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; P = .0269) in favor of EPL.

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

References

1. 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. Liver International. 2026;46(5). doi:https://doi.org/10.1111/liv.70601

2. Israelsen M, Francque S, Tsochatzis EA, Krag A. Steatotic liver disease. Lancet (London, England). 2024;404(10464):1761-1778. doi:https://doi.org/10.1016/S0140-6736(24)01811-7