Clinical Program Development Director Senior, Pipeline
Katie Lockhart
Senior Manager, Forecasting and Pharmacoeconomics
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Rothesia Stokes
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In recent years, a spotlight has been placed on the management of metabolic dysfunctionassociated steatohepatitis (MASH) given its rising prevalence and notable potential for morbidity and mortality.1
MASH is a type of nonalcoholic fatty liver disease characterized by the accumulation of fat in the liver that leads to damage and inflammation. 2
In more severe cases, advanced fibrosis, cirrhosis, end-stage liver disease, hepatocellular carcinoma, the need for liver transplantation, and death can result. 3,4 While MASH is typically a “silent disease” with no or few symptoms, patients with more progressive disease may experience fatigue, weight loss, general weakness and upper right
abdominal pain. 5 Current estimates suggest that approximately 22 million adults in the United States have MASH, and this number is anticipated to continue rising to 27 million individuals by 2030, bringing average total health care costs from $3,537 to $4,950 per patient.6 As such, the attention that MASH has garnered from the medical community is warranted, and there is a pressing demand for development of novel and effective treatment options for patients living with this disease.
2 Current state
Nomenclature
Prior to the adoption of new terminology, MASH was known as nonalcoholic steatohepatitis (NASH).7 The term NASH was established in 1980 to describe histologic changes in the liver from excess fat, including inflammation and damage, that occur without significant alcohol consumption. 8,9 A few years later, the term nonalcoholic fatty liver disease (NAFLD) was coined to describe a broader condition involving fat accumulation in the liver in the absence of heavy alcohol use.10,11
In June 2023, multinational liver societies released new names for fatty liver disease that are affirmative and nonstigmatizing, with steatotic liver disease (SLD) as the new overarching term, and with metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH replacing NAFLD and NASH, respectively.12
As such, the terms MASLD and MASH will be used throughout the remainder of the paper to describe each respective disease state.
New nomenclature definitions13
Abbreviation Nomenclature Meaning
SLD Steatotic liver disease
Overarching term to classify individuals with hepatic steatosis due to various etiologies
Presence of hepatic steatosis along with ≥ 1 cardiometabolic risk factor and no other evident causes of steatosis
Presence of MASLD and steatohepatitis
Presence of MASLD in the absence of steatohepatitis
Presence of MASLD and consumption of ≥ 140 grams (females) or ≥ 210 grams (males) of alcohol per week
MASH is a more severe form of MASLD
In 2023, the American Association for the Study of Liver Diseases (AASLD) estimated the prevalence of MASLD in U.S. adults to be 25% to 30%, with variance by clinical setting, race, ethnicity and geographic region.14 According to separate estimates, 80 to 100 million individuals in the United States have MASLD, and about 22 million American adults have MASH.15,16 Of those with MASH, almost 9 million have clinically significant (fibrosis stage F2 or F3) liver disease. In an analysis of data from 7,711 adults who participated in the National Health and Nutrition Examination Survey (NHANES) between 2017 and March 2020, results suggested that over 80 million American adults had SLD (35.7%) in that time frame, and of those, almost 46 million had MASLD (19.9%).17 Further, most SLD subcategories showed higher prevalence in males versus females, and MASLD rates were highest in Mexican American participants. From 1988 to 2018, rates of MASLD rose by 61% among Mexican Americans, by 127% among African Americans and by 133% among White Americans.
Notably, the Agency for Healthcare Research and Quality (AHRQ) has announced its partnership with other federal agency stakeholders to conduct a national study that will assess the prevalence of MASLD in the United States.18
Globally, MASLD is now the most common chronic liver disease and affects over 30% of the adult population; its prevalence has risen significantly from 25.3% between 1990 and 2006 to 38.2% between 2016 and 2019.19 Notably, rates of MASLD have risen in parallel with increasing rates of obesity, type 2 diabetes mellitus (T2DM) and metabolic syndrome. The prevalence of MASLD varies by country, with the highest rates reported in Latin America and the Middle East. 20,21 Progression to MASH is anticipated to affect about 5% of adults globally, with the highest prevalence identified in Latin America. 22
prevalence of MASLD in adults23
1 in 4 U.S. adults have MASLD
The prevalence of MASH has risen significantly from 25.3% between 1990 and 2006 to 38.2% between 2016 and 2019
Burden of disease
Data from a modeling study suggest that by 2030, the incidence of MASLD and MASH will increase by 21% and 63%, respectively. 25 During the same period, the average total health care cost of MASH is anticipated to increase from $3,537 to $4,950 per person.
A multitude of complications and comorbidities have been linked to MASLD and MASH. Patients may progress to cirrhosis, which involves liver scarring and damage that may be accompanied by variceal bleeding, ascites, encephalopathy and even liver failure. 26 Development of cirrhosis is often irreversible and can advance to end-stage liver disease, hepatocellular carcinoma (HCC) and the need for liver transplantation. 27 In fact, MASH is the fastest-growing cause of liver transplantation in the United States, and MASH-associated cirrhosis accounts for about 13% of HCC cases. 28,29 Between 2002 and 2016, the prevalence of HCC in liver transplant candidates with MASH increased over tenfold, and the proportion of MASH-related HCC cases increased from 2% to 16%. 30
Complications and costs of MASH in the United States31
Cirrhosis annually
~$100,000
Hepatocellular carcinoma annually
~$124,000
Estimated average liver transplant $8.6B
Estimated total liver transplant costs (2023)
$878,400
Cardiovascularrelated deaths expected annually by 2030
~228,750
Liver-related deaths expected annually by 2030
The average total health care cost of MASH is anticipated to increase from $3,537 to $4,950 per person by 2030
~78,300
MASH-associated cirrhosis accounts for about 13% of HCC cases 13%
Global mortality rates in patients with MASLD32,33
All-cause mortality
12.6 per 1,000 person-years
Cardiac-specific mortality per 1,000 person-years
4.2
2.8
Extrahepatic cancerspecific mortality per 1,000 person-years
*Data are from a systemic review and meta-analysis of population-based studies between 1990 and 2019.
