STEP-HFpEF: Semaglutide in patients with HF & ejection fraction >=45% & obesity, with or without diabetes

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Pooled analysis of STEP-HFpEF & STEP-HFpEF DM. Lancet 2024

STEP-HFpEF main paper. NEJM 2023;389:1069-84.

STEP-HFpEF DM main paper. NEJM 2024;390:1394-407.

Bottom line: In patients with symptomatic HF, ejection fraction >=45% & BMI >=30, semaglutide improved quality of life & reduced weight (average ~11% weight loss at 1 year), but increased the risk of discontinuation due to GI intolerance. For every 100 patients treated for 1 year, 12 patients will get a noticeable improvement in their quality of life because of semaglutide, & 8 patients will discontinue it due to intolerable side-effects (mostly gastrointestinal).

Patients (n=1145 randomized)

  • 13 countries, 2021-2022

  • Included:

    • Age >=18 years

    • Symptomatic (NYHA 2-4) HF with left ventricular ejection fraction >=45%

    • At least one of the following:

      • Elevated LV filling pressures;

      • Elevated BNP/NTproBNP plus echocardiographic abnormalities;

      • HF hospitalization in the last 12 months, plus ongoing treatment with diuretics OR echo abnormalities

    • BMI >=30

    • Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Summary Score (CSS) <90/100

    • 6-minute walk distance (6MWD) >=100 meters

    • STEP-HFpEF excluded patients with diabetes (prior dx, A1c >=6.5% at screening), whereas STEP-HFpEF DM required types 2 diabetes & A1c <=10%

  • Key exclusions:

    • ESRD or dialysis dependence

  • Baseline:

    • Age 70 y, male ~50%

    • White 90%, Black 4%

    • LVEF median 57% (45-49% in 16%)

    • NYHA 2 (69%), 3 (31%)

    • KCCQ-CSS median 59/100, 6MWD median 295 meters

    • HF hospitalization in last year 17%

    • Weight median 104 kg, BMI median 37 (66% BMI >=35)

    • Comorbidities: AF 45%, CAD 21%, HTN 84%

    • Meds: Loop diuretic 62%, ACE/ARB/ARNI 79%, beta-blocker 81%, MRA 34%, SGLT2i 20% (4% in those without T2DM)

Intervention: Semaglutide subcutaneous once weekly at “weight loss doses”

  • Starting dose: 0.25 mg q1w

  • Titration: Uptitrated every 4 weeks (to 0.5 -> 1.0 -> 1.7 -> 2.4 mg q1w) as tolerated

  • Target dose: 2.4 mg q1w (reached after 16 weeks)

    • 84% of those still taking the drug at 1 year received the target dose

Comparator: Matching placebo

Outcomes @ median 1.1 year

Co-primary outcomes: Mean change from baseline to week 52:

  • KCCQ-CSS mean difference +7.5

    • Clinically-important improvement (>=5-point improvement) in KCCQ-CSS: 74% vs 57% (+17%)

      • >=10-point improvement: 61% vs 43% (+18%)

    • Consistent mean improvement over placebo across KCCQ-Overall Summary Score (+7.4) & across all sub-scores

  • Weight mean difference -8.4% or -8.9 kg (greater weight loss in non-diabetic patients)

    • >=20% reduction: 12.2% vs 1.2% (NNT ~9)

Key secondary outcomes

  • 6MWD: mean +17 meters with semaglutide vs placebo

  • Exploratory composite (time to first HF hospitalization, urgent visit, or CV death): 2% vs 6% (hazard ration 0.31, 95% confidence interval 0.15-0.62)

Safety

  • Serious adverse events: Semaglutide 28.7 vs 52.7 %/y

  • Discontinued due to GI adverse events: 10.7 vs 3.3 %/y

Internal validity = low risk of bias

  • Computer-generated random sequence generation

  • Allocation concealment by centralized interactive web-based response system

  • Blinding by matching placebo & titration schedule

  • Intention-to-treat analysis

  • Loss to follow-up (LTFU): KCCQ data missing for 8% on semaglutide & 11% on placebo at 1 year

Generalizability & other considerations

  • Similar improvement (no significant treatment-subgroup interaction) in QoL with semaglutide across studied LVEF in mildly-reduced/preserved range (45% to >=60%)

  • In STEP-HFpEF, similar improvement in QoL with semaglutide regardless of BMI (but all >=30), but KCCQ-CSS improvement in the semaglutide group was associated with weight loss >=5%

    • Impossible to say whether lesser KCCQ improvement in patients who lost <5% of their body weight due to an actual cause-effect relationship between weight loss & QoL improvement, or whether this is confounded by some other factor (e.g. lower adherence to semaglutide could explain lack of both weight loss & QoL improvement)

  • Individual-patient-level meta-analysis of patients with HFmrEF/HFpEF in STEP-HFpEF, STEP-HFpEF-DM, SELECT, and FLOW trials

    • Reduction in HF composite (time to first worsening HF or CV death): HR 0.69 (0.53-0.89); absolute risk reduction ~0.9%/y

    • But no significant reduction in CV death (HR 0.82, 0.57-1.16)