Is it safe to start Mounjaro (tirzepatide) or Wegovy (semaglutide) in patients with Heart Failure with Reduced Ejection Fraction (HFrEF)?

GLP-1 Receptor Agonists in Heart Failure with Reduced Ejection Fraction

Tirzepatide (Mounjaro) and semaglutide (Wegovy) should be used with caution in patients with HFrEF, as current evidence primarily supports their use in HFpEF with obesity, not in HFrEF. 1, 2

Current Evidence for GLP-1 RAs in Heart Failure

• Recent clinical trials have demonstrated benefits of tirzepatide and semaglutide specifically in patients with heart failure with preserved ejection fraction (HFpEF) and obesity, not in HFrEF 1, 2
• The STEP-HFpEF trial showed that semaglutide 2.4mg led to significant improvements in symptoms, physical limitations, exercise function, and weight loss in patients with HFpEF and obesity 2
• Similarly, tirzepatide demonstrated comprehensive improvements in health status, quality of life, functional capacity, and reduced medication burden in patients with HFpEF and obesity 1

Established Guideline-Directed Medical Therapy for HFrEF

• The foundation of HFrEF treatment consists of four medication classes that should be initiated as soon as possible after diagnosis: 3

  • Renin-Angiotensin System Inhibitors (ACEIs, ARBs, or ARNIs)
  • Beta-blockers
  • Mineralocorticoid Receptor Antagonists (MRAs)
  • Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i)

• SGLT2 inhibitors have been shown to reduce cardiovascular and all-cause mortality in HFrEF patients regardless of diabetes status 4

Considerations Before Starting GLP-1 RAs in HFrEF

• Prioritize optimizing the four foundational medication classes for HFrEF before considering GLP-1 RAs 3, 5
• Only 46.9% of HFrEF patients receive all four recommended drug classes, indicating room for improvement in implementing established therapies 5
• Current guidelines do not specifically recommend GLP-1 RAs for HFrEF management 6, 3

Practical Approach

1. First ensure patient is on optimal doses of all four guideline-directed therapies for HFrEF 3, 5:

   • ARNI/ACEI/ARB
   • Beta-blocker
   • MRA
   • SGLT2 inhibitor

2. If considering GLP-1 RA therapy in a patient with HFrEF:

   • Recognize this would be an off-label use as current evidence is primarily for HFpEF with obesity 1, 2
   • Monitor closely for any signs of worsening heart failure
   • Consider starting at lower doses and titrating more slowly than standard protocols

Caveats and Pitfalls

• Avoid assuming that benefits seen in HFpEF with obesity will translate directly to HFrEF patients 1, 2
• Do not delay or substitute established guideline-directed medical therapy for HFrEF when considering GLP-1 RAs 3, 4
• Be aware that device therapies like cardiac resynchronization therapy and implantable cardioverter-defibrillators remain important considerations for appropriate HFrEF patients 3, 7

In summary, while GLP-1 RAs show promise in HFpEF with obesity, their role in HFrEF remains undefined. Focus first on optimizing the four pillars of guideline-directed medical therapy for HFrEF before considering GLP-1 RAs.