GLP-1 drugs and heart failure with preserved ejection fraction

Heart failure comes in two broad types. In reduced ejection fraction, the heart muscle pumps weakly. In preserved ejection fraction (HFpEF), it pumps normally but is stiff and fills poorly. HFpEF is common, it is strongly linked to obesity, and for years almost nothing improved how people with it felt or how long they lived. People with obesity-related HFpEF typically describe breathlessness, swollen ankles and an inability to walk far.

That made it a natural target for the GLP-1 drugs. Three trials have reported.

The trials at a glance

The KCCQ-CSS is the Kansas City Cardiomyopathy Questionnaire clinical summary score, a 0 to 100 scale of symptoms and physical limitation. Higher is better.

STEP-HFpEF: semaglutide without diabetes

529 people with HFpEF and a BMI of 30 or more were randomised to semaglutide 2.4 mg or placebo for 52 weeks. The two primary end points were symptoms and weight. KCCQ-CSS rose 16.6 points on semaglutide against 8.7 on placebo, an estimated difference of 7.8 points. Weight fell 13.3 percent against 2.6 percent.

The secondary results moved the same way. Six-minute walk distance improved by 21.5 metres against 1.2 (difference 20.3 m). CRP, an inflammation marker, fell 43.5 percent against 7.3 percent. Serious adverse events were reported in 13.3 percent on semaglutide and 26.7 percent on placebo.

STEP-HFpEF DM: the same question with diabetes

616 people with HFpEF, obesity and type 2 diabetes. The pattern repeated with slightly smaller numbers, which is typical: people with diabetes usually lose less weight on these drugs. KCCQ-CSS rose 13.7 against 6.4 points (difference 7.3), weight fell 9.8 against 3.4 percent, and walk distance improved by 14.3 metres more than placebo. Serious adverse events: 17.7 against 28.8 percent.

Neither STEP trial was large or long enough to test whether semaglutide reduces hospital admissions or deaths from heart failure. Pooled and secondary analyses have looked at events, but the primary results are about how people felt and functioned.

SUMMIT: tirzepatide and hard events

SUMMIT was built to test events. 731 people with heart failure, an ejection fraction of at least 50 percent and a BMI of at least 30 were randomised to tirzepatide up to 15 mg or placebo, with a median follow-up of 104 weeks.

The composite of cardiovascular death or a worsening heart failure event occurred in 36 people on tirzepatide (9.9 percent) and 56 on placebo (15.3 percent), a hazard ratio of 0.62. Almost all of that came from worsening heart failure events, 8.0 against 14.2 percent (HR 0.54). Cardiovascular deaths were few in both groups, 8 against 5, too few to say anything either way (HR 1.58, 95% CI 0.52 to 4.83). At 52 weeks KCCQ-CSS had risen 19.5 points on tirzepatide against 12.7 on placebo.

Adverse events leading to stopping the drug were 6.3 percent on tirzepatide and 1.4 percent on placebo, mainly gastrointestinal.

The honest reading is that SUMMIT is encouraging but small for an outcome trial. 92 events in total is enough to cross statistical significance and not much more, and the confidence interval runs from a 59 percent to a 5 percent reduction.

Where approval stands

Neither company has a specific HFpEF indication on its US label as of the reports below. Novo Nordisk withdrew its US filing for semaglutide in HFpEF in August 2024, after discussions with the FDA, which reportedly wanted more events to substantiate a treatment effect, and said it would resubmit with additional data. In Europe, the EMA's committee gave a positive opinion in September 2024 to add the STEP-HFpEF symptom results to the Wegovy label. Lilly withdrew its US tirzepatide HFpEF application in 2025 after the FDA indicated an additional trial was needed; Lilly noted that the people in SUMMIT are already covered by the obesity indication. Check the current label for any change since.

In practice that last point matters. Someone with HFpEF and a BMI of 30 or more already qualifies for Wegovy or Zepbound under the weight management indication. The HF trials tell the cardiologist what to expect.

Practical points

• Fluid shifts. People with heart failure often take diuretics. Vomiting, diarrhoea and eating less on a GLP-1 can lead to dehydration and low blood pressure, so diuretic doses may need review as weight falls. That is the cardiologist's call.
• Weight is a heart failure signal. In heart failure, a sudden gain of a kilo or two over a few days usually means fluid, not fat. On a GLP-1 the trend should be down; a jump against the trend is worth a call.
• Muscle. Physical function was a key outcome in these trials. Protein and some resistance work protect it. The muscle loss page covers how.

For the broader cardiovascular evidence, see the SELECT and heart trials page. For kidney function, which travels with heart failure, see the kidney page.

With heart failure, daily weight matters more than weekly weight. A morning weigh-in, the dose, ankle swelling, breathlessness on a set walk and diuretic doses on one timeline let a fluid gain stand out from the downward trend. The free GLP-1 tracker keeps the dose, the weight, side effects and, on Premium, lab results on one timeline, so the numbers your prescriber asks about are in one place rather than spread across portals and notes. It is free to download.