STEP-HFpEF: Measuring How People Actually Feel
Last verified May 2026 · Phase 3 · Finished; published September 2023 · NCT04788511 ↗
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
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| 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 meters | Estimated 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 semaglutide | Reference | Win 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 0.57 | Ratio to baseline 0.92 | Estimated 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 participants | Class improvement in 27.6% of participants | Odds 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 0.85 | Ratio to baseline 1.01 | Estimated 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 mmHg | Estimated 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/m² | Estimated treatment difference −3.8 kg/m² (95% CI −4.2 to −3.3) |
Adverse events
| Event | Treatment rate | Comparator 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 events | Lower |
| 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 discontinuations | Lower |
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 556 sellers on this register, 283 publish a standing monthly cash price for compounded semaglutide, from $79 a month, with a median of $174.
⛔ 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
References
- 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.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.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.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.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.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.