CE / CME
Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit
Nurses: 0.50 Nursing contact hour
Physicians: maximum of 0.50 AMA PRA Category 1 Credit™
Released: January 31, 2024
Expiration: January 30, 2025
The Evidence: MASLD Liver Fibrosis, A Risk for Adverse Outcomes
The risk for both severe liver disease and liver-related mortality in MASLD is related to the presence and severity of fibrosis, particularly advanced (stage III-IV) fibrosis and cirrhosis.5,6
The Evidence: Regression of MASH Cirrhosis Associated With Improved Clinical Outcomes
Similarly, as seen from a large study analysis comprising approximately 1100 patients, 16% of patients saw their MASH-related fibrosis stage improve via intervention with simtuzumab or selonsertib. Researchers associated this improvement with a 6-fold decrease in risk of liver-related events.7
In Absence of FDA-Approved Therapies, Early Intervention Is Key
Therefore, early intervention in MASH is critical to prevent the development of advanced fibrosis and cirrhosis when possible. There are currently no FDA-approved therapies for MASH, but a coordinated and patient-specific approach can be effective. This should include a treatment plan that addresses any contributing comorbidities, such as obesity, diabetes, and hyperlipidemia; prescribes lifestyle changes including diet modifications and/or exercise; and promotes the avoidance of alcohol, as it can potentiate fat-related hepatotoxicity.8-10
GLP-1 RAs: Semaglutide
In terms of currently available pharmacotherapy, there are GLP-1 RAs such as semaglutide or other incretin-based therapies that augment meal-induced β-cell insulin production. Furthermore, these agents also slow gastric emptying, leading to increased satiety, and affect central nervous system signaling to reduce food intake. The result is weight loss, improved glycemic control, and decreased liver fat.11,12
GLP-1 RAs: Liraglutide
One of the earliest placebo-controlled phase II studies of a GLP-1 RA was of liraglutide in patients with overweight and MASH. Study results demonstrated improvement in alanine aminotransferase concentration among patients receiving liraglutide vs patients receiving placebo. Furthermore, 39% of patients receiving liraglutide vs 9% of patients receiving placebo experienced resolution of MASH.13
GLP-1 RAs: Semaglutide
Can treatment with semaglutide be effective in managing MASH? A phase II trial studied patients with biopsy-confirmed MASH and stage I-III fibrosis who were receiving 0.1, 0.2, or 0.4 mg of semaglutide vs placebo. As the results indicate, 59% of participants experienced MASH resolution and 43% saw improvement in their fibrosis stage with the higher (0.4-mg) treatment dose vs placebo. However, semaglutide is not approved by the FDA for managing MASLD at present.14,15
GLP-1 RAs: Effect on Adiponectin
Next, I will discuss the impact of GLP-1 RAs on adiponectin, which is involved in glucose uptake and lipid metabolism by reducing gluconeogenesis and enhancing fatty acid oxidation in the liver. GLP-1 RAs—and liraglutide in particular—are associated with significant increases in adiponectin concentrations among treated individuals.16,17
SGLT2 Inhibitors: Antioxidant Effects
Another class of glucose-lowering medications being studied in MASH is sodium-glucose cotransporter 2 (SGLT2) inhibitors. These agents are associated with decreased oxidative stress in several organs, including the liver, which can help with normalizing liver enzyme levels, reducing fat, and having favorable impacts on fibrosis.18
SGLT2 Inhibitor: Empagliflozin
On this slide, one can see that treatment with empagliflozin—an SGLT2 inhibitor—among patients with T2D and MASH was associated with significantly reducing liver fat, as measured by MRI proton density fat fraction.19
PPAR: Pioglitazone
Lastly, pioglitazone is a PPAR agonist from the thiazolidinedione class of antidiabetic medications that has shown potential in the treatment of MASH. A meta-analysis of randomized, controlled trials of patients with MASH, with or without T2D, showed that pioglitazone improves liver enzymes, inflammation, steatosis, and fibrosis.20
Weight Loss Thresholds and Impact on MASLD
Weight loss repeatedly has had a positive impact on MASLD and MASH. The degree/goal of weight loss by percentage of body weight varies based on disease severity. For example, losing 3% to 5% of one’s body weight can lead to improved steatosis, yet ≥10% sustained weight loss is needed for regression of fibrosis.21
Weight Loss Strategies
It can, unfortunately, be challenging for patients to lose weight. Therefore, healthcare professionals (HCPs) should individualize patients’ weight loss plans. Furthermore, these plans are usually most successful if they involve a structured program consisting of a restricted diet, with or without an exercise program; pharmacotherapy, including GLP-1 RAs; or bariatric surgery or other procedures.
