← Trials/Trial dossier/NCT03914326

SOUL

CompletedPhase 3Results posted

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

Semaglutide Cardiovascular Outcomes Trial in Patients With Type 2 Diabetes

Lead sponsor

Novo Nordisk A/S

Asset

Semaglutide

Oral · GLP-1 agonist

Listed sites

492

Recruiting sites

—

Enrollment

9,651

actual

Study population

Cardiovascular disease, Chronic kidney disease, Type 2 diabetes

Key I/E criteria

•HbA1c 6.5-10%•eGFR ≤60

Primary endpoint

•3-point MACE (Cardiovascular death, Non-fatal MI, Non-fatal stroke)

Footprint

Where this trial recruits

Site locations as reported to ClinicalTrials.gov. Site count is not enrollment count; per-site enrollment is not available from source.

Identifiers

Registered as

NCT IDNCT03914326

Org study IDEX9924-4473

Secondary ID2018-003141-42European Medicines Agency (EudraCT)

Secondary IDU1111-1218-5368World Health Organization (WHO)

Timeline

Milestones

Study first posted2019-04-16actual

Study start2019-06-17actual

Primary completion2024-08-23actual

Study completion2024-08-23actual

Results first posted2025-09-22actual

Last update posted2025-12-11actual

Assets

Investigational agents

Semaglutide

Study populations

Who this study enrolls

Cardiovascular diseaseChronic kidney diseaseType 2 diabetes

Eligibility

Who can enroll

Minimum age50 Years

SexAll

Healthy volunteersNot accepted

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

Endpoints (50)

What's being measured

Protocol endpoints and posted registry outcome measures, grouped into outcome categories. Composite endpoints show their component event types. Standard codes (LOINC, SNOMED CT) are shown where available.

Coverage by outcome category

Cardiovascular outcomes

Renal / kidney

Heart failure

Safety / tolerability / PK

Weight & body composition

Glycemic / diabetes

Cardiovascular outcomes

24 endpoints

Primary/registry result

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

3-point MACE

time to event, event

componentsCardiovascular death, Non-fatal MI, Non-fatal stroke

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	579	—
Placebo	668	—

Hazard Ratio (HR)0.8695% CI0.77 – 0.96p0.0028Regression, Cox

Primary/protocol endpoint

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

3-point MACE

time to event, event

componentsCardiovascular death, Non-fatal MI, Non-fatal stroke

Secondary/registry result

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

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

Cardiovascular death

time to event, event

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	301	—
Placebo	320	—

Secondary/registry result

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

MALE composite (major adverse limb events)

time to event, event

componentsAcute limb ischemia

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	71	—
Placebo	99	—

Secondary/registry result

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

5-point MACE

time to event, event

componentsCardiovascular death, Non-fatal MI, Non-fatal stroke, Coronary revascularization, Unstable angina hospitalization

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	670	—
Placebo	777	—

Secondary/registry result

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

Expanded / custom MACE composite

time to event, event

componentsAll-cause death, Non-fatal MI, Non-fatal stroke

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	779	—
Placebo	902	—

Secondary/registry result

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

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

All-cause death

time to event, event

SNOMED 419620001

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	528	—
Placebo	577	—

Secondary/registry result

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

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

Non-fatal MI

time to event, event

SNOMED 22298006

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	191	—
Placebo	253	—

Secondary/registry result

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

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

Non-fatal stroke

time to event, event

SNOMED 230690007

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	144	—
Placebo	161	—

Secondary/registry result

Number of Participants From Randomisation to First Occurrence of Coronary Revascularisation

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

Coronary revascularization

time to event, event

SNOMED 415070008

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	200	—
Placebo	263	—

Secondary/registry result

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

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

Unstable angina hospitalization

time to event, event

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	74	—
Placebo	80	—

Secondary/registry result

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

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

Acute limb ischemia

time to event, event

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	16	—
Placebo	17	—

Secondary/registry result

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

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

Peripheral-artery outcome composite

time to event, event

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	63	—
Placebo	88	—

Secondary/protocol endpoint

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

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

Cardiovascular death

time to event, event

Secondary/protocol endpoint

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

MALE composite (major adverse limb events)

time to event, event

componentsAcute limb ischemia, Peripheral-artery outcome composite

Secondary/protocol endpoint

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

5-point MACE

time to event, event

componentsCardiovascular death, Non-fatal MI, Non-fatal stroke, Coronary revascularization, Unstable angina hospitalization

