, whereas rosiglitazone was withdrawn due to cardiovascular side effects. Pioglitazone remains the only drug in this class recommended for the treatment of diabetes mellitus.
      • Consoli A.
      • Formoso G.
      Do thiazolidinediones still have a role in treatment of type 2 diabetes mellitus?.
      Pioglitazone, on the other hand, reduces cardiovascular events in diabetic patients.
      • Soccio R.E.
      • Chen E.R.
      • Lazar M.A.
      Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes.
      In diabetic patients, who had a previous cerebrovascular event, pioglitazone reduces incidence of stroke and myocardial infarction.
      • Kernan W.N.
      • Viscoli C.M.
      • Furie K.L.
      • et al.
      IRIS trial investigators. Pioglitazone after ischemic stroke or transient ischemic attack.
      It is felt that pioglitazone, with its safety and efficacy demonstrated in NASH, may emerge as the first-line therapy for NASH.
      • Bril F.
      • Cusi K.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis.
      It is abundantly clear that pioglitazone is the most promising drug currently available to treat NASH. The benefits of pioglitazone have been demonstrated both in patients with NASH without diabetes mellitus and in patients with NASH and type 2 diabetes. Although we await further data from longer term drug trials and regulatory approval to use pioglitazone to treat NAFLD, are we underutilising this drug at present to treat NAFLD?
      The main drawback of the use of pioglitazone in patients with NASH is weight gain, which is a disincentive in patients who are already obese. A proportion of patients with NASH are not overweight or obese (the so-called “lean NASH” phenotype).
      • Das K.
      • Chowdhury A.
      Lean NASH: distinctiveness and clinical implication.
      In India, 16–75% of patients with NASH/NAFLD have been reported to have normal body mass index or were underweight.
      • Das K.
      • Das K.
      • Mukherjee P.S.
      • et al.
      Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease.
      ,
      • Singh S.P.
      • Kar S.K.
      • Panigrahi M.K.
      • et al.
      Profile of patients with incidentally detected nonalcoholic fatty liver disease (IDNAFLD) in coastal eastern India.
      In patients with lean NASH, the decision to treat with pioglitazone needs to be considered.

      Biomarkers to Identify Which Patient with NAFLD Would Respond to Pioglitazone

      All patients treated with pioglitazone did not show favourable response on liver biopsy. Measuring plasma adiponectin level
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      and assaying plasma levels of pioglitazone and its metabolites (“pioglitazone exposure index”), as well as baseline NAS score
      • Kawaguchi-Suzuki M.
      • Bril F.
      • Kalavalapalli S.
      • Cusi K.
      • Frye R.F.
      Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis.
      have been suggested as ways to identify patients with NASH likely to respond to treatment with pioglitazone. However, although more data are needed to validate these observations, these do not appear to be easily available tests to decide on therapy in patients with NASH.

      Vitamin E to Treat NAFLD

      Oxidant stress is another mechanism of disease in patients with NAFLD which has emerged as a therapeutic target. Patients with NASH seem to have higher degree of oxidant stress when compared with patients with chronic viral hepatitis.
      • Madan K.
      • Bhardwaj P.
      • Thareja S.
      • Gupta S.D.
      • Saraya A.
      Oxidant stress and antioxidant status among patients with nonalcoholic fatty liver disease (NAFLD).
      ,
      • Kumar A.
      • Sharma A.
      • Duseja A.
      • et al.
      Patients with nonalcoholic fatty liver disease (NAFLD) have higher oxidative stress in comparison to chronic viral hepatitis.
      The antioxidant effects of vitamin E (ᾳ tocopherol) have been used to treat NASH. Vitamin E therapy lead to improvement in serum transaminases,
      • Madan K.
      • Batra Y.
      • Gupta D.S.
      • et al.
      Vitamin E-based therapy is effective in ameliorating transaminasemia in nonalcoholic fatty liver disease.
      ,
      • Parikh P.
      • Ingle M.
      • Patel J.
      • Bhate P.
      • Pandey V.
      • Sawant P.
      An open-label randomized control study to compare the efficacy of vitamin e versus ursodeoxycholic acid in nondiabetic and noncirrhotic Indian NAFLD patients.
      as well as improvement in all components of NAS score – ballooning, steatosis and lobular inflammation – on liver histology; however, liver fibrosis did not improve.
      • Sanyal A.J.
      • Chalasani N.
      • Kowdley K.V.
      • Nash C.R.N.
      • et al.
      Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      ,
      • Dufour J.F.
      • Oneta C.M.
      • Gonvers J.J.
      • et al.
      Swiss Association for the Study of the Liver. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis.
      ,
      • Harrison S.A.
      • Torgerson S.
      • Hayashi P.
      • Ward J.
      • Schenker S.
      Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis.
      Vitamin E appears well tolerated in the short-term to treat patients with NAFLD. However, few concerns about safety with longer term vitamin E therapy remain.
      • Issa D.
      • Wattacheril J.
      • Sanyal A.J.
      Treatment options for nonalcoholic steatohepatitis - a safety evaluation.
      Increased risk of all cause mortality,
      • Miller 3rd, E.R.
      • Pastor-Barriuso R.
      • Dalal D.
      • Riemersma R.A.
      • Appel L.J.
      • Guallar E.
      Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality.
      hemorrhagic stroke
      • Schürks M.
      • Glynn R.J.
      • Rist P.M.
      • Tzourio C.
      • Kurth T.
      Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials.
      and prostate cancer
      • Klein E.A.
      • Thompson Jr., I.M.
      • Tangen C.M.
      • et al.
      Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT).
      ,
      • Kristal A.R.
      • Till C.
      • Song X.
      • et al.
      Plasma vitamin D and prostate cancer risk: results from the selenium and vitamin E cancer prevention trial.
      are concerns with long-term vitamin E therapy.

