Zobair Younossi, MD, MPH, is chairman of the Global NASH/MASH Council and professor and chairman of Beatty Liver and Obesity Research at Inova Health System.

Zobair Younossi, MD, MPH

Lifestyle, Pharmacologic Therapies, and EXCEL Trial Data Reshape MASLD Treatment Framework

Lifestyle intervention remains the foundation of care in 

metabolic dysfunction–associated steatotic liver disease (MASLD)

, but the delivery may be more effective if given as a structured, prescription-like intervention, outsourcing appropriate clinical support.

“In my view, lifestyle is the foundation, you have to always start with lifestyle, because that is just not, you know, eat less and exercise, that's just, that's not going to work,” Zobair Younossi, MD, MPH, chairman of the Global NASH Council and professor of medicine and chairman of the Global Center for Liver Outcomes & Policy Research at Georgetown University School of Medicine, told HCPLive. “You have to really do this in a way that's similar to a prescription, so you're giving patients adequate support, even a nutrition consult available, or dietitian, to make sure not only they're going to eat right, or what is eating right, eating right is not just cutting calories, but also avoiding ultra-processed food, eating a diet that's similar to a Mediterranean diet.”

He noted that Mediterranean-style dietary patterns should be understood as diets rich in fruits and vegetables, with protein sourced from healthier options, while minimizing ultra-processed food intake.

Alcohol consumption, even in moderation, may be harmful in MASLD, particularly given patterns of binge drinking that can exacerbate liver injury. Smoking cessation and increased physical activity, including resistance training to support muscle health,were also emphasized as key components of care.

Expanding Pharmacologic Options in MASLD and MASH

Beyond lifestyle intervention, pharmacologic therapies are increasingly shaping the MASLD and metabolic dysfunction–associated steatohepatitis (MASH) treatment landscape.

In the United States, approved therapies include resmetirom, a thyroid hormone receptor-β agonist, and semaglutide, a GLP-1 receptor agonist. These agents reflect a broader shift toward targeting metabolic dysfunction underlying hepatic steatosis and fibrosis.

Metabolic Burden and Symptom Underrecognition in MASLD

Hepatic steatosis is increasingly recognized as a surrogate marker of systemic metabolic dysfunction, with implications that extend beyond the liver. Patients with MASLD face increased risks of progression to MASH and cirrhosis, as well as cardiometabolic comorbidities including cardiovascular disease, type 2 diabetes, and chronic kidney disease.

Fatigue remains one of the most common but underrecognized symptoms in MASLD, despite its impact on quality of life.

EXCEL Trial Demonstrates Improvements in Hepatic Steatosis and Fatigue

Emerging clinical data from the phase 4 EXCEL trial support a multidimensional approach to MASLD treatment outcomes.

The double-blind, randomized, placebo-controlled study evaluated essential phospholipids (EPL) added to standard of care in patients with MASLD and metabolic comorbidities. EPL met its primary endpoint, demonstrating a statistically significant reduction in hepatic steatosis compared with placebo, as measured by controlled attenuation parameter (CAP) on FibroScan.

Improvements in hepatic fat were observed as early as 3 months and remained significant during follow-up. At 6 months, the least-squares mean difference (LSMD) in CAP score was −14.81 dB/m (SE, 6.63; 95% Confidence Interval [CI], −27.89 to −1.72;  

The trial also included patient-reported outcomes. EPL was associated with a statistically significant improvement in fatigue at 6 months compared with placebo (LSMD, 0.31; SE, 0.13; 95% CI, 0.04–0.58;

= .0229). Improvements in HbA1c were also observed (LSMD, −0.55%; SE, 0.20; 95% CI, −0.95 to −0.15; 

= .0069), suggesting broader metabolic effects beyond hepatic endpoints.

While quality-of-life improvements did not reach statistical significance, numerical trends favored EPL across multiple time points.

A Multi-Domain Framework for Evaluating MASLD Outcomes

Experts emphasize that MASLD should be evaluated across three domains: clinical outcomes such as progression to cirrhosis, patient-reported outcomes including fatigue and quality of life, and economic outcomes reflecting healthcare utilization and societal burden.

“At the end, it looks like we do have good drugs, not perfect drugs for treatment of MASH, but pretty good drugs, and we're going to have better drugs in the near future,” Younossi said. “When you look at what a drug works or an intervention works, it's absolutely important to not only look at clinical outcomes but also patiently reported.”

Editor’s Note: Younossi reports relevant disclosures with Boehringer Ingelheim, Ipsen, Gilead Sciences, BMS, GSK, NovoNordisk, Siemens, Madrigal Pharmaceuticals, Merck, and Abbott.

