A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity: The SUMMIT Trial
ID: NCT04847557
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The main purpose of this study is to assess the efficacy and safety of Tirzepatide (LY3298176) in participants with heart failure with preserved ejection fraction and obesity.
Read Full Scientific Objectives & Methods
The study will continue until approximately 52 weeks after the last participant is randomized. The maximum duration of an individual's participation is estimated to be \~120 weeks and will depend on duration of study enrollment.
Administered SC
Administered SC
Treatment Arms Description
Participants received a starting dose of 2.5 milligrams (mg) tirzepatide administered subcutaneously (SC) once weekly (QW) and escalated by 2.5 mg every 4 weeks to a maximum of 15 mg QW or maximum tolerated dose (MTD) tolerated by the participant (5 mg QW or 10 mg QW).
Participants received placebo administered SC QW.
- Have a diagnosis of stable heart failure (NYHA class II-IV) and left ventricular ejection fraction (LVEF) ≥50%
- Elevated NT-proBNP (N-terminal pro B-type natriuretic peptide) \> 200 picogram/milliliter (pg/ml) for participants without atrial fibrillation (AF), or \>600 pg/ml for participants with AF, Structural heart disease (Left atrial enlargement) or Elevated left ventricular filling pressure
- Estimated glomerular filtration rate (eGFR) \<70 milliliter (ml)/minute (min)/1.73m² at screening, or HF decompensation within 12 months of screening,
- Stable dose of heart failure medications within 4 weeks of screening
- Body mass index (BMI) ≥30 kilograms per meter squared (kg/m²)
- 6MWD 100-425 meters
- KCCQ CSS ≤80
- Have had a major cardiovascular event within the last 90 days of screening
- Have had acute decompensated heart failure within 4 weeks of screening
- Have non cardiac causes of functional impairment such as pulmonary arterial hypertension (PAH), severe chronic obstructive pulmonary disease (COPD), anemia, thyroid disease, musculoskeletal disease or orthopedic conditions
- Presence of cardiac amyloidosis, cardiac accumulation disease, cardiomyopathy and severe valvular heart disease
- 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
Primary Outcome Measures
- Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) — Time Frame: Baseline, Week 52
The KCCQ is a 23-item, participant self-administered questionnaire that assesses impacts of heart failure "over the past 2 weeks" on the following 7 domains: * Physical Limitation (6) * Symptom Stability (1) * Symptom Frequency (4) * Symptom Burden (3) * Self-Efficacy (2) * Quality of Life (3) * Social Limitation (4) Each of the 23 individual items are answered on Likert scales of varying lengths (5, 6, or 7-point scales). KCCQ-CSS includes the symptom and physical limitation domains of the KCCQ. Scores are obtained by averaging the associated individual items and transforming the score to a 0 to 100 range. Higher scores indicate better health status. Least Square (LS) mean was determined using ANCOVA model with Baseline + HF Decompensation Within 12 Months of Screening + T2DM Status + Baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables .
- First Occurrence of the Composite Endpoint of Heart Failure (HF) Outcomes — Time Frame: Baseline Up To 160 weeks
Clinical Endpoint Committe confirmed Occurrences of CV outcomes were reported here. HF outcomes consisted of cardiovascular death and HF events. The HF events were defined as worsening clinical symptoms or signs related to HF, which are meaningful to the participant and require intensification of treatment characterized by 1 or more of the following: * hospitalization for heart failure regardless of duration or treatment received * use of intravenous drug, usually an intravenous diuretic, but may include intravenous vasodilators or positive inotropic drugs, or * augmentation or increase in oral diuretic therapy.
View Secondary Outcome Measures (9)
- Change From Baseline in Exercise Capacity as Measured by 6-Minute Walk Distance (6MWD) — Time Frame: Baseline, Week 52
Participants performed an exercise capacity assessment using the 6-Minute Walk Test (6MWT) and the distance covered (6MWD) was assessed in meters. The 6MWT was performed indoors on a straight, flat, hard surface that is at least 30 meters in length. The greater distance walked meant better physical capacity. LS Mean was determined using ANCOVA model with Baseline + HF Decompensation Within 12 Months of Screening + T2DM Status + Baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables.
- Percent Change From Baseline in Body Weight — Time Frame: Baseline, Week 52
Percent change in bodyweight was reported. LS mean was determined using ANCOVA model with Baseline + HF Decompensation Within 12 Months of Screening + T2DM Status + Baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables.
- Percent Change From Baseline in High-Sensitivity C-Reactive Protein (hsCRP) — Time Frame: Baseline, Week 52
Percent change from baseline in hsCRP was reported. LS Mean was determined using ANCOVA model with log (actual measurement/baseline) = log (baseline) + HF decompensation within 12 months of screening + T2DM status + baseline BMI group (\<35, \>=35 kg/m2) + Treatment (Type III sum of squares) as variables.
