Metabolic%20dysfunction-associated%20steatotic%20liver%20disease Treatment

• Essential principle of MASLD therapy is to treat the underlying cause   
• Patients should be assessed for other components of metabolic syndrome and treated accordingly 
  • Patients with metabolic syndrome (eg dyslipidemia, hypertension and DM) should be identified early and treated accordingly to reduce the risk for CVD and kidney disease 
• Pharmacologic treatments for MASLD/MASH are targeted at underlying metabolic syndrome-related diseases such as obesity, T2DM, dyslipidemia and hypertension as well as liver dysfunction itself   
  • Pharmacological therapy is aimed at reducing intrahepatic fat, stimulating metabolic processes, improving liver damage, maintaining low circulating lipid and glucose levels, and preventing CV events  
• Pharmacological therapy is indicated in patients with biopsy-proven progressive MASH and in those in early stage of MASH with increased risk of progressing to fibrosis (age >50 years, diabetes, metabolic syndrome, increased ALT or active MASH with high necroinflammatory activity)   

Goals of Therapy 

• Reduce steatosis and liver injury 
• Improve metabolic sequelae and CV risk closely associated to MASLD   
  • Improve insulin resistance and liver enzyme levels and improve histologic features

Antihypertensives

Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin II Receptor Antagonists (ARBs)    

• Preferred first-line antihypertensive therapy for MASLD patients    
• Inhibit fibroblast activity resulting in inhibition of tissue fibrosis in several organs

Antioxidants, Cytoprotective and Lipid-lowering Agents

Aspirin   

• Recommended in patients with atherosclerosis    
• Has been shown to prevent CV events and reduce risk of hepatic fibrosis 

Ezetimibe and HMG-CoA Reductase Inhibitors (Statins)   

• May be used in patients with MASLD/MASH and hypercholesterolemia to prevent CV risk 
• In patients already taking statins, it is advised to continue with the medication and only consider stopping when liver enzyme levels double within 3 months of starting statins
• Associated with survival benefit in post-liver transplant and is therefore recommended in patients with dyslipidemia and/or pre-existing CVD
• Avoid giving statins in patients with decompensated cirrhosis   

Vitamin E   

• A free radical scavenger and a chain-breaking antioxidant in free radical reactions such as lipid peroxidation
• Has been shown to be effective in improving liver histology in patients with steatohepatitis    
• Studies have shown improvement in hepatic biological and histological parameters in non-diabetic patients with biopsy-proven MASH  
• Further studies are needed for Vitamin E to be used in cirrhotic or diabetic MASH patients

Insulin Sensitizers

Dipeptidyl Peptidase-4 Inhibitors (DPP-4i) 

• Eg Alogliptin, Linagliptin, Sitagliptin, Vildagliptin
• A single arm, multicenter, non-randomized study has shown that Alogliptin is a potential new therapeutic strategy for the prevention of MASLD progression in patients with T2DM
• Further studies are needed to conclude the beneficial effects of DPP4i therapy on hepatic enzymes to prevent disease progression in MASLD patients with T2DM 

Glucagon-like Peptide-1 Analogues (GLP-1a)   

• Eg Liraglutide, Semaglutide   
• Act on glucose-insulin interplay and have shown favorable results in pre-marketing studies on liver enzymes   
• May be used in MASLD patients with DM and/or obesity 
• Reduces body weight 
• Showed benefits in CV outcomes in patients with T2DM   
• Tirzepatide, which is a dual GLP-1a and glucose-dependent insulinotropic polypeptide (GIP), may have beneficial effects on hepatic fat content and visceral and abdominal subcutaneous adipose tissue volume    

Metformin  

• Has been shown to improve metabolic parameters and may be used in MASLD patients with DM 

Sodium Glucose Linked Transporter/Co-Transporter 2 (SGLT2) Inhibitors    

• Eg Empagliflozin   
• May be used in MASLD patients with DM   
• Has been shown to improve metabolic syndrome and CV outcomes and may be used for the treatment of steatohepatitis    

Thiazolidinediones  

• Eg Pioglitazone   
• Peroxisome proliferator-activated receptor agonists with insulin-sensitizing effects   
• Recommended for patients with insulin resistance
• In steatohepatitis patients with prediabetes or T2DM, Pioglitazone has been shown to improve hepatic steatosis, ballooning necrosis, inflammation and hepatic fibrosis
• It was shown in clinical trials that Pioglitazone improves liver histology in patients with biopsy-proven MASH with and without T2DM
• Main side effects of Pioglitazone are weight gain, bone fractures in women, and rarely congestive heart failure (CHF) 

Other Agents

Obeticholic Acid

• Studies show improvement of fibrosis with Obeticholic acid in MASH   

Omega-3 Fatty Acids

• May be considered in patients with MASLD for the treatment of hypertriglyceridemia

Pentoxifylline   

• Recommended in patients with MASH 
• Considered to have both antioxidant and anti-TNF alpha effects
• Has been found to improve lobular inflammation without affecting lipid profiles but has no significant effect on steatosis, ballooning or fibrosis  

Saroglitazar

• Peroxisome proliferator-activated receptor α/γ dual agonist approved in India for non-cirrhotic MASH