What are the considerations for using Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors in patients with cirrhosis?

SGLT2 Inhibitors in Cirrhotic Patients

SGLT2 inhibitors can be safely used in patients with compensated cirrhosis (Child-Pugh class A and B) and should be strongly considered for those with concurrent type 2 diabetes, but must be avoided in decompensated cirrhosis due to significant risks of hemodynamic instability and acute kidney injury. 1

Patient Selection Algorithm by Cirrhosis Severity

Compensated Cirrhosis (Child-Pugh A)

• SGLT2 inhibitors are appropriate and safe for patients with Child-Pugh class A cirrhosis, particularly when diabetes management is needed beyond metformin 1
• These patients demonstrate the strongest safety profile with evidence supporting both glycemic control and potential hepatic benefits 2
• No dose adjustment is required for compensated cirrhosis, though baseline eGFR must be ≥30 mL/min/1.73 m² 3

Child-Pugh Class B Cirrhosis

• SGLT2 inhibitors can be used with appropriate monitoring in Child-Pugh B cirrhosis based on emerging evidence 1, 2
• A 48-month cohort study demonstrated significant improvements in renal function (GFR increased by +13.5 mL/min/1.73 m²), liver stiffness reduction (-4.0 kPa by transient elastography), and improved MELD-Na and CTP scores in Child-Pugh B patients receiving SGLT2 inhibitors compared to insulin 2
• Monitor closely for volume depletion and acute kidney injury, as these patients have reduced physiologic reserve 3

Decompensated Cirrhosis (Child-Pugh C)

• Avoid SGLT2 inhibitors entirely in decompensated cirrhosis due to unacceptable risks 1
• The osmotic diuresis induced by SGLT2 inhibitors can precipitate hemodynamic instability, acute kidney injury, and hepatorenal syndrome in patients with already compromised circulatory function 3, 4
• If diabetes management is required, insulin is the preferred agent for glycemic control in decompensated cirrhosis 1

Specific Clinical Benefits Beyond Glycemic Control

Ascites Management

• All studies of decompensated cirrhosis (n=11) reported ascites reduction with SGLT2 inhibitor use, with particularly robust evidence in refractory ascites 4
• The mechanism involves natriuresis and osmotic diuresis without activating the renin-angiotensin-aldosterone system, unlike traditional loop diuretics 5
• Eight studies specifically focused on refractory ascites demonstrated consistent benefit 4

Disease Progression

• Seven of nine studies showed SGLT2 inhibitors slowed cirrhosis progression by reducing clinical decompensation events (n=4 studies) or improving laboratory markers (n=3 studies) 4
• A Veterans Affairs cohort study of 846 patients demonstrated reduced mortality risk (adjusted HR 0.33,95% CI 0.11-0.99) in SGLT2 inhibitor users compared to DPP-4 inhibitor users 6
• Liver stiffness measured by ARFI-SWV declined significantly in SGLT2 inhibitor users (2.5 m/s) versus increased in insulin users (3.2 m/s) over 48 months 2

Renal Protection

• GFR improved by +13.5 mL/min/1.73 m² in SGLT2 inhibitor users versus declined by -4.2 mL/min/1.73 m² in insulin users over 48 months in Child-Pugh B cirrhosis 2
• A greater proportion of patients transitioned from CKD stage 3a to stage 2 with SGLT2 inhibitor therapy 2
• This renal benefit is particularly important given that MASLD-related cirrhosis significantly increases CKD risk 2

Critical Safety Considerations and Monitoring

Volume Status and Hemodynamic Monitoring

• Assess for hypovolemia before initiation as SGLT2 inhibitors cause intravascular volume contraction through osmotic diuresis 3
• Patients with ascites, concurrent diuretic use, or baseline hypotension require particularly careful evaluation 3
• Consider temporarily reducing thiazide or loop diuretic doses when initiating SGLT2 inhibitors to avoid excessive volume depletion 7

Renal Function Surveillance

• Evaluate eGFR prior to initiation and monitor periodically, with more frequent monitoring when eGFR <60 mL/min/1.73 m² 3
• SGLT2 inhibitors are contraindicated when eGFR <30 mL/min/1.73 m² and not recommended when eGFR is persistently <45 mL/min/1.73 m² 3
• Expect an initial "eGFR dip" of 3-5 mL/min/1.73 m² that typically returns to baseline within weeks 7
• Temporarily discontinue during acute illness, prolonged fasting, or surgery to prevent acute kidney injury 3