Stefan N, Hartleb M, Fan J, et al. Effect of Essential Phospholipids in Metabolic Dysfunction‐Associated Steatotic Liver Disease: A Randomised Phase 4 Clinical Trial. 

Israelsen M, Francque S, Tsochatzis EA, Krag A. Steatotic liver disease. 

https://doi.org/10.1016/S0140-6736(24)01811-7

Videos

Zobair Younossi, MD, explains how lifestyle, drugs, and EXCEL data show steatosis and fatigue improvements in MASLD.


EPL Improves Steatosis, Fatigue in Patients With MASLD, WIth Zobair Younossi, MD

In EXCEL, the first double-blind, randomized, placebo-controlled clinical trial to assess the impact of essential phospholipids (EPL) in addition to standard of care on liver steatosis and quality of life in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic comorbidities, treatment with EPL resulted in a statistically significant reduction in hepatic steatosis compared with placebo, meeting the study's primary endpoint.

Measured by controlled attenuation parameter (CAP), a noninvasive FibroScan-based assessment of hepatic fat content, the reduction in steatosis was evident as early as 3 months and remained significant through 3 months after treatment discontinuation.

“There has been a lack of understanding and awareness about this disease at all levels of the health system in the United States, as well as the rest of the world,” Zobair Younossi, MD, chairman of the Global NASH Council and professor of medicine and chairman of the Global Center for Liver Outcomes & Policy Research at Georgetown University School of Medicine, told HCPLive.

The standard of care for first-line MASLD management remains lifestyle intervention, including dietary modification and physical activity. More recently, the treatment landscape has expanded with FDA approvals for metabolic liver disease, including resmetirom (Rezdiffra) for adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced fibrosis and semaglutide (Wegovy) for MASH in adults with moderate-to-advanced fibrosis.

The prevalence of MASLD continues to rise alongside obesity and type 2 diabetes mellitus (T2DM), with estimates suggesting approximately 38% of adults globally are affected. Individuals with MASLD, particularly those with MASH and hepatic fibrosis, are at increased risk for T2DM, cardiovascular disease, chronic kidney disease, and several extrahepatic malignancies.

Recently, a Consensus Report from the American Diabetes Association addressed the MASLD nomenclature change, risk stratification, current treatment approaches, and long-term monitoring strategies while emphasizing the need for multidisciplinary disease management.

Beyond its clinical burden, MASLD substantially affects health-related quality of life (HRQoL), with common symptoms including fatigue, abdominal discomfort, and sleep disturbances.

“A lot of these patients actually do have significant fatigue,” Younossi said. “The problem is that they may not recognize that fatigue to be associated with their liver disease.”

The phosphatidylcholine pathway is an important driver of MASLD pathogenesis. Patients with MASLD and MASH have been shown to have lower levels of polyunsaturated phosphatidylcholine, an important component of hepatocyte cell membranes involved in lipid transport and membrane integrity.

EPL, or polyene phosphatidylcholine, is derived from highly purified soybean extracts and contains >72% 3-sn-phosphatidylcholine, with 1,2-dilinoleoylphosphatidylcholine as its primary active component. Previous studies evaluating EPL in patients with MASLD have suggested benefits on liver enzyme levels, lipid profiles, and hepatic steatosis, although robust placebo-controlled data have been limited.

EXCEL was a phase 4, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the efficacy and safety of EPL added to standard of care in patients with MASLD and at least 1 metabolic comorbidity, including T2DM, hyperlipidemia, or obesity.

The primary endpoint was change in hepatic steatosis from baseline to month 6, assessed by CAP score. Secondary endpoints included changes in HRQoL and symptom assessments for asthenia, depressed mood, abdominal pain or discomfort, and fatigue. Safety assessments included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest.

Eligible patients were 18-70 years of age with MASLD, steatosis grades S1-S3 (CAP score >248 dB/m), liver fibrosis stages F1-F3 based on liver stiffness measurement scores of 5-13 kPa by vibration-controlled transient elastography, and at least 1 metabolic comorbidity.

In the intention-to-treat population, 193 patients were randomized 1:1 to EPL (n = 97) or placebo (n = 96). The modified intention-to-treat population included 165 patients with evaluable baseline and postbaseline CAP assessments who received study treatment (EPL, n = 82; placebo, n = 83).

Baseline characteristics were balanced between treatment groups. More than three-quarters of patients were obese, more than 80% had severe steatosis (CAP ≥280 dB/m), and most had mild fibrosis at study entry.

A statistically significant reduction in CAP score was observed among patients treated with EPL compared with placebo.

