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STEP-HFpEF: Measuring How People Actually Feel

Last verified May 2026 · Phase 3 · Finished; published September 2023 · NCT04788511 ↗

By Ruth Calder · Enforcement Editor
Editorially reviewed (not clinically reviewed). Not medical advice · How we verify contentLast reviewed

Patient-reported outcomes are sometimes treated as softer evidence than mortality, and in heart failure that view is hard to defend: the disease is defined largely by what it stops people doing. The KCCQ is validated, scored 0 to 100, and widely used precisely because it captures the thing patients bring to the clinic. STEP-HFpEF also reported improvement in six-minute walk distance, an objective measure moving in the same direction, which makes the symptomatic finding harder to dismiss as expectation.

Enrollment
529
Duration
52 weeks of treatment plus 5 weeks of follow-up after the drug stopped
Drug
Semaglutide 2.4 mg (Wegovy)
Population
Adults 18 and over with heart failure of the preserved-ejection-fraction type — a pumping fraction of 45% or higher — with symptoms limiting them day to day, a BMI of 30 or above, a symptom score below 90 indicating real burden, and the ability to walk at least 100 meters in six minutes. Type 2 diabetes was an exclusion. ⚠ This was an older and sicker group than the weight trials enroll: median age 69, median weight 105.1 kg at a BMI of 37.0, and 56% women. About 80% were already on diuretics and fewer than 5% on an SGLT2 inhibitor at the start.

Primary endpoint

How much better people said they felt after a year, on a validated heart-failure questionnaire

Treatment arm

+16.6 points

Comparator

+8.7 points

Treatment difference: Estimated treatment difference +7.8 points (95% CI 4.8 to 10.9; P<0.001)

★ Five points on this scale is the usual bar for a change a patient would notice. The gap between the two arms alone was nearly eight, and the drug group improved by 16.6 — the largest symptom effect any randomized drug trial in this condition had produced at the time.

Secondary endpoints

EndpointTreatmentComparatorDifference
How much body weight came off

13.3%, close to what the same drug achieves in ordinary weight trials — notable given this group was older, sicker and mostly on diuretics.

−13.3%−2.6%Estimated treatment difference −10.7 percentage points (95% CI −11.9 to −9.4; P<0.001)
How much further people could walk in six minutes

★ The row that makes the symptom result hard to dismiss. Questionnaires can move on expectation; walking distance is measured with a stopwatch, and it moved 21.5 meters against essentially nothing — comparable to what cardiac rehabilitation achieves.

+21.5 meters+1.2 metersEstimated treatment difference +20.3 meters (95% CI 8.6 to 32.1; P<0.001)
A combined ranking of deaths, heart-failure events, symptom improvement and walking distance

⚠ The win ratio of 1.72 favors the drug, but read where the wins came from: symptoms and walking distance, not deaths or hospitalizations. This trial was not built to count events.

Win ratio 1.72 favoring semaglutideReferenceWin ratio 1.72 (95% CI 1.37 to 2.15; P<0.001)
Inflammation in the blood

Down about 39% against almost nothing on placebo, which supports the idea that obesity-driven inflammation is part of what causes this form of heart failure rather than just accompanying it.

Ratio to baseline 0.57Ratio to baseline 0.92Estimated treatment ratio 0.61 (95% CI 0.51 to 0.72; P<0.001)
How many people improved enough to notice

⚠ Worth reading both columns: 61.4% of the placebo group also improved by at least 5 points. Heart-failure symptoms fluctuate, and trial participation itself changes care.

76.7%61.4%Odds ratio favored semaglutide; nominal P<0.001 per the publication
Lost at least a tenth of body weight

63.2% against 8.0% on placebo.

63.2%8.0%Odds ratio favored semaglutide; nominal P<0.001 per the publication
Moved up a functional class — the standard grading of how limited someone is

★ Two in five moved up a class, generally from being limited by ordinary activity to being comfortable with it. This is the plainest translation of what the questionnaire numbers mean.

Class improvement in 41.8% of participantsClass improvement in 27.6% of participantsOdds ratio 2.17 (95% CI 1.50 to 3.16); nominal P<0.001
NT-proBNP, the blood marker of cardiac strain

⚠ Down modestly, and by less than SGLT2 inhibitors achieve in the same condition. That fits a drug working through weight and inflammation rather than through fluid.

Ratio to baseline 0.85Ratio to baseline 1.01Estimated treatment ratio 0.84 (95% CI 0.74 to 0.95); nominal P=0.006 per the publication
Top blood-pressure number

Down 3 points against no change on placebo.

−3.0 mmHg+0.2 mmHgEstimated treatment difference −3.2 mmHg (95% CI −5.5 to −1.0)
BMI points lost

Nearly 5 points, against under 1 on placebo.

−4.7 kg/m²−0.9 kg/m²Estimated treatment difference −3.8 kg/m² (95% CI −4.2 to −3.3)

Adverse events

EventTreatment rateComparator rate
Any serious adverse event

★ Half the placebo rate — 13.3% against 26.7% — and the difference was mostly fewer serious cardiac events. A drug arm with fewer serious events than placebo is unusual and worth registering.

13.3% (35/263)26.7% (71/266)
Stopped the drug because of a side effect

⚠ The mirror image of the row above: 13.3% against 5.3%, almost all stomach and bowel effects during dose escalation. Fewer serious problems, more people giving up.

13.3% (35/263)5.3% (14/266)
Stomach and bowel problems

Nausea and diarrhea led, mostly mild to moderate, clustered into the 16 weeks of dose increases — the same pattern as every trial of this drug.

