NCT02692716: PIONEER 6

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

Completed Phase 3 Results posted Last updated 20 July 2022

What this trial tests

Phase 3 trial testing semaglutide in Diabetes in 3,183 participants. Completed in 25 September 2018.

Timeline

17 January 2017

Primary endpoint
25 September 2018

25 September 2018

Quick facts

Lead sponsor	Novo Nordisk A/S
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	3,183
Start date	17 January 2017
Primary completion	25 September 2018
Estimated completion	25 September 2018
Sites	228 locations across Italy, Malaysia, Taiwan, Poland, Denmark, Netherlands, Mexico, Thailand

Drugs / interventions tested

• semaglutide (semaglutide) — full drug profile →
• placebo

Conditions studied

• Diabetes — all drugs for Diabetes →
• Diabetes Mellitus, Type 2 — all drugs for Diabetes Mellitus, Type 2 →

Sponsor

Novo Nordisk A/S — full company profile →

Who can join

50 and older, any sex, with Diabetes or Diabetes Mellitus, Type 2. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

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.

Group	Value	95% CI
Oral Semaglutide	61
Placebo	76

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

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.

Group	Value	95% CI
Oral Semaglutide	83
Placebo	100

Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint Secondary · Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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.

Cardiovascular death

Group	Value	95% CI
Oral Semaglutide	15
Placebo	30

Non-fatal myocardial infarction

Group	Value	95% CI
Oral Semaglutide	37
Placebo	31

Non-fatal stroke

Group	Value	95% CI
Oral Semaglutide	12
Placebo	16

Unstable angina requiring hospitalisation

Group	Value	95% CI
Oral Semaglutide	11
Placebo	7

Heart failure requiring hospitalisation

Group	Value	95% CI
Oral Semaglutide	21
Placebo	24

Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke Secondary · Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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.

Group	Value	95% CI
Oral Semaglutide	69
Placebo	89

Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction Secondary · Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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.

Group	Value	95% CI
Oral Semaglutide	37
Placebo	35

Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke Secondary · Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period.

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.

Group	Value	95% CI
Oral Semaglutide	13
Placebo	17

Time From Randomisation to All-cause Death Secondary · Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 5 weeks of follow-up period.

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.

Group	Value	95% CI
Oral Semaglutide	23
Placebo	45

Time to First AE Leading to Permanent Trial Product Discontinuation Secondary · Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.

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).

Group	Value	95% CI
Oral Semaglutide	184
Placebo	104

Number of Serious Adverse Events Secondary · Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window.

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).

Group	Value	95% CI
Oral Semaglutide	545
Placebo	618

Change in Eye Examination Category Secondary · Week -3, End of treatment

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.

Left eye fundoscopy (week -3): Normal

Group	Value	95% CI
Oral Semaglutide	848
Placebo	843

Left eye fundoscopy (week -3): Abnormal NCS

Group	Value	95% CI
Oral Semaglutide	657
Placebo	673

Left eye fundoscopy (week -3): Abnormal CS

Group	Value	95% CI
Oral Semaglutide	86
Placebo	74

Right eye fundoscopy (week -3): Normal

Group	Value	95% CI
Oral Semaglutide	845
Placebo	858

Right eye fundoscopy (week -3): Abnormal NCS

Group	Value	95% CI
Oral Semaglutide	659
Placebo	661

Right eye fundoscopy (week -3): Abnormal CS

Group	Value	95% CI
Oral Semaglutide	86
Placebo	72

Left eye fundoscopy (EOT): Normal

Group	Value	95% CI
Oral Semaglutide	783
Placebo	790

Left eye fundoscopy (EOT): Abnormal NCS

Group	Value	95% CI
Oral Semaglutide	599
Placebo	597

Change in Pulse Rate Secondary · Week 0, End of treatment

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).

