← Trials/Trial dossier/NCT02692716

PIONEER 6

CompletedPhase 3Results posted

A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes

Lead sponsor

Novo Nordisk A/S

Asset

Semaglutide

Oral · GLP-1 agonist

Listed sites

228

Recruiting sites

—

Enrollment

3,183

actual

Study population

Cardiovascular disease, Type 2 diabetes

Key I/E criterion

—

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 IDNCT02692716

Org study IDNN9924-4221

Secondary ID2015-003563-10

Secondary IDNL56580.091.16CCMO

Secondary IDU1111-1173-0750WHO

Timeline

Milestones

Study first posted2016-02-26estimated

Study start2017-01-17actual

Primary completion2018-09-25actual

Study completion2018-09-25actual

Results first posted2020-02-27actual

Last update posted2022-07-20actual

Assets

Investigational agents

Semaglutide

Study populations

Who this study enrolls

Cardiovascular diseaseType 2 diabetes

Eligibility

Who can enroll

Minimum age50 Years

SexAll

Healthy volunteersNot accepted

Inclusion criteria

•Male or female diagnosed with type 2 diabetes

•Age at least 50 years at screening and presence of cardiovascular disease, or age at least 60 years at screening and presence of at least one cardiovascular risk factor

Exclusion criteria

•Current or previous (within 90 days prior to screening) treatment with any GLP-1 (glucagon-like peptide-1) receptor agonist, DPP-4 (dipeptidyl peptidase-4) inhibitor or pramlintide

•Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid carcinoma (MTC)

•History of pancreatitis (acute or chronic)

•History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)

•Subjects presently classified as being in New York Heart Association (NYHA) Class IV heart failure

•Planned coronary, carotid or peripheral artery revascularisation known on the day of screening

•Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 60 days prior to screening

•Chronic or intermittent hemodialysis or peritoneal dialysis or severe renal impairment (corresponding to eGFR (glomerular filtration rate, estimated) below 30 mL/min/1.73 m^2)

•History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and carcinoma in situ)

Endpoints (36)

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

Cardiometabolic biomarkers

Safety / tolerability / PK

Weight & body composition

Glycemic / diabetes

Other clinical outcomes

Cardiovascular outcomes

14 endpoints

Primary/registry result

Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE) Composite Endpoint Consisting of: Cardiovascular Death, Non-fatal Myocardial Infarction or Non-fatal Stroke

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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	61	—
Placebo	76	—

Hazard Ratio (HR)0.7995% CI0.57 – 1.11p< 0.0001Regression, Cox

Hazard Ratio (HR)0.7995% CI0.57 – 1.11p= 0.1749Regression, Cox

Primary/protocol endpoint

Time From Randomisation to First Occurrence of a Major Adverse Cardiovascular Event (MACE) Composite Endpoint Consisting of: Cardiovascular Death, Non-fatal Myocardial Infarction or Non-fatal Stroke

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

3-point MACE

time to event, event

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

Secondary/registry result

Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Endpoint Consisting of: Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, UAP Requiring Hospitalisation or Hospitalisation for Heart Failure

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Expanded / custom MACE composite

time to event, event

componentsCardiovascular death, Non-fatal MI, Non-fatal stroke, Unstable angina hospitalization, Heart-failure hospitalization

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	83	—
Placebo	100	—

Hazard Ratio (HR)0.8295% CI0.61 – 1.10p= 0.1827Regression, Cox

Secondary/registry result

Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Expanded / custom MACE composite

time to event, event

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral SemaglutideCardiovascular death	15	—
Non-fatal myocardial infarction	37	—
Non-fatal stroke	12	—
Unstable angina requiring hospitalisation	11	—
Heart failure requiring hospitalisation	21	—
PlaceboCardiovascular death	30	—
Non-fatal myocardial infarction	31	—
Non-fatal stroke	16	—
Unstable angina requiring hospitalisation	7	—
Heart failure requiring hospitalisation	24	—