- Win Percentage of the Hierarchical Composite Endpoint — Time Frame: Baseline Up To 160 Weeks
Hierarchical Composite Endpoint included time to all-cause death, number of HF events, time to first HF events, KCCQ-CSS, 6MWD. The winner was determined in each pair-wise comparison in the following order: * A delayed first occurrence of all-cause death * If the pair cannot be differentiated based on death, winner has fewer HF events * If the pair cannot be differentiated by number of HF events, winner has delayed time to occurrence of first HF event * If the pair still cannot be differentiated, winner has a more favorable category for change from baseline in 6MWD * If the pair still cannot be differentiated, winner has a more favorable category for change from baseline in KCCQ-CSS * Otherwise the pair will be recorded as tied. Reported unit is the total percent of "wins" for each treatment group from performing such a hierarchical comparison across stratification factors in the study.
- Percentage of Participants With New York Heart Association (NYHA) Class Change — Time Frame: Week 52
Percentage of participants with NYHA class change at Week 52 was reported.
- Number of Participants With Time to All-Cause Death — Time Frame: Baseline Up To 160 Weeks
All-cause mortality is death due to any cause. Number of participants with time to all-cause mortality are presented.
- Number of Participants With Time to First Occurrence of HF Events — Time Frame: Baseline Up To 160 Weeks
Number of participants with time to first occurrence of HF events are reported.
- Number of HF Events and All-Cause Death — Time Frame: Baseline Up To 160 Weeks.
Number of HF events and all-cause death are reported.
- Number of Recurrent HF Events — Time Frame: Baseline Up To 160 Weeks.
Number of recurrent HF events were reported.
This trial is recruiting at 146 study facilities worldwide. Click below to see if there is a clinic or hospital in your area:
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- Borlaug BA, Zile MR, Kramer CM, Litwin SE, Ye W, Ou Y, Hurt K, Murakami M, Packer M; SUMMIT Trial Group. Effects of Tirzepatide in Obesity-Related HFpEF by Sex: A Prespecified Secondary Analysis From the SUMMIT Trial. JACC Heart Fail. 2026 Jul 7:103218. doi: 10.1016/j.jchf.2026.103218. Online ahead of print.PubMed ↗
- Packer M, Zile MR, Kramer CM, DiMaria JM, Baum SJ, Litwin SE, Murakami M, Zhou C, Ou Y, Koeneman L, Borlaug BA; SUMMIT Trial Study Group. Influence of Type 2 Diabetes on the Effects of Tirzepatide in Patients With Heart Failure and a Preserved Ejection Fraction With Obesity: A Prespecified Stratification-Based Analysis. J Am Coll Cardiol. 2025 Sep 9;86(10):696-707. doi: 10.1016/j.jacc.2025.06.058.PubMed ↗
- Borlaug BA, Zile MR, Kramer CM, Ye W, Ou Y, Hurt K, Murakami M, Packer M; SUMMIT Trial Study Group. Impact of Body Mass Index, Central Adiposity, and Weight Loss on the Benefits of Tirzepatide in HFpEF: The SUMMIT Trial. J Am Coll Cardiol. 2025 Jul 29;86(4):242-255. doi: 10.1016/j.jacc.2025.04.059.PubMed ↗
- Packer M, Zile MR, Kramer CM, Murakami M, Ou Y, Borlaug BA; SUMMIT Trial Study Group. Interplay of Chronic Kidney Disease and the Effects of Tirzepatide in Patients With Heart Failure, Preserved Ejection Fraction, and Obesity: The SUMMIT Trial. J Am Coll Cardiol. 2025 May 13;85(18):1721-1735. doi: 10.1016/j.jacc.2025.03.009. Epub 2025 Mar 31.PubMed ↗
- Kramer CM, Borlaug BA, Zile MR, Ruff D, DiMaria JM, Menon V, Ou Y, Zarante AM, Hurt KC, Murakami M, Packer M; SUMMIT Trial Study Group. Tirzepatide Reduces LV Mass and Paracardiac Adipose Tissue in Obesity-Related Heart Failure: SUMMIT CMR Substudy. J Am Coll Cardiol. 2025 Feb 25;85(7):699-706. doi: 10.1016/j.jacc.2024.11.001. Epub 2024 Nov 18.PubMed ↗
View Official Medical/Scientific Title
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Comparing the Efficacy and Safety of Tirzepatide Versus Placebo in Patients With Heart Failure With Preserved Ejection Fraction and Obesity (SUMMIT)