Example Diet: Mediterranean Diet
Dietary changes beyond simply reducing one’s caloric intake can include the adoption of a Mediterranean diet that is rich in vegetables, fruits, whole grains, nuts, seeds, and fish/olive oil, while limiting simple sugars and red or processed meats. The Mediterranean diet is associated with reduced hepatic steatosis, improved insulin sensitivity, and decreased overall mortality.3
Exercise
Regular physical activity—weekly moderate-intensity (150-300 minutes) or vigorous-intensity (75-150 minutes) aerobic exercise—can decrease hepatic steatosis by improving insulin sensitivity, even in the absence of weight loss. Resistance training should be complementary to aerobic exercise, not a replacement, except for patients with poor cardiorespiratory fitness and those who cannot participate in aerobic exercise. When weight loss is the goal, more intense (or vigorous) exercise is superior to minimal or low-intensity exercise.3,22,23
Bariatric Surgery and MASLD
Bariatric surgery is an important tool to assist in meeting weight loss goals and should be considered appropriate for patients with significant fibrosis, obesity, and/or other comorbidities.2,4 The option of receiving bariatric surgery should be offered to patients with a BMI ≥35 kg/m2 without regard to comorbidities and to patients with a BMI 30-34.9 kg/m2 who have metabolic comorbidities. In patients with Asian ethnicity, BMI thresholds should be adjusted, such that a BMI ≥25 kg/m2 indicates the presence of clinical obesity and surgery is offered when BMI exceeds 27.5 kg/m2.24 Sleeve gastrectomy or Roux-en-Y gastric bypass are equally effective options.25 Although several studies demonstrated improvement in MASLD/MASH histology after bariatric surgery, patients who do not experience a reversal of their disease are less likely to see improvement in their fibrosis; by contrast, MASH resolution and fibrosis decrease at 1 year continued at 5 years.26,27
A recent observational study (BRAVES) evaluated patients with obesity and MASH, with or without T2D, who received lifestyle modifications plus best medical care or bariatric surgery. This study demonstrated that 70% of patients who received Roux-en-Y or sleeve gastrectomy saw resolution of MASH without worsening of fibrosis at 1 year post intervention.27
Screening for MASLD/MASH
Screening for MASLD/MASH should occur in the primary care setting, ensuring timely and evidence-based diagnosis. First, HCPs should identify those who are at risk, whether they have T2D, ≥2 metabolic risk factors, or proof of steatosis on imaging. The next step is to understand patients’ complete medical history and order laboratory tests to confirm liver function and blood count. The clinical pathway for screening at-risk patients also indicates that fibrosis should be assessed through noninvasive modalities. These can include serum-based tests, such as FIB-4, and imaging, such as elastography.2
MASLD/MASH Management by Fibrosis Stage
Once fibrosis stage has been confirmed, patients then can be classified as those who are at low, intermediate, or high risk for liver-related complications. Lifestyle interventions, including weight loss, are indicated for all at-risk groups. Among intermediate- and high-risk populations, a greater emphasis is placed on pharmacotherapy that is aimed at diabetes management and/or weight loss, particularly involving GLP-1 RAs and pioglitazone.2
Summary
In summary, assessing the presence and severity of liver fibrosis and cirrhosis is key when assessing the risk patients may have of liver-related MASLD/MASH complications. It is imperative for HCPs to intervene early in this process to prevent the development or progression of fibrosis. Furthermore, if caught earlier, you have the chance to promote regression of any fibrosis that has developed.
A holistic management approach is necessary, and every patient with MASLD/MASH should be counseled on and supported in maintaining lifestyle modifications with a goal of weight loss. HCPs should prescribe pharmacotherapy to those who are at intermediate and high risk. Finally, HCPs also should look forward to emerging therapies and guidance as the treatment landscape for MASLD/MASH rapidly evolves.
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