At 6 months, the mean change from baseline in CAP score was −23.0 dB/m (standard deviation [SD], 46.50) in the EPL arm and −11.5 dB/m (SD, 42.83) in the placebo arm. Least-squares mean changes were −24.6 dB/m and −9.8 dB/m, respectively, corresponding to a least-squares mean difference (LSMD) of −14.81 dB/m (standard error [SE], 6.63; 95% Confidemce Interval [CI], −27.89 to −1.72; 

Notably, improvements in steatosis were evident by month 3 and remained significant 3 months after treatment discontinuation. At month 3, the LSMD was −16.11 dB/m (SE, 5.65; 95% CI, −27.27 to −4.96; 

 = .0049), while the post-treatment assessment showed an LSMD of −15.19 dB/m (SE, 6.65; 95% CI, −28.29 to −2.09; 

Subgroup analyses demonstrated significant CAP score reductions among patients with baseline HbA1c <8.0% (LSMD, −15.39 dB/m; SE, 7.39; 95% CI, −30.02 to −0.77; 

 = .0392) and among those with baseline BMI <30 kg/m² (LSMD, −41.0 dB/m; SE, 18.89; 95% CI, −79.8 to −2.19; 

Investigators also observed significant improvements in glycemic control. At 6 months, EPL was associated with a significant reduction in HbA1c compared with placebo (LSMD, −0.55%; SE, 0.20; 95% CI, −0.95 to −0.15;

 = .0069), with the effect persisting numerically through the 9-month follow-up period.

The mean change from baseline to 6 months in the QoL total score was greater in the EPL arm than the placebo arm, although the difference did not reach statistical significance (LSMD, 0.17; SE, 0.08; 

= .2445). Numerical improvements in QoL were observed at months 3, 6, and 9 among patients receiving EPL.

When analyzed by symptom subscore, EPL treatment was associated with a statistically significant improvement in fatigue at 6 months compared with placebo (LSMD, 0.31; SE, 0.13; 95% CI, 0.04-0.58; 

Overall, 56.7% of patients receiving EPL and 52.1% of those receiving placebo experienced at least 1 TEAE. The most commonly reported TEAEs were headache, diarrhea, and nasopharyngitis.

Investigators reported a safety profile comparable to placebo, with no new safety concerns identified during the study.

At 6 months, a greater proportion of patients receiving EPL reported high satisfaction with treatment effectiveness compared with placebo (53.7% vs 50.6%), while fewer patients reported dissatisfaction (1.2% vs 9.6%). However, differences in total satisfaction scores were not statistically significant (OR, 1.14; 95% CI, 0.62-2.10; 

Although EPL did not significantly improve liver stiffness measurements, a post hoc analysis demonstrated a significant improvement in FibroScan-AST (FAST) score compared with placebo at 6 months (LSMD, −0.05; SE, 0.03; 95% CI, −0.10 to −0.00; 

 = .0437), suggesting a potential benefit in reducing the risk of progressive MASH.

EPL reduced hepatic steatosis vs placebo in EXCEL MASLD trial, meeting primary endpoint at 6 months by CAP FibroScan assessment.

EPL Improves Steatosis, Fatigue in Patients With MASLD, With Zobair Younossi, MD

From Validation to Implementation: Scaling NITs in MASLD Care, With Zobair Younossi, MD, MPH

As the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to climb in parallel with obesity and type 2 diabetes, clinicians face a pressing question regarding how at-risk patients should be identified and managed in routine practice.

Although noninvasive tests (NITs) have been validated for fibrosis risk stratification and are increasingly incorporated into society guidelines, their adoption remains inconsistent across care settings. At the same time, therapeutic options for metabolic dysfunction-associated steatohepatitis (MASH) are expanding, raising the stakes for early and accurate case finding. Against this backdrop, the conversation is shifting from whether to use noninvasive testing to how quickly and broadly it should be implemented and what barriers must be addressed to make risk-based MASLD care a standard part of clinical workflows.

, Zobair Younossi, MD, MPH, professor and chairman of the Global NASH Council, makes a clear and urgent case that the time to implement NIT-based risk stratification for MASLD is now.

Check out part 1 of the interview with Younossi 

While no test is perfect, he argues the data are sufficiently strong to support widespread adoption across clinical settings, most recently from his trio of sequentially published papers on how NITs perform across regions, how well they predict liver-related outcomes compared with biopsy, and how their accuracy varies in key subgroups.

“I think we should adopt it now,” Younossi said. “The data is not perfect, but it's pretty good, and these tests should be adopted in every clinical practice.”

He stresses that waiting for a flawless diagnostic tool risks further delay in addressing a disease that is already a leading cause of liver transplantation and hepatocellular carcinoma in the United States. Instead, he calls for implementation across primary care, endocrinology, diabetology, gastroenterology, and hepatology. MASLD, he notes, should be viewed similarly to other diabetes-related complications. Just as clinicians routinely screen for retinopathy and nephropathy, liver risk assessment should become standard practice in patients with metabolic disease.

