Section of Gastroenterology and Hepatology, Dipartimento Di Promozione Della Salute, Materno Infantile, Medicina Interna e Specialistica Di Eccellenza (PROMISE), University of Palermo, Italy.
Dipartimento di Scienze Economiche, Aziendali e Statistiche, University of Palermo, 90133 Palermo, Italy.
Nutr Metab Cardiovasc Dis. 2022 Oct;32(10):2279-2288. doi: 10.1016/j.numecd.2022.07.001. Epub 2022 Jul 16.
The aims of this study were to quantify the histological improvement and its risk factors in patients with NASH enrolled in the placebo arms of randomized controlled trials (RCTs), and to indirectly compare the effect of several investigational drugs for NASH on validated histological outcomes.
A comprehensive search was conducted to detect phase 2 and 3 RCTs comparing pharmacological interventions in patients with NASH. According to Food and Drug Administration (FDA) recommendations, primary outcomes included: 1) NASH resolution without worsening of fibrosis; 2) At least 1-point reduction in fibrosis without worsening of NASH. Meta-analysis and meta-regressions were conducted on placebo arms, while network meta-analysis was performed on intervention arms. A total of 15 RCTs met the eligibility criteria. The meta-analysis on placebo arms showed a pooled estimate rate of 17% (95%C.I. 12%-23%;I = 86%; p < 0.01) for NASH resolution without worsening of fibrosis and of 21% (95%C.I. 13%-31%;I = 84%; p < 0.01) for ≥1stage improvement of fibrosis without worsening of NASH. Phase 3 (vs Phase 2)RCTs, older age and higher AST levels were significantly associated with progression of liver disease by univariate meta-regression. At network meta-analysis, Semaglutide (P-score 0.906), Pioglitazione alone (score 0.890) and plus Vitamin E (0.826) had the highest probability of being ranked the most effective intervention for NASH resolution without worsening of fibrosis, while Aldafermin (0.776), Lanifibranor (0.773) and Obeticholic acid (0.771) had the highest probability to achieve ≥1 stage of fibrosis improvement without worsening of NASH.
This study confirms the heterogeneity of histological progression of untreated patients with NASH and provides evidence to stratify patients according to identified risk factors in future RCTs of combination therapies. PROSPERO CRD42021287205.
本研究旨在量化纳入随机对照试验（RCT）安慰剂组的 NASH 患者的组织学改善及其危险因素，并间接比较几种 NASH 研究药物对验证组织学结局的影响。
进行了全面检索，以检测比较 NASH 患者药物干预的 2 期和 3 期 RCT。根据美国食品和药物管理局（FDA）的建议，主要结局包括：1）NASH 缓解且纤维化无恶化；2）纤维化至少改善 1 级且 NASH 无恶化。对安慰剂组进行了荟萃分析和荟萃回归分析，对干预组进行了网络荟萃分析。共有 15 项 RCT 符合入选标准。安慰剂组的荟萃分析显示，NASH 缓解且纤维化无恶化的总体估计率为 17%（95%CI 12%-23%；I=86%；p<0.01），纤维化至少改善 1 级且 NASH 无恶化的总体估计率为 21%（95%CI 13%-31%；I=84%；p<0.01）。单变量荟萃回归分析显示，3 期（vs 2 期）RCT、年龄较大和较高的 AST 水平与肝病进展显著相关。在网络荟萃分析中，司美格鲁肽（P 评分 0.906）、吡格列酮单独治疗（评分 0.890）和加用维生素 E（0.826）具有最高的可能性被列为 NASH 缓解且纤维化无恶化的最有效干预措施，而奥贝胆酸（0.771）、利那列净（0.773）和阿得贝利单抗（0.776）具有最高的可能性实现纤维化至少改善 1 级且 NASH 无恶化。
本研究证实了未经治疗的 NASH 患者组织学进展的异质性，并为未来的联合治疗 RCT 中根据确定的危险因素对患者进行分层提供了证据。PROSPERO CRD42021287205。
