The classic website will no longer be available as of June 25, 2024. Please use the modernized ClinicalTrials.gov.
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes (PIONEER 6)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02692716
Recruitment Status : Completed
First Posted : February 26, 2016
Results First Posted : February 27, 2020
Last Update Posted : July 20, 2022
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Diabetes
Diabetes Mellitus, Type 2
Interventions Drug: semaglutide
Drug: placebo
Enrollment 3183
Recruitment Details The study was conducted at 214 sites in 21 countries: Algeria (4), Argentina (6), Brazil (1), Canada (7), Denmark (5), Germany (10), India (16), Israel (8), Italy (7), Malaysia (10), Mexico (6), Netherlands (5), Poland (5), Romania (8), South Africa (9), Spain (9), Taiwan (4), Thailand (7), Turkey (9) and United Kingdom (9), United Stated (69).
Pre-assignment Details Data presented in "participant flow" is based on the in-trial observation period, which was 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.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description Participants 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. Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Period Title: Overall Study
Started 1591 1592
Full Analysis Set (FAS) 1591 1592
Exposed 1591 1591
Completed 1586 1586
Not Completed 5 6
Reason Not Completed
Lost to Follow-up             2             5
Withdrawal by Subject             3             1
Arm/Group Title Oral Semaglutide Placebo Total
Hide Arm/Group Description Participants 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. Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks. Total of all reporting groups
Overall Number of Baseline Participants 1591 1592 3183
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1591 participants 1592 participants 3183 participants
66  (7) 66  (7) 66  (7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1591 participants 1592 participants 3183 participants
Female
507
  31.9%
500
  31.4%
1007
  31.6%
Male
1084
  68.1%
1092
  68.6%
2176
  68.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1591 participants 1592 participants 3183 participants
Hispanic or Latino
253
  15.9%
261
  16.4%
514
  16.1%
Not Hispanic or Latino
1338
  84.1%
1331
  83.6%
2669
  83.9%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1591 participants 1592 participants 3183 participants
White
1148
  72.2%
1152
  72.4%
2300
  72.3%
Black or African American
89
   5.6%
103
   6.5%
192
   6.0%
Asian
324
  20.4%
306
  19.2%
630
  19.8%
American Indian or Alaska native
14
   0.9%
15
   0.9%
29
   0.9%
Native Hawaiian or Other Pacific Islander
5
   0.3%
1
   0.1%
6
   0.2%
Other
11
   0.7%
15
   0.9%
26
   0.8%
Baseline cardiovasular disease (CVD)/chronic kidney disease (CKD) risk details   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 1591 participants 1592 participants 3183 participants
Established CVD and/or CKD, age ≥ 50 years
1350
  84.9%
1345
  84.5%
2695
  84.7%
Evidence of CV risk factors, age ≥ 60 years
241
  15.1%
247
  15.5%
488
  15.3%
[1]
Measure Description: This table describes the baseline details of subjects in the study with the risk of CVD and/or CKD.
1.Primary Outcome
Title 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
Hide 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.
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.
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = full analysis set (FAS) which comprised all randomised participants.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1591 1592
Measure Type: Count of Participants
Unit of Measure: Participants
61
   3.8%
76
   4.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first event adjudication committee (EAC) confirmed MACE was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Non-Inferiority
Comments This hypothesis was controlled for multiplicity. Non-inferiority of oral semaglutide versus placebo was considered confirmed if the upper limit of the two-sided 95% confidence interval for the HR was strictly below 1.8.
Statistical Test of Hypothesis P-Value < 0.0001
Comments Unadjusted two-sided p-value for test of no difference from the non-inferiority margin (non-inferiority).
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.57 to 1.11
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first EAC-confirmed MACE was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Superiority
Comments This hypothesis was controlled for multiplicity.
Statistical Test of Hypothesis P-Value = 0.1749
Comments Unadjusted two-sided p-value from test of no difference from 1 (superiority).
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.57 to 1.11
Estimation Comments [Not Specified]
2.Secondary Outcome
Title 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
Hide 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.
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.
