SGLT2 Inhibitors in Cirrhosis with HFmrEF on Diuretics
SGLT2 inhibitors (dapagliflozin or empagliflozin) should be initiated in patients with cirrhosis and HFmrEF who are on diuretics, as they reduce heart failure hospitalizations and cardiovascular mortality while potentially offering liver-protective benefits. 1, 2
Guideline-Directed Recommendations for HFmrEF
SGLT2 inhibitors have a Class 2a recommendation (moderate strength) for patients with HFmrEF (LVEF 41-49%), indicating they can be beneficial in decreasing HF hospitalizations and cardiovascular mortality. 1 This recommendation applies regardless of diabetes status and is supported by the DELIVER trial showing a 21% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization. 3
The 2024 ESC guidelines for chronic coronary syndromes further reinforce that SGLT2 inhibitors (dapagliflozin or empagliflozin) are recommended in patients with HFmrEF to reduce the risk of HF hospitalization or cardiovascular death. 1
Specific Considerations in Cirrhosis
Emerging Evidence for Liver Protection
Recent cohort data from 10,660 propensity-matched patients with cirrhosis receiving furosemide and spironolactone demonstrated that adding SGLT2 inhibitors was associated with a 32% reduction in serious liver events (HR 0.68,95% CI 0.66-0.71). 2 This included:
- 53% reduction in hepatorenal syndrome (HR 0.47) 2
- 45% reduction in spontaneous bacterial peritonitis (HR 0.55) 2
- 46% reduction in need for paracentesis (HR 0.54) 2
- 33% reduction in all-cause hospitalizations (HR 0.67) 2
Diuretic Interactions and Volume Management
Diuretics are recommended in patients with HFmrEF who have signs or symptoms of fluid congestion to improve symptoms. 1 In cirrhotic patients already on furosemide and spironolactone, SGLT2 inhibitors provide complementary natriuretic effects through a different mechanism—blocking sodium-glucose reabsorption in the proximal tubule rather than acting on the loop of Henle or distal tubule. 4
SGLT2 inhibitors increase urinary volume and sodium excretion, which may enhance diuretic efficacy without significantly increasing hypotension risk. 4, 5 A meta-analysis of 10,050 HFrEF patients found no clinically significant increase in hypotension (RR 1.09,95% CI 0.91-1.31, p=0.36) or volume depletion (RR 1.07,95% CI 0.95-1.21, p=0.25) with SGLT2 inhibitors. 5
Safety Profile in This Population
Renal Function Monitoring
SGLT2 inhibitors actually reduce the risk of acute kidney injury by 31% (RR 0.69,95% CI 0.51-0.93) in heart failure populations. 5 This is particularly relevant in cirrhosis where hepatorenal syndrome is a major concern.
Dapagliflozin can be initiated in patients with eGFR as low as 25 mL/min/1.73 m² for heart failure indications, and patients do not need to discontinue if eGFR falls below this threshold after initiation. 4 However, regular monitoring of renal function is recommended when initiating SGLT2 inhibitors. 3
Hypotension and Volume Status
Despite concerns about hypotension in cirrhotic patients on multiple diuretics, SGLT2 inhibitors do not significantly increase this risk. 5 The fragility analysis showed robust findings (RFI of 21) for the lack of increased hypotension risk. 5
Volume status should be assessed regularly in patients with HFmrEF taking SGLT2 inhibitors due to their diuretic effects. 3 In cirrhotic patients with ascites, this means monitoring for:
- Clinical signs of volume depletion (orthostatic hypotension, decreased skin turgor)
- Electrolyte abnormalities (particularly hyponatremia, which was actually reduced in the cirrhosis cohort) 2
- Worsening renal function
Hepatic Impairment
No dose adjustment is required for dapagliflozin in patients with mild, moderate, or severe hepatic impairment, though the benefit-risk should be individually assessed in severe hepatic impairment. 4 This FDA labeling provides reassurance for use in cirrhotic patients.
Practical Implementation Algorithm
Step 1: Confirm Eligibility
- LVEF 41-49% (HFmrEF) 1
- eGFR ≥25 mL/min/1.73 m² (not on dialysis) 4
- No type 1 diabetes mellitus 3, 4
- Not polycystic kidney disease or recent immunosuppressive therapy for kidney disease 4
Step 2: Optimize Baseline Therapy
Continue furosemide and spironolactone for volume management in cirrhosis. 1, 2 The evidence specifically supports adding SGLT2 inhibitors to this regimen rather than replacing it. 2
Consider adding or optimizing ACE inhibitors/ARBs (Class 2b), beta-blockers (Class 2b), or MRAs (Class 2b) for HFmrEF, particularly in patients with LVEF on the lower end of the spectrum. 1
Step 3: Initiate SGLT2 Inhibitor
Start dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily. 1 These are the two agents with the strongest evidence in HFmrEF. 1
Step 4: Monitor
- Renal function and electrolytes within 1-2 weeks of initiation 3
- Volume status and blood pressure at each visit 3
- Symptoms of diabetic ketoacidosis if patient has diabetes (though risk is low in type 2 diabetes) 3
Common Pitfalls to Avoid
Do not withhold SGLT2 inhibitors due to concerns about "too many diuretics." The mechanism of action differs from loop and potassium-sparing diuretics, and the combination appears safe and potentially synergistic in cirrhosis. 2
Do not discontinue SGLT2 inhibitors if eGFR declines modestly after initiation. Small initial decreases in eGFR are expected and do not require discontinuation unless eGFR falls below 25 mL/min/1.73 m² or dialysis is initiated. 4
Do not assume SGLT2 inhibitors are contraindicated in hepatic impairment. The FDA label explicitly states no dose adjustment is needed, and emerging evidence suggests potential liver-protective effects. 4, 2
Do not delay initiation waiting for "optimization" of other therapies. Current guidelines support early initiation of SGLT2 inhibitors as foundational therapy alongside other guideline-directed medical therapy. 3
Discontinuation Rates
Real-world data shows discontinuation rates of 13.1% at 6 months and 20.0% at 12 months in HFrEF populations. 6 This relatively low discontinuation rate supports the tolerability of SGLT2 inhibitors even in complex patients on multiple medications.