Background & Aims: While glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) show promise for hepatoprotection in type 2 diabetes mellitus (T2DM), the magnitude of hepatocellular carcinoma (HCC) risk reduction and optimal patient selection remain unclear. This is particularly relevant given that metabolic dysfunction‐associated steatotic liver disease (MASLD) affects 70% of patients with T2DM and represents a major HCC risk factor. We conducted a comprehensive meta‐analysis to quantify GLP‐1RA efficacy in HCC prevention and inform clinical implementation strategies. Methods: We systematically searched PubMed, Embase, and Web of Science through June 2025 for cohort studies comparing HCC incidence between GLP‐1RA users and nonusers with T2DM. Random‐effects meta‐analysis, network meta‐analysis, and meta‐regression were performed. Heterogeneity was explored through stratified analyses and quantitative bias assessment. Results: Nine studies encompassing 2,283,835 total patients (analyzed cohorts: 1,012,482) were included. GLP‐1RA use was associated with a 42% reduced HCC risk (pooled HR 0.60, 95% CI: 0.41–0.88; I ² = 86.2%). Effect magnitude varied significantly by comparator: versus insulin (HR 0.29, 95% CI: 0.13–0.67), versus oral agents (HR 0.81, 95% CI: 0.63–1.05), versus no treatment (HR 0.77, 95% CI: 0.52–1.14). Meta‐regression identified insulin as comparator as the primary driver of heterogeneity, explaining 55% of the between‐study variance. Benefits were greatest in patients without cirrhosis (HR 0.41, 95% CI: 0.29–0.58). Network meta‐analysis ranked GLP‐1RAs highest for HCC prevention (SUCRA 0.89), with insulin ranking lowest (0.08). The number needed to treat ranged from 24 to 476. Conclusions: GLP‐1RAs substantially reduce HCC risk in T2DM, with benefits partly attributable to avoiding insulin's potential hepatotoxicity. These findings support the preferential use of GLP‐1RAs over insulin in patients at HCC risk.

Statins have been proposed as hepatoprotective agents in chronic liver disease (CLD); however, evidence from existing systematic reviews-including observational studies and clinical trials-is inconsistent and affected by substantial overlap. We conducted an umbrella review to synthesize the available evidence on the associations between statin use and hepatological outcomes in CLD patients, while addressing study overlap. PubMed, EMBASE, and Cochrane Library were searched up to September 2025 for systematic reviews of statin therapy in CLD. Methodological quality was evaluated using AMSTAR-2. Study overlap was assessed using corrected covered area (CCA) and minimized via hierarchical exclusion prioritizing methodological quality, comprehensiveness, and recency. Random-effects meta-analyses with bias assessments were conducted. Of 850 records screened, 17 systematic reviews (229 unique studies; 10,515,877 participants from 34 countries) were included after overlap adjustment (CCA = 5.79%). Statin therapy was associated with 46% reduction in hepatocellular carcinoma (HCC) risk (HR 0.54, 95% CI 0.48-0.59; I² = 46.7%) and 46% reduction in hepatic decompensation (HR 0.54, 95% CI 0.49-0.59; I² = 0.1%); these estimates derive predominantly from observational studies and should be interpreted as associations rather than causal effects. Geographic heterogeneity was observed: Asian populations showed stronger benefits (HCC HR 0.49, 95% CI 0.45-0.53; I² = 0%) compared with Western populations (HCC HR 0.71, 95% CI 0.52-0.96; I² = 95.7%; p = 0.003). Statin use also associated with reduced all-cause mortality (HR 0.65, 95% CI 0.52-0.81), though with substantial heterogeneity (I² = 80%). In contrast, available RCT-based evidence does not consistently confirm these associations for decompensation or mortality outcomes. Statin use is consistently associated with reduced HCC risk and hepatic decompensation in CLD patients, particularly in Asian populations, though these findings derive predominantly from observational evidence subject to potential confounding. These associations support the continued use of statins in patients with CLD and cardiovascular indications where these are otherwise indicated, with potential additive hepatoprotective effects. These results underscore the urgent need for adequately powered randomized trials to clarify the boundaries of safety and efficacy in this high-risk population.

Hepatocellular carcinoma (HCC) represents a major health burden, historically treated with tyrosine kinase inhibitors (TKIs). The advent of immune checkpoint inhibitors (ICIs) has reshaped treatments, with pivotal trials (IMbrave150 and HIMALAYA) establishing ICI-based combinations as first-line therapy. Traditional statistical metrics may not fully capture the robustness of trial outcomes. The Survival-Inferred Fragility Index (SIFI) quantifies trial stability as the minimum number of additional survival events required to lose statistical significance. We systematically searched PubMed, Embase, Scopus for phase III randomized controlled trials comparing ICIs and TKIs in HCC published up to 31 May 2025. Trials reporting statistically significant time-to-event outcomes were included. Individual survival data were reconstructed from Kaplan-Meier curves using validated methods, SIFI was calculated using specific R algorithms. Six trials (4570 patients) were included for primary analysis (IMbrave150, COSMIC-312, ORIENT-32, CARES-310, HIMALAYA; CheckMate 9DW analyzed separately for its heterogeneous control arm). Median SIFI was 10 (range 5-18) for overall survival, 8 (range 6-19) for progression-free survival. SIFI corresponded to <1% of enrolled patients in most trials. Asian- trials (ORIENT-32, CARES-310) showed higher stability (SIFI 16-20) compared to global trials. SIFI analysis revealed heterogeneous stability across pivotal HCC trials. Incorporating fragility metrics with conventional statistics may improve interpretation and support balanced interpretation of trial outcomes.