      Biomarkers to Identify Which Patient with NAFLD Would Respond to Vitamin E

      Metabolomic profiling of patients with NASH who were studied in the PIVENS trial has been reported to try and identify biomarkers of response to vitamin E therapy.
      • Cheng J.
      • Joyce A.
      • Yates K.
      • Aouizerat B.
      • Sanyal A.J.
      Metabolomic profiling to identify predictors of response to vitamin E for non-alcoholic steatohepatitis (NASH).
      Haptoglobin genotype may determine response to vitamin E therapy in patients with NASH.
      • Banini B.A.
      • Cazanave S.C.
      • Yates K.P.
      • et al.
      Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)
      Haptoglobin 2 allele is associated with histologic response to vitamin E in subjects with nonalcoholic steatohepatitis.

      Statin Use in Patients with NAFLD

      There is limited data on the use of lipid lowering therapies to treat NAFLD per se, in the absence of dyslipidemia.
      However, the need for lipid lowering therapy is often encountered in patients with NAFLD, who also have dyslipidemia. Statins can be used safely in patients with NAFLD, with monitoring for hepatitis.
      • Duseja A.
      • Singh S.P.
      • Saraswat V.A.
      • et al.
      Non-alcoholic fatty liver disease and metabolic syndrome-position paper of the Indian national association for the study of the liver, endocrine society of India, Indian college of cardiology and Indian society of gastroenterology.
      In patients given statins, although mild hepatitis maybe encountered, the risk of severe liver injury appears to be rare. In patients with NAFLD with mild to moderate hepatitis, statin use (mainly atorvastatin) was associated with normalization of liver enzymes.
      • Athyros V.G.
      • Tziomalos K.
      • Gossios T.D.
      • et al.
      GREACE Study Collaborative Group
      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.
      Statins are best avoided in patients with decompensated cirrhosis and in patients with acute liver failure. Hypertriglyceridemia is often present in patients with NAFLD in India
      • Mehta M.
      • Satsangi S.
      • Duseja A.
      • Taneja S.
      • Dhiman R.K.
      • Chawla Y.
      Can alcoholic liver disease and nonalcoholic fatty liver disease Co-exist?.
      ; in such patients, treatment with fibrates needs to be considered.

      Pharmacological Therapy for Paediatric NAFLD

      The only randomised controlled drug trial in children with NAFLD did not show a benefit with the use of vitamin E or metformin.
      • Lavine J.E.
      • Schwimmer J.B.
      • Van Natta M.L.
      • et al.
      Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial.

      What are the New Advances in our Knowledge About the Currently Available Drugs to Treat NAFLD?

