STEP-HFpEF

In Review

Kosiborod MN, et al. "Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity". The New England Journal of Medicine. 2023. 389(12):1069-1084.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with heart failure with preserved ejection fraction (HFpEF) and obesity (BMI ≥30 kg/m²), does treatment with once-weekly semaglutide 2.4mg improve symptoms, physical limitations, exercise function, and induce weight loss compared to placebo?

Bottom Line

In patients with HFpEF and obesity, semaglutide 2.4 mg once weekly significantly improved heart failure–related symptoms and physical limitations, increased exercise capacity, and led to substantial weight loss over 52 weeks compared to placebo.

Major Points

Over a 52-week period, semaglutide led to significant improvements in heart failure symptoms and physical limitations (measured by the KCCQ-CSS), increased the 6-minute walk distance, and resulted in substantial weight loss compared to placebo. Additionally, semaglutide reduced C-reactive protein levels, suggesting decreased inflammation. The treatment was associated with fewer serious adverse events, primarily a reduction in cardiac events, and generally well tolerated. These findings suggest that semaglutide may be an effective therapeutic option for managing HFpEF in patients with obesity, addressing a significant unmet need in this population.

Guidelines

AHA/ACC/HFSA Heart Failure Guidelines (2022) None to date.

Design

• Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
• N=529
  • Semaglutide group (n=263)
  • Placebo group (n=266)
• Setting: 96 sites across 13 countries in Asia, Europe, North America, and South America
• Enrollment: March 2021 to March 2022
• Mean follow-up: 52 weeks of treatment plus a 5-week follow-up period
• Analysis: Intention-to-treat, per-protocol
• Dual primary end points:
  • Change from baseline to week 52 in the KCCQ-CSS (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score): 23 item instrument scored on 100 point scale quantifying heart failure related symptoms (frequency, severity, recent change), physical function, quality of life, social function.
  • Percentage change from baseline to week 52 in body weight

Population

Inclusion Criteria

• Age ≥18 years
• Diagnosed with HFpEF:
  • Left ventricular ejection fraction ≥45%
  • NYHA functional class II–IV symptoms
• Evidence of elevated left ventricular filling pressures, elevated natriuretic peptide levels with echocardiographic abnormalities, or recent hospitalization for heart failure with ongoing diuretic treatment or echocardiographic abnormalities
• KCCQ-CSS score <90
• 6-minute walk distance ≥100 meters
• Body mass index (BMI) ≥30 kg/m²

Exclusion Criteria

• Body weight change >5 kg within 90 days before screening
• History of diabetes (glycated hemoglobin ≥6.5% or known diagnosis)
• Recent or planned bariatric surgery
• Use of other weight-management pharmacotherapy
• Conditions interfering with trial participation or data interpretation

Baseline Characteristics

• Median age: 69 years
• Female: 56.1%
• White: 95.8%
• Median BMI: 37.0 kg/m²
• Median body weight: 105.1 kg
• Median KCCQ-CSS score: 58.9 points
• Median 6-minute walk distance: 320.0 meters
• Median NT-proBNP level: 450.8 pg/mL
• NYHA class II: 66.2%; class III or IV: 33.8%
• History of atrial fibrillation: 52%
• Medications at baseline:
  • Renin–angiotensin system blockers (ACEI, ARB, ARNI) (80.2%)
  • Mineralocorticoid receptor antagonists (34.8%)
  • Diuretic (80.7%), Loop diuretic (62.2%), Thiazide (17.0%)
  • Beta-blockers (79.0%)
  • SGLT2 inhibitors (3.6%)

Interventions

• Semaglutide Group
  • Semaglutide 2.4 mg administered once weekly via subcutaneous injection
  • Dose escalation from 0.25 mg to 2.4 mg over 16 weeks
• Placebo Group: Matching placebo administered once weekly via subcutaneous injection with identical dose escalation schedule.

Outcomes

Comparisons are semaglutide therapy vs. placebo.

Primary Outcomes

Mean change in KCCQ-CSS from baseline to week 52

+16.6 vs. +8.7; difference 7.8 [95% CI 4.8-10.9]; P<0.001

Mean percentage change in body weight from baseline to week 52

-13.3% vs. -2.6%; difference -10.7 [95% CI -11.9 to -9.4]; P<0.001

Secondary Outcomes

Change in 6-minute walk distance from baseline to week 52

21.5 m vs. 1.2 m; difference 20.3 m [95% CI 8.6-32.1]; P<0.001

Hierarchical composite endpoint (death, heart failure events, changes in KCCQ-CSS and 6-minute walk distance), crude win percentage

60.1 vs. 34.9; Win Ratio 1.72 [95% CI 1.37-2.15); P<0.001

Percentage change in C-reactive protein (CRP) levels from baseline to week 52

-43.5% vs. -7.3%; treatment ratio 0.61 [95% CI 0.51-0.72]; P<0.001

Subgroup Analysis

No detailed subgroup analysis. Effects of semaglutide were consistent across various prespecified subgroups, including age, sex, baseline BMI, and NYHA class.

Adverse Events

Comparisons are semaglutide vs. placebo

Serious adverse events

35 (13.3%) vs. 71 (26.7%) P<0.001

Cardiac: 7 (2.7%) vs. 30 (11.3%) P<0.001

Infection: 4 (1.5%) vs. 17 (6.4%) P=0.006

GI: 7 (2.7%) vs. 7 (2.6%) P=1.00

Nervous system: 8 (3.0%) vs. 7 (2.6%) P=0.80

Renal/GU: 6 (2.3%) vs. 4 (1.5%) P=0.54

Adverse events leading to discontinuation

35 (13.3%) vs. 14 (5.3%)

Fatal events

3 (1.1%) vs. 4 (1.5%)

Criticisms

• Limited diversity, 95.8% were white, which may limit generalizability
• Relatively short follow-up duration. Semaglutide requires continued use to maintain weight loss
• Low Use of SGLT2 Inhibitors: Only 3.6% of participants were on SGLT2 inhibitors, which are guideline directed in HFpEF management
• Exclusion of patients with diabetes

Funding

• Sponsor: Novo Nordisk, the manufacturer of semaglutide.
• Conflicts of Interest: Several authors disclosed relationships with pharmaceutical companies, including Novo Nordisk.