Introduction

Positive effects on markers of metabolic dysfunction–associated steatotic liver disease (MASLD) have already been demonstrated for sodium–glucose cotransporter-2 (SGLT2) inhibitors. Pre-clinical evidence from rodent models also suggests MASLD benefits of endothelin-A receptor antagonism. Zibotentan, the most selective endothelin A receptor antagonist, is currently under clinical investigation in combination with dapagliflozin for treatment of chronic kidney disease (CKD) and for liver cirrhosis. Advanced CKD is also recognized to occur concomitantly with liver cirrhosis.

Aims & Methods

The aim of this exploratory analysis was to evaluate the effect of zibotentan combined with dapagliflozin and dapagliflozin alone on a non-invasive measure of MASLD in patients with CKD recruited into the ZENITH-CKD phase 2b study.

447 patients in the ZENITH-CKD study were treated for 12 weeks with either zibotentan 0.25 mg in combination with dapagliflozin 10 mg (n = 91), or zibotentan 1.5 mg in combination with dapagliflozin 10 mg (n = 179), or dapagliflozin 10 mg alone (active control) (n = 177). The primary outcome was urinary albumin creatinine ratio at week 12. The presented results are from patients with non-alcoholic fatty liver disease fibrosis score (NFS) > 0.675, indicating high risk for advanced fibrosis and included 39 patients treated with combination therapy with either dose of zibotentan, and 27 patients treated with dapagliflozin alone.

Results

Conclusion

A reduction in NFS was observed in this small exploratory analysis of patients with CKD and high risk for advanced liver fibrosis across all three active arms of the study. These data support further exploration of the effects of zibotentan and dapagliflozin in patients with liver cirrhosis as part of the ongoing ZEAL part B study. Further data from both the CKD and liver study programs are awaited.

Disclosure

PA, PG, EW, KP, JO, KF and SR are employees of, and hold stakes in, AstraZeneca. HJLH has received funding from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novartis. HJLH has received consulting fees from Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Dimerix, Eli Lilly, Janssen, Novartis, Novo Nordisk, Roche, Travere Therapeutics and Vifor Pharma.

Introduction

Aims & Methods

Results

Conclusion

Introduction

The availability of new drugs for the treatment of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) underlines the need of early predictors of response to such therapies. This study evaluated the impact of 1-year changes in liver stiffness measurement by Vibration-Controlled Transient Elastography (LSM by VCTE), controlled attenuation parameters (CAP), and serum alanine aminotransferase (ALT) on liver outcomes in patients with MASLD.

Aims & Methods

A large multicenter cohort of MASLD patients with LSM≥8kPa and prospective follow-up was enrolled. Liver-related events (LRE), including hepatocellular carcinoma (HCC) and liver decompensation (LD), were evaluated during follow-up. LSM, CAP, and ALT were assessed at baseline and at 1-year follow-up. Cumulative incidence functions and cause-specific Cox regression analyses were performed to correlate 1-year reduction in LSM, CAP, and ALT with the risk of developing LRE, LD and HCC.

Results

In 2443 patients with MASLD and LSM≥8kPa, a 1-year reduction in ALT of 17 IU/L (HR 0.62; 95% CI 0.41-0.95; p=0.02) and a 20% reduction in LSM (HR 0.44; 95% CI 0.29-0.67; p<0.001) were both independently associated with a lower risk of LRE. Similarly, in 1412 patients with MASLD and LSM≥10kPa, a 1-year reduction in ALT of at least 17 IU/L (HR 0.62; 95% CI 0.39-0.98; p=0.04) and a 20% reduction in LSM (HR 0.42; 95% CI 0.27-0.66; p<0.001) were independently associated with a decreased risk of LRE. Comparable results were observed when considering LD separately, but not for HCC. One-year changes in CAP did not predict liver outcomes. When combining 1-year reduction in ALT of 17 IU/L and a 1-year 20% reduction in LSM, the 5-year probabilities of LRE ranged from 2.1% in the best profile to 5% in the worst profile in patients with LSM≥8kPa, and from 3.3% to 8.1% in those with LSM≥10kPa.

Conclusion

One-year reductions in ALT of 17 IU/L and in LSM by 20%, but not changes in CAP, reduce long-term liver outcomes in patients with MASLD, providing suggestion on monitoring therapy effectiveness.

Introduction

EUS-guided Gastroenterostomy (EUS-GE) represents a recent breakthrough in therapeutic endosonography, with most existing data derived from retrospective studies focused on short-term technical outcomes. Limited information is available on long-term outcomes, the need for reinterventions and modifications of Lumen Apposing Metal Stents (LAMS) over time.

Aims & Methods

All consecutive EUS-GE performed in a single institution with the Wireless Simplified Technique (WEST) between 2020 and 2024 were enrolled in a prospective registry (PROTECT, ClinicalTrials.gov NCT04813055), with efficacy and safety outcomes assessed every 60 days. The primary outcomes were symptom recurrence after initial clinical success (rate, proportion) and dysfunction-free survival (DyFS) estimated using Kaplan Meier curves. Endoscopic LAMS reassessments were used to calculate the time to first modification of the stent and surrounding tissues, whilst Radiologic imaging was used to estimate the change in stent calibre (linear regression).

Results

164 EUS-GEs (median age 66 [60-74], male 52.4%, malignant indication 99.4% [pancreatic cancer 73.2%, metastatic 58.3%]) were included. A 20 mm LAMS was used in 98.8%, dilated up to 18 mm in 98.8% of cases. Technical and Clinical success rates were 98.8% and 96.3%, respectively. Adverse events (AEs) were registered in 15.2% (procedure-related 6.1%, severe/fatal 3.7%).
Over a median follow-up of 112 [40-190] days, symptom recurrence occurred in 9.1%, but was related to stent dysfunctions in 10/154 (6.5%) cases. Stent dysfunctions happened after a median of 231 [67-321] days from the procedure, all of which (100%) were successfully managed endoscopically. Estimated DyFS at 6 and 12 months was 97.5% and 82.6%, respectively.
Among 38 patients undergoing endoscopic LAMS re-evaluation for different reasons, tissue reactions on the gastric or jejunal side were observed in 34.2% after a median of 190 [33-351] days, and LAMS ingrowth was seen in 13.2% after a median of 421 [250-560] days. A total of 132 CT scans from 75 patients were analysed, with regression analysis revealing a reduction in LAMS diameter of ≈ 0.25 mm + 0.03 every 2 months (F-test p<.0001).

Conclusion

In the natural history of EUS-GE, subclinical LAMS changes and tissue reactions can be frequently detected during follow-up along with a progressive narrowing of LAMS diameter. However, most of these modifications are asymptomatic, with a 6.5% rate of endoscopic reinterventions, all performed successfully. Analysis of these curves may be helpful to plan scheduled reinterventions, especially in cases with benign indication or in long-term survivors.