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = FAS which comprised all randomised participants.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1591 1592
Measure Type: Count of Participants
Unit of Measure: Participants
83
   5.2%
100
   6.3%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first EAC-confirmed expanded cardiovascular outcome was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value = 0.1827
Comments Unadjusted two-sided p-value for test of no difference from 1.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
0.61 to 1.10
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint
Hide 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.
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.
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = FAS which comprised all randomised participants.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1591 1592
Measure Type: Count of Participants
Unit of Measure: Participants
Cardiovascular death
15
   0.9%
30
   1.9%
Non-fatal myocardial infarction
37
   2.3%
31
   1.9%
Non-fatal stroke
12
   0.8%
16
   1.0%
Unstable angina requiring hospitalisation
11
   0.7%
7
   0.4%
Heart failure requiring hospitalisation
21
   1.3%
24
   1.5%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first EAC-confirmed cardiovascular death (including undetermined cause of death) was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value = 0.0261
Comments Unadjusted two-sided p-value for test of no difference from 1.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.49
Confidence Interval (2-Sided) 95%
0.27 to 0.92
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first EAC-confirmed non-fatal myocardial infarction was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value = 0.5044
Comments Unadjusted two-sided p-value for test of no difference from 1.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.18
Confidence Interval (2-Sided) 95%
0.73 to 1.90
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first EAC-confirmed non-fatal stroke was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value = 0.4350
Comments Unadjusted two-sided p-value for test of no difference from 1
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.35 to 1.57
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first EAC-confirmed unstable angina pectoris requiring hospitalisation was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value = 0.3605
Comments Unadjusted two-sided p-value for test of no difference from 1.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.56
Confidence Interval (2-Sided) 95%
0.60 to 4.01
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first EAC-confirmed hospitalisation for heart failure was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value = 0.6227
Comments Unadjusted two-sided p-value for test of no difference from 1.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.48 to 1.55
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke
Hide 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.
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.
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = FAS which comprised all randomised participants.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1591 1592
Measure Type: Count of Participants
Unit of Measure: Participants
69
   4.3%
89
   5.6%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first EAC-confirmed all-cause death, non-fatal myocardial infarction or non-fatal stroke was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value = 0.0952
Comments Unadjusted two-sided p-value for test of no difference from 1.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.77
Confidence Interval (2-Sided) 95%
0.56 to 1.05
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction
Hide 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.
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.
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = FAS which comprised all randomised participants.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1591 1592
Measure Type: Count of Participants
Unit of Measure: Participants
37
   2.3%
35
   2.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the on-treatment observation period. Time from first dose of trial product to first EAC-confirmed fatal or non-fatal myocardial infarction was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their on-treatment observation period.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value 0.8583
Comments Unadjusted two-sided p-value for test of no difference from 1.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.04
Confidence Interval (2-Sided) 95%
0.66 to 1.66
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke
Hide 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.
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.
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = FAS which comprised all randomised participants.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1591 1592
Measure Type: Count of Participants
Unit of Measure: Participants
13
   0.8%
17
   1.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first EAC-confirmed fatal or non-fatal stroke was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value 0.4485
Comments Unadjusted two-sided p-value for test of no difference from 1.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.37 to 1.56
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Time From Randomisation to All-cause Death
Hide 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.
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.
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = FAS which comprised all randomised participants.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1591 1592
Measure Type: Count of Participants
Unit of Measure: Participants
23
   1.4%
45
   2.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from the in-trial observation period. Time from randomisation to first EAC-confirmed all-cause death was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the end of their in-trial observation period.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value 0.0078
Comments Unadjusted two-sided p-value for test of no difference from 1.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.51
Confidence Interval (2-Sided) 95%
0.31 to 0.84
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Time to First AE Leading to Permanent Trial Product Discontinuation
Hide 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).
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.
