The key point: The SUMMIT trial showed that tirzepatide (Mounjaro, a dual GIP/GLP-1 agonist, up to 15 mg/week) reduced the risk of the composite outcome of cardiovascular death or a worsening heart failure event by 38% in patients with HFpEF and obesity (HR 0.62; 95% CI 0.41-0.95; P=0.026). Quality of life also improved significantly. However, cardiovascular death alone was numerically more frequent with tirzepatide than with placebo, and a protocol amendment changed the primary outcomes during the trial.
Clinical context: why test tirzepatide in HFpEF
Most patients with heart failure with preserved ejection fraction (HFpEF) also have obesity. Visceral adiposity directly contributes to disease progression, inducing systemic inflammation that spreads to the myocardium through epicardial adipose tissue. HFpEF risk increases progressively with body mass index (BMI).
Two previous semaglutide trials (STEP-HFpEF and STEP-HFpEF DM) suggested that GLP-1 agonism could reduce symptoms and potentially decrease adverse heart failure events. However, these findings came from exploratory analyses with only 52 weeks of follow-up.
Tirzepatide is a long-acting agonist of the GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide type 1, glucagon-like peptide-1) receptors. In obesity and diabetes trials, it produces weight loss of 12 to 21%. SUMMIT was designed to assess its long-term effects on cardiovascular outcomes in HFpEF.
Key SUMMIT study data
- N = 731 patients (364 tirzepatide, 367 placebo) at 129 centers in 9 countries
- Median follow-up: 104 weeks (2 years)
- Primary composite outcome (CV death or worsening HF): HR 0.62 (95% CI 0.41-0.95; P=0.026). Incidence: 9.9% vs 15.3%
- KCCQ-CSS at 52 weeks: difference of 6.9 points (95% CI 3.3-10.6; P<0.001)
- Weight loss: −13.9% vs −2.2% (difference −11.6 pp; P<0.001)
- CV death alone: HR 1.58 (95% CI 0.52-4.83). Events: 8 vs 5
Study design
SUMMIT was an international, double-blind, randomized, placebo-controlled trial (NCT04847557). Recruitment took place between April 20, 2021 and June 30, 2023.
Inclusion criteria
Men and women aged at least 40 years with chronic heart failure (NYHA II to IV), left ventricular ejection fraction ≥50% and BMI ≥30 were included. Patients also needed a 6-minute walk test (6MWT) distance between 100 and 425 meters and a KCCQ-CSS score ≤80.
At least one additional criterion was required: elevated NT-proBNP (>200 pg/mL in sinus rhythm or >600 pg/mL in atrial fibrillation), left atrial enlargement on echocardiography, or elevated filling pressures at rest or during exercise. Patients also had to have had HF decompensation in the preceding 12 months or an estimated glomerular filtration rate <70 mL/min/1.73 m².
Intervention
Tirzepatide was started at 2.5 mg subcutaneously each week, with increases of 2.5 mg every 4 weeks up to a maximum dose of 15 mg/week after 20 weeks. Background HF treatment could be adjusted at the treating physician's discretion.
Protocol amendment: changes to the primary outcomes
The trial originally had two primary outcomes: (1) a hierarchical composite combining all-cause death, worsening HF events, change in KCCQ-CSS and 6MWT distance; and (2) change in 6MWT distance at 52 weeks.
In August 2023, after publication of STEP-HFpEF suggested a substantial reduction in events with GLP-1 agonism (observed HR 0.08, based on 13 events), the steering committee proposed separating the components of the hierarchical composite into two distinct primary outcomes. Following discussions with the FDA, the outcomes were revised approximately 1 year before the end of the trial, while investigators and the sponsor remained unaware of the unblinded data.
The two final primary outcomes were: (1) a composite of adjudicated cardiovascular death or a worsening HF event, analyzed as time to first event (alpha allocation 0.04); and (2) change in KCCQ-CSS at 52 weeks (alpha allocation 0.01). Deaths from undetermined causes were classified as cardiovascular deaths.
Main results
Baseline characteristics
The mean age was 65.2 years, 53.8% were women and mean BMI was 38.3. The mean baseline KCCQ-CSS score was 53.5 points and mean 6MWT distance was 302.8 meters. Approximately 46.9% of patients had been hospitalized or treated urgently for worsening HF in the preceding 12 months. Atrial fibrillation was present in approximately 25% of patients. Median baseline NT-proBNP was 196 pg/mL in the tirzepatide group and 169 pg/mL in the placebo group.
Primary composite outcome
Cardiovascular death or a worsening HF event occurred in 36 patients (9.9%) in the tirzepatide group and 56 patients (15.3%) in the placebo group (HR 0.62; 95% CI 0.41-0.95; P=0.026). Worsening HF events alone occurred in 29 patients (8.0%) versus 52 (14.2%) with placebo (HR 0.54; 95% CI 0.34-0.85). Hospitalization for worsening HF occurred in 12 (3.3%) versus 26 (7.1%), respectively (HR 0.44; 95% CI 0.22-0.87).