Hazard Ratio (HR)0.4995% CI0.27 – 0.92p= 0.0261Regression, Cox

Hazard Ratio (HR)1.1895% CI0.73 – 1.90p= 0.5044Regression, Cox

Hazard Ratio (HR)0.7495% CI0.35 – 1.57p= 0.4350Regression, Cox

Hazard Ratio (HR)1.5695% CI0.60 – 4.01p= 0.3605Regression, Cox

Hazard Ratio (HR)0.8695% CI0.48 – 1.55p= 0.6227Regression, Cox

Secondary/registry result

Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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	69	—
Placebo	89	—

Hazard Ratio (HR)0.7795% CI0.56 – 1.05p= 0.0952Regression, Cox

Secondary/registry result

Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Myocardial infarction (any)

time to event, event

SNOMED 22298006

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	37	—
Placebo	35	—

Hazard Ratio (HR)1.0495% CI0.66 – 1.66p0.8583Regression, Cox

Secondary/registry result

Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Stroke (any)

time to event, event

SNOMED 230690007

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	13	—
Placebo	17	—

Hazard Ratio (HR)0.7695% CI0.37 – 1.56p0.4485Regression, Cox

Secondary/registry result

Time From Randomisation to All-cause Death

Time frame:Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 5 weeks of follow-up period.

All-cause death

time to event, event

SNOMED 419620001

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	23	—
Placebo	45	—

Hazard Ratio (HR)0.5195% CI0.31 – 0.84p0.0078Regression, Cox

Secondary/protocol endpoint

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

5-point MACE

time to event, event

componentsCardiovascular death, Non-fatal MI, Non-fatal stroke, Unstable angina hospitalization, Heart-failure hospitalization

Secondary/protocol endpoint

Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Expanded / custom MACE composite

time to event, event

Secondary/protocol endpoint

Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Expanded / custom MACE composite

time to event, event

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

Secondary/protocol endpoint

Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Myocardial infarction (any)

time to event, event

SNOMED 22298006

Secondary/protocol endpoint

Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke

Time frame:Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

Stroke (any)

time to event, event

SNOMED 230690007

Secondary/protocol endpoint

Time From Randomisation to All-cause Death

Time frame:Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 5 weeks of follow-up period.

All-cause death

time to event, event

SNOMED 419620001

Weight & body composition

2 endpoints

Secondary/registry result

Change in Body Weight

Time frame:Week 0, End of treatment

Body weight, absolute change (kg)

change from baseline, improvement

Posted result

Group	Value (mean), Kg	95% CI
Oral Semaglutide	-4.2	—
Placebo	-0.8	—

Secondary/protocol endpoint

Change in Body Weight

Time frame:Week 0, End of treatment

Body weight, absolute change (kg)

change from baseline, improvement

Glycemic / diabetes

2 endpoints

Secondary/registry result

Change in Glycosylated Haemoglobin (HbA1c)

Time frame:Week 0, End of treatment

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Posted result

Group	Value (mean), Percentage of HbA1c	95% CI
Oral Semaglutide	-1.0	—
Placebo	-0.3	—

Secondary/protocol endpoint

Change in Glycosylated Haemoglobin (HbA1c)

Time frame:Week 0, End of treatment

HbA1c, change

change from baseline, improvement

LOINC 4548-4

Cardiometabolic biomarkers

12 endpoints

Secondary/registry result

Change in Pulse Rate

Time frame:Week 0, End of treatment

Heart rate, change

change from baseline, improvement

Posted result

Group	Value (mean), Beats/minute	95% CI
Oral Semaglutide	4	—
Placebo	-0	—

Secondary/registry result

Change in Systolic and Diastolic Blood Pressure

Time frame:Week 0, End of treatment

change from baseline, improvement

componentsSystolic BP, change, Diastolic BP, change

Posted result

Group	Value (mean), mmHg	95% CI
Oral SemaglutideSystolic blood pressure	-5	—
Diastolic blood pressure	-1	—
PlaceboSystolic blood pressure	-2	—
Diastolic blood pressure	-2	—

Secondary/registry result

Change in Total Cholesterol - Ratio to Baseline

Time frame:Week 0, End of treatment

Total cholesterol, change

ratio, improvement

LOINC 2093-3

Posted result

Group	Value (geometric_mean), Ratio of total cholesterol	95% CI
Oral Semaglutide	0.97	—
Placebo	0.98	—