Secondary/protocol endpoint

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

Expanded / custom MACE composite

time to event, event

componentsAll-cause death, Non-fatal MI, Non-fatal stroke

Secondary/protocol endpoint

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

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

All-cause death

time to event, event

SNOMED 419620001

Secondary/protocol endpoint

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

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

Non-fatal MI

time to event, event

SNOMED 22298006

Secondary/protocol endpoint

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

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

Non-fatal stroke

time to event, event

SNOMED 230690007

Secondary/protocol endpoint

Number of Participants From Randomisation to First Occurrence of Coronary Revascularisation

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

Coronary revascularization

time to event, event

SNOMED 415070008

Secondary/protocol endpoint

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

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

Unstable angina hospitalization

time to event, event

Secondary/protocol endpoint

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

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

Acute limb ischemia

time to event, event

Secondary/protocol endpoint

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

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

time to event, event

Weight & body composition

2 endpoints

Secondary/registry result

Change From Baseline in Body Weight

Time frame:Baseline (Week 0), Week 104

Body weight, absolute change (kg)

change from baseline, improvement

Posted result

Group	Value (mean), Kilograms	95% CI
Oral Semaglutide	-4.21	—
Placebo	-1.28	—

Secondary/protocol endpoint

Change From Baseline in Body Weight

Time frame:Baseline (Week 0), Week 104

Body weight, absolute change (kg)

change from baseline, improvement

Glycemic / diabetes

2 endpoints

Secondary/registry result

Change From Baseline in Glycosylated Haemoglobin (HbA1c)

Time frame:Baseline (Week 0), Week 104

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Posted result

Group	Value (mean), Percentage of HbA1c	95% CI
Oral Semaglutide	-0.71	—
Placebo	-0.15	—

Secondary/protocol endpoint

Change From Baseline in Glycosylated Haemoglobin (HbA1c)

Time frame:Baseline (Week 0), Week 104

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Heart failure

4 endpoints

Secondary/registry result

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

Heart-failure composite

time to event, event

componentsCardiovascular death, Heart-failure hospitalization, Urgent heart-failure visit

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	405	—
Placebo	443	—

Secondary/registry result

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

Heart-failure composite

time to event, event

componentsHeart-failure hospitalization, Urgent heart-failure visit

SNOMED 84114007

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	146	—
Placebo	167	—

Secondary/protocol endpoint

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

Heart-failure composite

time to event, event

componentsCardiovascular death, Heart-failure hospitalization, Urgent heart-failure visit

Secondary/protocol endpoint

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

Heart-failure composite

time to event, event

componentsHeart-failure hospitalization, Urgent heart-failure visit

SNOMED 84114007

Renal / kidney

14 endpoints

Secondary/registry result

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

Custom renal composite

time to event, event

componentsCardiovascular death, Renal death, eGFR, change, End-stage renal disease, Kidney-replacement therapy

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	403	—
Placebo	435	—

Secondary/registry result

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

Custom renal composite

composite event, event

componentsRenal death, eGFR, change, End-stage renal disease, Kidney-replacement therapy

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	112	—
Placebo	129	—

Secondary/registry result

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

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

Renal death

time to event, event

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	1	—
Placebo	7	—

Secondary/registry result

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

Custom renal composite

time to event, event

LOINC 98979-8

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	71	—
Placebo	86	—

Secondary/registry result

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

End-stage renal disease

time to event, event

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	23	—
Placebo	33	—

Secondary/registry result

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

Kidney-replacement therapy

time to event, event

componentsKidney-replacement therapy

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	40	—
Placebo	48	—

Secondary/registry result

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

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

eGFR slope (total)

change from baseline, improvement

LOINC 98979-8

Posted result

Group	Value (mean), ml/min/1.73 m^2 per year	95% CI
Oral Semaglutide	-1.67	—
Placebo	-2.06	—

Secondary/protocol endpoint

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

Custom renal composite

time to event, event

componentsCardiovascular death, Renal death, eGFR, change, End-stage renal disease, Kidney-replacement therapy

Secondary/protocol endpoint

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

Custom renal composite

time to event, event

componentsRenal death, eGFR, change, End-stage renal disease, Kidney-replacement therapy