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = FAS which comprised all randomised participants.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1591 1592
Measure Type: Count of Participants
Unit of Measure: Participants
184
  11.6%
104
   6.5%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Oral Semaglutide, Placebo
Comments Data from date of first dose of trial product to date of end of treatment visit. Time from first dose to first AE leading to permanent trial product discontinuation was analysed using a Cox proportional hazards model with treatment as categorical fixed factor and stratified by evidence of cardiovascular disease at screening. Participants were censored at the date of their end of treatment visit or at their end of study date, whichever came first.
Type of Statistical Test Other
Comments This hypothesis was not controlled for multiplicity.
Statistical Test of Hypothesis P-Value <0.0001
Comments Unadjusted two-sided p-value for test of no difference from 1.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.81
Confidence Interval (2-Sided) 95%
1.42 to 2.30
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Number of Serious Adverse Events
Hide 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).
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.
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = FAS which comprised all randomised participants.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1591 1592
Measure Type: Number
Unit of Measure: Events
545 618
10.Secondary Outcome
Title Change in Eye Examination Category
Hide 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.
Time Frame Week -3, End of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = FAS which comprised all randomised participants. Number Analyzed = number of participants with available data.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1591 1592
Measure Type: Count of Participants
Unit of Measure: Participants
Left eye fundoscopy (week -3): Normal Number Analyzed 1591 participants 1590 participants
848
  53.3%
843
  53.0%
Left eye fundoscopy (week -3): Abnormal NCS Number Analyzed 1591 participants 1590 participants
657
  41.3%
673
  42.3%
Left eye fundoscopy (week -3): Abnormal CS Number Analyzed 1591 participants 1590 participants
86
   5.4%
74
   4.7%
Right eye fundoscopy (week -3): Normal Number Analyzed 1590 participants 1591 participants
845
  53.1%
858
  53.9%
Right eye fundoscopy (week -3): Abnormal NCS Number Analyzed 1590 participants 1591 participants
659
  41.4%
661
  41.5%
Right eye fundoscopy (week -3): Abnormal CS Number Analyzed 1590 participants 1591 participants
86
   5.4%
72
   4.5%
Left eye fundoscopy (EOT): Normal Number Analyzed 1465 participants 1449 participants
783
  53.4%
790
  54.5%
Left eye fundoscopy (EOT): Abnormal NCS Number Analyzed 1465 participants 1449 participants
599
  40.9%
597
  41.2%
Left eye fundoscopy (EOT): Abnormal CS Number Analyzed 1465 participants 1449 participants
83
   5.7%
62
   4.3%
Right eye fundoscopy (EOT): Normal Number Analyzed 1462 participants 1450 participants
780
  53.4%
787
  54.3%
Right eye fundoscopy (EOT): Abnormal NCS Number Analyzed 1462 participants 1450 participants
601
  41.1%
599
  41.3%
Right eye fundoscopy (EOT): Abnormal CS Number Analyzed 1462 participants 1450 participants
81
   5.5%
64
   4.4%
11.Secondary Outcome
Title Change in Pulse Rate
Hide 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).
Time Frame Week 0, End of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = number of participants with available data.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1345 1411
Mean (Standard Deviation)
Unit of Measure: Beats/minute
4  (11) -0  (11)
12.Secondary Outcome
Title Change in Systolic and Diastolic Blood Pressure
Hide 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).
Time Frame Week 0, End of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = number of participants with available data.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1345 1411
Mean (Standard Deviation)
Unit of Measure: mmHg
Systolic blood pressure -5  (18) -2  (18)
Diastolic blood pressure -1  (11) -2  (10)
13.Secondary Outcome
Title Change in Glycosylated Haemoglobin (HbA1c)
Hide 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.
Time Frame Week 0, End of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = number of participants with available data.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1489 1473
Mean (Standard Deviation)
Unit of Measure: Percentage of HbA1c
-1.0  (1.4) -0.3  (1.3)
14.Secondary Outcome
Title Change in Body Weight
Hide 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.
Time Frame Week 0, End of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = number of participants with available data.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1510 1493
Mean (Standard Deviation)
Unit of Measure: Kg
-4.2  (5.7) -0.8  (4.5)
15.Secondary Outcome
Title Change in Total Cholesterol - Ratio to Baseline
Hide 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.
