A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity - SUMMIT

Contribution To Literature:

Highlighted text has been updated as of December 20, 2024.

The SUMMIT trial showed that among obese patients with HFpEF, once weekly subcutaneous tirzepatide was superior to placebo in improving the composite endpoint of CV death and HF-related events over 104 weeks of follow-up.

Description:

The goal of the trial was to compare the safety and efficacy of tirzepatide among patients with heart failure with preserved ejection fraction (HFpEF) and obesity.

Study Design

Patients were randomized in a 1:1 double-blind fashion to once weekly subcutaneous tirzepatide (n = 364) or matching placebo (n = 367) for 52 weeks. Randomization was stratified according to baseline body mass index (BMI) (<35 vs. ≥35 kg/m2), history of HF decompensation within 12 months before baseline (Y/N), or history of type 2 diabetes mellitus (Y/N). Tirzepatide treatment was initiated at a dose of 2.5 mg once weekly, and the dose was escalated every 4 weeks with the aim of reaching the maintenance dose of 15 mg by week 20.

  • Total screened participants: 1,494
  • Total randomized participants: 731
  • Median duration of follow-up: 104 weeks
  • Median patient age: 65 years
  • Percentage female: 53%
  • New York Heart Association (NYHA) class III/IV: 28%

Inclusion criteria:

  • Have a diagnosis of stable HF (NYHA class II-IV) and left ventricular ejection fraction (LVEF) ≥50%
  • Elevated N-terminal pro–B-type natriuretic peptide (NT-proBNP) >200 pg/mL for participants without atrial fibrillation (AF), or >600 pg/mL for participants with AF
  • Structural heart disease (left atrial enlargement) or elevated LV filling pressure
  • Estimated glomerular filtration rate (eGFR) <70 mL/min/1.73 m² at screening, or HF decompensation within 12 months of screening
  • Stable dose of HF medications within 4 weeks of screening
  • BMI ≥30 kg/m²
  • Six-minute walk distance (6MWD) 100-425 m
  • Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) ≤80

Exclusion criteria:

  • Have had a major cardiovascular (CV) event within the last 90 days of screening
  • Have had acute decompensated HF within 4 weeks of screening
  • Have noncardiac causes of functional impairment such as pulmonary arterial hypertension, severe chronic obstructive pulmonary disease, anemia, thyroid disease, musculoskeletal disease, or orthopedic conditions
  • Presence of cardiac amyloidosis, cardiac accumulation disease, cardiomyopathy, and severe valvular heart disease
  • Glycemic hemoglobin (HbA1c) ≥9.5% or uncontrolled diabetes
  • History of proliferative diabetic retinopathy or diabetic maculopathy
  • Have a history of pancreatitis
  • eGFR <15 mL/min/1.73 m² or requiring dialysis at screening

Other salient features/characteristics:

  • White race: 70%
  • Median body weight: 103 kg
  • Median BMI: 38 kg/m2
  • Region: United States (20%), Latin America (53%)
  • Median baseline NT-proBNP: 182 pg/mL
  • Hospitalization or urgent care visit for HF within 1 year: 47%
  • AF: 26%
  • Baseline medications: diuretic, 74%; mineralocorticoid receptor antagonist, 35%; sodium–glucose cotransporter-2 inhibitor (SGLT2i), 17%

Principal Findings:

The primary endpoint, CV death or worsening HF event, for tirzepatide vs. placebo, was: 9.9% vs. 15.3% (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41-0.95), p = 0.026.

  • CV death: 2.2% vs. 1.4% (HR 1.58, 95% CI 0.52-4.83)
  • Worsening HF event: 8.0% vs. 14.2% (HR 0.54, 95% CI 0.34-0.85)

Key secondary outcomes for tirzepatide vs. placebo:

  • All-cause mortality: 5.2% vs. 4.1% (HR 1.25, 95% CI 0.63-2.45)
  • Change in KCCQ-CSS from baseline to 52 weeks: 19.5 vs. 12.7, p < 0.001
  • Change in 6MWD from baseline to week 52: 26.0 vs. 10.1 m, p < 0.001
  • Systolic blood pressure: -4.6 vs. 0.1 mm Hg, p < 0.05
  • Percent change in high-sensitivity C-reactive protein (hsCRP) between baseline and 52 weeks: -38.8% vs. -5.9%, p < 0.001
  • Mean percent change in body weight between baseline and 52 weeks: -13.9% vs. -2.2%, p < 0.001 

Sensitivity analysis:

  • All-cause mortality or worsening HF event: 11.8% vs. 16.9% (HR 0.67, 95% CI 0.46-0.99)
  • Worsening HF event: 8.0% vs. 14.2% (HR 0.54, 95% CI 0.34-0.85)
  • Increase in EQ-5D-5L health state index at 52 weeks: 0.12 vs. 0.06 (p < 0.001)

Interpretation:

The results of this trial show that among obese patients with HFpEF, once weekly subcutaneous tirzepatide was superior to placebo in improving body weight (~11-12% greater weight loss) and patient-oriented quality of life outcomes including KCCQ-CSS, EQ-5D-5L, and 6MWD at 52 weeks. A reduction in the composite endpoint of CV death and HF-related events was noted, primarily driven by a reduction in HF events. These are landmark findings and concordant with the results of the STEP-HFpEF trial with semaglutide.

One limitation of this trial is that only about 17% were on SGL2Ti at baseline. It is also unclear if the improvement in outcomes was driven by weight loss (suggesting that other weight loss measures could be considered and potentially beneficial) or independent of this. An interesting observation is that hsCRP, a marker for inflammation, was reduced with tirzepatide, which could represent a mechanism for its benefit.

References:

Zile MR, Borlaug BA, Kramer CM, et al. Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, a Preserved Ejection Fraction, and Obesity. Circulation 2024;Nov 18:[Epub ahead of print].

Packer M, Zile MR, Kramer CM, et al., for the SUMMIT Trial Study Group. Tirzepatide for Heart Failure With Preserved Ejection Fraction and Obesity. N Engl J Med 2024;Nov 16:[Epub ahead of print].

Presented by Dr. Milton Packer at the American Heart Association Scientific Sessions, Chicago, IL, November 16, 2024.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention

Keywords: Glucagon-Like Peptide-1 Receptor, Heart Failure, Preserved Ejection Fraction, Obesity, AHA24, AHA Annual Scientific Sessions


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