How do GLP-1 (Glucagon-like peptide-1) agonists help with heart failure (HF) management?

GLP-1 Receptor Agonists in Heart Failure Management

GLP-1 receptor agonists (GLP-1 RAs) should be used with caution in heart failure management, as they have uncertain or potentially harmful effects in heart failure with reduced ejection fraction (HFrEF), while they may be beneficial for preventing heart failure in patients without established heart failure. 1

Differential Effects Based on Heart Failure Status

Patients Without Established Heart Failure

• GLP-1 RAs reduce the risk of major adverse cardiovascular events (MACE) by 13-26% in patients with type 2 diabetes and established cardiovascular disease 1
• Meta-analysis shows GLP-1 RAs may prevent new-onset heart failure and reduce mortality in patients with type 2 diabetes without heart failure (HR 0.84,95% CI: 0.76-0.92) 2
• Specific cardiovascular benefits include:
  • Liraglutide: 13% reduction in MACE (HR 0.87,95% CI 0.78-0.97) 1
  • Semaglutide: 26% reduction in MACE (HR 0.74,95% CI 0.58-0.95) 1
  • Albiglutide: 22% reduction in MACE (HR 0.78,95% CI 0.68-0.90) 1
  • Dulaglutide: 12% reduction in MACE (HR 0.88,95% CI 0.79-0.99) 1

Patients With Established Heart Failure

• In patients with established heart failure, the effects vary by ejection fraction status:

Heart Failure with Preserved Ejection Fraction (HFpEF)

• GLP-1 RAs do not reduce heart failure hospitalizations but may reduce atherosclerotic events 3
• Use may be considered on an individualized basis for patients with HFpEF 3

Heart Failure with Reduced Ejection Fraction (HFrEF)

• Caution is warranted due to potential risk of worsening heart failure events and arrhythmias 1, 3
• Small trials in HFrEF have shown concerning signals:
  • LIVE trial: More serious adverse cardiac events with liraglutide than placebo (10.0% vs 3.0%; P=0.04) 4
  • FIGHT trial: Numerically increased risk for composite outcome of death and HF hospitalization with liraglutide (HR 1.30 [95% CI, 0.92–1.83]) 4

Mechanisms of Action in Heart Failure

GLP-1 RAs may affect heart failure through several mechanisms:

1. Indirect cardiovascular benefits:

   • Reduction in hyperglycemia
   • Weight reduction
   • Decreased inflammation
   • Blood pressure reduction
   • Improved postprandial lipid profile 5

2. Direct cardiac effects:

   • GLP-1 receptors are expressed at low levels in the heart and vasculature 6
   • May have both direct and indirect actions on the cardiovascular system 6

Current Guideline Recommendations

• American Heart Association/Heart Failure Society of America (2019): GLP-1 RAs have no effect on heart failure hospitalization risk, suggesting they are safe but not beneficial in preventing heart failure in at-risk patients 1

• European Society of Cardiology Guidelines on Diabetes (2019): Consider GLP-1 RAs in patients with type 2 diabetes and heart failure 1

• European Association for the Study of Diabetes (2019): If heart failure predominates, SGLT-2 inhibitors should be preferred; if SGLT-2 inhibitors are not tolerated or contraindicated, GLP-1 RAs may be used 1

Practical Approach to Using GLP-1 RAs in Heart Failure

1. Screen for heart failure before initiating GLP-1 RAs:

   • Directed clinical history
   • Physical examination
   • Echocardiogram
   • Natriuretic peptide measurement 3

2. Treatment algorithm based on heart failure status:

   • No heart failure: Recommend GLP-1 RAs to reduce risk of myocardial infarction, stroke, and possibly heart failure hospitalizations
   • HFpEF: Consider individualized use of GLP-1 RAs
   • HFrEF: Use with caution due to potential risk of worsening outcomes 3

Conclusion

While GLP-1 RAs offer significant cardiovascular benefits for patients without established heart failure, their role in heart failure management is complex. They should be used cautiously in patients with HFrEF due to potential adverse effects, while they may be considered in patients with HFpEF on an individualized basis. SGLT-2 inhibitors remain the preferred agents for patients with established heart failure.