Time Frame Week 0, End of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = number of participants with available data.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1472 1469
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Ratio of total cholesterol
0.97
(21.9%)
0.98
(21.1%)
16.Secondary Outcome
Title Change in LDL-cholesterol - Ratio to Baseline
Hide 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.
Time Frame Week 0, End of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = number of participants with available data.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1466 1467
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Ratio of LDL-cholesterol
0.96
(36.6%)
0.97
(34.5%)
17.Secondary Outcome
Title Change in HDL-cholesterol - Ratio to Baseline
Hide 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.
Time Frame Week 0, End of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = number of participants with available data.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1468 1467
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Ratio of HDL-cholesterol
1.05
(16.9%)
1.02
(15.9%)
18.Secondary Outcome
Title Change in Triglycerides - Ratio to Baseline
Hide 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.
Time Frame Week 0, End of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Overall number of participants analyzed = number of participants with available data.
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description:
Participants 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.
Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
Overall Number of Participants Analyzed 1468 1467
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Ratio of triglycerides
0.92
(41.8%)
0.97
(39.8%)
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.
Adverse Event Reporting Description Systematic collection of AEs was limited to SAEs, AEs leading to permanent discontinuation of trial product, medication errors leading to SAEs, severe hypoglycaemic episodes, hepatic events, pregnancies and AEs related to technical complaints and were summarised. Non-serious AEs not fulfilling the above criteria were not systematically collected.
 
Arm/Group Title Oral Semaglutide Placebo
Hide Arm/Group Description Participants 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. Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks.
All-Cause Mortality
Oral Semaglutide Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   23/1591 (1.45%)      45/1591 (2.83%)    
Hide Serious Adverse Events
Oral Semaglutide Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   301/1591 (18.92%)      358/1591 (22.50%)    
Blood and lymphatic system disorders     
Anaemia † 1  2/1591 (0.13%)  2 2/1591 (0.13%)  2
Autoimmune haemolytic anaemia † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Iron deficiency anaemia † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Leukocytosis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Splenic haemorrhage † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cardiac disorders     
Acute coronary syndrome † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Acute left ventricular failure † 1  2/1591 (0.13%)  2 2/1591 (0.13%)  2
Acute myocardial infarction † 1  21/1591 (1.32%)  25 22/1591 (1.38%)  25
Angina pectoris † 1  8/1591 (0.50%)  9 7/1591 (0.44%)  7
Angina unstable † 1  19/1591 (1.19%)  20 15/1591 (0.94%)  18
Arrhythmia † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Arteriosclerosis coronary artery † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Arteriospasm coronary † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Atrial fibrillation † 1  6/1591 (0.38%)  8 14/1591 (0.88%)  14
Atrial flutter † 1  3/1591 (0.19%)  3 1/1591 (0.06%)  1
Atrioventricular block complete † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Atrioventricular block first degree † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Atrioventricular block second degree † 1  3/1591 (0.19%)  3 1/1591 (0.06%)  1
Bradycardia † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cardiac arrest † 1  5/1591 (0.31%)  6 0/1591 (0.00%)  0
Cardiac failure † 1  2/1591 (0.13%)  2 7/1591 (0.44%)  8
Cardiac failure acute † 1  2/1591 (0.13%)  3 2/1591 (0.13%)  2
Cardiac failure chronic † 1  5/1591 (0.31%)  5 8/1591 (0.50%)  9
Cardiac failure congestive † 1  9/1591 (0.57%)  12 9/1591 (0.57%)  11
Cardiac flutter † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Cardio-respiratory arrest † 1  1/1591 (0.06%)  1 3/1591 (0.19%)  3
Cardiogenic shock † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Cardiomyopathy † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cardiopulmonary failure † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Cardiorenal syndrome † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Coronary artery disease † 1  9/1591 (0.57%)  9 13/1591 (0.82%)  13
Coronary artery stenosis † 1  1/1591 (0.06%)  1 3/1591 (0.19%)  3
Coronary artery thrombosis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Degenerative aortic valve disease † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Hypertensive heart disease † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Ischaemic cardiomyopathy † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Left ventricular failure † 1  0/1591 (0.00%)  0 4/1591 (0.25%)  4
Mitral valve incompetence † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Myocardial infarction † 1  11/1591 (0.69%)  11 9/1591 (0.57%)  9
Myocardial ischaemia † 1  2/1591 (0.13%)  2 3/1591 (0.19%)  3
Myocarditis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Prinzmetal angina † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pulseless electrical activity † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Sinus node dysfunction † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Supraventricular tachycardia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Tachycardia † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Ventricular fibrillation † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Ventricular tachycardia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Ear and labyrinth disorders     
Vertigo † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Endocrine disorders     
