Sitagliptin Use in Heart Failure

Evidence on DPP-4 Inhibitors and Heart Failure

Different DPP-4 inhibitors have shown varying effects on heart failure outcomes in cardiovascular outcome trials, with saxagliptin showing a 27% relative increase in the risk of heart failure hospitalization in the SAVOR-TIMI 53 trial, and is not recommended in patients with heart failure, whereas alogliptin showed no significant difference in heart failure hospitalization risk in the EXAMINE trial, and sitagliptin demonstrated no impact on heart failure hospitalization risk in the TECOS trial 1, 2, 3
The American Heart Association and Heart Failure Society of America indicate that sitagliptin specifically has not been associated with increased heart failure risk, making it a safer choice among DPP-4 inhibitors for patients with heart failure 1, 2

The TECOS trial demonstrated that sitagliptin had no impact on the risk of cardiovascular events or heart failure hospitalization compared to placebo, with a neutral effect on heart failure risk 1
The European Society of Cardiology guidelines state that sitagliptin has a neutral effect on the risk of heart failure and may be considered in patients with diabetes and heart failure 3

SGLT2 inhibitors are preferred first-line agents for patients with diabetes and heart failure as they have been shown to reduce heart failure hospitalizations, according to the European Heart Journal and Diabetes Care 3, 4
Thiazolidinediones have a strong and consistent relationship with increased risk of heart failure and should be avoided in patients with heart failure, as stated in the Circulation and Diabetes Care journals 4, 5
Metformin remains a first-line agent for diabetes that can be safely used in stable heart failure patients with adequate renal function, according to Diabetes Care 4
When comparing antidiabetic medications, the risk of heart failure was higher with DPP-4 inhibitors as a class than with either GLP-1 receptor agonists or SGLT-2 inhibitors, but sitagliptin specifically has shown a neutral effect, as reported in the Circulation and European Heart Journal 1, 3

The American Diabetes Association recommends that among patients with type 2 diabetes who have established atherosclerotic cardiovascular disease or kidney disease, an SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated cardiovascular benefit is recommended, excluding DPP-4 inhibitors like sitagliptin from this recommendation 6
Major adverse cardiovascular events (MACE) occurred at identical rates: 11.4% with sitagliptin versus 11.6% with placebo (hazard ratio 0.98, 95% CI 0.89-1.08), demonstrating cardiovascular safety but no benefit 6
Cardiovascular death showed no difference: HR 1.03 (95% CI 0.89-1.19) 6
Myocardial infarction rates were similar: HR 0.95 (95% CI 0.81-1.11) 6
Stroke risk was unchanged: HR 0.98 (95% CI 0.76-1.26) 6
Heart failure hospitalization occurred at identical rates in both groups: 3.1% (1.07 per 100 person-years) with sitagliptin versus 3.1% (1.09 per 100 person-years) with placebo (HR 1.00, 95% CI 0.83-1.20) 6

SGLT2 inhibitors (empagliflozin, canagliflozin) reduce cardiovascular death, heart failure hospitalization by 33-35%, and slow kidney disease progression 6, 7
GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) reduce major adverse cardiovascular events by approximately 12-26% in patients with established cardiovascular disease 6, 7
The American Heart Association and Heart Failure Society of America state that there is no evidence that DPP-4 inhibitors provide cardiovascular benefit 8

When cardiovascular protection is the goal in patients with type 2 diabetes and established cardiovascular disease, choose an SGLT2 inhibitor or GLP-1 receptor agonist instead of sitagliptin 6, 7
Sitagliptin provides glucose lowering (HbA1c reduction of 0.3%) without cardiovascular benefit 6

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, according to the European Society of Cardiology guidelines (Class III recommendation) 9, 10, 11
The European Society of Cardiology explicitly states saxagliptin is not recommended (Class III recommendation) for diabetes treatment in patients at risk of heart failure or with previous heart failure 10
Sitagliptin and linagliptin have neutral effects on heart failure hospitalization risk and may be considered for continued use in heart failure patients, with a Class IIb recommendation (may be considered) from the European Society of Cardiology 10

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 9
Monitor for fluid retention, dyspnea, orthopnea, and weight gain in patients on DPP-4 inhibitors with heart failure 9
Patients with renal impairment are at higher risk and require closer monitoring when taking DPP-4 inhibitors 9

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%, with a Class I recommendation from the European Society of Cardiology 10
Metformin should be considered if eGFR is stable and >30 mL/min/1.73 m², according to the European Society of Cardiology 10
GLP-1 receptor agonists have a neutral effect on heart failure hospitalization and may be considered, according to the European Society of Cardiology 10

Do not assume all DPP-4 inhibitors have the same heart failure risk profile—saxagliptin is distinctly more dangerous, as stated by the American College of Cardiology and the European Society of Cardiology 9, 10
Avoid combining DPP-4 inhibitors with thiazolidinediones, which carry an FDA Black Box Warning for causing or exacerbating heart failure, as recommended by the American Heart Association 9