CARDIOVASCULAR AND MORTALITY OUTCOMES WITH GLP-1 RECEPTOR AGONISTS VS. OTHER GLUCOSE-LOWERING DRUGS IN PATIENTS WITH NAFLD AND TYPE 2 DIABETES: A NATIONWIDE MULTICENTER MATCHED COHORT STUDY

Background: Hepatic encephalopathy (HE) is associated with increased mortality, falls, and frequent hospitalizations. Patient reported outcomes (PROs) are useful tools to assess health-related quality of life (HRQOL) measures such as impairment of sleep, cognition, or activity. PROs have also been shown to be reliable & valid tools to detect early signs of HE. Many clinicians initiate lactulose when patients present with poor PROs without cognitive testing, however data are limited regarding the efficacy of this strategy.
Methods: The Mi-Kristal trial is a single-center, randomized study to determine whether a 28-day regimen of Kristalose^®, a crystalline lactulose therapy (20g BID) improves HRQOL in people with poor PROs. We enrolled patients with cirrhosis, portal hypertension, no prior HE, & Activity Impairment attributed to cirrhosis >3 (scale 0-10) because this score was highly predictive of overt HE in prior studies. Endpoints included the short form-8 (SF-8), animal naming test (ANT), falls, and a 4-point Likert scale rating sleep quality (very bad to very good).
Results: Fifty-six subjects were randomized, 52 subjects completed the protocol; 25 Kristalose and 27 no treatment. Median Baseline MELD-Na was 11 and ANT was 19 without differences between the groups at baseline. At Day 28 no significant difference was observed using the SF-8: subjects on Kristalose had an 8.1 point increase (95%CI 3.7-12.4) compared to 6.6 (95%CI 2.3-10.8) in control (p=0.6). Significant improvements were observed in subjects on Kristalose using the ANT which increased by 3.7 (95%CI 2.1-5.4) vs control - -0.2 (95%CI -1.7-1.4); 32% on Kristalose had a 5-point increase in ANT vs 11% of control. Falls were reported by 11% in control and 4% on Kristalose. At the end of the trial, 92% on Kristalose reported good sleep compared to 52% of control. Compared to control, Kristalose was associated with a significant 0.6 (95%CI0.3-1.0) point improvement in sleep quality and a significant 1.7 (95%CI0.3-3.1) point decrease in activity impairment.
Conclusion: Among patients with activity impairment at risk for HE, a 28-day crystalline lactulose regimen led to improved sleep, cognitive function & activity impairment. No significant difference in HRQOL was observed using the SF-8 possibly because the instrument is insensitive to change in this context or a longer treatment duration is required. A 6-month trial is planned. Our findings support the use of PROs to assess for benefit of HE-therapy and that early treatment improves select PROs.

