August 30, 2024The Lancet
Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials
Key result
Semaglutide reduces CV death or worsening heart failure ~31% vs. placebo in HFpEF.
- HR 0.69
- 95% CI 0.53-0.89
- P=0.0045
- n=3,743
Why the study?
Few treatment options exist to reduce clinical heart failure events in patients with HFpEF, especially those with overweight, obesity, or type 2 diabetes.
Does once-weekly subcutaneous semaglutide reduce the risk of cardiovascular death or worsening heart failure events in patients with HFpEF?
Key Points
- To determine whether semaglutide reduces clinical heart failure events and cardiovascular death in patients with heart failure and mildly reduced or preserved ejection fraction.
- Conducted a post-hoc pooled participant-level analysis of four completed randomized, placebo-controlled trials (SELECT [NCT03574597], FLOW [NCT03819153], STEP-HFpEF [NCT04788511], and STEP-HFpEF DM [NCT04916470]).
- Included 3743 participants with a history of heart failure with mildly reduced or preserved ejection fraction assigned to weekly subcutaneous semaglutide (1.0 mg or 2.4 mg) or placebo.
- Evaluated the composite outcome of cardiovascular death or first worsening heart failure event, as well as each component separately, using intention-to-treat analysis.
- Semaglutide significantly reduced the composite endpoint of cardiovascular death or worsening heart failure events compared with placebo (103 [5.4%] of 1914 vs 138 [7.5%] of 1829; HR 0.69 [95% CI 0.53-0.89]; p=0.0045).
- Worsening heart failure events occurred in 54 (2.8%) participants on semaglutide versus 86 (4.7%) on placebo (HR 0.59 [95% CI 0.41-0.82]; p=0.0019).
- Cardiovascular death occurred in 59 (3.1%) participants in the semaglutide group compared with 67 (3.7%) in the placebo group (HR 0.82 [95% CI 0.57-1.16]; p=0.25).
Study Design
Type
Meta-Analysis (n=3,743)
Blinding
placebo-controlled
Randomization
randomised
Multicenter
Yes
Structured PICO
Does once-weekly subcutaneous semaglutide reduce the risk of cardiovascular death or worsening heart failure events in patients with HFpEF?
P
Population
3,743 participants with a history of heart failure with mildly reduced or preserved ejection fraction (HFpEF) and overweight, obesity, or type 2 diabetes pooled from four randomized trials.
I
Intervention
Semaglutide subcutaneous once-weekly (2.4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1.0 mg in FLOW)
C
Comparator
Placebo
O
Outcome
Composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure)composite
Main Result
Hazard Ratio: 0.69 (95% CI 0.53–0.89)
Absolute Event Rate: 5.4% vs 7.5%
p-value: p=0.0045
In patients with mildly reduced or preserved ejection fraction, semaglutide safely and significantly reduced the composite risk of cardiovascular death or worsening heart failure events.
Limitations
- Post-hoc analysis
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Due in part to the obesity epidemic, HFpEF has emerged as the most common type of heart failure. Patients with obesity-related HFpEF are at high risk for serious complications including hospitalizations and death, and have limited treatment options. Collectively, this new analysis is the most comprehensive evaluation of semaglutide to date that assesses clinically relevant HF events, such as CV death and hospitalization.”
Implication
Semaglutide lowers CV death or worsening HF events in HFpEF; extends prior symptom benefits to clinical outcomes in obesity-related disease.
Abstract
BACKGROUND Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established. METHODS We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete. FINDINGS Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%]). INTERPRETATION In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or worsening heart failure events, and worsening heart failure events alone, whereas its effect on cardiovascular death alone was not significant. These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available.
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Cite This Study
Kosiborod et al. (2024) conducted a meta-analysis in Heart failure with mildly reduced or preserved ejection fraction (HFpEF) (n=3,743). Semaglutide vs. Placebo was evaluated on Composite endpoint of time to cardiovascular death or first worsening heart failure event (HR 0.69, 95% CI 0.53-0.89, p=0.0045). In patients with HFpEF, semaglutide significantly reduced the risk of the composite of cardiovascular death or worsening heart failure events by 31% compared with placebo (HR 0.69).