Summary: In a prespecified secondary analysis of the pooled STEP-HFpEF and STEP-HFpEF DM trials (1,145 randomised; 71% with C-reactive protein at least 2 mg/L), once-weekly semaglutide 2.4 mg over 52 weeks improved heart-failure symptoms, body weight, and 6-minute walk distance consistently across baseline inflammation categories, with all interaction P values nonsignificant. Semaglutide also lowered CRP more than placebo irrespective of baseline CRP (P interaction = 0.32) or magnitude of weight loss (P interaction = 0.91).
PICO Summary
| Element | Detail |
|---|---|
| Population | 1,145 adults with obesity-related HFpEF pooled from two international, double-blind, placebo-controlled randomised trials (STEP-HFpEF and STEP-HFpEF DM); stratified by baseline CRP (<2, ≥2 to <10, and ≥10 mg/L). 71% had CRP ≥2 mg/L. |
| Intervention | Once-weekly subcutaneous semaglutide 2.4 mg for 52 weeks. |
| Comparison | Matching placebo once weekly over the same 52 weeks. |
| Outcome | Improvements in KCCQ-CSS, body weight, 6-minute walk distance, and the hierarchical composite (death, HF events, KCCQ-CSS and 6MWD change) were consistent across all three baseline CRP categories (all P interaction nonsignificant). Semaglutide reduced CRP more than placebo regardless of baseline CRP (P interaction = 0.32), and CRP change was similar regardless of weight-loss magnitude (P interaction = 0.91). No 95% CIs, absolute risk reduction, or NNT were reported for this interaction-focused secondary analysis. |
Expert Commentary
This secondary analysis is best read as reassurance rather than discovery. The primary STEP-HFpEF findings already established that semaglutide 2.4 mg improves symptoms, function, and weight in obesity-related HFpEF; here the question is whether those benefits depend on how inflamed a patient is at baseline. The answer is that they do not. Across CRP strata, the treatment effect was preserved, and every interaction test was nonsignificant. That consistency is clinically useful, because it means a high CRP need not be treated as a reason to expect more or less benefit. The verdict is that semaglutide works across the inflammatory spectrum studied, and the additional CRP-lowering signal, independent of weight loss, is biologically interesting and hypothesis-generating. The central limitation is that nonsignificant interaction tests in subgroups are underpowered by design and cannot prove the absence of effect modification; this is an associational, exploratory layer on top of the trials, not a new outcome trial. Industry involvement also warrants caution, as the manufacturer co-authored and funded the work. Can I use this with my patients? Yes, for an adult with obesity-related HFpEF who already meets the trial profile, an elevated CRP should not change the decision to consider semaglutide. Confirmatory dedicated anti-inflammatory endpoint trials would strengthen the mechanistic claim.
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