      Longer term data on the use of pioglitazone (for a period of 36 months) has now been reported.
      • Cusi K.
      • Orsak B.
      • Bril F.
      • et al.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial.
      This study shows benefits of the longer duration of treatment with pioglitazone, with improvement in hepatic fibrosis on serial liver biopsies. No serious drug-induced adverse event was noted in this study.
      Attempts are being made to identify which patient with NASH is likely to respond to pioglitazone
      • Kawaguchi-Suzuki M.
      • Bril F.
      • Kalavalapalli S.
      • Cusi K.
      • Frye R.F.
      Concentration-dependent response to pioglitazone in nonalcoholic steatohepatitis.
      ,
      • Kawaguchi-Suzuki M.
      • Cusi K.
      • Bril F.
      • Gong Y.
      • Langaee T.
      • Frye R.F.
      A genetic score associates with pioglitazone response in patients with non-alcoholic steatohepatitis.
      and to vitamin E.
      • Cheng J.
      • Joyce A.
      • Yates K.
      • Aouizerat B.
      • Sanyal A.J.
      Metabolomic profiling to identify predictors of response to vitamin E for non-alcoholic steatohepatitis (NASH).
      ,
      • Banini B.A.
      • Cazanave S.C.
      • Yates K.P.
      • et al.
      Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)
      Haptoglobin 2 allele is associated with histologic response to vitamin E in subjects with nonalcoholic steatohepatitis.
      It is also being recognized that liver fibrosis in serial liver biopsies is currently the best surrogate marker of clinical outcome in NASH drug trials. Over 12.6 (0.3–35.1) years, (median, range), follow-up of 619 patients with biopsy-proven NAFLD, only the stage of liver fibrosis and no other histologic features of steatohepatitis was independently associated with overall mortality, liver transplantation, and liver-related events.
      • Angulo P.
      • Kleiner D.E.
      • Dam-Larsen S.
      • et al.
      Liver fibrosis, but No other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
      NAS does not include liver fibrosis. Newer and more accurate ways of assessing liver fibrosis are being explored, for use in NASH drug trials.
      • Agrawal S.
      • Hoad C.L.
      • Francis S.T.
      • Guha I.N.
      • Kaye P.
      • Aithal G.P.
      Visual morphometry and three non-invasive markers in the evaluation of liver fibrosis in chronic liver disease.
      ,
      • Thomas J.A.
      • Gupta R.
      • Aithal G.P.
      Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis.

      In Which Patients Should we Consider use of the Currently Available Drugs to Treat NAFLD?

      NASH has been identified as the part of the spectrum of NALFD at risk of progressive liver disease and hence has been the target for drug trials to treat NAFLD. However, we may encounter clinical scenarios wherein the need for pharmacological therapy for NAFLD appears even more urgent. Some such scenarios are patients with recurrence of NASH after liver transplantation for NAFLD-related decompensated cirrhosis or hepatocellular carcinoma; patients with NAFLD-related hepatocellular carcinoma who have undergone curative treatment such as radiofrequency ablation or surgical resection; patients with NAFLD with significant family history of hepatocellular carcinoma due to NAFLD or deaths due to NAFLD cirrhosis.
      It has been suggested that while we await the results of on-going randomised clinical trials, the use of pioglitazone or statins or both drugs in combination maybe considered in patients with NAFLD who are at high risk for cardiovascular disease or for hepatocellular carcinoma, as primary or secondary prevention of cardiovascular disease and to avoid progressive liver disease.
      • Athyros V.G.
      • Alexandrides T.K.
      • Bilianou H.
      • et al.
      The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. an expert panel statement.

      Newer Drugs to Treat Metabolic Syndrome in Patients with NAFLD

      Multiple novel drugs are currently being researched to address the epidemic of NAFLD. Some of these new classes of drugs target the metabolic syndrome in patients with NAFLD. Examples of such drugs include antidiabetic drugs such as glucagon-like peptide-1 receptor agonist,
      • Eguchi Y.
      • Kitajima Y.
      • Hyogo H.
      • et al.
      Japan Study Group for NAFLD (JSG-NAFLD). Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J).
      sodium-glucose cotransporter-2 inhibitors
      • Lai L.L.
      • Vethakkan S.R.
      • Nik Mustapha N.R.
      • Mahadeva S.
      • Chan W.K.
      Empagliflozin for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes mellitus.
      and PPAR α/γ agonist.
      • Jain M.R.
      • Giri S.R.
      • Bhoi B.
      • et al.
      Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models.
      Pioglitazone and vitamin E are the most promising of the currently available drugs which have been tested as treatment of NAFLD. Most of the currently available drugs to treat NAFLD have not been tested in the long-term as treatments for NAFLD in head to head trials.
      • Sridharan K.
      • Sivaramakrishnan G.
      • Sequeira R.P.
      • Elamin A.
      Pharmacological interventions for non-alcoholic fatty liver disease: a systematic review and network meta-analysis.
      A variety of research trials into newer drugs aimed at newer therapeutic targets in patients with NAFLD are underway, a response to address the global epidemic of NAFLD. Till such data is available, the currently available drugs are used by clinicians to treat the ‘nonliver’ components of metabolic syndrome, often seen in patients with NAFLD. In patients with NAFLD at increased risk of cardiovascular events or progressive liver disease, the use of the currently available drugs to treat NAFLD needs to be considered. In view of its insulin-sensitizing role, clinicians may need to consider adding on pioglitazone/switching antidiabetic drugs to pioglitazone in patients with NAFLD who also have type 2 diabetes mellitus.

      CRediT authorship contribution statement

      Deepu David: interpretation of data, Writing - review & editing. C.E. Eapen: Conceptualization, Methodology, Writing - review & editing.

      Conflicts of interest

      The authors have none to declare.

      Funding

      None.

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