Background
Endoscopic “palpation” of the liver is possible via endoscopic ultrasound (EUS). Regardless of body habitus, the EUS probe can be reproducibly positioned close to the liver surface. With a standard turn of the big wheel, the EUS probe indents the liver surface, and the level of indentation can be measured with sonographic calipers. Our hypothesis is that a fibrotic liver is harder to indent and the degree of indentation correlates with liver fibrosis severity. We aim to correlate EUS liver palpation with histology in patients with NAFLD and compare its predictive value for fibrosis staging to more conventional screening methods.
Methods
This was a cross sectional study of prospectively collected data. Consecutive patients at 3 hospitals between June 2021 and Nov 2022 underwent EUS liver palpation with subsequent liver biopsy. Index scores of Fibrosis-4 Index (FIB-4), AST to Platelet Ratio Index (APRI), NAFLD Fibrosis Score (NFS), and Agile 3+/4 per transient elastography (TE, i.e. Fibroscan) were calculated. Comparisons between EUS liver palpation and index scores/TE were performed using area under the curve (AUC) analysis.
Results
61 patients were evaluated. The mean age was 50. 64.5% were female. Average BMI was 41.2. EUS liver palpation significantly correlated with fibrosis stage on liver biopsy (p=0.0002) with lower indentation values at higher fibrosis stages [Figure 1A]. EUS palpation had AUC of 0.73, 0.80, and 0.98 for discriminating significant fibrosis (F0-1 vs F2-4), advanced fibrosis (F0-2 vs F3-4), and cirrhosis (F0-3 vs F4) respectively [Figure 1B]. EUS liver palpation was superior to APRI and NFS in predicting cirrhosis (p=0.004 and 0.038 respectively).. Indentation of ≤3.5mm yields sensitivity, specificity, positive predictive value, and negative predictive value of 64.7%, 100%, 100%, and 88% respectively for detecting advanced fibrosis.
35/61 (57%) patients had TE performed. In this sub-cohort, EUS palpation had higher AUC values than TE and Agile 3+/4 but this was not significantly different [Figure 2A]. Combination of palpation + Agile 3+/4 for advanced fibrosis and cirrhosis cutoffs were superior to TE alone (p=0.0018 and 0.017 respectively). Lastly, we discovered body mass index (BMI) may be a confounder for TE (Pearson coefficient r=0.70, p=0.0005) but not for EUS liver indentation (r=-0.30, p=0.062) [Figure 2B].
Conclusions
EUS liver palpation is a reliable, novel, and easy-to-use tool to screen for advanced fibrosis in patients with NAFLD, and may be superior to APRI and NFS in predicting cirrhosis. This can be useful in patients with obesity in which an elevated BMI may confound TE results, and may be a valuable minimally invasive tool for endohepatologists in liver fibrosis screening for the NAFLD population. Larger multicenter studies will help to better define the utility and reproducibility of EUS liver palpation.

Background: There is high prevalence of metabolic co-morbidities among U.S. veterans, and hence a high prevalence of metabolic dysfunction associated fatty liver disease (MAFLD). The long-term incidence of cirrhosis among veterans with MAFLD has not been well studied. We aimed to evaluate the overall risk of cirrhosis as well as disparities in cirrhosis incidence among a national cohort of U.S. Veterans with MAFLD.
Methods: We retrospectively evaluated the Veterans Affairs Corporate Data Warehouse from 2010-2021, which captures data on veterans receiving health care across the U.S. MAFLD was identified using established definitions: presence of hepatic steatosis (defined by hepatic steatosis index >36) plus >1 of the following: 1) body mass index >25 kg/m2 in non-Asians or >23 kg/m2 in Asians, 2) concurrent diabetes mellitus, or 3) >2 metabolic risk factors (Eslam, et al. J Hepatol 2020;73:202–209). Overall, 5-year and 10-year incidence of cirrhosis (defined by ICD-9/10) among non-cirrhotic patients was compared between groups using competing-risks Kaplan Meier methods and log-rank testing. Incidence of cirrhosis was further stratified by patient demographics and other relevant clinical variables, and comparisons were made between groups. Adjusted multivariate Cox proportional hazard models were utilized to determine significant predictors of cirrhosis.
Results: Our cohort included 969,253 patients with non-cirrhotic MAFLD, a majority of which were male (94.5%) and non-Hispanic white (70.2%) with mean age of 62.7 ± 12.2 years and mean BMI of 32.7 ± 12.2 kg/m². 5-year incidence of cirrhosis was 2.42% (95% CI 2.39 – 2.45) and 10-year incidence of cirrhosis was 3.70% (95% CI 3.66 – 3.74) (Table 1). When stratified by race/ethnicity, 10-year incidence of cirrhosis was lowest among Asians (2.63%, 95% CI 2.37-2.88) and highest among Hispanics (4.60%, 95% CI 4.45-4.75). Compared to MAFLD patients with no substance use, those with high-risk alcohol use (7.00%, 95% CI 6.83-7.17) or active tobacco use (3.63%, 95% CI 3.63-5.37) had significantly higher 10-year incidence of cirrhosis. On adjusted multivariate analyses, risk of cirrhosis was significantly higher among Hispanics compared to non-Hispanic whites (HR 1.80, 95% CI 1.48-2.19, p<0.0001) (Table 2).
Conclusion: Among a national cohort of U.S. veterans with MAFLD, we identified racial/ethnic differences and other comorbidities which influenced the incidence of cirrhosis. More awareness of the underlying racial/ethnic disparities driving cirrhosis development, particularly for Hispanics, is important to guide future interventions to improve quality of care and clinical outcomes among patients with MAFLD.

