CMHC Pulse Blog

In Part 1, we explored the foundational elements of MASH management, including lifestyle modifications and initial assessments. In this post, we’ll focus on pharmacotherapy, emerging strategies, and practical treatments for managing MASH in patients with cardiometabolic conditions. 

Pharmacotherapy for Cardiometabolic and Liver Health 

Medications that target both metabolic and liver health are critical for managing MASH. Healthcare professionals should consider pharmacotherapy options that address T2D, obesity, and liver disease: 

1. Statins: Statins are first-line therapies for managing dyslipidemia and reducing cardiovascular risk in patients with MASH. Despite concerns about elevated liver enzymes, statins are generally safe and should not be discontinued unless liver failure is evident. Since cardiovascular disease is a leading cause of death among MASH patients, statin therapy is critical for long-term management. 

2. GLP-1 Receptor Agonists: Drugs like semaglutide are highly effective for glycemic control, weight loss, and liver fat reduction. In MASH patients, semaglutide has been shown to reduce liver inflammation and potentially reverse fibrosis. GLP-1 receptor agonists not only improve metabolic outcomes but also provide cardiovascular and renal benefits, making them a cornerstone of comprehensive MASH treatment. 

3. Tirzepatide (Dual GLP-1 and GIP Agonist): Tirzepatide is a dual agonist that activates both GLP-1 and GIP receptors, resulting in greater weight loss than GLP-1 agonists alone. It significantly reduces liver fat content and improves glycemic control and insulin sensitivity. This dual action makes tirzepatide a promising option for treating MASH in patients with T2D and obesity. 

4. Thiazolidinediones (TZDs): Pioglitazone, a PPAR gamma activator, is well-studied for its effectiveness in reducing liver inflammation and fibrosis in patients with MASH and T2D. While pioglitazone can cause weight gain, combining it with a GLP-1 receptor agonist helps mitigate this effect. Long-term use of pioglitazone has shown significant improvements in liver health, including reduced steatosis, inflammation, and fibrosis. 

New Developments: Resmetirom 

Resmetirom is an FDA-approved thyroid hormone receptor beta agonist and the first drug specifically designed to treat MASH with fibrosis (F2 and F3). It decreases liver fat, improves mitochondrial function, and reduces inflammation and fibrosis. Unlike previous treatment options, resmetirom does not require invasive liver biopsies for diagnosis, making it more accessible to patients. 

Consider Bariatric Surgery for Early Intervention 

Bariatric surgery offers significant benefits for patients with obesity and MASH, especially if considered early in the disease course. A long-term study shows that one year after surgery, 84% of patients experience MASH resolution without worsening fibrosis, and at five years, fibrosis regresses in 70% of patients by at least one stage. Despite these positive outcomes, bariatric surgery is often underutilized and should be considered earlier in the treatment process for eligible patients. 

Looking Ahead: Emerging Therapies 

Several promising therapies are in late-stage clinical trials for MASH treatment, including: 

1. Retatrutide (Dual Incretin Agonist): Retatrutide targets GLP-1, GIP, and glucagon receptors, showing significant results in reducing liver fat content. In clinical trials, over 90% of patients achieved MASH resolution after 48 weeks of treatment. 

2. Lanifibranor (Pan-PPAR Agonist): Lanifibranor activates PPAR-alpha, -gamma, and -delta receptors, which regulate lipid metabolism and reduce liver inflammation and fibrosis. It is currently in a Phase 3 trial, with promising results in improving both liver and metabolic health. 

3. FGF21 Analogs: These agents mimic the fibroblast growth factor 21 hormone, which plays a key role in glucose and lipid metabolism. FGF21 analogs have demonstrated early success in resolving liver inflammation and fibrosis. 

Conclusion: Practical Treatments for Managing MASH 

1. Prioritize Lifestyle Modification: Weight loss and exercise are essential for improving liver and metabolic health. 

2. Leverage Medications with Dual Benefits: GLP-1 agonists, statins, and pioglitazone offer broad benefits for managing both MASH and cardiometabolic risk factors. 

3. Utilize New Therapies: Treatments like resmetirom provide targeted, non-invasive options for managing MASH with fibrosis. 

4. Monitor Cardiovascular Risk: Statin therapy and managing conditions like hypertension and T2D are crucial for reducing the risk of cardiovascular events in MASH patients. 

By integrating liver health into cardiometabolic care, healthcare providers can help patients manage MASH more effectively and reduce their long-term risk of complications.