Systematic review with network meta‐analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH

Abstract

Summary 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.

Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets

“…Therefore, this may lead to response rate variability in this group, ultimately conditioning the final net effect observed in the therapeutic arm. In line with this, only lanifibranor OCA and pioglitazone have exhibited beneficial effects in fibrosis improvement compared to placebo, whereas semaglutide, liraglutide, and pioglitazone achieved NASH resolution in comparison to the placebo group, as described in a recent meta-analysis [296]. Accordingly, further research is required to define these critical aspects.…”

“…On the other hand, NAFLD patients with T2DM or obesity seem to be the ideal candidates for antihyperglycemic drugs and lipogenesis inhibitors, respectively. However, both NAFLD and metabolic comorbidities are also well-known inflammatory conditions, so the combination of drugs with activity on different therapeutic targets could improve the outcomes [ 87 , 296 ]. Therefore, identifying the type of patient eligible for each type of treatment could help to unravel new pathological mechanisms and therapeutic implications.…”

“…Moreover, NAFLD is a multifactorial disorder; hence, combinatorial approaches targeting different mechanisms may enable the synergism of beneficial effects while minimizing risks. Thus, some authors have already proposed to further explore the therapeutic impact of combining anti-fibrotic drugs with compounds proven to resolve NASH, suggesting that it could result in an augmented response rate [ 296 ]. Therefore, taking into consideration the increased evidence of immunological mechanisms in NAFLD, the addition of anti-inflammatory drugs could boost the effects of this combined treatment strategy.…”

Meta‐analysis: analysis of mechanistic pathways in the treatment of non‐alcoholic steatohepatitis. Evidence from a Bayesian network meta‐analysis

“…In turn, it is imperative to target key pathways to optimise improvements in outcomes in NASH to serve as the backbone in combination therapies. Majzoub et al conducted a network meta‐analysis with a surface under the curve cumulative ranking probabilities analysis 9 and building on this, we sought to examine the comparative efficacy of specific drug classes and targets that can achieve improvements in histological endpoints. To address this knowledge gap, we performed a network meta‐analysis comparing the histological outcomes of various classes and targets of drugs used in the treatment of NASH.…”

Analysis of Mechanistic Pathways in the Treatment of Non-Alcoholic Steatohepatitis. Evidence from a Bayesian Network Meta-Analysis

“…In turn, it is imperative to target key pathways to optimize improvements in outcomes in NASH to serve as the backbone in combination therapies. A previous meta-analysis done by Majzoub et al conducted a surface under the curve cumulative ranking probabilities analysis 11 and building on this, we sought to examine the comparative efficacy of specific drug classes and targets that can achieve improvements in histological endpoints. To address this knowledge gap, we performed a network meta-analysis comparing the histological outcomes of various classes and targets of drugs used in the treatment of NASH.…”