Both metabolic dysfunction–associated steatotic liver disease (MASLD) and metabolic dysfunction–associated steatohepatitis (MASH) are projected to increase considerably over the next few decades. Gastroenterologists treating these diseases are tasked with designing interventions that can both promote weight loss and address underlying metabolic conditions, two outcomes that glucagon-like peptide 1 (GLP-1) receptor agonists have proven resoundingly successful at achieving across a broad spectrum of patients.
Medscape contributor Nancy S. Reau, MD, spoke with Sujit V. Janardhan, MD, PhD, medical director of liver transplant, director of the Weight Intervention in Liver Disease clinical program, and assistant professor at Rush University Medical Center in Chicago, Illinois. His clinical focus is providing comprehensive metabolic care to patients with MASLD/MASH. Janardhan is a key opinion leader in MASLD/MASH and also serves as a principal investigator on several clinical trials in this area. Reau, who serves as chief of the hepatology section at Rush University Medical Center, asked Janardhan about the latest findings around GLP-1 receptor agonists in these indications, which patients might be ideal candidates for receiving them, and why the treatment of MASLD/MASH is about “finding agents that kill the dragon, not just one of its heads.”
Current Treatment Strategies
Why is addressing MASLD so important?
MASLD is a new nomenclature for a condition that involves fat infiltration of the liver due to metabolic diseases such as obesity, diabetes, high triglycerides, and hypertension.
MASLD affects 35% of the population in North America and has a high prevalence worldwide as well. Among those with MASLD, approximately 20% have the higher-risk version called MASH. These individuals are at risk for a progressive form of this disease that can lead to cirrhosis, liver failure, liver cancer, and death.
MASH is currently the second leading cause for liver transplants overall and the leading cause for women, people over 54 years old, and those with liver cancer.
In addition to adverse liver-related outcomes, MASH increases the risk for cardiovascular (CV) events such as heart attacks and strokes as well as CV event–related death.
Although that is very concerning, the encouraging aspect of this disease is that it is very treatable and reversible when caught early. The foundation of treatment for this disease is a dedicated and focused effort to make healthy lifestyle changes that result in weight loss and improved metabolic health. Depending on the severity of the disease, it may also be appropriate to consider additional adjunctive therapies such as pharmacotherapy and even surgical options.
How do you identify a person with MASLD who should be considered for pharmacotherapy?
Most patients with MASLD do not need medications for treatment of their liver disease. The focus should be on optimizing metabolic health and, when appropriate, weight loss. Of course, treating other metabolic conditions that lead to MASLD (eg, diabetes) may require medications, but only patients who have evidence of liver damage related to MASH require liver-directed pharmacotherapy.
Liver damage is traditionally defined by the amount of scarring in the liver. The presence of moderate to severe liver scarring greatly increases the future risk of developing liver-related complications and death. This is the population that we must identify and aggressively treat, which includes considering pharmacotherapy.
Unfortunately, MASH can lead to significant liver damage without any symptoms. Liver blood tests are often not indicative of the level of liver damage and can even be normal in patients with advanced liver scarring from MASH.
A great deal of research has been dedicated to finding clinical and biochemical risk factors that increase the likelihood of a patient having MASH with moderate to severe liver scarring.
The current American Association for the Study of Liver Diseases (AASLD) MASLD guidelines have identified patients that should be screened for advanced liver scarring from MASLD. This includes patients with significant metabolic risk: those with diabetes and medically complicated obesity (that is, obesity with other metabolic risk factors such as hypertension, low high-density lipoprotein cholesterol, or high triglycerides). Other groups that should be screened include patients with MASLD who consume moderate (not necessarily excessive) amounts of alcohol and those with a first-degree relative with MASH-related cirrhosis.
The guidelines recommend patients be screened with a Fibrosis-4 (FIB-4) Index for Liver Fibrosis assessment. The FIB-4 test is a calculation based on three commonly ordered lab tests (serum glutamic oxaloacetic transaminase, serum glutamate pyruvate transaminase, and platelets) and age.
The FIB-4 is not a perfect test, but it is easily available, which is critical in any screening initiative that involves such a large portion of the population. It is best at ruling out advanced liver disease, but we must still use clinical judgment and consider alternative or confirmatory testing in patients with a high suspicion for advanced liver disease or cirrhosis.
The guideline recommends that patients with a low FIB-4 score (< 1.3) not be referred to specialty care with gastroenterology/hepatology but be treated to optimize their metabolic health and undergo repeat FIB-4 screening every 1-3 years depending on the level metabolic risk. Patients with an intermediate FIB-4 require secondary testing with either transient elastography or the Enhanced Liver Fibrosis test. Any patients with intermediate to high risk for advanced liver scarring based on this secondary testing should be referred and considered for treatment. Patients with a high FIB-4 score (> 2.67) should be referred to gastroenterology/hepatology for further evaluation and management.
Although that seems like an arduous screening process, screening care pathways are being explored to reduce provider burden and maximize patient access.
The reason it’s critical that we identify these patients with high-risk MASH is that there is now a pharmacotherapeutic agent that can be used to complement lifestyle-based treatment of MASH.
Resmetirom is a thyroid hormone receptor beta agonist approved by the US Food and Drug Administration (FDA) for nonalcoholic steatohepatitis (NASH, the prior term for MASH) with moderate to advanced fibrosis. The approval was based on phase 3 clinical trial data that demonstrated a statistically significant increase in NASH resolution (up to 30% vs 10%) and fibrosis improvement (up to 26% vs 14%) compared with placebo after 52 weeks of treatment. The medication was generally well tolerated in clinical trials, with self-limited diarrhea and nausea being the most common side effects.
Emerging Evidence on GLP-1s and MASLD
What’s behind the hype surrounding GLP-1 receptor agonists in this indication?
