Drug Update · Cardiology

Semaglutide Cuts HF Event Risk 31% in HFpEF (HR 0·69)

July 10, 2026

HFpEF subgroup size

3743 of 22 282 participants (16·8%) [1]

Semaglutide vs placebo (composite endpoint)

103 [5·4%] of 1914 vs 138 [7·5%] of 1829; HR 0·69 (95% CI 0·53-0·89); p=0·0045 [1]

Worsening HF events

54 [2·8%] vs 86 [4·7%]; HR 0·59 (0·41-0·82); p=0·0019 [1]

Cardiovascular death alone

59 [3·1%] vs 67 [3·7%]; HR 0·82 (0·57-1·16); p=0·25 [1]

Serious adverse events in HFpEF subgroup

572 [29·9%] semaglutide vs 708 [38·7%] placebo [1]

Clinical Perspective

Cardiologists, heart failure specialists, and clinicians managing patients with obesity-related HFpEF may consider these pooled data when evaluating the potential role of semaglutide for patients with HFpEF who meet the populations described in the component trials. The source-confirmed data support a reduced risk of the composite endpoint of cardiovascular death or worsening heart failure events and a reduction in worsening heart failure events alone in patients with HFpEF treated with semaglutide versus placebo. Which HFpEF patients derive the greatest absolute benefit and how semaglutide integrates with contemporary HFpEF management remain open clinical questions?

Dr. Arjun Sharma · Cardiology

Semaglutide (Wegovy) reduced the risk of the composite of cardiovascular death or first worsening heart failure event by 31% in patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF) in a pooled participant-level analysis of SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials (HR 0·69; 95% CI 0·53-0·89) ^[1]. In the HFpEF subgroup, 103 [5·4%] of 1914 semaglutide-treated patients had the combined event versus 138 [7·5%] of 1829 placebo-treated patients ^[1].

Clinical Context

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist marketed as WEGOVY by Novo Nordisk and available as subcutaneous and oral formulations per prescribing information ^[2]^[3]. The pooled analysis focused on patients with a history of HFpEF enrolled across four large randomized, placebo-controlled trials, including the STEP-HFpEF studies that enrolled participants with obesity-related HFpEF and investigator-reported HFpEF cases identified within SELECT and FLOW ^[1]. WEGOVY currently carries multiple FDA indications in its label, and its safety profile and common adverse reactions are described in the prescribing information ^[2]^[3].

Key Findings

The pooled participant-level analysis of SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM showed semaglutide reduced the risk of the composite endpoint of cardiovascular death or first worsening heart failure event by 31% versus placebo in patients with HFpEF (HR 0·69; 95% CI 0·53-0·89; p=0·0045). In this subgroup, 103 [5·4%] of 1914 semaglutide patients had events versus 138 [7·5%] of 1829 placebo patients ^[1].
Semaglutide also reduced the risk of worsening heart failure events alone (hospitalisation or urgent visit due to heart failure): 54 [2·8%] versus 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019 ^[1].
No statistically significant effect on cardiovascular death alone was seen in the pooled HFpEF subgroup: 59 [3·1%] versus 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25 ^[1].
Across the four trials, the HFpEF subset comprised 3743 (16·8%) of 22 282 participants, with 1914 randomly assigned to semaglutide and 1829 to placebo ^[1].

Safety & Tolerability

In the pooled HFpEF subgroup, a lower proportion of patients treated with semaglutide experienced serious adverse events than did those treated with placebo: 572 [29·9%] versus 708 [38·7%] ^[1].
The WEGOVY prescribing information lists the most common adverse reactions (incidence ≥5%) as nausea, diarrhea, vomiting, constipation, abdominal pain, dysesthesia, headache, fatigue, dyspepsia, dizziness, abdominal distension, eructation, hypoglycemia in patients with type 2 diabetes, flatulence, gastroenteritis, gastroesophageal reflux disease, and hair loss ^[2].

Study Design

The reported results derive from a post-hoc pooled, participant-level analysis of four randomized, placebo-controlled trials: SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM; the analysis included all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW ^[1]. Once-weekly subcutaneous semaglutide dosing in the component trials was 2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM and 1·0 mg in FLOW, as reported in the pooled analysis ^[1]. Clinicians should consult current prescribing information for full dosing guidance. The main outcomes were time to cardiovascular death or first worsening heart failure event, time to first worsening heart failure event, and time to cardiovascular death; efficacy and safety endpoints were analysed in the full analysis set using intention-to-treat principles ^[1].

FAQ

Q1 What did the pooled analysis of SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM show?

The pooled participant-level analysis found that semaglutide reduced the risk of the composite of cardiovascular death or first worsening heart failure event by 31% in patients with a history of HFpEF (HR 0·69; 95% CI 0·53-0·89; p=0·0045). Semaglutide also reduced worsening heart failure events alone (HR 0·59; 95% CI 0·41-0·82; p=0·0019) while showing no significant reduction in cardiovascular death alone (HR 0·82; 95% CI 0·57-1·16; p=0·25).

Q2 Who was enrolled in the pooled HFpEF analysis?

The HFpEF subgroup comprised 3743 of 22 282 participants enrolled across the four trials; 1914 were assigned to semaglutide and 1829 to placebo. The STEP-HFpEF and STEP-HFpEF DM trials enrolled participants with obesity-related HFpEF, SELECT enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and FLOW enrolled participants with type 2 diabetes and chronic kidney disease; for the pooled HFpEF analysis, all STEP-HFpEF participants and investigator-reported HFpEF cases from SELECT and FLOW were included.

Q3 What were the side effects in the trials and label?

In the pooled HFpEF subgroup a smaller proportion of semaglutide-treated patients experienced serious adverse events than placebo (572 [29·9%] vs 708 [38·7%]). The WEGOVY label lists common adverse reactions (≥5%) including nausea, diarrhea, vomiting, constipation, abdominal pain, dysesthesia, headache, fatigue, dyspepsia, dizziness, abdominal distension, eructation, hypoglycemia in patients with type 2 diabetes, flatulence, gastroenteritis, gastroesophageal reflux disease, and hair loss. Clinicians should consult current prescribing information for complete dosing guidance.

Q4 What does this pooled analysis mean for clinical practice?

The pooled, participant-level data support an association between semaglutide treatment and lower risk of the composite of cardiovascular death or worsening heart failure events, and lower risk of worsening heart failure events alone, in patients with a history of HFpEF enrolled across these trials. These findings raise specific questions about patient selection, duration of benefit, and integration with established HFpEF therapies that require prospective, dedicated HFpEF trials and further subgroup analyses.

Clinicians should consult current prescribing information for complete dosing guidance.

Semaglutide Cuts HF Event Risk 31% in HFpEF (HR 0·69)

Semaglutide Cuts HF Event Risk 31% in HFpEF (HR 0·69)

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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