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Trial · Interventional

CompletedPhase 3Results postedRegistry data

A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes

Short name SOUL

NCTNCT03914326 (opens ClinicalTrials.gov in a new tab)Other idEX9924-4473Other id2018-003141-42Other idU1111-1218-5368Other id2018

Overview

Status
Completed
Phase
Phase 3
Enrollment
9,651 participants (actual)
Sponsor
Novo Nordisk A/S · Industry
Design
Randomized · Quadruple masking
Countries
30 countries

United States, Algeria, Argentina, Austria, Belgium, Brazil, Canada, China, Colombia, Croatia, Czechia, Denmark, France, Germany, Hong Kong, India, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Taiwan

Start
17 Jun 2019
Primary completion
23 Aug 2024
Completion
23 Aug 2024
First posted
16 Apr 2019
Last update posted
11 Dec 2025
Conditions
Diabetes Mellitus, Type 2

Timeline

1 trial · 1 completed · 1 with posted results

  • Completed
  • Ongoing
  • Not yet recruiting
  • Stopped
  • Estimated dates (est.)
  • Results posted
2019202020212022202320242025
  1. Ph 3

    SOUL

    NCT03914326

    17 Jun 2019 to 23 Aug 2024

Registry summary

Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.

The researchers are doing this study to look whether the type 2 diabetes medicine, semaglutide, has a positive effect on heart disease. Participants will either get semaglutide tablets or placebo tablets ("dummy" medicine) - which treatment is decided by chance. Participants must take one tablet with water every morning on an empty stomach and not eat or drink anything for at least 30 minutes. The study will last for about 3.5-5 years. Participants will have up to 25 clinic visits and 1 phone call with the study doctor. Women cannot be in the study if pregnant, breast-feeding or if they plan to become pregnant during the study period.

Interventions

  • SemaglutideDrug
  • Placebo (semaglutide)Drug

Arms2

  • Experimental

    Oral semaglutide

    One tablet daily for 3.5 to 5 years

  • Placebo comparator

    Placebo

    One tablet daily for 3.5 to 5 years

Primary outcomes1

Outcomes the sponsor listed as primary.

  1. Number of Participants From Randomization to First Occurrence of a Major Adverse Cardiovascular Event (MACE), a Composite Endpoint Consisting of: Cardiovascular (CV) Death/Non-fatal Myocardial Infarction/Non-fatal Stroke

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    Number of participants with first occurrence of EAC (event adjudication committee) confirmed major adverse cardiovascular event (MACE), a composite end-point. i.e., from time of randomization to first occurrence of cardiovascular (CV) death, non-fatal myocardial infarction and non-fatal stroke combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Secondary outcomes(20)
  1. Number of Participants From Randomization to First Occurrence of CV Death;Renal Death;Onset of Persistent≥50% Reduction in eGFR(CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73m^2;Initiation of Chronic Renal Replacement Therapy

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    Number of participants with first occurrence of a composite endpoint. i.e., from time of randomization to first occurrence of CV death, renal death, onset of persistent greater than or equal to (≥) 50% reduction in estimated glomerular filtration rate (eGFR) (chronic kidney disease epidemiology collaboration CKD-EPI), onset of persistent eGFR (CKD-EPI) less than (\<)15 milliliters per minute per 1.73 square meters (mL/min/1.73 m\^2), initiation of chronic renal replacement therapy (dialysis or kidney transplantation) combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  2. Number of Participants From Randomization to Time of Occurrence of CV Death

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    Number of participants from time of randomization to time to occurrence of EAC confirmed CV death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  3. Number of Participants From Randomization to First Occurrence of Major Adverse Limb Events (MALE), a Composite Endpoint Consisting of: Acute Limb Ischemia Hospitalisation/Chronic Limb Ischemia Hospitalisation

