What are the effects of semaglutide on Heart Failure with preserved Ejection Fraction (HFpEF)?

Semaglutide Effects in HFpEF

Semaglutide 2.4 mg once weekly significantly improves heart failure symptoms, physical function, and reduces heart failure events in patients with obesity-related HFpEF, with or without type 2 diabetes, making it a disease-modifying therapy for this population. 1

Symptom and Functional Improvements

Semaglutide produces clinically meaningful improvements in heart failure-related symptoms and physical limitations:

• Kansas City Cardiomyopathy Questionnaire (KCCQ) scores increase by 7.3 points more than placebo (13.7 vs 6.4 points), representing substantial symptom relief 2
• 6-minute walk distance improves by 14.3 meters more than placebo, demonstrating enhanced exercise capacity 2
• NYHA functional class improvements occur in 32.6% of semaglutide-treated patients vs 21.5% with placebo (OR: 2.20), with only 2.09% experiencing deterioration vs 5.24% with placebo 3
• The magnitude of symptom improvement is particularly pronounced in NYHA class III/IV patients (10.5-point KCCQ improvement vs 6.0 points in class II patients) 3

Cardiac Structural Benefits

Semaglutide attenuates adverse cardiac remodeling in HFpEF:

• Left atrial volume progression is reduced by 6.13 mL compared to placebo, indicating improved atrial remodeling 4
• Right ventricular end-diastolic area decreases by 1.99 cm² and end-systolic area by 1.41 cm², demonstrating RV reverse remodeling 4
• Diastolic function markers improve: E-wave velocity decreases by 5.63 cm/s, E/A ratio by 0.14, and E/e' ratio by 0.79 4
• These structural improvements occur independently of diabetes or atrial fibrillation status 4

Clinical Heart Failure Event Reduction

Semaglutide reduces hard clinical endpoints in HFpEF:

• The composite of cardiovascular death or worsening heart failure events is reduced by 31% (HR 0.69; 5.4% vs 7.5% with placebo) in pooled analysis of 3,743 HFpEF patients 5
• Worsening heart failure events alone are reduced by 41% (HR 0.59; 2.8% vs 4.7% with placebo) 5
• Cardiovascular death alone showed no significant reduction (HR 0.82), suggesting the benefit is primarily driven by preventing heart failure decompensation 5

Weight Loss and Metabolic Effects

Semaglutide produces substantial weight reduction that contributes to clinical benefits:

• Mean weight loss is 9.8% with semaglutide vs 3.4% with placebo (6.4 percentage point difference) 2
• Weight loss is consistent across NYHA functional classes (8.3-8.4% reduction regardless of baseline severity) 3
• Greater weight loss correlates with greater reduction in left atrial volume, though improvements in diastolic parameters and RV size occur independently of weight loss magnitude 4

Anti-inflammatory and Decongestion Effects

Semaglutide reduces biomarkers of inflammation and congestion:

• C-reactive protein levels decrease by 33% (treatment ratio 0.67) compared to placebo 2
• NT-proBNP levels are reduced, indicating improved hemodynamic status 3
• In a pre-specified analysis, 17% of semaglutide-treated patients had loop diuretic dose reductions vs 2% increase in placebo group 1

Effects Across Glycemic Control Levels

Semaglutide benefits are independent of baseline diabetes control:

• KCCQ improvements range from 6.7 to 9.6 points across HbA1c categories (<6.5%, 6.5-7.5%, ≥7.5%), with no significant interaction (p=0.64) 6
• Weight loss is consistent across HbA1c categories (5.0-7.5% greater than placebo), though slightly attenuated at higher baseline HbA1c (p for trend=0.083) 6
• Hypoglycemia rates are lower with semaglutide (10% vs 7% with placebo, but fewer events per person-year: 22.9 vs 29.5) despite well-controlled baseline glycemia 6

Guideline Recommendations

Current guidelines support semaglutide use in HFpEF with obesity:

• Semaglutide should be considered for persons with type 2 diabetes and HFpEF, particularly those with obesity 1
• The American Heart Association and American College of Cardiology acknowledge semaglutide's benefits in HFpEF with improvements in symptoms and exercise function 7, 8
• GLP-1 receptor agonists have neutral effects on heart failure hospitalization in general diabetes populations, but semaglutide specifically shows benefit in obesity-related HFpEF 1

Safety Considerations

Semaglutide demonstrates favorable safety in HFpEF:

• Serious adverse events occur less frequently with semaglutide (17.7% vs 28.8% with placebo) 2
• Gastrointestinal side effects (nausea, vomiting, diarrhea) are the most common adverse events 8
• Slow dose titration improves tolerability 8
• Unlike earlier GLP-1 RA trials in HFrEF (LIVE, FIGHT), which showed neutral or potentially harmful effects, semaglutide in HFpEF demonstrates clear benefit 1

Clinical Implementation

Practical approach to semaglutide in HFpEF:

• Target population: HFpEF patients (LVEF ≥45%) with BMI ≥30 kg/m², with or without type 2 diabetes 2
• Dosing: Subcutaneous semaglutide 2.4 mg once weekly (requires titration from lower doses) 2
• Expected timeline: Symptom improvements and weight loss become apparent within 52 weeks, with cardiac remodeling benefits demonstrable by echocardiography 4
• Monitoring: Track KCCQ scores, weight, NYHA class, and consider loop diuretic dose adjustments as symptoms improve 1, 3
• Benefits are consistent regardless of baseline NYHA class, diabetes status, or atrial fibrillation presence 4, 6, 3