Summary: In a secondary, pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials (n=1,145), 71% of participants with obesity-related HFpEF had baseline C-reactive protein (CRP) of 2 mg/L or higher. Once-weekly semaglutide 2.4 mg improved heart failure symptoms, body weight, and 6-minute walk distance consistently across baseline CRP strata (all P for interaction nonsignificant), and lowered CRP more than placebo regardless of baseline inflammation or the magnitude of weight loss.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 adults with obesity-related heart failure with preserved ejection fraction (HFpEF), stratified by baseline CRP (<2, ≥2 to <10, and ≥10 mg/L); pooled secondary analysis of two international, double-blind, placebo-controlled randomised trials (STEP-HFpEF and STEP-HFpEF DM). 71% had CRP ≥2 mg/L. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks. |
| Comparison | Matching once-weekly placebo for 52 weeks. |
| Outcome | Effect modification by baseline inflammation, not a fresh efficacy test. Semaglutide improved the dual primary endpoints (KCCQ-CSS health status and body weight), 6-minute walk distance, and the hierarchical composite consistently across CRP strata, with all P for interaction nonsignificant (KCCQ-CSS P interaction = 0.34). Semaglutide reduced CRP more than placebo across all baseline CRP categories (P interaction = 0.32), and the CRP reduction was similar irrespective of weight-loss magnitude (P interaction = 0.91). The analysis reports interaction tests; absolute between-group effect sizes with 95% CI are reported in the parent trials, not re-derived here. |
Expert Commentary
This is a secondary, hypothesis-generating analysis rather than a new efficacy trial, and it should be read as such. Its question is one of effect modification: does baseline systemic inflammation, indexed by CRP, change how well semaglutide works in obesity-related HFpEF? The answer is reassuringly negative. Across CRP strata, the symptomatic, functional, and weight benefits were preserved, with nonsignificant interaction terms throughout, and semaglutide lowered CRP independently of how much weight was lost, which hints at an anti-inflammatory action only partly mediated by adiposity. The chief caveat is statistical: subgroup interaction tests in a pooled sample of this size are underpowered, so a nonsignificant P for interaction confirms the absence of a large modifier, not the absence of any. Inflammation here is also a single biomarker measured once, and the analysis is associational, so mechanism remains inferred. Industry sponsorship by the manufacturer, Novo Nordisk, with several authors employed by the sponsor, warrants the usual circumspection. Can I use this with my patients? Yes, in a practical sense: it supports offering semaglutide to an eligible obese HFpEF patient without first checking or worrying about their CRP, since the benefit appears uniform. The figures should prompt prospective work testing whether the CRP-lowering effect translates into hard cardiovascular outcomes.
References
Verma S, Petrie MC, Borlaug BA, et al. Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program. J Am Coll Cardiol. 2024;84(17):1646-1662. doi:10.1016/j.jacc.2024.08.028