Abstract: We identified 77 trials including 6287 participants that met the inclusion criteria of this review. Forty-one trials (3829 participants) provided information for one or more outcomes. Only one trial was at low risk of bias in all domains. All other trials were at high risk of bias in one or more domains. Overall, all the evidence was very low quality. Thirty-five trials included only participants with non-alcohol related steatohepatitis (NASH) (based on biopsy confirmation). Five trials included only participants with diabetes mellitus; 14 trials included only participants without diabetes mellitus. The follow-up in the trials ranged from one month to 24 months. We present here only the comparisons of active intervention versus no intervention in which two or more trials reported at least one of the following outcomes: mortality at maximal follow-up, serious adverse events, and health-related quality of life, the outcomes that determine whether a treatment should be used. Antioxidants versus no intervention There was no mortality in either group (87 participants; 1 trial; very low quality evidence). None of the participants developed serious adverse events in the trial which reported the proportion of people with serious adverse events (87 participants; 1 trial; very low quality evidence). There was no evidence of difference in the number of serious adverse events between antioxidants and no intervention (rate ratio 0.89, 95% CI 0.36 to 2.19; 254 participants; 2 trials; very low quality evidence). None of the trials reported health-related quality of life. Bile acids versus no intervention There was no evidence of difference in mortality at maximal follow-up (OR 5.11, 95% CI 0.24 to 107.34; 659 participants; 4 trials; very low quality evidence), proportion of people with serious adverse events (OR 1.56, 95% CI 0.84 to 2.88; 404 participants; 3 trials; very low quality evidence), or the number of serious adverse events (rate ratio 1.01, 95% CI 0.66 to 1.54; 404 participants; 3 trials; very low quality evidence) between bile acids and no intervention. None of the trials reported health-related quality of life. Thiazolidinediones versus no intervention There was no mortality in either group (74 participants; 1 trial; very low quality evidence). None of the participants developed serious adverse events in the two trials which reported the proportion of people with serious adverse events (194 participants; 2 trials; very low quality evidence). There was no evidence of difference in the number of serious adverse events between thiazolidinediones and no intervention (rate ratio 0.25, 95% CI 0.06 to 1.05; 357 participants; 3 trials; very low quality evidence). None of the trials reported health-related quality of life. Source of funding Twenty-six trials were partially- or fully-funded by pharmaceutical companies that would benefit, based on the results of the trial. Twelve trials did not receive any additional funding or were funded by parties with no vested interest in the results. The source of funding was not provided in 39 trials. Due to the very low quality evidence, we are very uncertain about the effectiveness of pharmacological treatments for people with NAFLD including those with steatohepatitis. Further well-designed randomised clinical trials with sufficiently large sample sizes are necessary.

Plain-language summary: We included 77 randomised clinical trials that involved a total of 6287 participants. Of these, 41 trials (3829 participants) provided information for one or more outcomes for this review. Thirty-five trials only included participants with NASH; five included only people with diabetes mellitus; and 14 included only people who did not have diabetes mellitus. The average follow-up period in the trials ranged from one month to two years in the trials that reported this information. We excluded trials in which participants with NAFLD had undergone liver transplantation before the trial. As well as conducting standard Cochrane analysis, we also planned to conduct network meta-analysis (a technique that enables comparison of different treatments that are not directly compared to each other in the trials). However, the nature of available information meant we could not determine if the network meta-analysis results were reliable. Specific outcomes we looked for were numbers of deaths, adverse events, and assessment of health-related quality of life. Twelve trials did not receive any additional funding or were funded by sources with no vested interest in the results; 26 were funded by drug companies that could potentially benefit from trial results; and the funding source was not available from 39 trials. Included trials compared drug treatments such as bile acids, antioxidants, phosphodiesterase type 4 inhibitor, glucocorticosteroid inhibitor, anti-cholesterol drugs and anti-diabetes drugs with a fake treatment (placebo) or no treatment. There were no deaths in either group (87 participants, 1 trial). None of the participants developed serious adverse events in the trial which reported the percentage of people with serious adverse events (87 participants, 1 trial). There was no evidence of difference in the number of serious adverse events between antioxidants and no intervention (254 participants, 2 trials). There was no evidence of difference in deaths at maximal follow-up (659 participants, 4 trials), percentage of people with serious adverse events (404 participants, 3 trials), or the number of serious adverse events (404 participants, 3 trials) between bile acids and no intervention. None of the trials reported health-related quality of life. There were no deaths in either group (74 participants, 1 trial). None of the participants developed serious adverse events in the two trials which reported the percentage of people with serious adverse events (194 participants, 2 trials). There was no evidence of difference in the number of serious adverse events between thiazolidinediones and no intervention (357 participants, 3 trials). None of the trials reported health-related quality of life. We found no evidence of benefit from any of the compared interventions in people with fatty liver disease. There is significant uncertainty in this issue, and we need further high quality randomised clinical trials with sufficiently large group of participants. Evidence quality was very low overall, and there was a high risk of bias. This means there is a possibility of making conclusions that wrongly interpret benefits or harms of treatments because of the ways the studies were conducted.