A woman in her 60s with a history of atrial fibrillation, hypertension and dyslipidaemia was admitted to the Intensive Care Unit with hypotension, dehydration and acute kidney injury after 20 days of watery diarrhoea. Although initial investigations did not detect an evident infectious aetiology, a diagnosis of infectious colitis was hypothesised. After supportive care and quick recovery, she was discharged and instructed to resume her prior medications, including olmesartan (used for 1 year) for hypertension. Diarrhoea and renal failure recurred promptly, leading to readmission. Gastroscopy revealed severe villous atrophy and inflammation of the duodenum. However, serological tests for coeliac disease were negative. Olmesartan-related sprue-like enteropathy was diagnosed after discontinuing olmesartan, leading to clinical improvement without a gluten-free diet. This case emphasised the importance of considering iatrogenic causes in severe enteropathy differential diagnosis, particularly olmesartan-related complications in patients presenting with sprue-like symptoms, watery diarrhoea and acute renal failure.

Background: Visceral adipose tissue (VAT) and epicardial adipose tissue (EAT) are increasingly recognized as relevant contributors to cardiometabolic alterations and subclinical myocardial dysfunction, independently of overall obesity. Their pathogenic role extends beyond simple fat accumulation, encompassing inflammatory activation, lipotoxicity, and altered myocardial metabolism. Objective: This narrative review synthesizes current evidence on the relationships between VAT/EAT and myocardial strain parameters, with emphasis on subclinical cardiovascular risk detection and nutritional interventions. Methods: We conducted a comprehensive review of studies published between 2003–2025, focusing on imaging-based assessments of adipose tissue distribution and strain parameters using echocardiography, computed tomography, and cardiac magnetic resonance. Results: Increased EAT and, to a lesser extent, VAT showed significant associations with impaired global longitudinal strain (GLS) across imaging-based studies. In patients with type 2 diabetes, VAT mediated a substantial proportion of the association between insulin resistance and left ventricular dysfunction. Mediterranean diet adherence was associated with lower epicardial adipose tissue burden, while higher EAT was associated with persistent atrial fibrillation among patients with atrial fibrillation undergoing catheter ablation. Speckle-tracking echocardiography consistently showed superior prognostic value compared to ejection fraction for detecting subclinical dysfunction. Conclusions: VAT and EAT represent important mechanistic links between body composition and early myocardial dysfunction, identifiable through advanced strain imaging before clinical disease becomes apparent. These findings support the integration of multimodal cardiac imaging and nutritional interventions into cardiovascular prevention strategies, providing novel opportunities for early risk stratification and personalized treatment approaches.

Objectives: The combination of atezolizumab plus bevacizumab (A+B) represents one of the standards first-line treatments for unresectable hepatocellular carcinoma (HCC). Metformin has garnered attention for its potential antitumour and immunomodulatory properties beyond glycaemic control. This study aimed to assess metformin’s impact in patients with type 2 diabetes mellitus (T2DM) receiving A+B therapy. Methods: This retrospective analysis of a prospectively-maintained multicentre database included 523 patients with HCC treated with A+B from the ARTE (Atezolizumab-bevacizumab Real-life Experience for Treatment of Hepatocellular Carcinoma) dataset across 18 Italian centres (May 2020–January 2024). We evaluated objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and time to progression (TTP) using Cox regression analysis and Inverse Probability of Treatment Weighting (IPTW) to address confounding. Results: Among 523 patients, 341 (65.2%) did not have diabetes and 182 (34.8%) had T2DM. In the overall population, metformin showed no significant benefit for PFS (HR = 1.15, 95% CI [0.88–1.50], p = 0.316) or OS (HR = 1.28, 95% CI [0.94–1.74], p = 0.124). In the subgroup with T2DM (N = 180), metformin showed no significant benefit for PFS (HR = 1.41, 95% CI [0.97–2.05], p = 0.069), OS (HR = 1.23, 95% CI [0.81–1.86], p = 0.333), or TTP (HR = 0.82, 95% CI [0.53–1.26], p = 0.363). IPTW analysis confirmed these negative findings. Conclusion: This study found no evidence of improved outcomes with metformin use in patients with HCC in particular with T2DM receiving A+B therapy. Routine metformin use should not be expected to enhance A+B efficacy based on current evidence.