Are SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors indicated in the management of MAFLD (Metabolic Associated Fatty Liver Disease)?

SGLT2 Inhibitors in MASLD: Current Evidence and Recommendations

SGLT2 inhibitors are not currently recommended as MASLD-targeted therapy due to insufficient evidence from controlled trials with histological endpoints, but they are safe to use in MASLD and should be prescribed for their approved indications (type 2 diabetes, heart failure, chronic kidney disease) given their proven cardiovascular and renal benefits. 1

Primary Indication Status

• There is insufficient evidence to recommend SGLT2 inhibitors as MASH-targeted therapies because controlled clinical trials with liver histological endpoints are currently not available 1
• However, SGLT2 inhibitors should be used for their respective indications—namely type 2 diabetes, heart failure, and chronic kidney disease—as they are safe in MASLD and provide significant cardiometabolic benefits 1

Evidence for Hepatic Effects

The available data on SGLT2 inhibitors in MASLD comes primarily from trials in patients with type 2 diabetes, not specifically designed for liver outcomes:

• Trials with empagliflozin and dapagliflozin have shown moderate reduction in liver lipid content in patients with T2DM (though not all had MASLD and some excluded high ALT values) 1
• Reductions in ALT levels were demonstrated with empagliflozin and licogliflozin 1
• Recent real-world data suggests SGLT2 inhibitors may reduce progression to advanced liver disease and improve long-term survival in MASLD patients, though this requires validation in prospective trials 2

Guideline-Recommended Use in MASLD

The 2024 EASL-EASD-EASO guidelines provide clear direction on when to use SGLT2 inhibitors in MASLD patients:

For Non-Cirrhotic MASLD/MASH (F0-F3):

• SGLT2 inhibitors (empagliflozin, dapagliflozin) are the preferred pharmacological option for treating comorbid type 2 diabetes in patients with MASLD without cirrhosis 1
• This recommendation prioritizes their proven cardiovascular and renal benefits over unproven direct liver effects 1

For Compensated Cirrhosis (F4):

• SGLT2 inhibitors can be used in adults with Child-Pugh class A and B cirrhosis according to their approved indications 1
• They should be continued for cardiovascular and kidney benefit until dialysis or transplantation, even when glucose-lowering effect is minimal at eGFR <45 mL/min/1.73 m² 1

Mechanism and Cardiometabolic Benefits

SGLT2 inhibitors provide multiple benefits relevant to MASLD patients beyond direct liver effects:

• They induce renal glucosuria, weight loss, blood pressure reduction, and protection from major cardiovascular outcomes including heart failure 1
• Weight loss occurs through renal energy loss and reduction in fat mass, with reductions in both visceral and abdominal subcutaneous adipose tissue—key contributors to MASLD pathophysiology 1
• They are approved for chronic kidney disease and heart failure (empagliflozin, dapagliflozin) due to beneficial cardiovascular and renal outcomes 1

Clinical Considerations and Safety

Important safety considerations when using SGLT2 inhibitors in MASLD patients:

• Monitor for diabetic ketoacidosis (DKA), particularly in insulin-deficient patients; discontinue 3-4 days before scheduled surgery, during critical illness, or prolonged fasting 1
• Genital mycotic infections are common; mitigate risk with genital hygiene and avoid in high-risk individuals 1
• Volume depletion can occur; monitor volume status, blood pressure, and kidney function upon initiation, especially when combined with diuretics 1
• Glucose-lowering effect is minimal at eGFR <45 mL/min/1.73 m², but continue for cardiovascular and kidney benefit 1

Comparison with Other Agents

The guidelines clearly prioritize other agents for MASLD-specific treatment:

• GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) and co-agonists (tirzepatide) are the preferred MASH-targeted therapies for patients with comorbid obesity, as they have demonstrated histological benefits 1
• Resmetirom is recommended as MASH-targeted therapy for non-cirrhotic patients with significant fibrosis (≥F2) where locally approved 1
• SGLT2 inhibitors occupy a complementary role focused on managing T2DM and its complications rather than directly targeting liver histology 1

Emerging Evidence

While not yet sufficient to change guideline recommendations, emerging data suggests potential benefits:

• Case-control studies indicate exposure to SGLT2 inhibitors in people with T2DM is associated with reduction in liver-related outcomes 1
• Recent studies show improvements in hepatic steatosis measured by MRI-PDFF and reductions in fibrosis indices over 24 weeks 3
• Large real-world cohorts demonstrate reduced progression to advanced liver disease and improved 10-year survival, though these require validation in randomized controlled trials 2

Practical Algorithm

When encountering a patient with MASLD:

1. Assess for comorbidities: Type 2 diabetes, obesity, cardiovascular disease, chronic kidney disease, heart failure
2. If T2D present without cirrhosis (F0-F3): Use SGLT2 inhibitors as preferred glucose-lowering agent 1
3. If T2D present with compensated cirrhosis (Child-Pugh A or B): SGLT2 inhibitors can be used safely 1
4. If obesity is primary concern: Prioritize GLP-1 RAs or co-agonists for both weight loss and potential liver histological benefit 1
5. Continue SGLT2 inhibitors for cardiovascular/renal protection even when eGFR falls below glucose-lowering threshold 1

The key clinical takeaway: Use SGLT2 inhibitors in MASLD patients when indicated for diabetes, heart failure, or CKD—not as liver-specific therapy—while recognizing they may provide additional hepatic benefits that are currently being investigated.