Should DPP-4 Inhibitors Be Discontinued in Heart Failure Patients?
Saxagliptin must be discontinued in patients with heart failure or at risk for heart failure, but sitagliptin and linagliptin can be continued with careful monitoring as they have demonstrated neutral effects on heart failure hospitalization risk. 1
Agent-Specific Recommendations
Saxagliptin - Discontinue
- Saxagliptin is associated with a 27% relative increase in heart failure hospitalization risk and is not recommended for patients with heart failure or at risk for heart failure. 1, 2
- The SAVOR-TIMI 53 trial demonstrated a 26% increase in heart failure hospitalization with saxagliptin, with no clear mechanistic explanation. 1
- The European Society of Cardiology guidelines explicitly state saxagliptin is not recommended (Class III recommendation) for diabetes treatment in patients at risk of heart failure or with previous heart failure. 1
Sitagliptin and Linagliptin - May Continue
- Sitagliptin and linagliptin have neutral effects on heart failure hospitalization risk and may be considered for continued use in heart failure patients. 1, 2
- The TECOS trial showed sitagliptin had identical heart failure hospitalization rates compared to placebo (3.1% vs 3.1%, HR 1.00,95% CI 0.83-1.20). 2
- The American Heart Association and Heart Failure Society of America specifically indicate that sitagliptin has not been associated with increased heart failure risk, making it a safer choice among DPP-4 inhibitors. 2
- The European Society of Cardiology gives sitagliptin and linagliptin a Class IIb recommendation (may be considered) for diabetes treatment in patients with heart failure. 1
Alogliptin - Intermediate Risk
- Alogliptin showed no significant difference in heart failure hospitalization in the EXAMINE trial, though there was a trend toward increased risk. 1, 2
- Both alogliptin and saxagliptin carry relevant warnings in their FDA labels regarding heart failure risk. 1
Clinical Monitoring Requirements
All patients on DPP-4 inhibitors with heart failure should be monitored for signs and symptoms of worsening heart failure, particularly peripheral edema, which is common with this drug class. 1
- Monitor for fluid retention, dyspnea, orthopnea, and weight gain. 1
- Consider discontinuation if heart failure develops or worsens during therapy. 1
- Patients with renal impairment are at higher risk and require closer monitoring. 1
Preferred Alternatives for Heart Failure Patients
SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) are strongly recommended as first-line agents for patients with diabetes and heart failure, as they reduce heart failure hospitalization by 32-35%. 1
- SGLT2 inhibitors carry a Class I recommendation from the European Society of Cardiology for lowering heart failure hospitalization risk. 1
- Metformin should be considered if eGFR is stable and >30 mL/min/1.73 m². 1
- GLP-1 receptor agonists have a neutral effect on heart failure hospitalization and may be considered. 1
Mechanistic Considerations
The divergent heart failure risk among DPP-4 inhibitors may relate to differences in renal excretion and sodium handling. 3
- Sitagliptin and alogliptin are primarily renally excreted and suppress renal sodium-hydrogen exchanger 3 activity, which may provide natriuretic benefit. 3
- DPP-4 inhibitors as a class may cause sympathetic activation, potentially increasing heart failure risk. 3
- The modest natriuretic effect of DPP-4 inhibitors occurs at the distal (rather than proximal) renal tubules, limiting their protective effect against fluid retention. 4
Common Pitfalls
- Do not assume all DPP-4 inhibitors have the same heart failure risk profile—saxagliptin is distinctly more dangerous. 1
- Avoid combining DPP-4 inhibitors with thiazolidinediones, which carry an FDA Black Box Warning for causing or exacerbating heart failure. 1
- Do not use DPP-4 inhibitors as first-line therapy when SGLT2 inhibitors are available and appropriate for heart failure patients. 1, 2