Role of GLP-1 Receptor Agonists in Heart Failure with Preserved Ejection Fraction (HFpEF)
GLP-1 receptor agonists (GLP-1 RAs) may benefit patients with HFpEF, particularly those with obesity or diabetes, though dedicated clinical trials are still needed to confirm their efficacy and safety in this specific heart failure phenotype. 1, 2
Current Evidence and Recommendations
- GLP-1 RAs have shown potential benefits in HFpEF through theoretical mechanisms, including reduction in epicardial adipose tissue, which may serve as a therapeutic target in HFpEF 1
- Recent meta-analysis data indicates GLP-1 RAs significantly reduce worsening heart failure events (HR: 0.56 [0.38-0.82]) and the composite outcome of cardiovascular death or worsening heart failure (HR: 0.68 [0.51-0.89]) in patients with HFpEF 2
- The American Heart Association and Heart Failure Society of America note that while GLP-1 RAs appear safe to use in patients at risk for heart failure, there is insufficient evidence specifically supporting their use in established HFpEF 1
- Current guidelines make a crucial distinction between prevention of heart failure in at-risk patients versus treatment of manifest heart failure, with limited evidence for the latter 1
Patient Selection and Considerations
- GLP-1 RAs may be particularly beneficial in HFpEF patients with comorbid type 2 diabetes and obesity, as these conditions frequently coexist and contribute to HFpEF pathophysiology 1
- Recent observational data suggests GLP-1 RAs may provide superior cardiovascular protection compared to SGLT2 inhibitors in patients with both diabetes and HFpEF over a 3-year follow-up period (HR 0.825; 95% CI, 0.717-0.950) 3
- Benefits appear to extend to non-obese patients with type 2 diabetes and HFpEF, with lower rates of heart failure exacerbation events (HR 0.60,95% CI 0.58-0.62) compared to those not on GLP-1 RAs 4
- GLP-1 RAs may provide incremental benefits when added to SGLT2 inhibitors in patients with type 2 diabetes, obesity, and HFpEF, with significantly lower risk of heart failure exacerbations 5
Important Distinctions Between HFpEF and HFrEF
- There is a critical need to differentiate between heart failure phenotypes when considering GLP-1 RA therapy 1
- While GLP-1 RAs may benefit HFpEF patients, caution is warranted in HFrEF due to potential safety concerns 6
- Small randomized trials in HFrEF (LIVE and FIGHT) showed no improvement in left ventricular ejection fraction and concerning trends toward increased cardiac events with liraglutide 1
- The LIVE trial reported more serious adverse cardiac events with liraglutide than placebo (10.0% versus 3.0%; P=0.04) in HFrEF patients 1
Clinical Approach and Monitoring
- Before initiating GLP-1 RAs in patients with or at risk for heart failure, consider active heart failure screening with clinical assessment, echocardiogram, and natriuretic peptide measurement 6
- Patients with HFpEF on GLP-1 RAs should be monitored for heart rate increases (3-10 beats/min), which could potentially impact cardiac function 1
- Monitor for common adverse effects including nausea, vomiting, and potential increased risk of cholelithiasis 1
- In patients with both diabetes and HFpEF, consider GLP-1 RAs for their potential dual benefits on glycemic control and heart failure outcomes, particularly in those with obesity 2
Future Directions
- Dedicated trials with GLP-1 RAs specifically in HFpEF patients are needed to definitively establish their efficacy, safety, and risk-benefit profile 1
- Current evidence suggests GLP-1 RAs may have different effects across the spectrum of heart failure, with potentially greater benefits in HFpEF compared to HFrEF 6
- The role of combination therapy with SGLT2 inhibitors and GLP-1 RAs in HFpEF requires further investigation through prospective clinical trials 5