Michelle Theresa Long

In the SELECT trial, once-weekly subcutaneous semaglutide reduced major adverse cardiovascular events (MACE) by 20% versus placebo in patients with atherosclerotic cardiovascular disease and obesity but without diabetes. We examined semaglutide in SELECT patients at high risk for substantial liver fibrosis in a prespecified secondary analysis. Liver biochemical tests and steatosis risk according to fatty liver index were assessed over 104 weeks. Subgroup analyses of the primary MACE (a composite endpoint including cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) outcome used baseline Fibrosis-4 scores ≥ 1.3, age-specific (≥1.3 ( 2.67. MACE was reduced by 26% (hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.63–0.88; P = 0.0004), 21% (HR 0.79; 95% CI 0.63–0.98; P = 0.035) and 34% (HR 0.66; 95% CI 0.39–1.10; P = 0.11), respectively. Semaglutide led to a 28% greater decrease in fatty liver index versus placebo (HR 0.72; 95% CI 0.71–0.73; P < 0.0001). In conclusion, semaglutide reduced MACE versus placebo in patients at risk for substantial liver fibrosis, as seen in the overall SELECT population. ClinicalTrials.gov registration no. NCT03574597

Background: Weight reduction through lifestyle, activity, and dietary interventions are the mainstay of initial therapy for metabolic dysfunction associated steatotic liver disease. Data on the relative effectiveness and metabolic pathways linking weight loss and decreased hepatic steatosis are lacking. We sought to identify coordinated changes between the circulating proteome and hepatic steatosis within a randomized clinical trial of alternate day fasting and exercise and prioritize proteins relevant to hepatic steatosis within a broader context using a community cohort. Methods and Results: We quantified a broad cardiometabolic proteome (>300 proteins) in 67 individuals randomized in a 2×2 factorial design to alternate day fasting and exercise before and after the 3‐month intervention to identify proteomic signatures of hepatic steatosis (measured by magnetic resonance imaging proton density fat fraction). Then, we analyzed the cross‐sectional relationship of overlapping proteins (≈170) with hepatic attenuation (a computed tomographic technique linked to steatosis) in 707 participants from a community cohort. Principal component analysis demonstrated a proteomic signature associated with intrahepatic triglyceride content (Spearman rho=0.55, P P =0.001). Changes in this proteomic signature were associated with changes in intrahepatic triglyceride content over the intervention period (beta=0.12, P <0.001). Moreover, cross‐sectional analysis of overlapping proteins with hepatic attenuation in the community cohort showed generally, directionally consistent associations with hepatic steatosis. Conclusions: These findings highlight the potential for broad proteomic profiling in small nutritional interventional studies with serial phenotyping alongside confirmatory large cohort epidemiology to prioritize targets of hepatic steatosis and cardiometabolic risk for mechanistic study.

Background: Cigarette smoking has been associated with liver fibrosis in the setting of hepatitis C virus (HCV) infection but has not been studied among people with HIV (PWH) who consume alcohol. Methods: This is a cross-sectional study of PWH with heavy drinking and daily smoking in St. Petersburg, Russia. The primary independent variable was past 30-day cigarettes per day (cpd), and the secondary independent variable was pack-years at study entry. Advanced liver fibrosis was defined as FIB-4 > 3.25. Analyses were adjusted for gender, body mass index (BMI), past 30-day number of heavy drinking days, HCV and CD4 count. Results: Participants (n = 400) were two-thirds male (67.3%), young (median age 38 years), lean (median BMI 22), HCV antibody positive (84.5%) and not severely immune suppressed (median CD4 count 351). The median number of past-month cpd was 20 (IQR: 15–25), and the median pack-years was 24 (IQR: 17–31.8). The prevalence of advanced liver fibrosis was 11.3% (45/400). In the adjusted logistic regression analyses, we did not observe a significant association between cpd [middle (10.1–20 cigarettes) vs. lowest (5–10 cigarettes) category (adjusted odds ratio [aOR] (95% confidence interval [CI]): 1.06 (0.40–2.83), highest (>20.0 cigarettes) vs. lowest category aOR (95% CI): 0.65 (0.21–1.99), global p-value = 0.62]. The secondary analysis with pack-years yielded similar results [middle (20.1–30 pack-years) vs. lowest category (≤20 pack-years) aOR (95% CI): 0.81 (0.33–1.99), highest category (>30 pack-years) vs. lowest category aOR (95% CI): 0.91 (0.38–2.19); global p-value = 0.58]. Conclusions: In this Russian cohort of PWH, we did not detect an association between recent cigarette use or mean pack-years and advanced liver fibrosis.

