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Abstract Details
Systematic review and meta-analysis: analysis of variables influencing the interpretation of clinical trial results in NAFLD
Gastroenterol. 2022 May;57(5):357-371.doi: 10.1007/s00535-022-01860-0. Epub 2022 Mar 24.
1Digestive Disease Department, Virgen del Rocio University Hospital, Avenida Manuel Siurot s/n, 41013, Sevilla, Spain. jampuero-ibis@us.es.
2SeLiver Group, Instituto de Biomedicina de Sevilla/CSIC, Universidad de Sevilla, Sevilla, Spain. jampuero-ibis@us.es.
3Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain. jampuero-ibis@us.es.
4SeLiver Group, Instituto de Biomedicina de Sevilla/CSIC, Universidad de Sevilla, Sevilla, Spain.
5Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain.
6Digestive Disease Department, Virgen del Rocio University Hospital, Avenida Manuel Siurot s/n, 41013, Sevilla, Spain.
#Contributed equally.
Abstract
Background: NAFLD clinical trials have shown suboptimal results, particularly for liver fibrosis, despite the robust preclinical drug development. We aimed to assess the histological response after the experimental treatment versus placebo by carrying out a meta-analysis of NAFLD clinical trials.
Methods: After a systematic review of NAFLD clinical trials to May 2021, applying strict selection criteria, the following primary outcomes were observed: (a) NASH resolution, with no worsening of fibrosis when available; (b) fibrosis improvement ≥ 1 stage, with no worsening of NAS when available; (c) worsening of NAS; (d) worsening of liver fibrosis ≥ 1 stage, including the progression to cirrhosis on histopathology. Other histological, clinical, and biochemical outcomes were considered secondary endpoints. Heterogeneity was explored by subgroup and sensitivity analyses, and univariable meta-regression.
Results: Twenty-seven randomized clinical trials were included. The pooled efficacy for NASH resolution receiving experimental therapy was 19% (95%CI 15-23; I2 96.2%) compared with placebo 10% (95%CI 7-12; I2 85.8%) (OR 1.66 (95%CI 1.24-2.21); I2 57.8%), while it was 26% (95%CI 22-29); I2 90%)) versus 18% (95%CI 15-21; I2 59%)) for fibrosis improvement (OR 1.34 (95%CI 1.13-1.58); I2 25.4%). For these outcomes, the therapy showed higher efficacy in trials longer than 48 weeks, with < 60% of diabetic population, and when it targeted FXR, PPAR, and antidiabetic mechanisms, and with a NAS < 5 for NASH resolution. Also, NASH (OR 0.57 (95%CI 0.39-0.84); I2 67%) and fibrosis worsening (OR 0.65 (95%CI 0.46-0.92); I2 61.9%) were prevented with the therapy.
Conclusion: This meta-analysis provides information about the efficacy of the therapy versus placebo by comparing different and combined trial outcomes such as NASH resolution, fibrosis improvement, and NAS and fibrosis worsening. Changes in the experimental design and selection criteria of the clinical trials might be suitable to increase the efficacy.