What is the role of gliflozins (sodium-glucose cotransporter 2 inhibitors) in managing refractory ascites?

Role of Gliflozins in Refractory Ascites

Sodium-glucose cotransporter 2 inhibitors (gliflozins) are not currently recommended as standard therapy for refractory ascites in cirrhosis, as there is insufficient evidence from high-quality clinical trials to support their routine use.

Definition and Management of Refractory Ascites

Refractory ascites is defined as ascites that:

• Cannot be mobilized or recurs early despite sodium restriction and maximum diuretic therapy (spironolactone 400 mg/day and furosemide 160 mg/day)
• OR cannot be treated with diuretics due to development of complications 1

The standard management options for refractory ascites include:

1. Large-volume paracentesis (LVP) with albumin replacement

   • First-line therapy for most patients
   • Requires albumin administration (6-8 g per liter of ascites removed) 1
   • Provides rapid symptomatic relief but does not address underlying pathophysiology

2. Transjugular intrahepatic portosystemic shunt (TIPS)

   • Effective for controlling ascites but associated with 30-50% risk of hepatic encephalopathy 1
   • Should be considered in patients who repeatedly fail LVP and have relatively preserved liver function 1

3. Liver transplantation

   • Definitive treatment that should be considered for all eligible patients with refractory ascites 1
   • The development of refractory ascites indicates poor prognosis with median survival of approximately 6 months 1

Emerging Evidence for Gliflozins

Recent research suggests potential for SGLT2 inhibitors (gliflozins) in the management of refractory ascites:

• A 2024 study demonstrated that empagliflozin 10 mg daily was safe and tolerable in patients with advanced chronic liver disease, including those with decompensated cirrhosis 2
• The mechanisms by which gliflozins might reduce ascites include:
  • Natriuresis and osmotic diuresis
  • Improvement in glucose metabolism
  • Hepatoprotection via ketone bodies
  • Inhibition of the renin-angiotensin-aldosterone system 3

However, these findings are preliminary, and there are currently no large randomized controlled trials demonstrating efficacy and safety of gliflozins specifically for refractory ascites.

Adjunctive Medical Therapies

Current guidelines suggest limited options for adjunctive medical therapy in refractory ascites:

• Midodrine: An α-adrenergic agonist that may be considered on a case-by-case basis 1

  • Small studies show improved ascites control (94% vs 50%) with midodrine 7.5 mg three times daily compared to standard therapy
  • May increase mean arterial pressure and urine sodium excretion

• Discontinuation of certain medications:

  • NSBBs may need to be discontinued in patients with refractory ascites 1
  • NSAIDs, ACE inhibitors, and angiotensin receptor blockers should be avoided 1

Clinical Approach to Refractory Ascites

1. Confirm diagnosis:

   • Ensure patient has been on maximum diuretic therapy (spironolactone 400 mg/day and furosemide 160 mg/day) for at least one week
   • Verify compliance with sodium restriction (<88-90 mmol/day)
   • Rule out other causes of ascites (malignancy, infection)

2. Immediate management:

   • LVP with albumin replacement (6-8 g per liter removed)
   • Consider discontinuing diuretics unless urinary sodium excretion exceeds 30 mmol/day 1

3. Long-term strategy:

   • Refer for liver transplantation evaluation
   • Consider TIPS in appropriate candidates
   • Schedule regular LVP as needed

4. Experimental options:

   • Gliflozins may be considered in the context of clinical trials or when other options have failed
   • Current evidence is insufficient to recommend routine use

Conclusion

While emerging research on gliflozins shows promise for the management of refractory ascites in cirrhosis, current guidelines do not include these medications as standard therapy. The mainstays of treatment remain LVP with albumin replacement, TIPS in selected patients, and liver transplantation when feasible. Clinicians should prioritize these established approaches while awaiting results from larger clinical trials on the efficacy and safety of gliflozins in this setting.