MASLD and MASH are also strongly associated with cardiovascular disease (CVD). MASLD has been identified as an independent risk factor for CVD morbidity and mortality, and conversely, CVD is now the leading cause of death in patients with MASLD. 34-37 In patients with MASH, the likelihood of death from CVD is double that of death from liver disease. There are many mechanisms by which MASLD may increase the risk of CVD, including alterations in the lipid profile, insulin resistance, increased inflammation, oxidative stress and endothelial dysfunction.
Further, MASH and MASLD are frequently diagnosed in patients with T2DM. Estimates suggest that as many as 70% of patients with T2DM in the United States have MASLD. 38 Globally, data from a meta-analysis show that between 1990 and 2023, the pooled prevalence of MASLD among patients with T2DM was 65.3%, with prevalence increasing from 55.9% between 1990 and 2004 to 68.8% between 2016 and 2021. 39
0.92
Liver-specific mortality per 1,000 person-years
Although less robust, there are also data that suggest an association between MASLD and diseases such as chronic kidney disease (CKD), depression, cognitive impairment and extrahepatic malignancies. 40,41 Other comorbidities that may present in these patients include polycystic ovary syndrome (PCOS), osteopenia and sarcopenia, hypothyroidism, obstructive sleep apnea, psoriasis, growth hormone deficiency and hypogonadism. 42,43 While more research is needed to determine the degree of association between these diseases and MASLD, it has become apparent that many of the comorbidities associated with overweight and obesity are also linked to MASH and MASLD.
3 Diagnostic considerations
Risk factors
While the causes of MASLD and MASH are still under investigation, overweight and obesity are well-known risk factors, with MASLD occurring in approximately 75% of people with overweight and 90% of people with severe obesity. 44 Although there is a strong correlation between obesity and the presence of fat in the liver, it is important to note that not all patients with obesity will develop MASLD. Experts suggest that risk for MASLD may be more heavily correlated to the distribution and overall health of fatty tissue, rather than solely the amount of fatty tissue. 45,46 For instance, higher amounts of visceral fat and truncal subcutaneous fat have been shown to increase the risk of insulin resistance, CVD and hepatic fibrosis regardless of body mass index (BMI), while higher amounts of gynoid body fat (e.g., subcutaneous fat in the hips or buttocks) may offer protective benefits against MASLD.
Like obesity, T2DM has been identified as a strong risk factor for development of MASLD and MASH.47,48 The prevalence of MASLD in patients with T2DM is around 60% to 70%, while the prevalence of MASH is estimated to be 37% in these patients. While the mechanism by which T2DM relates to MASLD is complex, it is suggested that insulin resistance results in impaired lipolysis and fat accumulation, including within the liver. T2DM has been shown to accelerate disease progression, with higher rates of advanced fibrosis and other adverse outcomes occurring in patients with concomitant T2DM and MASLD.49 On a broader scale, metabolic syndrome and its characteristics, which include large waist circumference, elevated blood glucose, high triglycerides, low high-density lipoprotein (HDL) cholesterol and hypertension, have also been identified as risk factors for development of MASLD. 50,51
60%-70% of patients with T2DM have MASLD
37% of patients with T2DM have MASH
Risk factors for MASH
Overweight and obesity T2DM
Dietary choices
Gut microbiome
The quality of a patient’s diet is intricately linked to the development of obesity and T2DM, and as such, serves as a key risk factor for MASLD. 52,53 It has been proposed that overconsumption of fat and carbohydrates leads to oxidative stress and activation of inflammatory bodies in hepatocytes. Fructose, which is a simple sugar that is often used to sweeten foods and beverages, is also being studied as a leading dietary contributor to MASLD when consumed in excess. 54 Conversely, foods with antioxidant and anti-inflammatory effects, including those high in fiber, monounsaturated fatty acids, omega-3 fatty acids and phytosterols, may lower the risk of liver steatosis. 55
Closely related to dietary quality is composition of the gut microbiome, which is also under evaluation as a potential contributor to development of MASLD and MASH. 56 Patients with MASLD often have altered gut microbiota composition, including an increased quantity of certain species (e.g., Proteus, Enterobacter, Escherichia) and a reduced number of other species (e.g., Ruminococcus, Lactobacillus). These changes in gut flora may affect metabolism of glucose, lipids and choline. 57
Further, advanced age is a widely recognized risk factor for MASLD and its complications. 58 The liver undergoes a variety of changes as aging occurs, including reduced hepatic blood flow, hepatic volume and liver function; reduced bile acid synthesis and changes in cholesterol metabolism; and reduced number of mitochondria with subsequent increases in oxidative respiration. Changes in body composition that typically occur with aging, including decreases in muscle mass and increases in abdominal adiposity, also play a role.