Secondary/registry result

Change in LDL-cholesterol - Ratio to Baseline

Time frame:Week 0, End of treatment

LDL-C, change

ratio, improvement

LOINC 13457-7

Posted result

Group	Value (geometric_mean), Ratio of LDL-cholesterol	95% CI
Oral Semaglutide	0.96	—
Placebo	0.97	—

Secondary/registry result

Change in HDL-cholesterol - Ratio to Baseline

Time frame:Week 0, End of treatment

HDL-C, change

ratio, improvement

LOINC 2085-9

Posted result

Group	Value (geometric_mean), Ratio of HDL-cholesterol	95% CI
Oral Semaglutide	1.05	—
Placebo	1.02	—

Secondary/registry result

Change in Triglycerides - Ratio to Baseline

Time frame:Week 0, End of treatment

Triglycerides, change

ratio, improvement

LOINC 2571-8

Posted result

Group	Value (geometric_mean), Ratio of triglycerides	95% CI
Oral Semaglutide	0.92	—
Placebo	0.97	—

Secondary/protocol endpoint

Change in Pulse Rate

Time frame:Week 0, End of treatment

Heart rate, change

change from baseline, improvement

Secondary/protocol endpoint

Change in Systolic and Diastolic Blood Pressure

Time frame:Week 0, End of treatment

change from baseline, improvement

componentsSystolic BP, change, Diastolic BP, change

Secondary/protocol endpoint

Change in Total Cholesterol - Ratio to Baseline

Time frame:Week 0, End of treatment

Total cholesterol, change

ratio, improvement

LOINC 2093-3

Secondary/protocol endpoint

Change in LDL-cholesterol - Ratio to Baseline

Time frame:Week 0, End of treatment

LDL-C, change

ratio, improvement

LOINC 13457-7

Secondary/protocol endpoint

Change in HDL-cholesterol - Ratio to Baseline

Time frame:Week 0, End of treatment

HDL-C, change

ratio, improvement

LOINC 2085-9

Secondary/protocol endpoint

Change in Triglycerides - Ratio to Baseline

Time frame:Week 0, End of treatment

Triglycerides, change

ratio, improvement

Safety / tolerability / PK

4 endpoints

Secondary/registry result

Time to First AE Leading to Permanent Trial Product Discontinuation

Time frame:Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.

Discontinuation due to AE

time to event, event

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral Semaglutide	184	—
Placebo	104	—

Hazard Ratio (HR)1.8195% CI1.42 – 2.30p<0.0001Regression, Cox

Secondary/registry result

Number of Serious Adverse Events

Time frame:Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.

Serious AEs (any)

event count, event

Posted result

Group	Value (number), Events	95% CI
Oral Semaglutide	545	—
Placebo	618	—

Secondary/protocol endpoint

Time to First AE Leading to Permanent Trial Product Discontinuation

Time frame:Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.

Discontinuation due to AE

time to event, event

Secondary/protocol endpoint

Number of Serious Adverse Events

Time frame:Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.

Serious AEs (any)