Background and Aims: Individuals with steatotic liver disease (SLD) are at high cardiovascular disease (CVD) risk, but approaches to characterise and mitigate this risk are limited. By investigating relations, and shared metabolic pathways, of hepatic steatosis/fibrosis and cardiorespiratory fitness (CRF), we sought to identify new avenues for CVD risk reduction in SLD.Methods: In Framingham Heart Study (FHS) participants (N = 2722, age 54 ± 9 years, 53% women), vibration‐controlled transient elastography (VCTE) was performed between 2016–2019 to assess hepatic steatosis (continuous attenuation parameter [CAP]) and fibrosis (liver fibrosis measure [LSM]). Concurrently, participants underwent maximum effort cardiopulmonary exercise testing (CPET), and metabolomic profiling (201 circulating metabolites) was performed in a subsample (N = 1268).Results: Mean BMI was 28.0 ± 5.3, 27% had hepatic steatosis, 7.6% had fibrosis, and peak oxygen uptake (VO₂) was 26.2 ± 6.8 mL/kg/min in men and 20.7 ± 6.0 mL/kg/min in women (95% predicted overall). In linear models adjusted for cardiometabolic risk factors, greater CAP and LSM were associated with lower peak VO₂ (p ≤ 0.002 for all), and the CAP association remained significant after BMI adjustment (p < 0.0001). We observed shared metabolic architecture of CAP, LSM, and peak VO₂, with metabolites mediating up to 35% (for CAP) and 74% (for LSM) of the association with peak VO₂. Metabolite mediators included amino acids and derivatives implicated in cardiometabolic risk and both protective and deleterious lipid species.Conclusions: Hepatic steatosis and fibrosis are associated with CRF impairment in the community, and these relations are partly mediated by pathways of altered lipid metabolism and general cardiometabolic risk.

BACKGROUND: Arterial stiffening may contribute to the pathogenesis of metabolic dysfunction–associated steatotic liver disease. We aimed to assess relations of vascular hemodynamic measures with measures of hepatic steatosis and fibrosis in the community. METHODS: Our sample was drawn from the Framingham Offspring, New Offspring Spouse, Third Generation, Omni-1, and Omni-2 cohorts (N=3875; mean age, 56 years; 54% women). We used vibration-controlled transient elastography to assess controlled attenuation parameter and liver stiffness measurements as measures of liver steatosis and liver fibrosis, respectively. We assessed noninvasive vascular hemodynamics using arterial tonometry. We assessed cross-sectional relations of vascular hemodynamic measures with continuous and dichotomous measures of hepatic steatosis and fibrosis using multivariable linear and logistic regression. RESULTS: In multivariable models adjusting for cardiometabolic risk factors, higher carotid-femoral pulse wave velocity (estimated β per SD, 0.05 [95% CI, 0.01–0.09]; P =0.003), but not forward pressure wave amplitude and central pulse pressure, was associated with more liver steatosis (higher controlled attenuation parameter). Additionally, higher carotid-femoral pulse wave velocity (β=0.11 [95% CI, 0.07–0.15]; P P =0.01), and central pulse pressure (β=0.05 [95% CI, 0.01–0.09]; P =0.01) were associated with more hepatic fibrosis (higher liver stiffness measurement). Associations were more prominent among men and among participants with obesity, diabetes, and metabolic syndrome (interaction P values, P =0.02) and fibrosis (odds ratio, 1.40 [95% CI, 1.19–1.64]; P <0.001). CONCLUSIONS: Elevated aortic stiffness and pressure pulsatility may contribute to hepatic steatosis and fibrosis.

Introduction: The Hispanic population in the US faces a higher risk of nonalcoholic fatty liver disease (NAFLD). Multiple factors influence this risk, including genetics, environmental factors, and socioeconomic statuses. Inadequate access to nutritious foods, or food insecurity, is prevalent among Hispanic individuals and poses a metabolic risk for both the onset and development of NAFLD. Materials and Methods: We utilized the National Health and Nutrition Examination Survey (NHANES) 2017–2020 pre-pandemic data to analyze the association between Hispanic ethnicity, hepatic steatosis, fibrosis, and food insecurity. Vibration-controlled transient elastography (VCTE) was employed to assess liver stiffness (LSM) and controlled attenuation parameter (CAP) scores to determine fibrosis and steatosis, respectively. Linear and ordinal logistic regression models were applied to their continuous, log-transformed, and categorical forms, adjusting for demographics, metabolic comorbidities, and socioeconomic factors. Models were subsequently stratified based on food security statuses. Results: A total of 7396 Hispanic participants were included in the study. Under multivariable analysis, Hispanic individuals had higher CAP scores (Beta-coefficient: 10.2 dB/m, 95% CI: 6.1–14.4 dB/m, p = 0.001)) vs. non-Hispanic individuals, without statistically significant differences in fibrosis. Food-insecure participants exhibited higher CAP scores than their food-secure counterparts. After stratification, a stronger association between Hispanic ethnicity and CAP scores was evident in the food-insecure group (Beta-coefficient: 11.8 dB/m, 95% CI: 4.4–19.3 dB/m, p = 0.003). Discussion: This study demonstrates the heightened risk of hepatic steatosis among individuals with Hispanic ancestry in the US. The risk is exacerbated by food insecurity, particularly for Hispanic individuals. The contribution is linked to the dietary habits in this population that lead to metabolic risk factors associated with hepatic steatosis. Considering the rising prevalence of NAFLD and food insecurity, interventions focusing on nutritional support and healthcare access among this population could mitigate these burdens.