MASLD progression is primarily associated with five genetic variants: patatin-like phospholipase domaincontaining protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), glucokinase regulator (GCKR), membrane-bound O-acyltransferase domain containing 7 (MBOAT7 ) and 17ß-hydroxysteroid dehydrogenase type 13 (HSD17B13). 59,60 Variation in the PNPLA3 gene is most commonly seen in Hispanic individuals (49%), followed by non-Hispanic Whites (23%) and African
Variation in the PNPLA3 gene is most commonly seen in:
Americans (17%). More recently, a rare variant in the mesenchymal-epithelial transition (MET ) gene has been linked to MASLD.61 Notably, these genetic variants have only been found to account for a small portion of MASLD cases, and additional genes and polymorphisms are under investigation.62,63
Clinical diagnosis
Current clinical guidelines recommend primary care providers, endocrinologists, obesity specialists, gastroenterologists and hepatologists identify and screen those patients at increased risk of developing MASLD.64-66 All patients with T2DM, hepatic steatosis on imaging and abnormal liver function tests, or those with two or more risk factors (e.g., elevated fasting blood glucose, increased waist circumference or central obesity, elevated blood pressure), should be screened for MASLD. Assessment should begin with a thorough history that includes reviewing any family history of liver disease, quantification of alcohol use, physical exam and review of lab work and imaging suggesting underlying liver disease. Other causes of liver disease should be ruled out via lab testing and may necessitate a liver biopsy.
Although a liver biopsy is the gold standard for diagnosing and staging MASLD, and is the only method for confirming MASH, it is an invasive test with inherent risks.67-70 If other causes of liver disease have been ruled out, a liver biopsy may not be necessary, especially if the results have a low likelihood of altering clinical management. Once a diagnosis is established, noninvasive testing is used to assess for underlying liver damage (e.g., fibrosis). Noninvasive
testing includes calculations based on age and lab values (e.g., Fibrosis-4 [FIB-4]) versus other proprietary lab tests. The FIB-4 calculation is the most frequently used predictor of fibrosis, which identifies those at low risk for fibrosis (score < 1.3) versus those at intermediate risk (score 1.3 to 2.67) or high risk (score > 2.67).71,72 Patients with a FIB-4 score > 1.3 will require additional imaging, such as magnetic resonance elastography (MRE) or ultrasound with transient elastography to provide a fibrosis score (F0–F1 = normal
to mild fibrosis, F2–F3 = significant to advanced fibrosis, F4 = cirrhosis).73,74 Patients with moderate to severe fibrosis and/or cirrhosis should be referred to a gastroenterologist or hepatologist for further care and determination of need for a liver biopsy. Patients with confirmed advanced liver disease or cirrhosis require a higher level of longterm specialty care due to the potential complications of cirrhosis, such as liver failure and liver cancer.
Normal liver MASL MASH MASH with fibrosis
MASLD PROGRESSION
4 Treatment approaches
Lifestyle modifications
The 2023 AASLD practice guidance on clinical assessment and management of MASLD emphasizes the importance of a healthy diet and regular exercise as the mainstay of therapy for most patients with the disease, including those who do not have overweight or obesity.75 Given that diets containing excess calories from saturated fat, refined carbohydrates and sugar-sweetened beverages increase the risk for MASLD, MASH and advanced fibrosis, limiting these components through dietary changes and calorie reduction is recommended. Regarding fat intake, diets consisting primarily of monounsaturated fat (e.g., olive oil, nuts, avocado) may reduce triglyceride and low-density lipoprotein cholesterol (LDL-C) levels, resulting in benefits for MASLD patients.76 Increasing dietary fiber intake may also be valuable for patients with MASLD by reducing liver fat and inflammation. Minimizing consumption of fructose is also likely advantageous because of its potential role in the development of MASLD, MASH and advanced fibrosis.77,78
Multidisciplinary management of MASLD79
Primary care provider/Endocrinology
Initial risk stratification with FIB-4 +/- secondary testing
Management of metabolic comorbidities with preferential use of medications with potential MASLD benefit
Assessment of other endocrine drivers if indicated
Lifestyle changes
Gastroenterology/ Hepatology
HEALTH P S YCHOLOGY
Comprehensive liver risk stratification
Liver-directed therapies
Identification of additional comorbidities
Management of advanced fibrosis
Clinical trial opportunities as available
Nutrition/Lifestyle intervention
Assessment of dietary habits
Development of dietary plans/goals
Identification of barriers
Referral for behavioral intervention if needed
Prescriptive follow-up and management plan
MASLD patient
Lifestyle considerations for patients with MASLD
Veggies, fruit, whole grains, white meat, nuts, avocado, coffee, exercise
Alcohol, processed and sugary foods, red meat
The Mediterranean diet is specifically highlighted in the AASLD guidelines and by the American Association of Clinical Endocrinology (AACE) and the American Gastroenterological Association (AGA) as a dietary pattern that may be beneficial for patients with MASLD. 80,81 In fact, it is the most researched diet in patients with MASLD, and its benefits may extend to reducing risk of CVD and T2DM. 82 The Mediterranean diet typically includes higher intake of vegetables, fruits, whole grains, olive oil, nuts and white meat (e.g., seafood, poultry); low consumption of dairy, red meat and processed and sugary foods; and moderate alcohol intake.