Background: Hyperammonemia has been proven as a part of the development of hepatic encephalopathy (HE). However, the relationship between blood ammonia and the prediction of liver-related complications in patients with acute-on-chronic liver failure (ACLF) is less well defined. Therefore, this study aimed to evaluate the role of blood ammonia levels in predicting mortality, development, and progression of liver-related complications in patients with ACLF.

Methods: A prospective cohort of adult ACLF patients as per the APASL definition recruited from the ACLF Research Consortium (AARC, 31 centers) between April 2009 and December 2019; The total of 3,871 ACLF cases were enrolled, with the majority of them caused by alcohol (n = 3,279) and HBV infection (n=592). ACLF patients with the presence of arterial ammonia at baseline were enrolled for analysis. The primary outcome was death during follow-up. Liver-related complications were a composite endpoint of bacterial infection, overt HE, and ascites.

Results: A total of 701 ACLF patients were enrolled. Of these, 399 (56.9%) died during the mean follow-up of 31.3 ± 126.0 days. Mean CTP, MELD, and AARC score were 11.6 ± 1.6, 30.1 ± 7.8, and 9.5 ± 2.2, respectively. Within a month after admission, 170 (24.3%) and 282 (40.2%) patients developed or progressed to overt HE and liver-related complications, respectively. On multivariate cox-regression analysis, INR (HR=1.13, 95%CI: 1.05-1.22, p=0.001), serum creatinine (HR=1.01, 95%CI: 1.04-1.17, p=0.001), and arterial ammonia (HR=1.002, 95% CI: 1.001-1.002, p=0.001) were the independent predictors of death. ACLF caused by alcohol or hepatitis B did not show a significantly different level of arterial ammonia (p=0.41). Patients who developed or progressed from liver-related complications exhibited higher baseline ammonia levels than those who did not (146.3 ± 92.9 vs 122.1 ± 90.4 µmol/L, p<0.001). Subgroup analysis showed that ammonia level was associated with the development or progression of overt HE in 30 days but not ascites or bacterial infections. Ammonia level was significantly higher in patients who developed or progressed overt HE than in patients who did not (174.2 ± 114.2 vs 102.8 ± 67.7 µmol/L, p<0.001). On ROC analysis, arterial ammonia was a significant predictor for the development or progression of overt HE (AUROC = 0.72, 95%CI: 0.56-0.88, p=0.02). Arterial ammonia ≥ 161 µmol/L was an optimal cut-off for predicting the development or progression of overt HE with an AUROC of 0.68 (95% CI: 0.63-0.73, p=0.001), the positive predictive value of 66.7% and negative predictive value of 74.5%.

Conclusion: In ACLF patients, baseline arterial ammonia levels are associated with mortality, the development, and the progression of liver-related complications, particularly overt HE, but not ascites or bacterial infection.