Diabetic Ketoacidosis Risk

• Educate patients that diabetic ketoacidosis can occur even with normal glucose levels (150-250 mg/dL, "euglycemic DKA") 7, 3
• Risk factors include insulin dose reduction, acute illness, reduced caloric intake, pancreatic disorders, and alcohol abuse 3
• Discontinue SGLT2 inhibitors 3 days before elective procedures (4 days for ertugliflozin) 7
• Instruct patients to seek immediate medical attention for nausea, vomiting, abdominal pain, or malaise 7

Infection Surveillance

• Monitor for genital mycotic infections, which occur more frequently in patients with history of chronic or recurrent infections 3
• Two of five studies reported increased infection risk with SGLT2 inhibitor use in cirrhosis 4
• Serious urinary tract infections including urosepsis and pyelonephritis have been reported postmarketing 3

Comparative Medication Selection in Cirrhotic Patients with Diabetes

When to Choose SGLT2 Inhibitors Over Alternatives

• Prioritize SGLT2 inhibitors in Child-Pugh A or B cirrhosis when cardiovascular disease, heart failure, or CKD (eGFR 30-60 mL/min/1.73 m²) coexist 7
• SGLT2 inhibitors demonstrated superior mortality reduction compared to DPP-4 inhibitors in cirrhotic veterans (HR 0.33) 6
• Consider SGLT2 inhibitors first-line when refractory ascites is present, given consistent evidence of ascites reduction across all studies 4

GLP-1 Receptor Agonists as Alternative

• GLP-1 receptor agonists can be used only in Child-Pugh class A cirrhosis according to American Diabetes Association recommendations 1
• Use GLP-1 RAs when SGLT2 inhibitors are contraindicated due to eGFR <30 mL/min/1.73 m² or not tolerated 7
• GLP-1 RAs offer substantial weight loss benefit, which may be advantageous in MASLD-related cirrhosis 7

Metformin Considerations

• Metformin can be used in compensated cirrhosis with preserved renal function but must be discontinued immediately if decompensation occurs or GFR falls below 30 mL/min/1.73 m² 1
• The risk of lactic acidosis is significantly higher in decompensated cirrhosis with concurrent renal impairment 1

Medications to Avoid

• Sulfonylureas should be avoided in hepatic decompensation due to increased hypoglycemia risk from impaired hepatic metabolism 1
• Insulin remains the safest option for decompensated cirrhosis when SGLT2 inhibitors and GLP-1 RAs are contraindicated 1

Common Pitfalls and How to Avoid Them

Pitfall 1: Using SGLT2 Inhibitors in Decompensated Cirrhosis

• Never initiate SGLT2 inhibitors in Child-Pugh C cirrhosis despite emerging data on ascites benefit, as safety concerns outweigh potential benefits 1
• The minority of studies (2 of 9) showing hemodynamic instability and AKI occurred predominantly in decompensated patients 4

Pitfall 2: Failing to Discontinue During Acute Illness

• Always discontinue SGLT2 inhibitors during acute illness, reduced oral intake, or excessive fluid losses to prevent acute kidney injury 3
• This includes gastrointestinal illness, febrile illness, or prolonged fasting for any reason 3

Pitfall 3: Inadequate Patient Education on Euglycemic DKA

• Explicitly warn patients that DKA symptoms can occur with normal glucose readings, as this is counterintuitive and may delay care-seeking 7, 3
• Provide written instructions on when to seek emergency care 7

Pitfall 4: Avoiding SGLT2 Inhibitors in Compensated Cirrhosis Due to Liver Concerns

• Do not withhold SGLT2 inhibitors from Child-Pugh A or B patients with appropriate indications based on unfounded concerns about hepatotoxicity 1, 2
• Evidence demonstrates safety and potential hepatic benefit in compensated cirrhosis 2, 8

Pitfall 5: Ignoring Baseline Cardiovascular and Renal Comorbidities

• Recognize that SGLT2 inhibitors provide cardiovascular and renal benefits independent of glycemic control, making them particularly valuable in cirrhotic patients with these comorbidities 7, 2
• The 2022 KDIGO guidelines recommend SGLT2 inhibitors for all patients with eGFR >20 mL/min/1.73 m² independent of albuminuria presence 7

Specific Agent Selection

While class effects are generally consistent, canagliflozin should be avoided in patients with prior amputation, severe peripheral arterial disease, neuropathy, diabetic foot ulcers, or osteoporosis due to increased amputation and fracture risk observed in one trial 7. Empagliflozin and dapagliflozin have more favorable safety profiles in these populations 7.