Interestingly, some data have shown that consuming three or more cups of coffee per day in the absence of contraindications may reduce the risk for MASLD and liver fibrosis. 83 Coffee consumption may be associated with a reduction in certain liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT), and it has been shown to have an inverse relationship with nonalcoholic and alcoholic liver cirrhosis. 84
On the contrary, alcohol has been shown to contribute to MASLD progression, and moderate consumption increases the risk of advanced fibrosis, especially in patients with obesity and/or T2DM. 85 Together, alcohol consumption and obesity increase the risk of liver injury, cirrhosis, HCC and death from liver disease. The AASLD recommends regular assessment of alcohol consumption in patients with MASLD and complete avoidance of alcohol for patients with clinically significant fibrosis (≥ F2).
Another key lifestyle intervention with known hepatic and cardiovascular (CV) benefits is exercise. 86 While data vary regarding the type, intensity and duration of physical activity needed to result in meaningful benefits, the AASLD guidelines recommend patients increase their activity level to the extent possible and follow an exercise regimen that is sustainable. Some studies suggest that 150 minutes of moderate-intensity aerobic exercise per week can prevent or improve MASLD, while others have shown improvements with more vigorous aerobic exercise. Studies have also suggested that resistance training can increase the uptake of glucose and fatty acids, which ultimately leads to improvements in MASLD. 87 Notably, exercise has been shown to decrease hepatic steatosis even in the absence of major weight loss, and the benefits seem to be associated with intensity of and adherence to an exercise program rather than the type of exercise performed. 88
Role of weight management
Weight loss is recommended for all patients with MASLD who have overweight or obesity. 89,90 Even a 3% to 5% reduction in body weight can improve steatosis, although ≥ 10% weight loss is typically required to achieve improvements in MASH and fibrosis. 91 AACE recommends a goal of ≥ 5% and preferably ≥ 10% weight loss in patients with MASLD and excess adiposity, with greater weight loss being tied to increased liver histologic and cardiometabolic benefit. 92 Patients who can sustain their weight loss typically have less adipose tissue stress and improved insulin sensitivity, which can slow the progression of liver injury in MASH. 93 The AASLD recommends patients be
prescribed a diet that results in a caloric deficit, preferably consisting of high fiber and unsaturated fat, and limited carbohydrates and saturated fat (e.g., Mediterranean diet). The guideline also recommends the adoption of an individualized exercise regimen that is sustainable. Bariatric surgery can be considered for eligible patients as an effective method to resolve MASLD or MASH and reduce CVD- and malignancy-related mortality.
In its 2022 clinical practice guideline for the diagnosis and management of MASLD, AACE offers recommendations for weight management according to a patient’s fibrosis risk. 94 For all risk categories, lifestyle changes,
AACE weight management recommendations by fibrosis risk stratification
Weight loss tools
Behavioral modification counseling, in-person or remote programs
Medications phentermine, phentermine/ topiramate ER, naltrexone/bupropion, orlistat, liraglutide, semaglutide
Bariatric surgery
Consideration to treat obesity and comorbidities
ER = extended release; GLP-1 = glucagon-like peptide-1 receptor agonist
Greater intensity of weight loss to reverse steatohepatitis and fibrosis
GLP-1 preferred
Strong consideration to treat steatohepatitis and fibrosis
including reduced sedentary time and implementation of stress management techniques, are recommended. Additional recommendations include a caloric deficit achieved by reducing saturated fat, starch and added sugar intake; incorporation of aerobic exercise for 30 to 60 minutes (3 to 5 days per week); and resistance training for 20 to 30 minutes (2 to 3 times per week). Patients who fall into lowand intermediate-risk categories are recommended to minimize alcohol intake, while high-risk patients (F3 or F4) should avoid alcohol. Recommendations for weight loss tools, medications and bariatric surgery vary by risk category, as detailed in the table below.
Specialized obesity management with a structured program, anti-obesity medications, bariatric surgery
GLP-1 preferred
Stronger consideration to treat steatohepatitis and fibrosis; avoid in decompensated cirrhosis
Pharmacotherapy: Current landscape
Several organizations have published clinical practice guidelines with pharmacotherapy recommendations for the management of MASLD and MASH, including the American Association for the Study of Liver Diseases (AASLD), the American Association of Clinical Endocrinology (AACE), the American Gastroenterological Association (AGA) and the American Diabetes Association (ADA).
Prior to March 2024, there were no medications approved by the Food and Drug Administration (FDA) to treat MASLD or MASH at any stage of the disease. In its 2023 practice guidance, AASLD recommends that the glucagonlike peptide-1 (GLP-1) receptor agonist semaglutide be considered in patients with MASH who have an approved indication (e.g., T2DM, obesity) given its evidence for CV benefits. 95 The guidance also discusses a few off-label treatment options that can be considered for patients with MASH without cirrhosis, including the thiazolidinedione (TZD) pioglitazone for patients with concomitant T2DM based on potential improvements in histology and insulin resistance, and vitamin E for select patients without T2DM based on data showing improved steatosis. This AASLD
guidance recommends against treatment with metformin, ursodeoxycholic acid, dipeptidyl peptidase-4 (DPP-4) inhibitors, statins or silymarin for MASH due to lack of meaningful histologic benefit.
AACE provides similar recommendations in its 2022 guideline for diagnosis and management of MASLD; GLP-1s and pioglitazone are recommended for patients with T2DM and biopsy-proven MASH, and vitamin E can be considered in patients without T2DM or advanced fibrosis. 96
AACE also includes sodium-glucose cotransporter 2 (SGLT-2) inhibitors in its recommendations due to cardiometabolic benefits in patients with T2DM and MASLD but highlights that there is no evidence of benefit in the treatment of steatohepatitis for these agents. Medications noted for their lack of efficacy include metformin, acarbose, DPP-4 and insulin.
