Abstract and Introduction
Abstract
Background: Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. There is a major need to understand the efficacy of different pharmacological agents for the treatment of NASH.
Aim: To assess the relative rank-order of different pharmacological interventions in fibrosis improvement and NASH resolution.
Methods: A comprehensive search of several databases was conducted by an experienced librarian. We included randomised controlled-trials (RCTs) comparing pharmacological interventions in patients with biopsy-proven NASH. The primary outcome was ≥1 stage improvement in fibrosis. The secondary outcome was NASH resolution.
Results: A total of 26 RCTs with 23 interventions met the eligibility criteria. Lanifibranor and obeticholic acid had the highest probability of being ranked the most effective intervention for achieving ≥1 stage of fibrosis improvement (SUCRA 0.78) and (SUCRA 0.77), respectively. For NASH resolution, semaglutide, liraglutide and vitamin E plus pioglitazone had the highest probability of being ranked the most effective intervention for achieving NASH resolution (SUCRA 0.89), (SUCRA 0.84) and (SUCRA 0.83), respectively. Lanifibranor, obeticholic acid, pioglitazone and vitamin E were significantly better than placebo in achieving ≥1 stage of fibrosis improvement. Conversely, semaglutide, liraglutide, vitamine E plus pioglitazone, pioglitazone, lanifibranor and obeticholic acid were significantly better than placebo in achieving NASH resolution.
Conclusion: These data provide relative rank-order efficacy of various NASH therapies in terms of their improvements in liver fibrosis and NASH resolution. Therapies that have been shown to improve NASH resolution may be combined with therapies that have an antifibrotic effect to further boost treatment response rate in future.
Introduction
Nonalcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease in the United States (US).[1,2] NASH is a progressive liver disease and can lead to cirrhosis and hepatocellular carcinoma leading to increased liver-related morbidity and mortality.[3] It is the second leading indication of liver transplantation in the US.[1] NASH is commonly associated with obesity, insulin resistance and diabetes.[4] Due to rising rates of obesity and diabetes, the prevalence of NASH and NASH related cirrhosis and HCC is rising worldwide.[5]
Lifestyle interventions are the current main stay of the management of NASH including dietary caloric restriction, Mediterranean diet, and increased physical activity.[4] Several pharmacologic therapies are in various phases of clinical development for the management of NASH and NASH related fibrosis. However, there are no food and drug administration (FDA) approved therapies for the management of NASH.[6]
For therapies to be deemed effective by the FDA in NASH related fibrosis, they have to demonstrate benefit in improving long-term clinical outcomes. However, as part of the subpart H approval pathway, if a pharmacologic therapy is able to demonstrate either ≥1 stage improvement in fibrosis stage without worsening of NASH or NASH resolution without worsening of fibrosis it is eligible to receive conditional approval pending demonstration of long-term clinical benefit.
Emerging data from Phase 2b and 3 trials suggest that treatment effect relative to placebo is small. Furthermore, there is significant heterogeneity in treatment response and certain therapies are more likely to improve fibrosis whereas other agents are more likely to lead to resolution of NASH. There is a major unmet understanding of the relative efficacy of different pharmacological agents for the treatment of NASH.[7] Therefore, we aimed to perform a systematic review and network meta-analysis of studies that assess the effect of different pharmacological interventions on NASH in assessing their relative rank-order in fibrosis improvement as well as NASH resolution. An in-depth understanding of these two outcomes would help better synergise future combination therapeutic approaches in NASH to further improve treatment response rates.