Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program.
Level 2 - randomized trial
Secondary pooled analysis of two randomized controlled trials
PubMed 39217564 · doi:10.1016/j.jacc.2024.08.028
What was done
This was a secondary pooled analysis of 1,145 participants from two international, double-blind, placebo-controlled randomized trials (STEP-HFpEF and STEP-HFpEF DM) evaluating weekly semaglutide 2.4 mg versus placebo over 52 weeks in obesity-related heart failure with preserved ejection fraction (HFpEF). Patients were stratified by baseline C-reactive protein (CRP) categories (<2, ≥2 to <10, and ≥10 mg/L). Authors evaluated whether baseline CRP modified the therapeutic effects on dual primary endpoints (Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score [KCCQ-CSS] and body weight), 6-minute walk distance (6MWD), a hierarchical composite clinical endpoint, and CRP change, and examined whether CRP reduction depended on weight loss magnitude.
What was found
Inflammation (CRP ≥2 mg/L) was present in 71% of patients at baseline and was associated with younger age, female sex, higher body mass index, worse KCCQ-CSS, and shorter 6MWD. Semaglutide reduced heart failure symptoms, physical limitations, and body weight, while improving 6MWD and the hierarchical composite endpoint consistently across baseline CRP strata (all P-interaction non-significant; absolute numerical effect sizes not reported in abstract). Semaglutide decreased CRP more than placebo across all baseline CRP categories (P-interaction = 0.32), and the 52-week CRP reduction was similar regardless of the magnitude of weight loss (P-interaction = 0.91).
Why it matters
Systemic inflammation is highly prevalent in obesity-related HFpEF, and semaglutide provides consistent clinical, functional, and anti-inflammatory benefits across varying baseline inflammation levels. The anti-inflammatory effect appears partly uncoupled from the absolute amount of weight lost.
Limits
This is a secondary post hoc analysis rather than a prospectively powered trial stratified for baseline inflammation. Inflammation was assessed solely via CRP without broader biomarker panels. The abstract reports interaction P-values but omits specific numerical point estimates and confidence intervals for subgroup outcomes, and follow-up was limited to 52 weeks.
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