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    Number of participants from randomization to first occurrence of EAC confirmed major adverse limb events (MALE), a composite endpoint consisting of: acute limb ischemia hospitalisation/chronic limb ischemia hospitalisation combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  4. Number of Participants From Randomisation to First Occurrence of an Expanded MACE Composite Endpoint Consisting of: CV Death/Non-fatal Myocardial Infarction/ Non-fatal Stroke/Coronary Revascularisation/Unstable Angina Pectoris Requiring Hospitalisation

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of an expanded MACE composite endpoint consisting of: CV death/non-fatal myocardial infarction/ non-fatal stroke/coronary revascularisation/unstable angina pectoris requiring hospitalisation combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  5. Number of Participants From Randomisation to First Occurrence of a Composite Endpoint Consisting of : All-cause Death/ Non-fatal MI/ Non-fatal Stroke

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of EAC confirmed composite endpoint consisting of : all-cause death/ non-fatal MI/ non-fatal stroke combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  6. Number of Participants From Randomisation to First Occurrence of a Composite Heart Failure Endpoint Consisting of: CV Death/Heart Failure Requiring Hospitalisation/Urgent Heart Failure Visit

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    Number of participants from randomisation to first occurrence of EAC confirmed composite heart failure endpoint consisting of: CV death/heart failure requiring hospitalisation/urgent heart failure visit combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death

  7. Number of Participants From Randomization to First Occurrence of CKD Endpoint:Renal Death;Onset of Persistent≥50% Reduction in eGFR (CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73 m^2;Initiation of Chronic Renal Replacement Therapy

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomization to first occurrence of CKD endpoint:renal death;onset of persistent≥50% reduction in eGFR (CKD-EPI);onset of persistent eGFR(CKD-EPI)\<15 mL/min/1.73 m\^2;initiation of chronic renal replacement therapy combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  8. Number of Participants From Randomisation to Time to Occurrence of All-cause Death

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to time to occurrence of EAC confirmed all-cause death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  9. Number of Participants From Randomisation to First Occurrence of Non-fatal Myocardial Infarction (MI)

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of EAC confirmed non-fatal MI during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  10. Number of Participants From Randomisation to First Occurrence of Non-fatal Stroke

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of EAC confirmed non-fatal stroke during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  11. Number of Participants From Randomisation to First Occurrence of Heart Failure Requiring Hospitalisation or Urgent Heart Failure Visit

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of EAC confirmed heart failure requiring hospitalisation or urgent heart failure visit during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  12. Number of Participants From Randomisation to First Occurrence of Coronary Revascularisation

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of coronary revascularisation during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  13. Number of Participants From Randomisation to First Occurrence of Unstable Angina Requiring Hospitalisation

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of EAC confirmed unstable angina requiring hospitalisation during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  14. Number of Participants From Randomisation to Time to Occurrence of Renal Death

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to time to occurrence of EAC confirmed renal death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  15. Number of Participants From Randomisation to First Occurrence of Onset of Persistent 50% or More Reduction in eGFR

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of onset of persistent 50% or more reduction in eGFR during in-trial period were observed. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  16. Number of Participants From Randomisation to First Occurrence of Onset of Persistent eGFR (CKD-EPI) Below 15 mL/Min/1.73 m^2

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of onset of persistent eGFR (CKD-EPI) below 15 mL/min/1.73 m\^2 during in-trial period were observed. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  17. Number of Participants From Randomisation to First Occurrence of Initiation of Chronic Renal Replacement Therapy (Dialysis or Kidney Transplantation)

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of EAC confirmed initiation of chronic renal replacement therapy (dialysis or kidney transplantation) during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  18. Number of Participants From Randomisation to First Occurrence of Acute Limb Ischemia

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of EAC confirmed acute limb ischaemia hospitalization during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  19. Number of Participants From Randomisation to First Occurrence of Chronic Limb Ischemia Hospitalisation

    Time frame · From randomisation (week 0) up to week 265

    Registry description

    The number of participants from randomisation to first occurrence of EAC confirmed chronic limb ischaemia hospitalization during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

  20. Annual Rate of Change in eGFR (CKD-EPI) (Total eGFR Slope)

    Time frame · From randomisation (week 0) up to week 260

    Registry description

    Annual rate of change in eGFR in terms of chronic kidney disease CKD-EPI were reported during in trial period. eGFR was calculated using the CKD-EPI formula. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Posted results

Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.