Cardiovascular and all-cause mortality
Adjudicated cardiovascular death occurred in 8 patients (2.2%) in the tirzepatide group and 5 (1.4%) in the placebo group (HR 1.58; 95% CI 0.52-4.83). There were also 2 deaths of undetermined cause, both in the tirzepatide group, which were counted as cardiovascular deaths in the primary composite outcome. In total, 15 deaths were classified as cardiovascular; of these, 11 were not preceded by worsening HF, and 2 (both in the tirzepatide group) occurred more than 15 months after discontinuation of the study medication. Death from any cause occurred in 19 patients on tirzepatide and 15 on placebo (HR 1.25; 95% CI 0.63-2.45).
Quality of life and secondary outcomes
Mean change in KCCQ-CSS at 52 weeks was 19.5 points with tirzepatide versus 12.7 with placebo (median difference 6.9; 95% CI 3.3-10.6; P<0.001). Weight loss was −13.9% versus −2.2% (difference −11.6 percentage points; 95% CI −12.9 to −10.4; P<0.001). 6MWT distance increased by 26.0 m versus 10.1 m (median difference 18.3 m; 95% CI 9.9-26.7; P<0.001). High-sensitivity C-reactive protein decreased by −38.8% versus −5.9% (difference −34.9 pp; 95% CI −45.6 to −22.2; P<0.001).
Safety
Serious adverse events occurred at similar frequencies in both groups. Nonfatal adverse events leading to discontinuation occurred in 23 patients (6.3%) on tirzepatide and 5 (1.4%) on placebo. Gastrointestinal symptoms were the main reason: 15 patients (4.1%) in the tirzepatide group discontinued for this reason, compared with none in the placebo group.
Limitations and points to consider
Protocol amendment during the trial
The change in primary outcomes, although made without access to efficacy data and before any interim analysis, occurred approximately 1 year before the trial ended. This change inevitably raises questions about inferential integrity, even though the process was transparent and discussed with the FDA.
Cardiovascular death signal
Cardiovascular death was numerically more frequent with tirzepatide (10 vs 5 events; HR 1.58), although not statistically significant and with a small absolute number. The authors argue that most of these deaths were not preceded by worsening HF, consistent with the observation that CV death in HFpEF often does not reflect heart failure progression. In addition, deaths of undetermined cause (2, both in the tirzepatide group) were counted as cardiovascular deaths, unlike in other HFpEF trials.
Low baseline NT-proBNP
Median baseline NT-proBNP was below 200 pg/mL, substantially lower than in the STEP-HFpEF trials with semaglutide. The trial did not require elevated natriuretic peptide as a mandatory criterion, arguing that many patients with obesity-related HFpEF have normal NT-proBNP despite elevated filling pressures. This decision broadens the target population but makes direct comparison with other trials harder.
BMI criterion and limited representativeness
The trial included only patients with BMI ≥30. However, many patients with HFpEF and excess visceral adiposity have a BMI below 30 but an abnormal waist-to-height ratio (>0.5), a more reliable indicator of visceral adiposity. The authors themselves acknowledge this limitation and indicate the need for studies in this population.
What this means for clinical practice
SUMMIT is the first randomized trial to prospectively demonstrate that an incretin receptor agonist reduces worsening heart failure events as a primary outcome in patients with HFpEF and obesity. The magnitude of benefit (38% relative reduction in the composite, with an HR of 0.44 for HF hospitalization) is clinically relevant and adds to consistent improvements in quality of life, functional capacity and inflammatory markers.
The effects probably arise from reduced fat mass and the resulting decrease in plasma volume expansion and inflammatory response underlying HFpEF pathophysiology. The 34.9 percentage-point reduction in C-reactive protein supports this hypothesis. The presence of GIP receptors in epicardial adipose tissue suggests that dual GIP/GLP-1 agonism may have additional anti-inflammatory effects on adjacent cardiac tissue.
However, the cardiovascular death signal and protocol amendment require cautious interpretation. Long-term trials of GLP-1 agonists in diabetes and obesity show reduced CV and all-cause mortality, making a real harmful effect of tirzepatide unlikely. Definitive confirmation, however, will require additional data from larger studies with longer follow-up.
My perspective as an electrophysiologist: SUMMIT reinforces the idea that treating obesity is treating heart failure. In my practice, I frequently see patients with atrial fibrillation and HFpEF in whom obesity is the common denominator. Around 25% of the SUMMIT population had AF, and subgroup analyses showed consistent benefit regardless of the HFpEF-ABA score (which incorporates a history of AF). I believe incretin agonists should enter the joint treatment discussion for HF and AF associated with obesity. The CV death signal deserves monitoring, but it does not invalidate a robust clinical benefit on worsening HF events and quality of life.
