In a patient with liver cirrhosis and portal hypertension, can DPP‑4 inhibitors (gliptins) be used for glycaemic control, and what dosing and monitoring are required?

DPP-4 Inhibitors (Gliptins) in Cirrhosis with Portal Hypertension

DPP-4 inhibitors can be used cautiously in patients with compensated cirrhosis (Child-Pugh A) and portal hypertension, but require careful dose adjustment based on renal function and should be avoided in decompensated cirrhosis.

Glycemic Control Strategy in Compensated Cirrhosis (Child-Pugh A)

For patients with Child-Pugh class A cirrhosis and portal hypertension, DPP-4 inhibitors represent a reasonable second-line option after metformin, with specific agent selection driven by renal function. 1

Agent Selection Based on Renal Function

• Linagliptin 5 mg once daily is the preferred DPP-4 inhibitor because it requires no dose adjustment regardless of renal function (eGFR ≥15 mL/min/1.73 m²), making it ideal for cirrhotic patients who often have fluctuating renal function. 2

• Sitagliptin requires dose adjustment when eGFR falls below 45 mL/min/1.73 m²: 100 mg daily if eGFR ≥45; 50 mg daily if eGFR 30-44; 25 mg daily if eGFR <30. 2

• Saxagliptin and alogliptin should be avoided in cirrhotic patients with portal hypertension due to increased heart failure hospitalization risk (27% relative increase with saxagliptin in SAVOR-TIMI 53 trial). 1, 2

Contraindications in Decompensated Cirrhosis

DPP-4 inhibitors are not recommended in decompensated cirrhosis (Child-Pugh B or C) or in patients with ascites, as these conditions indicate advanced liver disease with unpredictable drug metabolism and increased risk of complications. 1

Specific Contraindications

• Avoid all DPP-4 inhibitors in patients with refractory ascites because beta-blockers (the cornerstone of portal hypertension management) require careful blood pressure and renal function monitoring, and adding DPP-4 inhibitors complicates management. 1

• Do not use in patients with hepatorenal syndrome or acute kidney injury, as drug accumulation and unpredictable pharmacokinetics pose significant risks. 3

• Avoid in patients with hyponatremia (serum sodium <130 mmol/L), as this indicates advanced hemodynamic derangement and increased risk of spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. 1

Monitoring Requirements

Baseline Assessment

• Measure eGFR, liver function tests (ALT, AST, bilirubin, albumin), and Child-Pugh score before initiating any DPP-4 inhibitor. 1

• Assess for signs of decompensation: ascites, variceal bleeding history, hepatic encephalopathy, and serum sodium levels. 1

Ongoing Monitoring

• Check eGFR every 3-6 months in patients on sitagliptin to ensure appropriate dosing, as renal function can deteriorate in cirrhosis. 2

• Monitor liver function tests monthly if using any DPP-4 inhibitor, though hepatotoxicity is rare with this class. 3

• Assess for hypoglycemia risk if combining with sulfonylureas (reduce sulfonylurea dose by 50% when adding DPP-4 inhibitor). 4

• Monitor blood pressure and renal function closely if patient is on beta-blockers for portal hypertension, as both drug classes can affect hemodynamics. 1

Preferred Alternative Agents

For patients with established cardiovascular disease, heart failure, or chronic kidney disease with albuminuria, SGLT2 inhibitors or GLP-1 receptor agonists are strongly preferred over DPP-4 inhibitors due to proven mortality and cardiovascular benefits. 1, 2

Specific Recommendations by Cirrhosis Stage

• Child-Pugh A (compensated): GLP-1 receptor agonists can be used according to indication; SGLT2 inhibitors can be used if eGFR ≥30 mL/min/1.73 m². 1

• Child-Pugh B: SGLT2 inhibitors can still be used cautiously; GLP-1 receptor agonists may be considered but data are limited. 1

• Child-Pugh C (decompensated): Insulin is the safest option; metformin should not be used due to lactic acidosis risk. 1

Dosing Algorithm

Step 1: Assess Liver Function

• Child-Pugh A → Proceed to Step 2
• Child-Pugh B or C → Use insulin instead; avoid DPP-4 inhibitors 1

Step 2: Assess Renal Function

• eGFR ≥45 mL/min/1.73 m² → Linagliptin 5 mg daily OR sitagliptin 100 mg daily 2
• eGFR 30-44 mL/min/1.73 m² → Linagliptin 5 mg daily (preferred) OR sitagliptin 50 mg daily 2
• eGFR <30 mL/min/1.73 m² → Linagliptin 5 mg daily (only option) 2

Step 3: Assess for Decompensation

• Ascites present → Do not use DPP-4 inhibitors 1
• Sodium <130 mmol/L → Do not use DPP-4 inhibitors 1
• History of hepatorenal syndrome → Do not use DPP-4 inhibitors 3

Step 4: Cardiovascular Risk Assessment

• Established ASCVD, HF, or CKD with albuminuria → Prefer SGLT2 inhibitor or GLP-1 RA over DPP-4 inhibitor 1, 2

Important Clinical Caveats

• Drug metabolism is unpredictable in cirrhosis, even for drugs sharing the same metabolic pathway, so empirical dose adjustments and close monitoring are essential. 3

• Linagliptin reduced portal pressure by 19.3% in experimental portal hypertension models but showed no significant effect in cirrhotic rats, suggesting limited direct benefit on portal hemodynamics in established cirrhosis. 5

• ACE inhibitors and ARBs are contraindicated in cirrhosis with ascites due to risk of excessive hypotension and acute renal failure, so avoid combining with DPP-4 inhibitors in this setting. 3

• NSAIDs are absolutely contraindicated in cirrhosis due to high risk of acute renal failure, hyponatremia, and diuretic resistance. 1

• Sulfonylureas should be avoided in hepatic decompensation due to hypoglycemia risk; if used in compensated cirrhosis, reduce dose by 50% when adding DPP-4 inhibitor. 1, 4