event count, event

Other clinical outcomes

2 endpoints

Secondary/registry result

Change in Eye Examination Category

Time frame:Week -3, End of treatment

categorical status, descriptive

Posted result

Group	Value (count_of_participants), Participants	95% CI
Oral SemaglutideLeft eye fundoscopy (week -3): Normal	848	—
Left eye fundoscopy (week -3): Abnormal NCS	657	—
Left eye fundoscopy (week -3): Abnormal CS	86	—
Right eye fundoscopy (week -3): Normal	845	—
Right eye fundoscopy (week -3): Abnormal NCS	659	—
Right eye fundoscopy (week -3): Abnormal CS	86	—
Left eye fundoscopy (EOT): Normal	783	—
Left eye fundoscopy (EOT): Abnormal NCS	599	—
Left eye fundoscopy (EOT): Abnormal CS	83	—
Right eye fundoscopy (EOT): Normal	780	—
Right eye fundoscopy (EOT): Abnormal NCS	601	—
Right eye fundoscopy (EOT): Abnormal CS	81	—
PlaceboLeft eye fundoscopy (week -3): Normal	843	—
Left eye fundoscopy (week -3): Abnormal NCS	673	—
Left eye fundoscopy (week -3): Abnormal CS	74	—
Right eye fundoscopy (week -3): Normal	858	—
Right eye fundoscopy (week -3): Abnormal NCS	661	—
Right eye fundoscopy (week -3): Abnormal CS	72	—
Left eye fundoscopy (EOT): Normal	790	—
Left eye fundoscopy (EOT): Abnormal NCS	597	—
Left eye fundoscopy (EOT): Abnormal CS	62	—
Right eye fundoscopy (EOT): Normal	787	—
Right eye fundoscopy (EOT): Abnormal NCS	599	—
Right eye fundoscopy (EOT): Abnormal CS	64	—

Secondary/protocol endpoint

Change in Eye Examination Category

Time frame:Week -3, End of treatment

categorical status, descriptive

Publications (15)

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

Effect of semaglutide versus placebo on cardiorenal outcomes by prior cardiovascular disease and baseline body mass index: Pooled post hoc analysis of SUSTAIN 6 and PIONEER 6.
Diabetes, obesity & metabolism2025 Oct (month)PMID40704485doi:10.1111/dom.16621via 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
Cardiovascular, Metabolic, and Safety Outcomes with Semaglutide by Baseline Age: Post Hoc Analysis of SUSTAIN 6 and PIONEER 6.
Diabetes therapy : research, treatment and education of diabetes and related disorders2025 Jan (month)PMID39520501doi:10.1007/s13300-024-01659-7via clinicaltrials gov reference derived + pubmed nct search
Effect of semaglutide on major adverse cardiovascular events by baseline kidney parameters in participants with type 2 diabetes and at high risk of cardiovascular disease: SUSTAIN 6 and PIONEER 6 post hoc pooled analysis.
Cardiovascular diabetology2023 Aug 24PMID37620807doi:10.1186/s12933-023-01949-7via clinicaltrials gov reference derived + pubmed nct search
Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6.
Stroke2022 Sep (month)PMID35582947doi:10.1161/STROKEAHA.121.037775via clinicaltrials gov reference derived + pubmed nct search
Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme.
Diabetes, obesity & metabolism2022 Jul (month)PMID35373893doi:10.1111/dom.14710via CT.gov reference
Semaglutide reduces cardiovascular events regardless of metformin use: a post hoc subgroup analysis of SUSTAIN 6 and PIONEER 6.
Cardiovascular diabetology2022 Apr 28PMID35484580doi:10.1186/s12933-022-01489-6via CT.gov reference + pubmed nct search
A population-adjusted indirect comparison of cardiovascular benefits of once-weekly subcutaneous semaglutide and dulaglutide in the treatment of patients with type 2 diabetes, with or without established cardiovascular disease.
Endocrinology, diabetes & metabolism2021 Jul (month)PMID34277983doi:10.1002/edm2.259via CT.gov reference
Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide.
Diabetes, obesity & metabolism2021 Jul (month)PMID33606902doi:10.1111/dom.14360via clinicaltrials gov reference derived + pubmed nct search
Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials.
Cardiovascular diabetology2020 Sep 30PMID32998732doi:10.1186/s12933-020-01106-4via clinicaltrials gov reference derived + 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 clinicaltrials gov reference derived + pubmed nct search
Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk.
Diabetes, obesity & metabolism2020 Mar (month)PMID31903692doi:10.1111/dom.13955via clinicaltrials gov reference derived + pubmed nct search
Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
The New England journal of medicine2019 Aug 29PMID31185157doi:10.1056/NEJMoa1901118via CT.gov reference + pubmed nct search
Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.
Diabetes, obesity & metabolism2019 Mar (month)PMID30284349doi:10.1111/dom.13553via CT.gov reference
Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors' Expert Forum.
Diabetes care2018 Jan (month)PMID29263194doi:10.2337/dci17-0057via CT.gov reference

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.