Semaglutide in patients with heart failure with reduced ejection fraction: safety and effectiveness – a target trial emulation

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Effectiveness study (incl. comparative)

  Method development or testing

  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

  Other
• Non-interventional study design, other:
  target trial emulation

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  SEMAGLUTIDE
• Anatomical Therapeutic Chemical (ATC) code:
  (A10BJ06) semaglutide

  semaglutide
• Medical condition to be studied:
  Heart failure with reduced ejection fraction

  Obesity

Population studied

• Short description of the study population:
  Adult patients with heart failure with reduced ejection fraction (HFrEF) and obesity in New York Heart Association (NYHA) classes II-IV.
• Age groups:
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)
• Special population of interest:
  Frail population

  Hepatic impaired

  Renal impaired

Study design details

• Study design:
  1) Design of a target trial (i.e. a randomised controlled trial protocol); 2) Emulation of the target trial with real-world data
• Main study objective:
  To evaluate effectiveness and safety of semaglutide in patients with heart failure with reduced ejection fraction (HFrEF) and obesity.
• Setting:
  TARGET TRIAL; The hypothetical target trial would most likely be conducted as a multi-centre, international trial. For further details, please refer to the uploaded target trial protocol (file: 2025-11-04a GLP-1 RA target trial protocol_Part Ib). ; ; EMULATED TRIAL; Patients registered to the Swedish Heart Failure Registry (SwedeHF) by participating healthcare centres in Sweden. Further details will be provided as soon as the observational study protocol is finalised.
• Comparators:
  TARGET TRIAL; Standard of care for HF incl. dietary and lifestyle advice for weight reduction plus: completely inert placebo, subcutaneous injection.; ; EMULATED TRIAL; Further details will be provided as soon as the observational study protocol is finalised.
• Outcomes:
  TARGET TRIAL; Co-primary endpoint (efficacy); • Time to first worsening heart failure event (i.e. heart failure hospitalisation or urgent out-patient visit due to heart failure) or cardiovascular death (efficacy / superiority); ; Co-primary endpoint (safety); • Time to first all-cause hospitalisation or all-cause death (safety / non-inferiority; ; For secondary and exploratory outcomes, please refer to the uploaded target trial protocol (file: 2025-11-04a GLP-1 RA target trial protocol_Part Ib).; ; EMULATED TRIAL; Further details will be provided as soon as the observational study protocol is finalised.
• Data analysis plan:
  TARGET TRIAL; Please refer to the uploaded target trial protocol (file: 2025-11-04a GLP-1 RA target trial protocol_Part Ib).; ; EMULATED TRIAL; Further details will be provided as soon as the observational study protocol is finalised.
• Summary results:
  The study group reached a consensus on the target trial protocol on November 1, 2025, after review by an external expert. The protocol was uploaded to the HMA-EMA Catalogues (file: 2025-11-04a GLP-1 RA target trial protocol_Part Ib).; The study group started working on the emulation into the observational study on November 10, 2025, after the target trial protocol had been finalised.