Can dapagliflozin (Forxiga) be used in patients with cirrhosis of the liver?

Dapagliflozin Use in Cirrhosis

Dapagliflozin can be used in patients with Child-Pugh class A and B cirrhosis according to the most recent EASL-EASD-EASO guidelines, but should be avoided in Child-Pugh class C cirrhosis and requires careful monitoring for acute kidney injury and infections. 1

Guideline-Based Recommendations by Cirrhosis Severity

Child-Pugh Class A (Compensated Cirrhosis)

• Dapagliflozin is safe and can be used without dose adjustment in patients with Child-Pugh class A cirrhosis 1
• The 2024 EASL-EASD-EASO guidelines specifically list SGLT2 inhibitors (including dapagliflozin) as preferred pharmacological options for treating type 2 diabetes in patients with MASLD and compensated cirrhosis 1
• No dose adjustment is required based on hepatic impairment alone in this population 2

Child-Pugh Class B (Decompensated Cirrhosis)

• Dapagliflozin can be used with caution in Child-Pugh class B cirrhosis according to EASL guidelines 1
• This represents a weak recommendation with consensus-level evidence, indicating the need for close monitoring 1
• Consider starting with a lower dose (5 mg daily) in this population, particularly if ascites is present 3

Child-Pugh Class C (Advanced Decompensated Cirrhosis)

• Dapagliflozin should be avoided in Child-Pugh class C cirrhosis 1
• Insulin therapy is the preferred glucose-lowering agent in this population 1
• The FDA label notes that safety and efficacy have not been specifically studied in severe hepatic impairment, and benefit-risk should be individually assessed 2

Renal Function Considerations

Renal function is critical when prescribing dapagliflozin in cirrhosis, as these patients are at higher risk for volume depletion and acute kidney injury:

• eGFR ≥45 mL/min/1.73 m²: No dose adjustment needed for glycemic control 2
• eGFR 30-44 mL/min/1.73 m²: Use is not recommended for glycemic control in patients without established cardiovascular disease or risk factors 2
• eGFR 25-29 mL/min/1.73 m²: Can be continued if already established for heart failure or CKD indications, but should not be initiated for glycemic control 2
• eGFR <25 mL/min/1.73 m² or dialysis: Efficacy and safety not established 2

Evidence from Recent Clinical Studies

Safety Profile in Cirrhosis

Recent research demonstrates both promise and significant safety concerns:

• A 2024 pilot study (n=40) showed dapagliflozin improved ascites control and increased natriuresis, but was associated with significantly higher rates of acute kidney injury (50% vs 15%, p=0.04) and infections (55% vs 20%, p=0.04) compared to placebo 4
• A separate 2024 study (n=200) found dapagliflozin was safe and effective in diabetic patients with cirrhosis, with lower rates of hypoglycemia, hepatic encephalopathy, and variceal bleeding compared to insulin 3
• A 2024 study of empagliflozin (another SGLT2 inhibitor) in advanced chronic liver disease showed 30% experienced serious adverse events, with one attributed to the drug 5

Potential Benefits Beyond Glycemic Control

• Ascites management: Dapagliflozin demonstrated better control of ascites at 6 months compared to placebo, with reduced need for diuretic dose escalation 3, 4
• Weight reduction: Significant decreases in weight and BMI were observed compared to insulin therapy 3
• Natriuresis: 24-hour urinary sodium excretion increased significantly with dapagliflozin treatment 4

Critical Safety Warnings and Monitoring

Acute Kidney Injury Risk

• Patients with cirrhosis and renal impairment using dapagliflozin are at higher risk for acute kidney injury secondary to volume depletion 2
• Monitor serum creatinine and eGFR before initiation and periodically during treatment 2
• The risk is particularly elevated in patients with ascites who are already on diuretics 4

Hepatotoxicity Concerns

• A 2016 case report documented acute-on-chronic liver injury in a patient with Child's Class A cirrhosis who started dapagliflozin, presenting with jaundice and acute cholestatic liver injury 6
• This raises awareness about potential hepatotoxic effects, particularly in patients with pre-existing chronic liver disease 6
• Monitor liver function tests at baseline and during treatment, especially in the first 3 months 7

Infection Risk

• Urinary tract infections and genital mycotic infections are more common with SGLT2 inhibitors due to increased urinary glucose excretion 2
• The infection rate was significantly higher (55% vs 20%) in cirrhotic patients receiving dapagliflozin compared to standard therapy 4
• Patients with cirrhosis may have impaired immune function, further increasing infection susceptibility 4

Volume Depletion and Hypotension

• Dapagliflozin increases urinary volume and can cause symptomatic hypotension, particularly in elderly patients (≥65 years) 2
• Patients with cirrhosis often have baseline hypotension and are on diuretics, compounding this risk 4
• Assess volume status before initiating therapy and monitor for orthostatic hypotension 2

Practical Dosing Algorithm

For Child-Pugh Class A:

• Start with dapagliflozin 10 mg once daily 3
• Ensure eGFR ≥45 mL/min/1.73 m² for glycemic control indication 2
• Monitor renal function, liver enzymes, and volume status monthly for first 3 months 7

For Child-Pugh Class B:

• Consider starting with dapagliflozin 5 mg once daily, particularly if ascites present 3
• Ensure eGFR ≥30 mL/min/1.73 m² 2
• Monitor renal function and liver enzymes every 2 weeks for first month, then monthly 7
• Assess for signs of infection, volume depletion, and worsening ascites at each visit 4

For Child-Pugh Class C:

• Do not use dapagliflozin 1
• Use insulin as first-line glucose-lowering therapy 1

Common Pitfalls to Avoid

• Do not ignore renal function: Always check eGFR before prescribing and monitor regularly, as cirrhotic patients are at high risk for AKI 2, 4
• Do not use in decompensated cirrhosis with renal impairment: The combination of hepatic and renal dysfunction significantly increases risk 2
• Do not overlook infection risk: Educate patients about signs of urinary tract infections and genital mycotic infections, which occur more frequently 4
• Do not assume all SGLT2 inhibitors are equivalent: While class effects exist, specific safety data in cirrhosis is limited primarily to dapagliflozin and empagliflozin 5, 3, 4
• Do not use as monotherapy in severe disease: In Child-Pugh B cirrhosis, consider combination with insulin if glycemic control is inadequate 1

Alternative Glucose-Lowering Agents in Cirrhosis

When dapagliflozin is contraindicated or not tolerated:

• Metformin: Can be used in compensated cirrhosis with eGFR >30 mL/min, but contraindicated in decompensated cirrhosis due to lactic acidosis risk 1, 8
• GLP-1 receptor agonists (semaglutide, liraglutide): Safe in Child-Pugh class A cirrhosis, but should be avoided in decompensated cirrhosis 1, 8
• Insulin: Preferred agent in decompensated cirrhosis, though requires careful monitoring to avoid hypoglycemia 1
• Sulfonylureas: Should be avoided in hepatic decompensation due to hypoglycemia risk 1, 8