Primary outcome results

Primary outcomeCount of participants· From randomisation (week 0) up to week 265

Number of Participants From Randomization to First Occurrence of a Major Adverse Cardiovascular Event (MACE), a Composite Endpoint Consisting of: Cardiovascular (CV) Death/Non-fatal Myocardial Infarction/Non-fatal Stroke

GroupValue (Participants)
Oral Semaglutide579
Placebo668
Secondary and other outcome results(7)
Secondary outcomeCount of participants· From randomisation (week 0) up to week 265

Number of Participants From Randomization to First Occurrence of CV Death;Renal Death;Onset of Persistent≥50% Reduction in eGFR(CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73m^2;Initiation of Chronic Renal Replacement Therapy

GroupValue (Participants)
Oral Semaglutide403
Placebo435
Secondary outcomeCount of participants· From randomisation (week 0) up to week 265

Number of Participants From Randomization to Time of Occurrence of CV Death

GroupValue (Participants)
Oral Semaglutide301
Placebo320
Secondary outcomeCount of participants· From randomisation (week 0) up to week 265

Number of Participants From Randomization to First Occurrence of Major Adverse Limb Events (MALE), a Composite Endpoint Consisting of: Acute Limb Ischemia Hospitalisation/Chronic Limb Ischemia Hospitalisation

GroupValue (Participants)
Oral Semaglutide71
Placebo99
Secondary outcomeCount of participants· From randomisation (week 0) up to week 265

Number of Participants From Randomisation to First Occurrence of an Expanded MACE Composite Endpoint Consisting of: CV Death/Non-fatal Myocardial Infarction/ Non-fatal Stroke/Coronary Revascularisation/Unstable Angina Pectoris Requiring Hospitalisation

GroupValue (Participants)
Oral Semaglutide670
Placebo777
Secondary outcomeCount of participants· From randomisation (week 0) up to week 265

Number of Participants From Randomisation to First Occurrence of a Composite Endpoint Consisting of : All-cause Death/ Non-fatal MI/ Non-fatal Stroke

GroupValue (Participants)
Oral Semaglutide779
Placebo902
Secondary outcomeCount of participants· From randomisation (week 0) up to week 265

Number of Participants From Randomisation to First Occurrence of a Composite Heart Failure Endpoint Consisting of: CV Death/Heart Failure Requiring Hospitalisation/Urgent Heart Failure Visit

GroupValue (Participants)
Oral Semaglutide405
Placebo443
Secondary outcomeCount of participants· From randomisation (week 0) up to week 265

Number of Participants From Randomization to First Occurrence of CKD Endpoint:Renal Death;Onset of Persistent≥50% Reduction in eGFR (CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73 m^2;Initiation of Chronic Renal Replacement Therapy

GroupValue (Participants)
Oral Semaglutide112
Placebo129

Adverse events, as posted

Adverse events as posted: participants affected out of participants at risk, by group
GroupDeathsSerious eventsOther events
Oral SemaglutideParticipants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).528 / 48252312 / 48251761 / 4825
PlaceboParticipants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).579 / 48252427 / 48251599 / 4825

Each cell reads participants affected / participants at risk, as the registry posted them.

Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works

Studies7

Studies that cite this trial.

Studies with results

6 studies on this page

Indexing hint: Randomized controlled trial · 2026

5 results

Impact of Oral Semaglutide on Kidney Outcomes in People With Type 2 Diabetes: Results From the SOUL Randomized Trial.

Mann et al. 2026Diabetes carecited by 9

PMID 41380027PMC12824789DOI 10.2337/dc25-1080PUB-41380027

Rights unknown5 results

Indexing hint: Randomized controlled trial · 2026

7 results

Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial.

