BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits marked heterogeneity in fibrosis progression and liver-related outcomes. Liver biopsy is not feasible for longitudinal risk stratification at scale, creating a need for validated non-invasive biomarkers, particularly imaging biomarkers, that can predict clinically meaningful disease progression and liver-related outcomes. AIMS:To describe the design and rationale of the GOLDMINE study, established to determine whether non-invasive imaging biomarkers predict MASLD progression and liver-related clinical outcomes. METHODS:GOLDMINE is an investigator-initiated, multi-centre, international longitudinal cohort enrolling up to 1000 adults with either biopsy-proven MASLD or MASLD cirrhosis across the full fibrosis spectrum. Participants are recruited from 15 sites in the US and 4 international sites (Japan, Singapore and France). At baseline, participants undergo clinical phenotyping, vibration-controlled transient elastography, and advanced magnetic resonance imaging (MRI), including proton-density-fat-fraction and magnetic resonance elastography (MRE). MRI (and biospecimen banking) is repeated at 2-year intervals (years 2 and 4), with annual follow-up visits for up to 10 years. Baseline liver histology is centrally processed, digitized and reviewed by a single expert hepatopathologist; all MRI/MREs are centrally interpreted. RESULTS:The prespecified clinical outcomes include progression to cirrhosis, clinically significant portal hypertension, major adverse liver-related outcomes (ascites, hepatic encephalopathy, portal hypertensive bleeding, liver transplantation/qualification), hepatocellular carcinoma, major adverse cardiovascular events, and all-cause mortality, with independent central adjudication of all events. CONCLUSIONS:GOLDMINE establishes a rigorously phenotyped MASLD cohort integrating centralized histology, advanced MRI-based biomarkers, longitudinal biobanking, and adjudicated outcomes, providing a platform to validate imaging and blood-based prognostic biomarkers in MASLD.
Background and Aims Accurate distinction between metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and the overlap MetALD is of utmost importance. Due to the potential for underreporting in alcohol use surveys, phosphatidylethanol (PEth) is increasingly utilized in clinical trials to rule out MetALD or ALD. This study examines the prevalence of elevated PEth and its effectiveness in separating phenotypes with dominant MASLD or MetALD/ALD in the clinical trial setting. Methods A multicenter database of patients screened for enrollment in clinical trials for MASLD pharmacologic therapies was reviewed, from which patients with PEth results were identified, then further stratified into low (<20 ng/mL), moderate (20-<100 ng/mL), or high (≥100 ng/mL) alcohol intake groups. Results Among 2870 patients with baseline PEth data, 2560 (89%) had low, 168 (6%) had moderate, and 142 (5%) had high PEth levels, including 92 with PEth ≥200 ng/mL. Higher hemoglobin A1C (HbA1c) was associated with lower PEth (p<0·001). AST (p<0.001), ALT (p<0.001), and gamma-glutamyl transferase (GGT; p<0.001) were elevated in patients with higher PEth results. Indeterminate fibrosis-4 scores were more prevalent in patients with PEth ≥100 ng/mL (p<0.001). In multivariable analysis, PEth ≥20 ng/mL was associated with higher GGT (per 10 U/L, aOR, 1.04; 95% CI, 1.03-1.06; p<0.001) and lower HbA1c (aOR, 0.68; 95% CI, 0.60-0.78; p<0.001). Conclusions In this prospective multicenter cohort of participants screened for MASLD clinical trials with systematically collected PEth, 11% had PEth ≥20 ng/mL, suggesting a level of alcohol consumption that may warrant further clinical evaluation for possible MetALD or ALD.
BACKGROUND:Metabolic dysfunction-associated steatohepatitis (MASH) is a major public health problem arising in the context of metabolic syndrome and obesity. DD01 is a liver-targeted GLP-1 receptor and glucagon dual agonist being investigated for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH. The DD01-DN-02 trial aimed to evaluate the efficacy and safety of DD01 in adults with MASLD or MASH; this initial analysis reports prespecified 12-week outcomes to assess early hepatic effects. METHODS:DD01-DN-02 is an ongoing, randomised, double-blind, multicentre, placebo-controlled, phase 2 trial conducted at 12 outpatient clinical sites in the USA. Adults aged 18-70 years with obesity or who were overweight (BMI ≥25 kg/m2) were included in the study. Patients with MASLD or MASH underwent liver biopsy and MRI-proton density fat fraction (PDFF) and were eligible if liver fat content was 10% or higher with metabolic risk factors, or if the biopsy confirmed MASH with a non-alcoholic fatty liver disease activity score of at least 4. Participants were randomly assigned (1:1) to receive once-weekly subcutaneous DD01 40 mg or matched placebo over 48 weeks, dose-escalated over 2 weeks, using a centrally administered interactive response technology system. The randomisation sequence was computer-generated by an independent statistician. Participants, investigators, study staff, outcome assessors, and the sponsor were masked to treatment assignment. The primary endpoint was the proportion of participants having at least a 30% relative reduction in liver fat by MRI-PDFF at week 12, which was analysed in all randomly assigned participants receiving at least one dose of study drug or placebo. Safety analyses included all participants who received at least one dose of study drug. Missing primary endpoint data were