Recommendations provided in the 2021 AGA clinical care pathway for management of MASLD align with those from AASLD and AACE. 97 Low-risk patients are not recommended for MASH pharmacotherapy but should implement lifestyle interventions and optimize the management of cardiometabolic risk factors (e.g., T2DM, hypertension), while intermediate- and high-risk patients
should be managed with medications that have efficacy in MASH (e.g., GLP-1, pioglitazone). AGA also recommends CVD risk reduction in all patients regardless of risk category.
In March 2024, Madrigal’s once-daily oral thyroid hormone receptor-beta (THRbeta) agonist resmetirom (Rezdiffra) received Accelerated Approval from the FDA, making it the first and only medication to be approved for treatment of MASH. 98 Approval was based on findings from the MAESTRO-NASH trial (n=966), which showed that treatment with Rezdiffra for 52 weeks led to resolution of steatohepatitis without worsening of fibrosis in 25.9% of patients with the 80 mg dose and 29.9% with the 100 mg dose compared to 9.7% with placebo. 99 Further, Rezdiffra treatment resulted in fibrosis improvement by at least one stage without worsening of NAFLD activity score in 24.2% of patients on the 80 mg dose and 25.9% of patients taking the 100 mg dose compared to 14.2% of placebo patients.
resmetirom (Rezdiffra)100-102
Approval NDA approval – March 2024; Accelerated Approval, Breakthrough Therapy, Fast Track, Priority Review
Indication In conjunction with diet and exercise for the treatment of adults with noncirrhotic, nonalcoholic steatohepatitis with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis)
Limitation of use
Dosage forms and strengths
Avoid in patients with decompensated cirrhosis
Oral tablets: 60 mg, 80 mg and 100 mg
Dosing Dosage is based on actual body weight (ABW):
Following the approval of Rezdiffra, the AASLD published an updated practice guidance with recommendations for its use in patients with MASLD.103 With regard to patient selection, the guidance states that Rezdiffra can be considered for adults with MASH and moderate to advanced liver fibrosis (F2–F3) who either have a noninvasive liver disease assessment (preferably imaging-based test results) consistent with MASH (F2–F3) or a historical liver biopsy that demonstrates MASH (F2–F3) without evidence of another cause of liver disease. The drug is not recommended for patients with compensated or decompensated cirrhosis, concomitant uncontrolled active liver diseases, symptomatic gallstone conditions or ongoing alcohol consumption > 20 grams/day (women) or > 30 grams/day (men). The AASLD guidance also includes suggestions for on-treatment monitoring, including continued monitoring of hepatic function, standard laboratory monitoring of thyroid function in patients with known thyroid disease and continued attention to the management of comorbidities (e.g., hyperlipidemia). The guidance suggests repeat liver stiffness measurements at 12 months in those whose eligibility for
treatment was determined by vibrationcontrolled transient elastography (VCTE) or MRE, with improvement of VCTE ≥ 25% or MRE ≥ 20% from baseline indicative of clinically meaningful improvement. Treatment can be continued for patients with significant fibrosis improvement but should be discontinued for those with evidence of worsening liver disease after 12 months.
The European Association for the Study of the Liver (EASL) collaborated with the European Association for the Study of Diabetes (EASD) and the European Association for the Study of Obesity (EASO) to produce a clinical practice guideline for management of MASLD in September 2024 which includes guidance on Rezdiffra.104 While recommendations for MASLD focus on implementation of lifestyle changes and management of comorbidities (e.g., T2DM, obesity), including with the use of GLP-1s, the guidance also states that Rezdiffra should be considered for adults with noncirrhotic MASH and significant liver fibrosis (stage ≥ 2). Additionally, an open recommendation suggests considering treatment with Rezdiffra in select patients with noncirrhotic MASLD who have documentation of either advanced fibrosis, at-risk steatohepatitis with significant fibrosis or risk of adverse liver-related outcomes. The guidance also states
that no pharmacotherapy options can currently be recommended for patients with MASH and cirrhosis.
The AGA published global consensus recommendations for MASLD in April 2025, which are based on a comprehensive review of 61 documents published between 2018 and 2025, and which include recommendations for use of Rezdiffra.105 With regard to pharmacotherapy, GLP-1s are considered the preferred treatment for T2DM and/ or obesity in patients with MASH, while pioglitazone, SGLT-2s and DPP-4s can be utilized for treatment of T2DM but are not considered to be MASH-targeted therapies. Rezdiffra should be considered for patients with MASH and F2–F3 fibrosis who meet noninvasive test criteria in the absence of cirrhosis. The consensus report also gives recommendations for use of Rezdiffra according to VCTE liver stiffness measurements.
Additionally, the ADA published a consensus report in May 2025 which addresses the use of Rezdiffra in patients with MASLD and diabetes.106 The guidance encourages lifestyle modifications for all patients with concomitant diabetes, overweight or obesity and MASLD, along with use of medications often used for comorbidities in MASLD (e.g., GLP-1s, dual gastric inhibitory peptide [GIP]/
GLP-1s, pioglitazone) for treatment of patients with early-stage fibrosis. The ADA highlights that Rezdiffra is currently the only medication approved for F2–F3 fibrosis and points out that limited information is available on combining Rezdiffra with GLP-1s, GIP/GLP-1s and pioglitazone. The consensus report recommends Rezdiffra be initiated by a hepatologist or gastroenterologist after treatment optimization of obesity and/or diabetes for at least 6 to 12 months.