Group	Value	95% CI
Oral Semaglutide	4	± 11
Placebo	-0	± 11

Change in Systolic and Diastolic Blood Pressure Secondary · Week 0, End of treatment

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).

Systolic blood pressure

Group	Value	95% CI
Oral Semaglutide	-5	± 18
Placebo	-2	± 18

Diastolic blood pressure

Group	Value	95% CI
Oral Semaglutide	-1	± 11
Placebo	-2	± 10

Adverse events — posted to ClinicalTrials.gov

Time frame: Week 0 to 87. SAEs and other AEs were based on the on-treatment observation period, i.e., the time period when a participant was on treatment with trial product, including any period after initiation of rescue medication. All-cause mortality were based on the in-trial observation period, i.e., the time period from when a participant was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Oral Semaglutide

Serious: 301/1591 (19%)

Deaths: 23/1591

Placebo

Serious: 358/1591 (23%)

Deaths: 45/1591

Serious adverse events (420 terms)

Reaction	System	Oral Semaglutide	Placebo
Acute myocardial infarction	Cardiac disorders	—	—
Pneumonia	Infections and infestations	—	—
Angina unstable	Cardiac disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Coronary artery disease	Cardiac disorders	—	—
Fall	Injury, poisoning and procedural complications	—	—
Ischaemic stroke	Nervous system disorders	—	—
Myocardial infarction	Cardiac disorders	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Cellulitis	Infections and infestations	—	—
Hypoglycaemic unconsciousness	Nervous system disorders	—	—
Non-cardiac chest pain	General disorders	—	—
Angina pectoris	Cardiac disorders	—	—
Cardiac failure chronic	Cardiac disorders	—	—
Cataract	Eye disorders	—	—
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—
Cardiac failure	Cardiac disorders	—	—
Peripheral arterial occlusive disease	Vascular disorders	—	—
Syncope	Nervous system disorders	—	—
Diabetic foot	Skin and subcutaneous tissue disorders	—	—
Sepsis	Infections and infestations	—	—
Transient ischaemic attack	Nervous system disorders	—	—
Cardiac arrest	Cardiac disorders	—	—

Most-reported serious reactions: Acute myocardial infarction, Pneumonia, Angina unstable, Acute kidney injury, Atrial fibrillation, Coronary artery disease, Fall, Ischaemic stroke.

Data from ClinicalTrials.gov NCT02692716 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
   Husain M, Birkenfeld AL, Donsmark M, Dungan K, et al · · 2019 · cited 1285× · PMID 31185157 · DOI 10.1056/nejmoa1901118
2. Diabetic vascular diseases: molecular mechanisms and therapeutic strategies.
   Li Y, Liu Y, Liu S, Gao M, et al · · 2023 · cited 392× · PMID 37037849 · DOI 10.1038/s41392-023-01400-z
3. 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.
   Das SR, Everett BM, Birtcher KK, Brown JM, et al · · 2018 · cited 222× · PMID 30497881 · DOI 10.1016/j.jacc.2018.09.020
4. GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential.
   Ma X, Liu Z, Ilyas I, Little PJ, et al · · 2021 · cited 189× · PMID 34131405 · DOI 10.7150/ijbs.59965
5. Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C₁₀).
   Twarog C, Fattah S, Heade J, Maher S, et al · · 2019 · cited 153× · PMID 30781867 · DOI 10.3390/pharmaceutics11020078
6. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk.
   Husain M, Bain SC, Jeppesen OK, Lingvay I, et al · · 2020 · cited 144× · PMID 31903692 · DOI 10.1111/dom.13955
7. GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data.
   Sposito AC, Berwanger O, de Carvalho LSF, Saraiva JFK. · · 2018 · cited 109× · PMID 30545359 · DOI 10.1186/s12933-018-0800-2
8. Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes.
   Mahapatra MK, Karuppasamy M, Sahoo BM. · · 2022 · cited 92× · PMID 34993760 · DOI 10.1007/s11154-021-09699-1