Hyperthyroidism † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Thyroid mass † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Eye disorders     
Cataract † 1  8/1591 (0.50%)  8 5/1591 (0.31%)  6
Retinal tear † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Retinopathy proliferative † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Gastrointestinal disorders     
Abdominal pain † 1  2/1591 (0.13%)  2 2/1591 (0.13%)  2
Abdominal pain upper † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Colitis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Colitis ischaemic † 1  2/1591 (0.13%)  2 0/1591 (0.00%)  0
Constipation † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Diarrhoea † 1  4/1591 (0.25%)  4 0/1591 (0.00%)  0
Duodenal ulcer † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Duodenal ulcer haemorrhage † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Dyspepsia † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Gastric ulcer † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Gastritis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Gastroduodenitis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Gastrointestinal haemorrhage † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  2
Gastrointestinal polyp haemorrhage † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Gastrooesophageal reflux disease † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Haematochezia † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Haemorrhoids † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Impaired gastric emptying † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Inguinal hernia † 1  2/1591 (0.13%)  2 2/1591 (0.13%)  2
Intestinal ischaemia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Intestinal mass † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Large intestine polyp † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Lower gastrointestinal haemorrhage † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Nausea † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Oesophageal haemorrhage † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Oesophageal varices haemorrhage † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Oesophagitis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Oesophagitis ulcerative † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pancreatitis † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Pancreatitis acute † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pancreatitis chronic † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Peptic ulcer haemorrhage † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Salivary gland calculus † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Umbilical hernia † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Vomiting † 1  4/1591 (0.25%)  4 0/1591 (0.00%)  0
General disorders     
Asthenia † 1  3/1591 (0.19%)  3 0/1591 (0.00%)  0
Chest pain † 1  1/1591 (0.06%)  1 2/1591 (0.13%)  2
Death † 1  1/1591 (0.06%)  1 3/1591 (0.19%)  3
Drowning † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Fatigue † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Hernia pain † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Non-cardiac chest pain † 1  9/1591 (0.57%)  11 7/1591 (0.44%)  9
Oedema peripheral † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Peripheral swelling † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pyrexia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Sudden cardiac death † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Systemic inflammatory response syndrome † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Vascular stent restenosis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Hepatobiliary disorders     
Bile duct stone † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Biliary fistula † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Cholangitis acute † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cholecystitis † 1  1/1591 (0.06%)  1 2/1591 (0.13%)  2
Cholecystitis acute † 1  3/1591 (0.19%)  3 2/1591 (0.13%)  2
Cholecystitis chronic † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cholelithiasis † 1  2/1591 (0.13%)  2 4/1591 (0.25%)  4
Drug-induced liver injury † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Gallbladder polyp † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Hepatic cirrhosis † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Hepatic steatosis † 1  1/1591 (0.06%)  1 2/1591 (0.13%)  2
Hepatitis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Liver disorder † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Immune system disorders     
Anaphylactic reaction † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Infections and infestations     
Abscess limb † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Anal abscess † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Biliary sepsis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Bronchitis † 1  1/1591 (0.06%)  1 3/1591 (0.19%)  4
Campylobacter gastroenteritis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Carbuncle † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cellulitis † 1  9/1591 (0.57%)  9 7/1591 (0.44%)  7
Cholecystitis infective † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Device related infection † 1  1/1591 (0.06%)  1 2/1591 (0.13%)  3
Diabetic foot infection † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Diabetic gangrene † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Diverticulitis † 1  3/1591 (0.19%)  3 2/1591 (0.13%)  2
Empyema † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Endocarditis bacterial † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Erysipelas † 1  0/1591 (0.00%)  0 3/1591 (0.19%)  3
Escherichia pyelonephritis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Folliculitis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Gallbladder empyema † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Gangrene † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Gastroenteritis † 1  5/1591 (0.31%)  5 5/1591 (0.31%)  5
Gastroenteritis viral † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Herpes zoster † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Infective tenosynovitis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Influenza † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Injection site abscess † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Intervertebral discitis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Lower respiratory tract infection † 1  2/1591 (0.13%)  2 0/1591 (0.00%)  0