In February 2025, Madrigal announced twoyear data from the active-treatment openlabel compensated MASH cirrhosis arm (n=101) of the Phase 3 MAESTRO-NAFLD-1 trial.107 Results suggest that Rezdiffra continues to improve key markers of MASH fibrosis (e.g., liver stiffness as measured by VCTE) for at least two years in patients with compensated MASH cirrhosis.
Rezdiffra continues to undergo evaluation in its ongoing Phase 3 MAESTRONASH-OUTCOMES clinical trial, which aims to evaluate progression to liver decompensation events in patients with compensated cirrhosis (F4) over approximately three years.108,109 Results from the trial are expected in 2027 and may support expanded approval for use in patients with compensated cirrhosis.110
Rezdiffra vs. GLP-1s for MASH
In April 2025, results were published from Part 1 of the Phase 3 ESSENCE trial (n=800) evaluating the GLP-1 semaglutide in adults with MASH and moderate to advanced liver fibrosis (F2–F3).111,112 After 72 weeks, treatment with semaglutide 2.4 mg subcutaneously (SC) once weekly led to statistically significant and superior improvement in liver fibrosis without worsening of MASH, and resolution of MASH without worsening of liver fibrosis, compared to placebo.
Rezdiffra and semaglutide have not been compared in a head-to-head trial but results from their respective Phase 3 trials are comparable.113 Current routes of administration differ between the two drugs, with Rezdiffra administered orally once daily and semaglutide given SC once weekly. Further, Rezdiffra has an annual wholesale acquisition cost (WAC) of $49,391 compared to an annual WAC of $16,188 for SC Wegovy.114,115 Another key difference is distribution and availability; Rezdiffra is a limited distribution drug that has primarily been marketed to hepatologists and gastroenterologists while GLP-1s, such as semaglutide, are widely prescribed with open distribution.116
While AASLD includes both Rezdiffra and GLP-1s in its recommendations for patients with MASH, the guidelines do not currently include suggestions for choosing between the two therapies.117
Rezdiffra is a limited distribution drug that has primarily been marketed to hepatologists and gastroenterologists while GLP-1s, such as semaglutide, are widely prescribed with open distribution.
Rezdiffra is administered orally 1x daily
Wegovy is administered subcutaneously 1x weekly and has an annual WAC of $49,391 and has an annual WAC of $16,188
Rezdiffra targets MASH through an intrahepatic mechanism given that THR-beta function is impaired in patients with the disease, while the GLP-1s seem to work primarily through extrahepatic mechanisms.118 For instance, GLP-1 use results in weight loss and increased insulin secretion, which in turn causes reduction in free fatty acids and reduced intrahepatic triglycerides.119 Additionally, GLP-1s have been shown to reduce de novo lipogenesis and triglyceride secretion, increase glucose uptake, and decrease gluconeogenesis. All of these effects may result in improved hepatic parameters. While further research is needed, one study suggests that since the two drugs have complimentary mechanisms, combining Rezdiffra and semaglutide may potentially offer a synergistic strategy for the treatment of MASH.120 Notably, about half of the patients who were assigned to Rezdiffra in the MAESTRO-NASH trial were taking a concomitant GLP-1.121
Phase 3 trial results for resmetirom and semaglutide in MASH122-124
Trial
(resmetirom) ESSENCE (semaglutide)
Patient population MASH (F2–F3) MASH (F2–F3)
Duration 52 weeks 72 weeks
Resolution of MASH without worsening of fibrosis
Improvement of fibrosis without worsening of MASH
80 mg: 26% to 27%
100 mg: 24% to 36%
Placebo: 9% to 13%
Treatment difference: 14% to 23%
80 mg: 23% to 25%
100 mg: 25% to 28%
Placebo: 13% to 15%
Treatment difference: 10% to 13%
Key potential mechanisms in MASH
Rezdiffra targets MASH through an intrahepatic mechanism
2.4 mg: 63%
Placebo: 34%
Treatment difference: 29%
2.4 mg: 37%
Placebo: 22.4%
Treatment difference: 15%
Semaglutide targets MASH through an extrahepatic mechanism
Pharmacotherapy: Pipeline
The pipeline for MASH is robust, with several medications currently in Phase 3 studies and one pursuing approval.125-131 The mechanisms of action for these medications vary from common (e.g., GLP-1, peroxisome proliferator-activated receptor [PPAR] agonist) to new (e.g., fibroblast growth factor, stearoyl-CoA desaturase 1 [SCD1] modulator). Novo Nordisk’s semaglutide, a GLP-1 that is already approved as Wegovy to reduce the risk of major adverse CV events and to reduce excess body weight and maintain weight reduction in the long term, is expected for approval in MASH in the third quarter of 2025. The Prime Therapeutics GLP-1 Pipeline Update features medications in the pipeline being studied in MASH, including semaglutide. Other drugs that are in Phase 3 trials are listed on the next page.
