What is the role of GIP/GLP-1 (Glucose-dependent Insulinotropic Polypeptide/Glucagon-like peptide-1) receptor agonists, such as dulaglutide (dulaglutide) or semaglutide (semaglutide), in the management of heart failure with preserved ejection fraction (HFpEF)?

Role of GIP/GLP-1 Receptor Agonists in Heart Failure with Preserved Ejection Fraction (HFpEF)

GLP-1 receptor agonists, particularly semaglutide, significantly reduce heart failure events and improve symptoms in patients with HFpEF, especially those with obesity, making them an important therapeutic option for this challenging condition. 1

Current Evidence for GLP-1 Receptor Agonists in HFpEF

Efficacy Data

• A 2024 pooled analysis of four randomized controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) demonstrated that semaglutide reduced:

  • Combined endpoint of cardiovascular death or heart failure events by 31% (HR 0.69,95% CI 0.53-0.89) 1
  • Worsening heart failure events by 41% (HR 0.59,95% CI 0.41-0.82) 1
  • No significant effect was observed on cardiovascular death alone (HR 0.82,95% CI 0.57-1.16) 1

• The STEP-HFpEF trial in patients with HFpEF and obesity showed semaglutide 2.4mg weekly led to:

  • Significant improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) by 7.8 points over placebo 2
  • 13.3% weight reduction compared to 2.6% with placebo 2
  • Improved 6-minute walk distance by 20.3m more than placebo 2
  • 43.5% reduction in C-reactive protein levels (vs 7.3% with placebo) 2

• The STEP-HFpEF DM trial in patients with HFpEF, obesity, and type 2 diabetes demonstrated:

  • Improvement in KCCQ-CSS by 7.3 points over placebo 3
  • 9.8% weight reduction compared to 3.4% with placebo 3
  • Improved 6-minute walk distance by 14.3m more than placebo 3

Placement in Treatment Algorithm

Current guidelines identify GLP-1 receptor agonists as an emerging therapy for HFpEF:

1. First-line disease-modifying therapies for HFpEF according to guidelines:

   • SGLT2 inhibitors (dapagliflozin or empagliflozin) are recommended as first-line disease-modifying therapy 4
   • Diuretics for symptom relief of congestion 5, 4

2. GLP-1 receptor agonists (particularly semaglutide):

   • Current guidelines identify a gap in evidence regarding the "prognostic role of GLP-1 receptor agonists" in HFpEF 5
   • Recent evidence supports their use, especially in patients with obesity-related HFpEF 1, 2, 3

Mechanism of Action in HFpEF

GLP-1 receptor agonists provide multiple beneficial effects in HFpEF:

• Weight reduction: Significant weight loss helps reduce cardiac workload and improve hemodynamics 2, 3
• Anti-inflammatory effects: Demonstrated by substantial reductions in C-reactive protein levels 2, 3
• Improved cardiac metabolism: Enhanced myocardial glucose uptake and improved cardiac efficiency 6
• Reduced symptom burden: Significant improvements in KCCQ scores indicate better quality of life 2, 3
• Enhanced exercise capacity: Improved 6-minute walk distance suggests better functional capacity 2, 3

Patient Selection for GLP-1 Receptor Agonist Therapy

GLP-1 receptor agonists are most beneficial for HFpEF patients with:

• Obesity (BMI ≥30 kg/m²) 2, 3
• Type 2 diabetes (particularly beneficial in this subgroup) 3
• Symptomatic HFpEF despite standard therapy 1, 2, 3

Practical Recommendations

1. Treatment sequence:

   • Start with SGLT2 inhibitors as first-line disease-modifying therapy 4
   • Add diuretics for symptom relief of congestion 5, 4
   • Consider adding semaglutide 2.4mg weekly for patients with obesity (BMI ≥30) 2, 3

2. Monitoring:

   • Assess symptom improvement using validated tools like KCCQ
   • Monitor weight reduction
   • Track exercise capacity (6-minute walk test)
   • Watch for gastrointestinal side effects, which are the most common adverse events 7

Limitations and Considerations

• Most studies have focused on semaglutide rather than other GLP-1 receptor agonists
• Long-term cardiovascular mortality benefit remains uncertain 1
• Optimal timing of initiation in the HFpEF treatment cascade needs further study
• Cost and accessibility may limit widespread use

Conclusion

GLP-1 receptor agonists, particularly semaglutide, represent an important addition to the therapeutic armamentarium for HFpEF, especially in patients with obesity. While SGLT2 inhibitors remain first-line disease-modifying therapy, the addition of semaglutide can provide significant improvements in symptoms, exercise capacity, and reduction in heart failure events.