Photo Credit: iStock.com/Mohammed Haneefa Nizamudeen

As rates of MASLD, which is linked to obesity and diabetes, rise, new therapies have emerged, but better diagnostic and monitoring strategies are needed.

“[Metabolic dysfunction-associated steatotic liver disease (MASLD)] closely relates to obesity, insulin resistance and type 2 diabetes, with which it shares many pathogenetic features” researchers wrote in Metabolism. “Further, MASLD it “has been recognized as an important risk factor for several other diseases including cardiovascular as well as other cardiac and arrhythmic complications, hepatocellular carcinoma (HCC), extra-hepatic malignancies and chronic kidney disease.”

 “We are at the beginning of a new era in obesity and MASLD therapeutics, with many options available. In the next 5 to 10 years, we will likely learn which treatments are the most effective, safe, and sustainable,” Robert J. Fontana, MD, who was not involved in the Metabolism study, tells Physician’s Weekly (PW). “This is a well-done and concise summary of where we are in 2024 in trying to tackle the immense public health problem of MASLD.”

Available and potential MASLD treatments discussed in the study include:

• Lifestyle changes that promote weight loss as the current standard MASLD treatment
• Bariatric surgery, which provides the greatest and longest-lasting improvement in histologic MASLD but has the highest risk for severe complications
• Drugs approved for weight loss including glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium-glucose cotransporter inhibitors, and metformin
• MASLD treatments with weight-loss–independent metabolic effects, including peroxisome proliferator-activated receptor (PPAR) agonists, dual alpha/delta PPAR agonists, pan-PPAR agonists, modulators of the mitochondrial pyruvate carrier , and fibroblast growth factor 21 analogs

The researchers noted that a more novel FDA-approved treatment for MASLD reveals “several yet unsolved issues in regard to pharmacological treatment strategies,” specifically that certain prescriptions do not require biopsy-confirmed metabolic dysfunction–associated steatohepatitis (MASH) and that noninvasive diagnostic criteria with moderate or even low accuracy may be applied.

As a result, “new diagnostic tools are urgently needed not only to aid prescription but also for monitoring of treatment success to avoid under- and overtreatment as well as futile long-term therapy,” the study authors wrote.

Dr. Fontana and Gitanjali Srivastava, MD, shared their perspectives with  PW about current and potential MASLD treatments and their impacts on patient care.

PW: Why was it important to do this study?

Dr. Fontana: Nearly all physicians in practice, including pediatricians, are encountering patients with MASLD and are uncertain how to triage those at risk for progressive liver disease versus those with benign mild liver steatosis. Also, since the burden of MASH and cirrhosis is increasing due to MASLD in the US and worldwide, we all need to better identify high-risk patients and target them for interventions to ward off future liver-related morbidity and mortality, which is currently on the rise.

Dr. Srivastava: This study is crucial because it provides robust evidence supporting weight loss as a primary intervention for MASLD. With the rising prevalence of obesity and related liver diseases, it is essential to have clear, evidence-based guidelines for managing these conditions. This study helps fill that gap and offers practical insights for clinicians.

 PW: For clinicians, what are the most important takeaways?

Dr. Srivastava: This study underscores the critical role of weight loss in MASLD. Even modest weight loss can significantly improve liver health by reducing steatosis and inflammation. This is pivotal for both specialists and general practitioners as it reinforces the importance of weight management in treating liver diseases.

Dr. Fontana: The authors are endocrine specialists who did a great job summarizing what we currently know about lifestyle changes and drugs used for obesity and diabetes that have shown secondary benefit in MASLD. They also nicely summarize drugs in development for MASLD and how various medications work in different ways to benefit the liver.

Hepatologists and gastroenterologists are seeing an increasing number of patients referred with hepatic steatosis detected on incidental imaging or in patients with various GI [gastrointestinal] symptoms such as abdominal pain. MASLD is the leading reason for referral to a hepatologist in many US medical centers. Also, primary care doctors are inundated with abnormal liver biochemistries in their patients with diabetes and in overweight patients during routine visits, and they are grappling with how to triage them and determine which should be referred to a specialist for further assessment and treatment.

The researchers note how some interventions like bariatric surgery, lifestyle, and diet appear to have their efficacy tied to weight loss. However, these approaches are not 100% effective, and even some patients with morbid obesity who lose a great deal of weight with bariatric surgery do not realize a liver benefit. The authors also talk about how some of the newer medications appear to confer benefit without any weight loss.

PW: How may this summary affect patient care?

Dr. Srivastava: The findings can significantly influence patient care by encouraging clinicians to prioritize weight management in MASLD treatment plans. It also emphasizes the need for a multidisciplinary approach that involves dietitians, physical therapists, and other clinicians to support patients in achieving and maintaining weight loss.

I would advise clinicians to adopt a holistic approach when treating patients with MASLD. Encourage lifestyle modifications, provide continuous support, and consider the psychological aspects of weight loss. Referral to a weight management center can help. Consider antiobesity medications, though they may not improve liver fibrosis. Collaboration with a multidisciplinary team can enhance patient outcomes. Remember, even small steps towards weight loss can lead to significant health benefits.

Dr. Fontana: The study provides a current-state map of where we are with MASLD therapeutics and a bit of a roadmap of where we may be heading. In March 2024, resmetirom was the first treatment for noncirrhotic MASLD approved by the FDA, which is quite exciting. However, as the authors point out, it is likely that combining drugs with differing mechanisms of action will likely lead to greater clinical benefit. For example, combining resmetirom with a GLP-1/ GIP [glucose-dependent insulinotropic peptide] agonist may prove even more effective. As a result, completing clinical trials of the new drugs as stand-alone and combination therapy is really important.

PW: What questions remain unanswered for you?

Dr. Srivastava: While the study provides valuable insights, it raises questions about the long-term sustainability of weight loss and its effects on MASLD. Further research is needed to explore the mechanisms behind weight loss-induced improvements in liver health and to identify the most effective strategies for maintaining weight loss over time.

Dr. Fontana: As this article highlights, we need to work in parallel to develop more sensitive and specific tools to detect liver inflammation and fibrosis. Development of those tools—blood-based biomarkers, improved liver imaging such as ultrasound-based elastography and MRI imaging—will help accelerate the clinical trials we are doing to more quickly identify the most effective and safest treatments, so we won’t need to rely on liver biopsy, which is cumbersome, has sampling artifact, and is unappealing to many physicians and their patients.