Placebo effect on progression and regression in NASH: Evidence from a meta‐analysis

Abstract

Background and Aims The evaluation of the natural history of NASH has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo‐controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta‐analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomized controlled trials (RCTs) to examine the natural history of NASH. Methods A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (1) the resolution of NASH without worsening of fibrosis, (2) two‐point reduction in NAFLD activity score without worsening of fibrosis, and (3) at least one‐point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences. Results This meta‐analysis of 43 RCTs included 2649 placebo‐treated patients. The pooled estimate of NASH resolution and two‐point NAFLD activity score reduction without worsening of fibrosis was 11.65% (95% CI: 7.98‐16.71) and 21.11% (95% CI: 17.24‐25.57). The rate of ≥1 stage reduction and progression of fibrosis was 18.82% (95% CI: 15.65‐22.47) and 22.74% (CI: 19.63‐26.17), respectively. Older age and African American ethnicity was associated with lower NASH resolution rate in placebo‐treated patients. Conclusions Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo‐treated patients is helpful in future design of phase 2B and phase 3 trials.

Comparison of FibroScan-Aspartate Aminotransferase (FAST) Score and Other Non-invasive Surrogates in Predicting High-Risk Non-alcoholic Steatohepatitis Criteria

“…Our study has several limitations. First, due to its retrospective nature and cross-sectional design, this study could have been subject to selection bias and may only present snapshots of NASH that could be resolved and/or progressed over time ( 29 ). Second, the availability of the XL probe in only one institute has limited further analysis regarding the probe type.…”

Nonalcoholic Steatohepatitis Drug Development Pipeline: An Update

“…All rights reserved. pharmacological interventions 218 , which is an important consideration for the assessment of histologic response in placebo-treated patients in designing future phase 2 and 3 trials.…”

The impact of health status, diet and lifestyle on non‐alcoholic fatty liver disease: Narrative review

“…11 Liver fibrosis, which was once thought to be irreversible, can be reversed if the underlying trigger resolves. 11 Therefore, because NAFLD and NASH are metabolic diseases, changes in lifestyle will mainly dictate the course of the disease. 11 The Middle East has one of the highest prevalence of NAFLD, which was found to be around 32%.…”

“…11 Therefore, because NAFLD and NASH are metabolic diseases, changes in lifestyle will mainly dictate the course of the disease. 11 The Middle East has one of the highest prevalence of NAFLD, which was found to be around 32%. 12 One study found a prevalence rate of about 58.5% which is the upper limit in the 95% CI (%), but this may be due to the high number of overweight and patients with obesity recruited for the sample population (Figure 1).…”

“…Indeed, NAFLD is not only associated with liver mortality but is also a risk factor for developing other comorbidities, such as T2DM and cardiovascular diseases 6 . The natural course of the disease may spontaneously progress or regress overtime, but it also aligns with changes in the metabolic state 11 . Liver fibrosis, which was once thought to be irreversible, can be reversed if the underlying trigger resolves 11 .…”