What is the role of Glucagon-like peptide-1 (GLP-1) receptor agonists in the management of Heart Failure with reduced Ejection Fraction (HFrEF)?

Role of GLP-1 Receptor Agonists in HFrEF

GLP-1 receptor agonists should be used with caution in patients with established HFrEF and recent decompensation, as they provide no benefit for heart failure outcomes and show a trend toward worse outcomes including increased heart failure readmissions and serious cardiac events. 1

Evidence from HFrEF-Specific Trials

The evidence base for GLP-1 RAs in HFrEF comes from three dedicated trials, all showing disappointing results:

FIGHT Trial (Most Definitive Evidence)

• Liraglutide showed no benefit in 300 patients with chronic HFrEF and recent hospitalization over 6 months 1
• Numerically increased risk of HF readmission: 41% versus 34% (HR 1.30,95% CI 0.89-1.88) 1
• Higher risk in diabetic subgroup: HR 1.54 (95% CI 0.97-2.46) for death and HF hospitalization 1
• No improvement in clinical stability, functional capacity, or quality of life 1

LIVE Trial (Safety Concerns)

• Serious adverse cardiac events occurred more frequently with liraglutide versus placebo: 10.0% versus 3.0% (P=0.04) 1
• Events included sustained ventricular tachycardia, atrial fibrillation requiring intervention, and aggravation of ischemic heart disease 1
• No improvement in LVEF, quality of life, or functional class at 24 weeks in 241 stable HFrEF patients 1
• Associated with increased heart rate and more serious cardiac events 1

Albiglutide Study

• No significant effect on LVEF, brain natriuretic peptide, 6-minute walk test, or quality of life in 82 patients with HFrEF over 12 weeks 1

Mechanistic Concerns in HFrEF

GLP-1 RAs cause physiologic changes that may be detrimental in HFrEF:

• Heart rate increase of 3-10 beats/min due to direct sinus node effects, which can worsen outcomes in decompensated HF 1, 2
• Systolic blood pressure reduction of 2-3 mm Hg 1
• These hemodynamic effects may explain the variable and concerning results in HF populations 1

Clinical Algorithm for GLP-1 RA Use Based on HF Status

Patients WITHOUT Established HF (Safe to Use)

• GLP-1 RAs are safe and beneficial for reducing major adverse cardiovascular events and mortality in diabetic patients at cardiovascular risk 1
• No impact on preventing HF hospitalization in large cardiovascular outcomes trials, but no harm signal 1
• Should be considered for ASCVD risk reduction in this population 1

Patients WITH Stable HFrEF (Use with Caution)

• Avoid in patients with recent decompensation given trend toward worse outcomes in FIGHT trial 1
• If diabetes management requires GLP-1 RA in stable HFrEF, monitor closely for:
  • Heart rate increases 1, 2
  • Signs of HF decompensation 1
  • Arrhythmias (atrial fibrillation, ventricular tachycardia) 1, 3

Patients WITH Recent HF Hospitalization (Avoid)

• Do not initiate GLP-1 RAs based on FIGHT trial showing no benefit and trend toward increased readmissions 1
• Consider alternative glucose-lowering agents, particularly SGLT2 inhibitors which have proven benefit in HFrEF 1

Guideline Recommendations

The American Heart Association and Heart Failure Society of America state explicitly: In patients with established HFrEF and recent decompensation, GLP-1 receptor agonists should be used with caution, given no evidence of benefit and a trend toward worse outcomes in 2 small RCTs 1

If HF or chronic kidney disease predominates, SGLT2 inhibitors are preferred over GLP-1 RAs according to consensus statements from the European Association for the Study of Diabetes and American Diabetes Association 1

Common Pitfalls to Avoid

• Do not assume cardiovascular benefits in general diabetic populations translate to HFrEF patients - the evidence shows potential harm in this specific subgroup 1
• Do not overlook the heart rate increase - this seemingly modest effect (3-10 bpm) can be clinically significant in decompensated HF 1, 2
• Do not use GLP-1 RAs as HF therapy - they provide no benefit for HF-specific outcomes (LVEF, functional capacity, HF hospitalizations) 1

Alternative Considerations

When diabetes management is needed in HFrEF patients, SGLT2 inhibitors demonstrate clear mortality and HF hospitalization benefits and should be prioritized over GLP-1 RAs 1