Beyond the medications that are being pursued for the MASH indication as monotherapy, combination therapy studies are in earlier phases. Galmed received a patent that covers the use of combination therapy of aramchol and resmetirom for the treatment of MASH and liver fibrosis.132 The Phase 2B EMMINENCE trial evaluated the TZD azemiglitazone, from Cirius Therapeutics, in patients with MASH and concomitant T2DM on a stable dose of a GLP-1.133,134
Inventiva conducted a Phase 2 study that evaluated the combination of lanifibranor with empagliflozin in patients with MASH and T2DM.135
Agents in development that are in Phase 3 trials for patients with MASH and moderate or advanced liver fibrosis, a patient population similar to those included in the FDA-approved indication for Madrigal’s Rezdiffra, include Novo Nordisk’s semaglutide (Wegovy), Galmed’s aramchol meglumine and Inventiva’s lanifibranor.136-139 Madrigal may extend the approved patient population for Rezdiffra to include patients with compensated MASH cirrhosis depending on results from the MAESTRO-NASH OUTCOMES trial; a trial which may also support full approval (from Accelerated Approval) of Rezdiffra in noncirrhotic MASH.140 Additionally, Akero’s efruxifermin, Boehringer Ingelheim’s and Zealand Pharma’s survodutide and 89bio’s pegozafermin are in Phase 3 trials in patients with MASH with moderate or advanced liver fibrosis and in patients with compensated MASH cirrhosis, a patient population that does not yet have an FDA-approved medication.141-143
Name Manufacturer Dosage form/ dosing interval
aramchol meglumine Galmed
lanifibranor Inventiva
resmetirom (Rezdiffra) Madrigal
survodutide Boehringer Ingelheim/ Zealand
Oral/daily SCD1 modulator
ARCON ARMOR
Oral/daily PPAR agonist NatiV3
Oral/daily THR-beta agonist
MAESTRO-NASH OUTCOMES
SC/weekly Dual glucagon/ GLP-1 agonist LIVERAGE
LIVERAGE-Cirrhosis
NCT04104321 MASH and moderate or advanced liver fibrosis
efruxifermin Akero
SC/weekly Fibroblast growth factor analog
SYNCHRONY
pegozafermin 89bio
SC/weekly or every two weeks Fibroblast growth factor 21 analog
SYNCHRONY
ENLIGHTEN-Fibrosis
NCT04849728 MASH and moderate or advanced liver fibrosis
NCT05500222 Compensated MASH cirrhosis
ENLIGHTEN-Cirrhosis
NCT04771273 MASH and moderate or advanced liver fibrosis
NCT06632457 Compensated MASH cirrhosis
NCT06215716 MASH and moderate or advanced liver fibrosis
NCT06528314 Compensated MASH cirrhosis
NCT06318169 MASH and moderate or advanced liver fibrosis
NCT06419374 Compensated MASH cirrhosis
5 Special populations
Pediatrics
Development of MASLD is not limited to adults; recent data have shown that MASLD also affects an estimated 5% to 10% of children, with 20% to 50% of those patients progressing to MASH.151 In fact, MASLD is the most common cause of chronic liver disease in children in the United States, with rates rising rapidly as the prevalence of childhood obesity increases. 152,153 MASLD incidence is highest in Hispanic children of Mexican descent, followed by Asian American children and White children. The disease is also more common in male versus female children and adolescents. While causes of MASLD in pediatric patients are still under investigation, known risk factors include overweight, obesity, insulin resistance, T2DM, high blood pressure, dyslipidemia and metabolic syndrome.154 Genetics likely also play a role, along with high or low birth weight, microbiome changes and diets high in fructose.
Just as the first-line treatment of adults with MASLD is lifestyle modification, the same is true for children and adolescents.155 Both the AASLD and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) recommend dietary restriction and increased exercise for pediatric patients with MASLD who have obesity. While several medications and supplements have been studied for pediatric use in MASLD, including probiotics, omega-3 fatty acids (e.g., docosahexaenoic acid [DHA], eicosapentaenoic acid [EPA]), vitamin E and metformin, current NASPGHAN guidelines recommend against these treatment options for pediatric patients given lack of benefit seen in clinical trials.156 Notably, AASLD has indicated that a guidance document will be published to focus on management of pediatric MASLD; however, an anticipated publication date is unknown at this time.157
5%-10% of children are affected by MASLD 20%-50% of children with MASLD progress to MASH MASLD is the most common cause of chronic liver disease in children in the United States, with rates rising rapidly as the prevalence of childhood obesity increases
Lean MASLD
While MASLD predominantly occurs in patients who have overweight or obesity, an estimated 7% to 20% of patients with MASLD in the United States are considered to be lean individuals, defined as having a BMI < 25 kg/m2 (< 23 kg/ m2 in Asian patients). 158,159 Given that differences in disease progression and associated conditions exist between lean and non-lean patients, AGA published a clinical practice update in 2022 to address diagnosis and management of lean MASLD. While routine screening for MASLD is generally not recommended for lean patients, it should be considered for patients > 40 years of age with T2DM as well as for patients who are lean but who have a metabolic disease (e.g., T2DM, dyslipidemia, hypertension), elevated liver biochemical tests or incidentally noted hepatic steatosis. According to the guidance, a liver biopsy should be considered if the contributing causes of liver injury and/or the stage of fibrosis is uncertain, with noninvasive testing (e.g., NAFLD fibrosis score, FIB-4 score) and imaging (e.g., transient elastography, MRE) as alternatives.