Pop-Busui et al. 2026JAMA internal medicinecited by 8

PMID 41627802PMC12865694DOI 10.1001/jamainternmed.2025.7774PUB-41627802

Free to read · publisher termsCC BY-NC-ND7 results

Indexing hint: Randomized controlled trial · 2026

11 results

Oral Semaglutide and Change in Cardiovascular Risk Factors in High-Risk Type 2 Diabetes: A Post Hoc Secondary Analysis of the SOUL Randomized Clinical Trial.

Mulvagh et al. 2026JAMA cardiologycited by 3

PMID 41879791PMC13019341DOI 10.1001/jamacardio.2026.0245PUB-41879791

Free to read · publisher termsCC BY-NC-ND11 results

Indexing hint: Meta-analysis (pooled) · 2025

15 results

Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes.

Natale et al. 2025The Cochrane database of systematic reviewscited by 8

PMID 39963952PMC11834151DOI 10.1002/14651858.cd015849.pub2PUB-39963952

Rights unknown15 results

Indexing hint: Randomized controlled trial · 2025

6 results

Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial.

Marx et al. 2025Circulationcited by 49

PMID 40156843PMC12144549DOI 10.1161/circulationaha.125.074545PUB-40156843

Free to read · publisher termsCC BY-NC-ND6 results

Indexing hint: Randomized controlled trial · 2025

4 results

Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes.

McGuire et al. 2025The New England journal of medicinecited by 252

PMID 40162642DOI 10.1056/nejmoa2501006PUB-40162642

Full text at the publisher4 results

More studies

1 study on this page

PubMed tag: none · 2026

Prevalence and Associations of Systemic Inflammation in Heart Failure Across the Spectrum of Ejection Fraction.

Borlaug et al. 2026JACC. Heart failurecited by 10

PMID 41099689PMC12614479DOI 10.1016/j.jchf.2025.102712PUB-41099689

Rights unknown
Source link

Eligibility

Who could join, as posted.

Sex
All
Age
from 50 Years
Healthy volunteers
Not accepted
Inclusion and exclusion criteria, as posted
Inclusion Criteria: * Male or female, age equal to or above 50 years at the time of signing informed consent * Diagnosed with type 2 diabetes mellitus * HbA1c 6.5% - 10.0% (47 - 86 mmol/mol) (both inclusive) (latest available and no more than 30 days old local laboratory assessment based on medical records or point of care measurement) * At least one of the below conditions (a-d): a) Coronary heart disease defined as at least one of the following: i. Prior myocardial infarction ii. Prior coronary revascularisation procedure iii. 50% or above stenosis in coronary artery documented by cardiac catheterisation, computerized tomography coronary angiography iv. Coronary heart disease with ischaemia documented by stress test with any imaging modality b) Cerebrovascular disease defined as at least one of the following: i. Prior stroke ii. Prior carotid artery revascularisation procedure iii.50% or above stenosis in carotid artery documented by X-ray angiography, magnetic resonance angiography, computerized tomography angiography or Doppler ultrasound c) Symptomatic peripheral artery disease (PAD) defined as at least one of the following: i. Intermittent claudication with an Ankle-brachial index (ABI) below 0.85 at rest ii. Intermittent claudication with a 50% or above stenosis in peripheral artery (excluding carotid) documented by X-ray angiography, magnetic resonance angiography, computerized tomography angiography or Doppler ultrasound iii. Prior peripheral artery (excluding carotid) revascularization procedure iv. Lower extremity amputation at or above ankle due to atherosclerotic disease (excluding e.g. trauma or osteomyelitis) d) Chronic kidney disease defined as: i. eGFR below 60 mL/min/1.73 m\^2 (based on medical records using latest available and no more than 6 months old assessment) Exclusion Criteria: * Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening * Planned coronary, carotid or peripheral artery revascularisation known on the day of screening * Heart failure presently classified as being in New York Heart Association Class IV * Treatment with any glucagon-like peptide-1 receptor agonist within 30 days before screening

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