GLP-1 Research in
Obesity-Related HFpEF

Heart failure with preserved ejection fraction (HFpEF) means the heart’s left-ventricular ejection fraction—the percentage of blood pumped out with each beat—is preserved, yet congestion, breathlessness, fatigue, and activity limits can still occur. These studies address adults with obesity and symptomatic HFpEF who met their entry criteria; they are not a verdict for everyone with heart failure. For general weight-treatment context, see Luma Health’s GLP-1 real-world effectiveness guide and treatment information.

What STEP-HFpEF and SUMMIT studied

STEP-HFpEF randomized 529 adults with HFpEF and BMI of at least 30 kg/m² to weekly semaglutide 2.4 mg or placebo for 52 weeks. The registry specifies New York Heart Association class II–IV symptoms and ejection fraction of at least 45%; it excluded hemoglobin A1c at least 6.5%, so it was not a core type 2 diabetes population. Its two primary outcomes were Kansas City Cardiomyopathy Questionnaire clinical-summary score (KCCQ-CSS) and body weight.^{[1] [3]}

SUMMIT randomized 731 adults with HFpEF, BMI of at least 30 kg/m², and additional clinical/functional criteria to weekly tirzepatide, up to 15 mg, or placebo. Participants had stable symptomatic heart failure, ejection fraction of at least 50%, KCCQ-CSS of 80 or less, and six-minute walk distance of 100–425 meters. Median follow-up was 104 weeks. Its two primary endpoints were time to first adjudicated cardiovascular death or worsening-HF event and KCCQ-CSS change at week 52.^{[2] [4]}

Symptoms and function: what STEP-HFpEF found

KCCQ-CSS is a 0-to-100 patient-reported symptoms/physical-limitations score; higher scores indicate better health status. At 52 weeks, mean change was +16.6 points with semaglutide and +8.7 with placebo, a +7.8-point difference. Mean body-weight change was −13.3% with semaglutide versus −2.6% with placebo, a difference of −10.7 percentage points. Six-minute walk distance changed by +21.5 meters and +1.2 meters, respectively, a difference of +20.3 meters.^[1]

The trial’s confirmatory hierarchical composite—ordering death, heart-failure events, KCCQ-CSS, and walking-distance differences—favored semaglutide with a win ratio of 1.72. It should not be simplified into a claim that STEP-HFpEF proved a standalone reduction in hospitalization, cardiovascular death, or all clinical events. Its co-primary outcomes were health status and body weight. Serious adverse events were reported in 13.3% of semaglutide participants and 26.7% of placebo participants; group results do not guarantee individual safety or benefit.^[1]

Clinical events: what SUMMIT found

SUMMIT provides the event outcome that STEP-HFpEF was not designed to answer as a primary endpoint. The composite of cardiovascular death or worsening heart failure occurred in 36 of 364 participants (9.9%) assigned tirzepatide and 56 of 367 (15.3%) assigned placebo. That is an absolute difference of 5.4 percentage points. The hazard ratio was 0.62 (95% confidence interval 0.41–0.95), an approximate 38% relative reduction in the hazard of a first composite event during follow-up.^[2]

The components matter. Worsening-heart-failure events occurred in 8.0% with tirzepatide and 14.2% with placebo (hazard ratio 0.54). Cardiovascular deaths occurred in 2.2% and 1.4%, respectively; the hazard ratio was 1.58 with a 95% confidence interval of 0.52–4.83. Those small numbers and wide interval mean SUMMIT should not be described as proving fewer cardiovascular deaths. At week 52, KCCQ-CSS improved by 19.5 points with tirzepatide and 12.7 with placebo, for a between-group difference of 6.9 points. Gastrointestinal adverse events led to trial-drug discontinuation in 6.3% and 1.4%, respectively.^[2]

Current approval is different from HFpEF research

Research results and FDA approval are different questions. The current Wegovy label lists, among other indications, long-term weight reduction/maintenance and a cardiovascular-risk-reduction indication for adults with established cardiovascular disease and obesity or overweight. That cardiovascular indication concerns major adverse cardiovascular events—cardiovascular death, nonfatal heart attack, or nonfatal stroke—not treatment of HFpEF. The current label does not list HFpEF as an indication.^{[5] [7]}

The current Zepbound label lists long-term weight reduction/maintenance for adults meeting its labeled weight criteria and treatment of moderate-to-severe obstructive sleep apnea in adults with obesity. It also does not list HFpEF as an indication.^[6] The studies discussed here concern the named medicines and trial programs. They do not establish the quality, safety, bioequivalence, effectiveness, or HFpEF outcomes of a compounded preparation.

What these results do not mean

Neither study says that HFpEF is cured or that a GLP-1–based medicine replaces established cardiology care. A heart-failure team may still need to address blood pressure, rhythm disorders, kidney disease, diabetes, sleep apnea, volume status, other medicines, and contributing conditions. Do not start, stop, or change a heart-failure medicine, diuretic, or GLP-1/GIP-GLP-1 medicine because of an article or a study percentage.

These findings also do not generalize to heart failure with reduced ejection fraction (HFrEF). The eligibility thresholds differed even within HFpEF: STEP-HFpEF used ejection fraction of at least 45%, whereas SUMMIT used at least 50% and additional criteria. The trials were not head-to-head, used different medicines and endpoints, and enrolled carefully screened participants. No cross-trial percentage can identify a “better” choice for one person.^{[1] [2] [3] [4]}

Both current labels have important product-specific contraindications and warnings. A personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 is a contraindication for each product. Severe gastrointestinal reactions, pancreatitis, gallbladder disease, volume-depletion-related kidney injury, hypersensitivity, and considerations around anesthesia or deep sedation are among the issues in the labels. A clinician and pharmacist need the full medication list, history, symptoms, and procedure plans—not just a diagnosis or BMI.^{[5] [6]}

Questions for a cardiology and prescribing conversation

1. Is my diagnosis documented as HFpEF, and what is my ejection fraction? Ask what may be causing symptoms and which findings guide the treatment plan.
2. Do I resemble either study population? Discuss obesity, symptom burden, diabetes status, kidney function, current medicines, and the specific trial criteria—not only a single BMI number.
3. Which goal is realistic and measurable? Clarify whether the priority is symptoms, daily activity, fluid-related events, weight, or another outcome, and how it will be monitored.
4. What established HF care continues? Confirm the cardiology plan, monitoring, and who to contact before any medicine is changed.
5. Which product-specific risks matter to me? Review thyroid-cancer history, gastrointestinal history, hydration, other medicines, and any upcoming anesthesia or sedation.

New or worsening shortness of breath, ankle swelling, or rapid weight change can signal fluid buildup in people with HF and should be reported according to the care team’s plan.^{[8] [9]} Call 911 immediately for severe chest pain, difficulty breathing, fainting or unconsciousness, stroke symptoms, severe allergic-reaction symptoms, or another life-threatening emergency. Do not wait for a routine telehealth or medication visit.^[10]

Frequently asked questions