Background: Autoimmune diseases can be associated with increased cardiovascular disease (CVD) risk. However, the magnitude of the risk of CVDs in patients with autoimmune Hepatitis (AIH) is not well established, and also risks have not been estimated at a population level. Hence, our study sought to assess whether AIH was associated with a risk for adverse cardiovascular events.
Methods: We conducted a population-based, multicenter, propensity score-matched cohort study with consecutive patients diagnosed with AIH using the TriNeTx research platform. The study group consisted of patients diagnosed with AIH. The control group consisted of patients who were never diagnosed with AIH or any other chronic liver disease (CLD). Patients who were diagnosed with CVDs prior to the index date were excluded from both cohorts. Patients in the AIH cohort were matched to the control group using 1:1 propensity score matching (PSM) to reduce confounding effects. The primary outcomes were defined as the first incidence of new-onset heart failure (HF), composite major adverse cardiovascular events (MACE) (unstable angina, myocardial infarction (MI), or cardiovascular interventions), MI, a composite of cerebrovascular disease (cerebral infarction, transient ischemic attack, ischemic or hemorrhagic stroke, carotid intervention). We performed secondary and sensitivity analyses to assess our findings' robustness. The incidence of adverse cardiovascular events was estimated using a Cox proportional hazards model with hazard ratios (HR) and 95% confidence intervals (CI).
Results: In the cohort, 11712 cases of AIH were matched to 8734379 controls. After PSM, both cohorts were well-matched (9075 patients). The mean duration of follow-up for the AIH and control cohorts were 5.9 ±1.3 and 6.7±1.1 years, respectively. Of the patients with AIH, 2118 (23.3%) had cirrhosis, and 6261 (69.1%) were on immunosuppressive treatment. During the follow-up, compared to controls, the AIH cohort had a significantly increased risk of MACE (217 vs 65; HR 4.36; 95% CI, 3.27-5.73), MI (94 vs 22; HR 5.86, 95% CI 3.66-9.39), HF (324 vs. 114; HR 3.61, 95% CI 2.91-4.48), and cerebrovascular diseases (314 vs 123; HR 3.32, 95% CI 2.69-4.11) (Table 1). In sensitivity analysis, by excluding the first-year outcomes, the risks of all the CVD outcomes persisted. In the secondary analysis, the risk of MACE (HR=2.64), HF (HR=2.38), and cerebrovascular disease (HR=4.05) remained significantly higher among AIH patients who had cirrhosis.
Conclusion: Patients with AIH have a substantially increased risk of adverse cardiovascular events. These findings warrant that targeted cardiovascular prevention measures to reduce cardiovascular events should become a routine part of the management of AIH. Further prospective studies are needed to confirm these findings.

Background: There is no therapy has been shown to reduce the risk of serious adverse outcomes in patients with nonalcoholic fatty liver disease (NAFLD). Hence, novel treatment strategies are needed. Here, we aimed to explore the macrovascular outcomes as well as mortality for patients with NAFLD and type 2 diabetes mellitus (T2DM) taking Glucagon-like Peptide-1 Receptor Agonists (GLP-1RA) compared to other glucose-lowering drugs.
Methods: We conducted a population-based, multicenter cohort study with consecutive patients diagnosed with NAFLD and T2DM using the TriNeTx. Cohort entry was defined as the date of the first-ever prescription for one of the drugs of interest (GLP-1 RAs) or SGLT-2 inhibitors or metformin or other second/third-line drugs during the study period. We used a lag of 6 months for all exposures to minimize protopathic bias. We performed a 1:1 propensity score matching (PSM) to reduce confounding effects. The primary outcomes were defined as the first incidence of new-onset heart failure (HF), composite major adverse cardiovascular events (MACE), and a composite of cerebrovascular disease, and the secondary outcome was mortality. We conducted a secondary analysis and sensitivity analysis to assess the robustness of our findings. The outcomes were estimated using a Cox proportional hazards model with hazard ratios (HR) and 95% confidence intervals (CI).
Results: In this cohort, 53249 patients received GLP-1A treatment, and 39795 patients received SGLT-2 inhibitor treatment and were included in the control. For sensitivity analysis, 103667 were in the Metformin, and 2638687 were in second/third line anti-diabetic treatment. The GLP-1RA group was non-inferior to the SGLT2 group in terms of CV outcomes: the incidence of MACE (HR, 1.06), HF (HR, 10.9), cerebrovascular diseases (HR, 0.99) was similar compared with the SGLT2 group (Table 1). Moreover, the mortality rates between the GLP-1RA were non-inferior to the SGLT2 group (HR, 1.06). When compared to patients taking metformin, a significantly lower risk of macrovascular and cerebrovascular diseases and HF was observed. Strikingly, mortality was significantly reduced in the GLP1R-A group compared to the metformin group (HR 0.70). When compared to patients taking second/third-line glucose-lowering drugs also, a significantly lower risk of macrovascular diseases, HF, and mortality was observed (HRs 0.90). Sensitivity analysis showed a similar magnitude to the one generated in the primary and secondary analyses.
CONCLUSION: Patients who started GLP1-RA treatment showed a significantly lower incidence of macrovascular diseases and all-cause mortality rates, and GLP1-RA was not inferior to SGLT2 inhibitors. Both GLP1-RA and SGLT2 inhibitors seem to be safe and efficacious drugs to lower the risk of CV outcomes in patients with NAFLD and T2DM.