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Trial · Interventional

CompletedPhase 3Results postedRegistry data

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

Short name PIONEER 6

NCTNCT02692716 (opens ClinicalTrials.gov in a new tab)Other idNN9924-4221Other id2015-003563-10Other idU1111-1173-0750Other idNL56580.091.16
Open at ClinicalTrials.govAsk about this trial

Overview

Status
Completed
Phase
Phase 3
Enrollment
3,183 participants (actual)
Sponsor
Novo Nordisk A/S · Industry
Design
Randomized · Double masking
Countries
21 countries

United States, Algeria, Argentina, Brazil, Canada, Denmark, Germany, India, Israel, Italy, Malaysia, Mexico, Netherlands, Poland, Romania, South Africa, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom

Start
17 Jan 2017
Primary completion
25 Sept 2018
Completion
25 Sept 2018
First posted
26 Feb 2016 (estimated)
Last update posted
20 Jul 2022
Conditions
Diabetes · Diabetes Mellitus, Type 2

Timeline

1 trial · 1 completed · 1 with posted results

  • Completed
  • Ongoing
  • Not yet recruiting
  • Stopped
  • Estimated dates (est.)
  • Results posted
201720182019
  1. Ph 3

    PIONEER 6

    NCT02692716

    17 Jan 2017 to 25 Sept 2018

Registry summary

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

This trial is conducted globally. The aim of the trial is to investigate the cardiovascular safety of oral semaglutide in subjects with type 2 diabetes.

Interventions

  • semaglutideDrug
  • placeboDrug

Arms2

  • Experimental

    Oral semaglutide

  • Placebo comparator

    Placebo

Primary outcomes1

Outcomes the sponsor listed as primary.

  1. 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.

    Registry description

    Number of participants experiencing a first event of a MACE, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

Secondary outcomes(17)

  1. 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.

    Registry description

    Participants experiencing first occurrence of an expanded composite CV endpoint \[defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, UAP (unstable angina pectoris) requiring hospitalisation or heart failure requiring hospitalisation\] are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  2. 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.

    Registry description

    Participants experiencing an event onset for each individual component of the expanded composite cardiovascular outcomes (defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring hospitalisation or heart failure requiring hospitalisation) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  3. 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.

    Registry description

    Participants experiencing first occurrence of a composite CV endpoint (defined as all-cause death, non-fatal myocardial infarction or nonfatal stroke) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  4. 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.

    Registry description

    Number of participants experiencing a first event of a fatal or non-fatal myocardial infarction are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  5. 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.

    Registry description

    Number of participants experiencing a first event of a fatal or non-fatal stroke are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  6. 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.

    Registry description

    Number of all-cause deaths in the study are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  7. 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.

    Registry description

    Number of participants who permanently discontinued trial product in ths study are presented. Results are based on the on-treatment observation period which starts at the date of first dose on trial product; ends on last date on trial product +38 days (ascertainment window).

  8. 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.

    Registry description

    Number of serious adverse events were recorded from week 0 to week 87 in the study. Results are based on the on-treatment observation period which started at the date of first dose on trial product and ended on last date on trial product +38 days (ascertainment window).

  9. Change in Eye Examination Category

    Time frame · Week -3, End of treatment

    Registry description

    Participants with eye examination findings, normal, abnormal non clinically significant (NCS) and abnormal clinically significant (CS) at baseline (week -3) and end of treatment visit (week 83) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  10. Change in Pulse Rate

    Time frame · Week 0, End of treatment

    Registry description

    Change from baseline (week 0) in pulse rate measured at the end of treatment visit (week 83) is reported. Results are based on the on-treatment observation period which started at the date of first dose on trial product, ended on last date on trial product +38 days (ascertainment window).

  11. Change in Systolic and Diastolic Blood Pressure

    Time frame · Week 0, End of treatment

    Registry description

    Change from baseline (week 0) in systolic and diastolic blood pressure measured at the end of treatment visit (week 83) is reported. Results are based on the on-treatment observation period which started at the date of first dose on trial product, ended on last date on trial product +38 days (ascertainment window).

  12. Change in Glycosylated Haemoglobin (HbA1c)

    Time frame · Week 0, End of treatment

    Registry description

    Change from baseline (week 0) in HbA1c measured at the end of treatment visit (week 83) is reported. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  13. Change in Body Weight

    Time frame · Week 0, End of treatment

    Registry description

    Change from baseline (week 0) in body weight measured at the end of treatment visit (week 83) is reported. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  14. Change in Total Cholesterol - Ratio to Baseline

    Time frame · Week 0, End of treatment

    Registry description

    Change from baseline (week 0) in total cholesterol (mmol/L) at the end of treatment (week 83) visit is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  15. Change in LDL-cholesterol - Ratio to Baseline

    Time frame · Week 0, End of treatment

    Registry description

    Change from baseline (week 0) in LDL cholesterol (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  16. Change in HDL-cholesterol - Ratio to Baseline

    Time frame · Week 0, End of treatment

    Registry description

    Change from baseline (week 0) in HDL cholesterol (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

  17. Change in Triglycerides - Ratio to Baseline

    Time frame · Week 0, End of treatment

    Registry description

    Change from baseline (week 0) in triglycerides (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment.