GLP-1 receptor agonists, such as semaglutide, have revolutionized the treatment of metabolic disease through improving glycemic control, inducing weight loss, and reducing cardiovascular risk. Data also suggest that the effects of these agents on the central nervous system may influence not only appetite but also other reward-based or addiction-related behavioral pathways that may regulate obesity.
The interest in GLP-1 receptor agonists to potentially treat MASH predated some of these more recent findings. Nonetheless, the broad treatment effects of these medications make them increasingly more compelling as a treatment for MASH.
I believe that MASLD and MASH cannot be treated without treating metabolic syndrome. Thus, medications such as GLP-1 receptor agonists that can potentially treat multiple facets of metabolic disease are likely to become a cornerstone of treatment.
Several studies have looked at GLP-1 receptor agonists in people with MASLD, yet they are not approved for its treatment. Was there no benefit observed in these studies?
The original small trial of liraglutide in patients with NASH showed improvement in liver histology and less progression of liver fibrosis compared with placebo.
Data from a recently completed phase 3 trial investigating the use of a 2.4-mg once-weekly dose of semaglutide in patients with MASH was presented at The Liver Meeting in November. Of the patients treated with semaglutide, 63% had resolution of MASH vs 34% with placebo. Additionally, 37% of patients treated with semaglutide had improvement in fibrosis vs 22.5% with placebo. Both findings were statistically significant. It will be interesting to see if the results of this study lead to the FDA approval of semaglutide as the first GLP-1 receptor agonist–based treatment of MASH.
Also, two phase 2 trials recently published preliminary data on GLP-1 receptor agonist–based combination medications in patients with MASH.
Tirzepatide, a GLP-1/GIP (glucose-dependent insulinotropic polypeptide) dual agonist, demonstrated MASH resolution in up to 62% of patients (vs 10% with placebo) and fibrosis improvement in up to 55% of patients (vs 30% with placebo). However, the study was underpowered to demonstrate statistical significance in fibrosis improvement.
Survodutide, a dual agonist of glucagon receptor and GLP-1 receptor, showed improvement in (but not resolution of) MASH in up to 62% of patients (vs 14% with placebo) and improvement in liver fibrosis in up to 36% (vs 22% with placebo).
I think there is an appropriate groundswell of excitement in the investigation of single or combination therapies such as these that target global metabolic dysregulation as potential treatments for MASH (as well as other agents such as fibroblast growth factor 21 agonists and pan-peroxisome proliferator-activated receptor agonists).
However, it cannot be stressed enough that several agents that have shown promising phase 2 data ended up failing in phase 3 studies. It will also be critical to understand which agent or combination of agents maximize the balance of efficacy in MASH, metabolic benefit, tolerability, and accessibility.
Who Might Benefit From GLP-1 Therapy?
Is there a type of patient with MASLD in whom you would recommend considering GLP-1 receptor agonist therapy?
Although no GLP-1 receptor agonist has been FDA approved for MASH, the AASLD guidelines do recommend consideration of GLP-1s for patients with MASH who otherwise have an indication for GLP-1 receptor therapy (eg, diabetes, obesity) based on the positive published preliminary data and the general benefit in metabolic health and weight loss. Additionally, the American Association for Clinical Endocrinology has released joint guidelines with the AASLD that recommend GLP-1 receptor agonist therapy be strongly considered for treatment of obesity and/or diabetes in diabetic patients with MASH with moderate to advanced fibrosis.
I think these guidelines highlight the fact that the treatment of metabolic diseases — from pharmacotherapy to dietary/lifestyle recommendations — needs to be tailored to the metabolic phenotype of the patient, including the presence of MASH.
Given the encouraging data for GLP-1 receptor agonists in improving MASH pathology, I often get asked about whether MASH patients with moderate to advanced fibrosis who are already on GLP-1 receptor agonists would benefit from starting resmetirom therapy. Although data on this combination are not extensive, 14% of the patients enrolled in the trial that led to its approval were on stable doses of GLP-1 receptor agonists. Accounting for the small and heterogenous patient sample, this positive response to resmetirom was unaffected by concurrent use of GLP-1s, implying that patients with moderate to advanced MASH who are on stable treatment with GLP-1 receptor agonists may still benefit from resmetirom therapy.
Resmetirom was also found to promote improvement in atherogenic dyslipidemia in patients with MASLD, which is consistent with the goal of treating metabolic dysregulation as a whole.
Do you think that a GLP-1 receptor agonist will be approved for MASLD in the future?
GLP-1 receptor agonists are part of what I view as a revolution in the care of metabolic diseases. Agents such as these that act on multiple facets of metabolic syndrome pathology highlight the fact that metabolic diseases, such as obesity, CV disease, chronic kidney disease, and MASH, exist as a single interrelated entity — a dragon with multiple heads, if you will. The key to treating metabolic syndrome is finding agents that kill the dragon, not just one of its heads. The approach to MASH must be similar.
Previous investigations of MASH therapeutics have been rather “liver focused,” highlighted by obeticholic acid, which provided modest benefits in regard to pathology but worsened markers of metabolic health.
The new era of MASH therapeutics has focused on agents that provide metabolic benefit while also treating MASH pathology.
Given the benefit of GLP-1 receptor agonists in multiple metabolic domains; the recent positive phase 3 data for semaglutide; and the encouraging, albeit preliminary, phase 2 data with GLP-1–based combination therapy, I would be surprised if GLP-1 receptor agonists were not part of a future treatment regimen for MASH, ideally one that is tailored to the metabolic phenotype of the patient.
Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair of the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.
https://www.medscape.com/viewarticle/what-role-can-glp-1s-play-treating-masld-mash-2024a1000n5j
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