At the same time, he notes that important gaps remain. While current NITs are highly effective for identifying advanced fibrosis, they are less precise in detecting patients with earlier yet clinically meaningful stage 2 (F2) fibrosis. Younossi points to ongoing work leveraging large datasets, machine learning, and artificial intelligence to develop more refined combination algorithms and calls for a paradigm shift in drug development. With NITs now guiding real-world clinical decisions, he argues that clinical trials should move away from mandatory biopsy-based enrollment and instead transition toward NIT-based designs that better reflect contemporary practice.

He also notes that barriers to adoption extend beyond diagnostics, with awareness remaining a major challenge requiring education at multiple levels: provider, public health policy, and global health leadership.

“I think in the next 5 years, you'll see additional drugs and more help for patients with progressive MASH,” Younossi said. “In that context, I think it’s going to be very important that we identify those patients, we develop care pathways where we connect these patients who are at risk with a care provider that will not only give them advice and properly manage their cardiometabolic risks with diet, exercise, and also the medication that we have available for diabetes and hypertension, but also, if they are candidates for treatment with MASH drugs, that they're offered. We'll have more drugs in the pipeline, and hopefully we'll have patients ready by then.”

Editors’ Note: Younossi reports relevant disclosures with Intercept, Cymabay, Boehringer Ingelheim, Ipsen, BMS, GSK, Novo Nordisk, Siemens, Madridgal, Merck, Aligos, Akero, Sanofi and Abbott.

Younossi ZM, de Avila L, Petta S, et al. Diagnostic Accuracy of Non-Invasive Tests for MASLD Across Age, Type 2 Diabetes, and Obesity Subgroups: A Multinational Study. 

. Published online January 28, 2026. doi:10.1016/j.cgh.2026.01.016

Younossi emphasizes the need for NIT-based risk stratification for MASLD, citing his research supporting their widespread adoption across clinical settings.

Diagnostic Performance of NITs Across MASLD Subgroups, With Zobair Younossi, MD

As metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise globally, the need for accurate, accessible risk stratification has never been greater. Historically, clinicians have relied on liver biopsy to identify the subgroup of patients with metabolic dysfunction–associated steatohepatitis (MASH) at the greatest risk for progression to cirrhosis, liver cancer, and liver-related mortality.

Because biopsy is invasive, costly, and not without risk, the field of hepatology has grown increasingly reluctant to rely on it for widespread screening and longitudinal monitoring. As Zobair Younossi, MD, professor and chairman of the Global NASH Council, explains in an interview with 

, the past decade has been defined by efforts to develop noninvasive alternatives that can match biopsy not only in staging accuracy but also in predicting long-term outcomes.

“NITs were first established on a liver biopsy to see if they're accurately predicting the stage that we want to look for,” he explained. “More recently, there is also data to suggest that these NITs predict outcome as well as liver biopsy, and maybe sometimes even better than a liver biopsy, which makes them ideal for clinical use and also for use in clinical trials.”

Specifically, Younossi references 3 main categories of noninvasive tests:

Imaging modalities like VCTE, shear wave elastography, and MRE

He additionally describes combination tests leveraging combined clinical data from existing NITs, including the FAST score, AGILE 3, and AGILE 4.

Younossi’s research, a trio of sequentially published papers, has explored how NITs perform across regions, how well they predict liver-related outcomes compared with biopsy, and how their accuracy varies in key subgroups.

Of note, while all NITs demonstrated outcome prediction comparable to, and in some cases better than, biopsy, their performance was not uniform. He says FIB-4, for example, performs less reliably in patients at extremes of age and in those with diabetes, and regional variability was observed, with weaker performance in South Asia and Latin America. In contrast, liver stiffness measurement was less affected by age or diabetes but was influenced by severe obesity. Among the available tools, AGILE 3 and AGILE 4 emerged as particularly stable across regions and subgroups.

Clinically, Younossi emphasizes a stepwise algorithm. FIB-4 remains the recommended first-line test to identify patients at low risk who can be monitored periodically versus those who warrant second-line assessment with VCTE or ELF. Beyond risk stratification, he says NITs now guide treatment selection, particularly for noncirrhotic MASH patients eligible for recently approved agents such as resmetirom or semaglutide and enable longitudinal monitoring.

Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed February 12, 2026. 

https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash

Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed February 12, 2026. 

https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash

Younossi explains the growing interest in NITs for MASLD and reviews his research on their performance in age, diabetes, and obesity subgroups.

Zobair Younossi, MD, MPH

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