2023 Top Story in Diabetes: The STEP-HFpEF Trial
Heart failure with preserved ejection fraction (HFpEF) is common, representing more than half of all cases of heart failure. Moreover, it is likely underdiagnosed and growing alongside the epidemic of obesity, which contributes to the pathophysiology of the condition. The STEP-HFpEF trial tested the hypothesis that high-dose semaglutide (2.4 mg SC weekly), a very potent GLP-1 receptor agonist, could improve symptoms and physical limitations in patients with HFpEF compared with placebo over 52 weeks. Symptoms and physical limitations were measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), a 23-item instrument that queries physical symptoms, physical function, quality of life, and social function. The dual primary endpoint of the STEP-HFpEF trial was the change in the KCCQ-CSS and percentage change in body weight from baseline to week 52.
The KCCQ is a valid and sensitive instrument that captures heart failure symptoms and is associated with heart failure events over time. It has been approved by the FDA as a Clinical Outcome Assessment that functions as a standardized history. It is scaled from 0 to 100, with lower scores reflecting more severe symptoms and functional limitations, and 100 indicating no symptoms or limitations with excellent quality of life. Scores from 0 to 24 represent very poor to poor health, 25 to 49 represent poor to fair, 50 to 75 represent fair to good, and 75 to 100 represent good to excellent health. A 5-point change in the score is considered to be small but clinically relevant.1 Although the symptoms queried by the KCCQ are common in heart failure, many are not specific to heart failure. For example, symptoms that are common in obesity without heart failure such as difficulty in walking, overall fatigue, and shortness of breath are included.
The STEP-HFpEF trial enrolled 529 adults with left ventricular (LV) ejection fraction of 45% or greater, BMI of 30 kg/m2 or greater, New York Heart Association class II, III, or IV symptoms, and a KCCQ-CSS of less than 90, and at least one other indicator of HF (elevated LV filling pressures, elevated natriuretic peptide levels, or hospitalization for heart failure within the last 12 months), plus treatment with diuretics or echocardiographic abnormalities. Patients with diagnosed diabetes or HbA1c greater than or equal to 6.5% were excluded.
Participants had median age of 69 years and were 96% White and 56% female. The baseline KCCQ-CSS was 69, and median baseline body weight was 105 kg (BMI, 37 kg/m2). The trial reported an improvement in KCCQ-CSS from baseline to week 52 of 16.6 points (moderate effect) in the semaglutide arm and 8.7 points (small to moderate effect) in the placebo arm. The corresponding change in body weight was −13.3% in the semaglutide arm and −2.6% in the placebo arm (both P < .001). Secondary endpoints were favorable and supportive, including an increased 6-minute walk distance, reduction in CRP, reduction in NT-proBNP, and reduction in hospitalization or urgent visit for heart failure (1 vs 12; HR, 0.08, 95% CI, 0.00–0.42).
This STEP-HFpEF trial is important because it demonstrates that treating obesity substantially improves heart failure symptoms along with weight. While semaglutide almost certainly has cardiovascular benefit independent of weight loss, weight reduction in the setting of HFpEF clearly impacts the pathophysiology of the condition. In a recent analysis, investigators reported that improvements in the KCCQ-CSS, 6-minute walk distance, and CRP were greater with greater weight reduction.2 The trial is also significant for its use of an FDA-approved, validated patient-reported outcome measure as a component of the primary outcome, which is appropriate given the severity of heart failure symptoms, their significant impact on quality of life, and the correlation of the instrument with clinical outcomes. The results of this trial, along with the finding of heart failure benefit in the much larger SELECT trial,3 Dr. Inzucchi’s Top Story of the Year, are likely to substantially expand the indication for treating obesity with semaglutide in patients with ASCVD and heart failure, even in the absence of type 2 diabetes.
Disclosure: DSMB for Novo Nordisk
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Additional Info
- Spertus JA, Jones PG, Sandhu AT, Arnold SV. Interpreting the Kansas City Cardiomyopathy Questionnaire in Clinical Trials and Clinical Care: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;76(20):2379-2390.
- Borlaug BA, Kitzman DW, Davies MJ, et al. Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial. Nat Med. 2023;29(9):2358-2365.
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;10.1056/NEJMoa2307563.
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