BACKGROUNDManagement of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH. METHODSIn this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis. RESULTSA total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo. CONCLUSIONSIn this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT03008070.
NFS threshold: -1.455 in patients <65 years old, 0.12 in patients ≥65 years old # FIB4 threshold: 1.30 in patients <65 years old, 2.0 in patients ≥65 years old
Diabetes was induced in female rats by streptozotocin administration prior to mating. Pregnant rats were divided into "severe diabetics" (blood glucose concentration above 300 mg/100 ml) and "mild diabetics" (blood glucose ranging from 100 to 200 mg/100 ml). When compared to control fetuses, fetuses from severely diabetic mothers showed a slight decrease of body weight on days 20.5 and 21.5. Fetal pancreatic insulin stores and plasma insulin concentrations were decreased at 19.5, 20.5 and 21.5 days. The insulin response to glucose was impaired both in vivo and in vitro. In contrast, fetuses from mildly diabetic females showed no change in body weight. Pancreatic and plasma insulin concentrations were increased at 19.5, 20.5 and 21.5 days. The response of the beta cells of term fetuses of mild diabetics to glucose stimulation was enhanced in vitro. These results are consistent with the hyperglycaemia-hyperinsulinaemia theory with regard to the fetuses from mildly diabetic rats and with an impairment of insulin biosynthesis and release in fetuses from severely diabetic females.
Objectives: We aimed to explore the prevalence of portal hypertension in the most common etiologies of patients with compensated advanced chronic liver disease (cACLD) and develop classification rules, based on liver stiffness measurement (LSM), that could be readily used to diagnose or exclude clinically significant portal hypertension (CSPH) in clinical practice. Methods: International cohort study including patients with paired LSM/hepatic venous pressure gradient (HVPG), LSM ≥10kPa and no prior decompensation. Portal hypertension was defined by an HVPG>5 mmHg. A positive predictive value (PPV) ≥90% was considered to validate LSM cut-offs for CSPH (HVPG≥10 mmHg), while a negative predictive value ≥90% ruled out CSPH. Results: 836 patients were evaluated: hepatitis C (HCV, n=358), non-alcoholic steatohepatitis (NASH, n=248), alcohol (ALD, n=203) and hepatitis B (HBV, n=27). Portal hypertension prevalence was >90% in all cACLD etiologies, except for NASH patients (60.9%), being even lower in NASH obese patients (53.3%); these lower prevalences of portal hypertension in NASH patients were maintained across different strata of LSM values. LSM≥25 kPa was the best cut-off to rule in CSPH in ALD, HBV, HCV and non-obese NASH patients, while in obese NASH patients the PPV was only 62.8%. A new model for NASH patients (ANTICIPATE-NASH model) to predict CSPH considering BMI, LSM and platelet count was developed and a nomogram constructed. LSM≤15 kPa plus platelets ≥150x10 9 /L ruled out CSPH in most etiologies. Conclusions: Patients with cACLD of NASH etiology, especially obese NASH patients, present lower prevalences of portal hypertension compared to other cACLD etiologies. LSM≥25 kPa is sufficient to rule in CSPH in most etiologies, including non-obese NASH patients, but not in obese NASH patients. Response to Reviewers:Point-by-point answers to reviewers' comments: Editor/Editorial Board Comments: Editors: After reviewing the manuscript and the comments from the peer reviewers, we would like to ask the authors to address the following issues raised by the editors:1. Was there any correlation of their findings with EGD, and specifically with the absence/presence of high-risk esophageal varices warranting prophylaxis with betablockers or endoscopic band ligation? This a very good point, but information regarding endoscopy was not requested to the participating centers (only LSM and HVPG were available) and it was not an objective of this study. Only the "ANTICIPATE" cohort had endoscopy data and this has been published in the "Anticipate" paper (Hepatology 2016; 64:2173-84) and the Expanded Baveno paper (Hepatology 2017; 66:1980-8).2. Can the authors please convert lab values in table 1 from SI to conventional units? Done.3. We request the authors provide clearer instructions on how to use the nomogram from figure 3. Maybe they can provide an example or improve the instructions, something similar to what was described for the nomogram in figure 4 of the Hepatology 2016 paper on the "Anticipate" study. Thank you for the...
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