Secondary/protocol endpoint

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

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

Renal death

time to event, event

Secondary/protocol endpoint

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

Custom renal composite

time to event, event

LOINC 98979-8

Secondary/protocol endpoint

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

End-stage renal disease

time to event, event

LOINC 98979-8 SNOMED 46177005

Secondary/protocol endpoint

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

Kidney-replacement therapy

time to event, event

componentsKidney-replacement therapy

Secondary/protocol endpoint

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

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

eGFR slope (total)

change from baseline, improvement

LOINC 98979-8

Safety / tolerability / PK

4 endpoints

Secondary/registry result

Number of Severe Hypoglycaemic Episodes

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

Severe hypoglycemia

event count, event

Posted result

Group	Value (number), Episodes	95% CI
Oral Semaglutide	88	—
Placebo	121	—

Secondary/registry result

Number of Participants From Randomisation to First Occurrence of a Severe Hypoglycaemic Episode

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

Severe hypoglycemia

time to event, event

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	76	—
Placebo	84	—

Secondary/protocol endpoint

Number of Severe Hypoglycaemic Episodes

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

Severe hypoglycemia

event count, event

Secondary/protocol endpoint

Number of Participants From Randomisation to First Occurrence of a Severe Hypoglycaemic Episode

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

Severe hypoglycemia

time to event, event

Publications (11)

Bibliography

Records linked to this trial through ClinicalTrials.gov references, PubMed NCT search, and curated study seeds. 'Canonical' marks design/result papers; others are registry references or candidates.

Registry references + supporting bibliography

Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial.
JAMA internal medicine2026 Apr 1PMID41627802doi:10.1001/jamainternmed.2025.7774via clinicaltrials gov reference derived + pubmed nct search
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.
JAMA cardiology2026 Mar 25PMID41879791doi:10.1001/jamacardio.2026.0245via clinicaltrials gov reference derived + pubmed nct search
Prevalence and Associations of Systemic Inflammation in Heart Failure Across the Spectrum of Ejection Fraction.
JACC. Heart failure2026 Feb (month)PMID41099689doi:10.1016/j.jchf.2025.102712via clinicaltrials gov reference derived + pubmed nct search
Impact of Oral Semaglutide on Kidney Outcomes in People With Type 2 Diabetes: Results From the SOUL Randomized Trial.
Diabetes care2026 Feb 1PMID41380027doi:10.2337/dc25-1080via pubmed nct search
Oral Semaglutide and Cardiovascular Outcomes in People With Type 2 Diabetes, According to SGLT2i Use: Prespecified Analyses of the SOUL Randomized Trial.
Circulation2025 Jun 10PMID40156843doi:10.1161/CIRCULATIONAHA.125.074545via clinicaltrials gov reference derived + pubmed nct search
Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes.
The New England journal of medicine2025 May 29PMID40162642doi:10.1056/NEJMoa2501006via clinicaltrials gov reference derived + pubmed nct search
Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes.
The Cochrane database of systematic reviews2025 Feb 18PMID39963952doi:10.1002/14651858.CD015849.pub2via clinicaltrials gov reference derived + pubmed nct search
Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: A review of their kidney and heart protection.
American journal of preventive cardiology2023 Jun (month)PMID37313358doi:10.1016/j.ajpc.2023.100502via pubmed nct search
Cardiovascular Safety and Benefits of Semaglutide in Patients With Type 2 Diabetes: Findings From SUSTAIN 6 and PIONEER 6.
Frontiers in endocrinology2021 (year)PMID33854484doi:10.3389/fendo.2021.645566via pubmed nct search
Cardiovascular outcomes, safety, and tolerability with oral semaglutide: insights for managed care.
The American journal of managed care2020 Dec (month)PMID33439583doi:10.37765/ajmc.2020.88555via pubmed nct search
Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme.
Diabetes, obesity & metabolism2020 Aug (month)PMID32267058doi:10.1111/dom.14054via pubmed nct search

Provenance

Sources

Trial identity, design, statusClinicalTrials.gov API v2

Snapshot dateJuly 1, 2026

Endpoint classificationDelfa endpoint taxonomy v2 (May 13, 2026)

Results tableClinicalTrials.gov results section

Trial facts come from public ClinicalTrials.gov records. Endpoint categories are Delfa's classification of those records, not a ClinicalTrials.gov field. All figures reflect the July 1, 2026 snapshot.