Higher with semaglutide; nausea and diarrhea were the most common individual eventsLower
Serious cardiac events

★ 2.7% against 10.9% — a fourfold difference. The authors flag it as a signal worth testing rather than a finding, because this trial was not designed or sized to count cardiac events. It is the reason the event-driven trials matter.

2.7% (7/263)10.9% (29/266)
Quit for good over stomach and bowel problems

The leading reason anyone stopped, consistent with the rest of this drug's program.

Reported as the leading category of discontinuationsLower

Clinical significance

This trial drove the 2024 EMA and FDA filings for semaglutide in HFpEF with obesity and is the clearest evidence in the class for symptomatic rather than purely preventive benefit. ⚠ It measures symptoms, not survival — SUMMIT is the trial that measured events, in the same disease with the other drug. Read as a pair, they are stronger than either alone.

Who sells semaglutide, and for how much

This trial tested Semaglutide 2.4 mg (Wegovy). Across the 584 sellers on this register, 327 publish a standing monthly cash price for compounded semaglutide, from $59 a month, with a median of $175.

⛔ None of those sellers was in this trial. A compounded preparation is not the product studied here: no agency has reviewed that specific preparation for safety, effectiveness or manufacturing quality, and its concentration is set by whichever pharmacy filled it. The result above is the strongest evidence available for semaglutide and it was generated on something else. Every seller, with its price record.

Frequently Asked Questions

On its primary endpoint — How much better people said they felt after a year, on a validated heart-failure questionnaire — the treatment arm recorded +16.6 points against +8.7 points for the comparator. Estimated treatment difference +7.8 points (95% CI 4.8 to 10.9; P<0.001). ★ Five points on this scale is the usual bar for a change a patient would notice. The gap between the two arms alone was nearly eight, and the drug group improved by 16.6 — the largest symptom effect any randomized drug trial in this condition had produced at the time.
529 participants, over 52 weeks of treatment plus 5 weeks of follow-up after the drug stopped. It was a Phase 3 trial, finished; published September 2023. Registered as NCT04788511, which you can look up yourself rather than taking anyone's summary for it.
Adults 18 and over with heart failure of the preserved-ejection-fraction type — a pumping fraction of 45% or higher — with symptoms limiting them day to day, a BMI of 30 or above, a symptom score below 90 indicating real burden, and the ability to walk at least 100 meters in six minutes. Type 2 diabetes was an exclusion. ⚠ This was an older and sicker group than the weight trials enroll: median age 69, median weight 105.1 kg at a BMI of 37.0, and 56% women. About 80% were already on diuretics and fewer than 5% on an SGLT2 inhibitor at the start. ⚠ A trial result describes the population it was measured in. If you differ from it materially — in age, in baseline weight, in whether you have diabetes — the number is context rather than a prediction.
The most commonly reported were any serious adverse event (13.3% (35/263) against 26.7% (71/266) on comparator), stopped the drug because of a side effect (13.3% (35/263) against 5.3% (14/266) on comparator), stomach and bowel problems (Higher with semaglutide; nausea and diarrhea were the most common individual events against Lower on comparator). ★ Half the placebo rate — 13.3% against 26.7% — and the difference was mostly fewer serious cardiac events. A drug arm with fewer serious events than placebo is unusual and worth registering. Rates come from this trial's population under its own dose-escalation schedule; a faster or slower titration changes what people experience.
Secondary endpoints included how much body weight came off (−13.3% against −2.6%); how much further people could walk in six minutes (+21.5 meters against +1.2 meters); a combined ranking of deaths, heart-failure events, symptom improvement and walking distance (Win ratio 1.72 favoring semaglutide against Reference). ⚠ Secondary endpoints are weaker evidence than the primary one — a trial is powered for its primary outcome, and the rest are read as supporting rather than as findings in their own right.
No, and this matters because the number gets used that way. STEP-HFpEF tested Semaglutide 2.4 mg (Wegovy) — the FDA-approved product, made by its manufacturer under Good Manufacturing Practice, at the doses and schedule the protocol specified. A compounded preparation of semaglutide is a different product: no agency has reviewed that specific preparation for safety, effectiveness or manufacturing quality, and its concentration is set by whichever pharmacy filled it. ⛔ A seller quoting this trial's result beside a compounded price is quoting evidence that was generated on something they are not selling. That is not the same as saying compounded semaglutide does not work — it is saying nobody measured it here.
It cannot tell you that. A trial reports an average across a defined population under a fixed protocol, with monitoring and adherence support most people do not get. It is the best evidence available and it is still a distribution rather than a promise — some participants lost far more than the mean and some lost nothing. What it is genuinely good for is comparing options against each other, which is what the rest of this section is for.

References

  1. 1.Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al.; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023. PMID: 37622681.
  2. 2.U.S. National Library of Medicine. Research Study on How Well Semaglutide Works in People Living With Heart Failure and Obesity (STEP-HFpEF) — Study Results. ClinicalTrials.gov, NCT04788511. 2023. https://clinicaltrials.gov/study/NCT04788511
  3. 3.Kosiborod MN, Petrie MC, Borlaug BA, et al.; STEP-HFpEF DM Trial Committees and Investigators. Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes. N Engl J Med. 2024. PMID: 38587233.
  4. 4.Butler J, Shah SJ, Petrie MC, et al. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet. 2024. PMID: 38599221.
  5. 5.Novo Nordisk Inc. WEGOVY (semaglutide) injection — Prescribing Information. DailyMed (NIH/NLM). 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ee06186f-2aa3-4990-a760-757579d8f77b
  6. 6.Packer M, Zile MR, Kramer CM, et al.; SUMMIT Trial Study Group. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025. PMID: 39555826.

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