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

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

GroupValue (Participants)
Oral Semaglutide61
Placebo76
Secondary and other outcome results(7)
Secondary outcomeCount of participants· Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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

GroupValue (Participants)
Oral Semaglutide83
Placebo100
Secondary outcomeCount of participants· Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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

GroupValue (Participants)
Oral Semaglutide15
Placebo30
Secondary outcomeCount of participants· Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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

GroupValue (Participants)
Oral Semaglutide69
Placebo89
Secondary outcomeCount of participants· Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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

GroupValue (Participants)
Oral Semaglutide37
Placebo35
Secondary outcomeCount of participants· Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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

GroupValue (Participants)
Oral Semaglutide13
Placebo17
Secondary outcomeCount of participants· Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 5 weeks of follow-up period.

Time From Randomisation to All-cause Death

GroupValue (Participants)
Oral Semaglutide23
Placebo45
Secondary outcomeCount of participants· Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.

Time to First AE Leading to Permanent Trial Product Discontinuation

GroupValue (Participants)
Oral Semaglutide184
Placebo104

Adverse events, as posted

Adverse events as posted: participants affected out of participants at risk, by group
GroupDeathsSerious eventsOther events
Oral SemaglutideParticipants were to take once-daily semaglutide tablets in a dose escalation manner for upto 82 weeks: 3 mg from week 0 to week 4, 7 mg from week 4 to week 8 and 14 mg from week 9 to upto week 82.23 / 1591301 / 15910 / 1591
PlaceboParticipants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.45 / 1591358 / 15910 / 1591

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

Studies13

Studies that cite this trial.

Studies with results

4 studies on this page

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
Source linkSee results (15)

Indexing hint: Meta-analysis (pooled) · 2022

4 results

Semaglutide reduces cardiovascular events regardless of metformin use: a post hoc subgroup analysis of SUSTAIN 6 and PIONEER 6.

Husain et al. 2022Cardiovascular diabetologycited by 16

PMID 35484580PMC9052629DOI 10.1186/s12933-022-01489-6PUB-35484580

CC BY4 results
Download PDFSee results (4)

Indexing hint: Randomized controlled trial · 2022

7 results

Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6.

Strain et al. 2022Strokecited by 62

PMID 35582947PMC9389936DOI 10.1161/strokeaha.121.037775PUB-35582947

CC BY7 results
Download PDFSee results (7)

Indexing hint: Clinical trial · 2019

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial.

Bain et al. 2019Diabetes, obesity & metabolismcited by 74

PMID 30284349PMC6587508DOI 10.1111/dom.13553PUB-30284349

Free to read · publisher termsCC BY-NC
Read at source

Indexing hint: Randomized controlled trial · 2019

6 results

Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

Husain et al. 2019The New England journal of medicinecited by 1,463

PMID 31185157DOI 10.1056/nejmoa1901118PUB-31185157

Full text at the publisher6 results
Publisher pageSee results (6)

More studies

8 studies on this page

PubMed tag: none · 2025

Cardiovascular, Metabolic, and Safety Outcomes with Semaglutide by Baseline Age: Post Hoc Analysis of SUSTAIN 6 and PIONEER 6.

Bain et al. 2025Diabetes therapy : research, treatment and education of diabetes and related disorderscited by 8

PMID 39520501PMC11759736DOI 10.1007/s13300-024-01659-7PUB-39520501

Free to read · publisher termsCC BY-NC
Read at source

PubMed tag: none · 2023

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.

Rossing et al. 2023Cardiovascular diabetologycited by 17

PMID 37620807PMC10463803DOI 10.1186/s12933-023-01949-7PUB-37620807

CC BY
Download PDF

PubMed tag: none · 2022

Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme.

Aroda et al. 2022Diabetes, obesity & metabolismcited by 32

PMID 35373893PMC9321749DOI 10.1111/dom.14710PUB-35373893

Free to read · publisher termsCC BY-NC
Read at source

PubMed tag: none · 2021

Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide.

Verma et al. 2021Diabetes, obesity & metabolismcited by 5

PMID 33606902PMC8251906DOI 10.1111/dom.14360PUB-33606902

Free to read · publisher termsCC BY-NC
Read at source

PubMed tag: none · 2021

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.

Evans et al. 2021Endocrinology, diabetes & metabolismcited by 10

PMID 34277983PMC8279621DOI 10.1002/edm2.259PUB-34277983

CC BY
Download PDF

PubMed tag: none · 2020

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk.

Husain et al. 2020Diabetes, obesity & metabolismcited by 154

PMID 31903692PMC7064975DOI 10.1111/dom.13955PUB-31903692

Free to read · publisher termsCC BY-NC
Read at source

Indexing hint: Review · 2020

Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme.

Thethi et al. 2020Diabetes, obesity & metabolismcited by 98

PMID 32267058PMC7384149DOI 10.1111/dom.14054PUB-32267058

Free to read · publisher termsCC BY-NC
Read at source

PubMed tag: none · 2020

Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials.

Husain et al. 2020Cardiovascular diabetologycited by 33

PMID 32998732PMC7526237DOI 10.1186/s12933-020-01106-4PUB-32998732

CC BY
Download PDF

Other registry references

References listed at the registry that are not in PepBank. They link to PubMed.

  • ResultCefalu WT, Kaul S, Gerstein HC, Holman RR, Zinman B, Skyler JS, Green JB, Buse JB, Inzucchi SE, Leiter LA, Raz I, Rosenstock J, Riddle MC. Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors' Expert Forum. Diabetes Care. 2018 Jan;41(1):14-31. doi: 10.2337/dci17-0057. PMID 29263194

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 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)

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