Lifestyle interventions are still recommended for patients with lean MASLD, including diet modification and exercise to achieve a modest weight loss of 3% to 5%.160 For lean patients with biopsy-confirmed MASH, vitamin E can be considered in the absence of T2DM or cirrhosis, and oral pioglitazone can be utilized in the absence of cirrhosis. AGA states that the role of GLP-1s and SGLT2s has not yet been determined in this patient population.
Health disparities
Prevalence data for MASLD and MASH in the United States point to evidence of disparities based on race, ethnicity, sex and socioeconomic status.161 With regard to race and ethnicity, MASLD and MASH are both seen more frequently in Hispanic individuals, followed by non-Hispanic White and non-Hispanic Black individuals. Further, data suggest that MASLD may present earlier in Hispanic individuals, with a mean age of onset of 37 years in Mexican Americans. MASLD rates are also higher in males compared to females. Additionally, risk of developing MASLD is higher in individuals living with food insecurity, which affects about 29% of U.S. adults in low-income households.
Disparities in adverse outcomes also seem to exist for certain groups.162 For example, research has shown that non-White women receive liver transplantation at a higher end-stage liver disease score and have lower graft and survival rates compared to White women and non-White males. Notably, U.S. women are 19% less likely to receive a liver transplant compared to men and appear to have a higher prevalence of MASH-related cirrhosis. Food insecurity has also been associated with higher risk for advanced fibrosis, and cirrhosis rates are highest in patients living in areas of the United States where low-income households are prevalent. It is crucial to recognize and address these disparities to move forward with optimizing care for all patients with MASLD and MASH.
MASLD and MASH are both seen more frequently in Hispanic individuals, followed by nonHispanic White and non-Hispanic Black individuals.
7%-20%
of patients with MASLD in the United States are considered to be lean individuals
6 Health outcomes and market trends
A GLP-1-Level Indication Prevalence (GLIP) tool by Prime Therapeutics (Prime) provides clients with detailed GLP-1 utilization by their membership’s medical diagnoses, as well as potential future GLP-1 pharmacy uptake and future costs by medical condition. In addition to MASH, conditions of special interest for the GLIP tool include recent indications for GLP-1 weight loss drugs, including semaglutide (Wegovy) for individuals with overweight and obesity who have pre-existing CVD without diabetes and tirzepatide (Zepbound) for sleep apnea.
Prime’s assessment of 17.6 million lives from the commercially insured book of business (BoB) found that 1.08% of the total population or slightly more than 1 in 100 members have MASH without another GLP-1 FDA-approved indication for which coverage is usually provided.
Source: Evaluate Pharma
The MASH market is projected to grow rapidly, reaching $1 billion in sales within two years of the first product, resmetirom (Rezdiffra), being approved.163 This growth is expected to persist, with a projected compound annual growth rate (CAGR) of 83% from 2025 to 2030. In comparison, the overall pharmaceutical market is expected to grow at a CAGR of 9% during the same period. As a result, the MASH indication's share of total pharmacy spend is projected to increase from 0.03% to 1% by 2030.
The figure to the right illustrates the projected distribution of the estimated $7 billion in MASH sales among approved products by 2030.164 Rezdiffra is projected to be the leading product, accounting for 34% of total MASH spend in 2030, likely due to its first-to-market advantage since its approval in 2024. Semaglutide is expected to generate 17% of total MASH spend, which is half of Rezdiffra's projected spend. With total MASH sales reaching $7 billion in 2030, both Rezdiffra and semaglutide are expected to generate over $1 billion annually. This would mark semaglutide's third indication generating over $1 billion annually, alongside its diabetes and obesity indications. Efruxifermin, pegozafermin and VK2809 (Phase 3 anticipated) are forecasted to generate $600 million to $800 million each in
MASH market share by total spend in 2030
Source: Evaluate Pharma
2030. Additionally, 16 other products are expected to individually generate under $500 million but collectively exceed $1.5 billion in sales. The MASH market appears crowded but is expected to be dominated by two key products: Rezdiffra and semaglutide.
With rising MASH prevalence and a rapidly expanding treatment landscape, payers and pharmacy benefit managers play a critical role in managing this chronic liver disease. A balanced
approach is essential — one that centers on clinical evidence while improving access to cost-effective therapies. A multidisciplinary care model, supported by a coordinated team of health care professionals, helps optimize outcomes. This approach emphasizes the importance of lifestyle modifications alongside drug therapy, ensuring whole-person care that supports long-term health.
7 Prime perspective
At Prime, we strive to provide the same care we would want for our loved ones. We are guided by three primary tenants of practice for MASH, centered on intelligently designed solutions and our Save, Simplify, Support™ approach.
Considering the total cost of care, Prime implements an evidence-based approach for the management of MASH through an integrated view of medical and pharmacy claims.
We take a holistic view of MASH, including lifestyle modifications and patient-centric, cohesive care to deliver a seamless and transparent experience for everyone.
Our goal is to educate and increase MASH health literacy for all stakeholders, with solutions anchored in clinical best practice to achieve better patient health.
8 Summary
The MASH space has seen rapid and impactful changes within the last few years, including the adoption of new nomenclature and FDA approval of the first medication for this specific indication. Several additional drugs in the pipeline could receive approval for MASH over the next few years, and even earlier for the SC GLP-1 semaglutide. Moreover, the cases of MASH are forecasted to increase. Hence, strategies for the management of this prevalent disease will need to evolve quickly. The health care community should be prepared to make holistic, evidence-based and cost-effective decisions to support all patients who are living with MASH and its comorbidities.
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