handled using multiple imputation under a missing-at-random assumption. This trial is registered with ClinicalTrials.gov (NCT06410924) and is ongoing but closed to new participants. FINDINGS:Between June 13, 2024, and Jan 30, 2025, 67 eligible participants were enrolled, of whom 33 were randomly assigned to DD01 and 34 to placebo. The mean age of participants was 48·4 years (SD 10·6), 42 (63%) were female, 25 (37%) were male, 57 (85%) were White, and 52 (78%) participants had biopsy-confirmed MASH. At week 12, 25 (76%) of 33 participants receiving DD01 had a 30% or higher reduction in liver fat versus four (12%) of 34 participants receiving placebo (adjusted common odds ratio 28·8 [95% CI 7·2-115·2]; adjusted relative risk 6·3 [95% CI 2·5-15·9]; p<0·0001). Treatment-emergent adverse events occurred in 28 (85%) of 33 participants receiving DD01 and 23 (68%) of 34 participants receiving placebo. The most common adverse events were nausea (18 [55%] of 33 participants assigned DD01; six [18%] of 34 participants assigned placebo), diarrhoea (nine [27%] of 33; six [18%] of 34), and vomiting (ten [30%] of 33; four [12%] of 34). Treatment-emergent adverse events led to treatment discontinuation in four (12%) of 33 participants in the DD01 group and one (3%) of 34 participants in the placebo group. Two (6%) treatment-emergent serious adverse events occurred in the DD01 group (abdominal pain and acute cholecystitis) and zero in the placebo group. No deaths occurred. INTERPRETATION:In this prespecified 12-week primary analysis, DD01 produced rapid reductions in liver fat compared with placebo, supporting further evaluation in long-term studies. FUNDING:D&D Pharmatech, Neuraly.
BACKGROUND/OBJECTIVES:Amid rising global obesity rates and advances in weight-loss therapies, monitoring body composition and ectopic fat could refine trial design. We quantified weight-related changes in body composition and liver steatosis prior to widespread adoption of incretin treatments. SUBJECTS/METHODS:Adults (N = 3070) from the UK Biobank with repeat abdominal MRI scans were included. Percent weight change from baseline was categorised: stable (0 ± 2%), mild change (2-5% weight gain/loss), moderate change (5-10% weight gain/loss), or large change (10-15% weight gain/loss). INTERVENTION/METHODS:MRI data were processed automatically from two visits, spaced 2.7 years apart, to derive volumetric visceral (VAT), subcutaneous adipose tissue (SAT), total skeletal muscle volume (SM, or indexed SM), muscle fat infiltration (MFISM), and psoas muscle cross-sectional area (CSA) in the abdominal region. Liver fat content (LFC) was assessed using LiverMultiScan. Dual-energy x-ray absorptiometry (DXA) measurements were compared. RESULTS:Weight gain occurred in 28% of all subjects (N = 3070, age 63 years, male 49%, 13% with obesity, 43% with overweight). Moderate or large weight gain increased LFC, VAT, SAT, MFISM, and SM (all p < 0.001). Weight loss also occurred in 28%. Decreases were observed with moderate or large weight loss in LFC, VAT, SAT, SM, SMI, and psoas CSA (all p < 0.001). MFISM was reduced with large weight loss. For VAT and liver fat, prevalent type 2 diabetes exacerbated weight gain-related increases, and blood pressure medication attenuated the impact of weight change. For individuals with overweight or obesity, for every 5% drop in weight, there was 16% reduction in VAT, 11% in SAT, 24% in liver fat, 2.3% in MFISM, 1.5% in SM (or 1.4% in SMI) and 2.1% in psoas CSA. DXA changes in lean mass correlated weakly with changes in SM volume (rho 0.28-0.47). CONCLUSIONS:Using MRI, relative changes in body composition and liver steatosis resulting from weight loss can inform clinical trials, including placebo arm design and power estimations. Weight changes affect body composition and liver fat and can inform obesity trial design.
BACKGROUND:Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly common globally and is associated with significant morbidity and mortality, necessitating effective treatments to stop its progression. Multiple pharmacologic treatments have been developed for MASH, targeting patients most likely to experience major adverse liver outcomes (MALO). It is therefore of utmost importance to accurately identify patients with at-risk MASH, those with the greatest likelihood of developing cirrhosis and other related MALO who would benefit from these treatments. AIMS:The goal of this review is to summarize expert opinion on the pharmacologic treatment of MASH following the recent approval of semaglutide for this condition in the United States. METHODS:An expert panel was convened as part of the Desert Liver Conference (Scottsdale, AZ, USA) in March 2025 to provide recommendations regarding guidelines for selecting patients who would benefit from MASH pharmacotherapy. RESULTS:The ESSENCE trial studied the safety and efficacy of 2.4 mg semaglutide in patients with biopsy-confirmed MASH, but liver biopsy is not widely deployed in clinical practice. Non-invasive tests (NITs) can be used to identify patients who are likely to have at-risk MASH. The panel recommended targeting patients with controlled attenuation parameter ≥ 280 dB/m and AST ≥ 17 IU/L (females) or ≥ 20 IU/L (males) for additional confirmatory testing, such as vibration-controlled transient elastography, magnetic resonance elastography, enhanced liver fibrosis score and/or combination imaging-serum biomarker tests. CONCLUSIONS:Pharmacologic treatment for MASH, including semaglutide, should be offered to patients with at-risk MASH who are at the highest risk of MALO.