Ludwig angina † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Meningitis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Murine typhus † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Myelitis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Oral infection † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Osteomyelitis † 1  5/1591 (0.31%)  5 1/1591 (0.06%)  1
Periorbital cellulitis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pneumonia † 1  12/1591 (0.75%)  13 21/1591 (1.32%)  21
Pneumonia acinetobacter † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Pneumonia escherichia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pneumonia influenzal † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Pneumonia klebsiella † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pneumonia streptococcal † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Post procedural cellulitis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Post procedural infection † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Post procedural pneumonia † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Postoperative wound infection † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Pulmonary tuberculosis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Pyelonephritis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pyelonephritis acute † 1  1/1591 (0.06%)  1 2/1591 (0.13%)  2
Rectal abscess † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Sepsis † 1  3/1591 (0.19%)  3 6/1591 (0.38%)  6
Septic shock † 1  2/1591 (0.13%)  2 3/1591 (0.19%)  3
Sialoadenitis † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Sinusitis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Staphylococcal bacteraemia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Tinea pedis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Tonsillitis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Upper respiratory tract infection † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Upper respiratory tract infection bacterial † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Urinary tract infection † 1  3/1591 (0.19%)  3 5/1591 (0.31%)  5
Urosepsis † 1  2/1591 (0.13%)  2 3/1591 (0.19%)  5
Wound sepsis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Injury, poisoning and procedural complications     
Accidental overdose † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Ankle fracture † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Brain contusion † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cervical vertebral fracture † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Chemical peritonitis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Comminuted fracture † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Coronary artery restenosis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Ear injury † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Facial bones fracture † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Fall † 1  5/1591 (0.31%)  5 11/1591 (0.69%)  11
Femoral neck fracture † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Femur fracture † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Foot fracture † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Forearm fracture † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Foreign body in ear † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Graft haemorrhage † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Hip fracture † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Humerus fracture † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Injury corneal † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Joint dislocation † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Joint injury † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Laceration † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Limb injury † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Open globe injury † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Patella fracture † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Pelvic fracture † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Post procedural bile leak † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Post procedural complication † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Post procedural haematuria † 1  2/1591 (0.13%)  2 0/1591 (0.00%)  0
Postoperative thoracic procedure complication † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Radius fracture † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Rib fracture † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Road traffic accident † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Spinal compression fracture † 1  1/1591 (0.06%)  1 2/1591 (0.13%)  2
Subdural haematoma † 1  3/1591 (0.19%)  3 0/1591 (0.00%)  0
Subdural haemorrhage † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Tendon injury † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Tendon rupture † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Thermal burn † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Upper limb fracture † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Vascular pseudoaneurysm † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Investigations     
Blood creatinine increased † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Blood potassium increased † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Clostridium test positive † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Ejection fraction decreased † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Hepatic enzyme increased † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Troponin increased † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Metabolism and nutrition disorders     
Dehydration † 1  3/1591 (0.19%)  3 2/1591 (0.13%)  2
Diabetes mellitus † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Diabetes mellitus inadequate control † 1  1/1591 (0.06%)  1 3/1591 (0.19%)  3
Diabetic ketoacidosis † 1  2/1591 (0.13%)  2 0/1591 (0.00%)  0
Hyperglycaemia † 1  2/1591 (0.13%)  2 4/1591 (0.25%)  4
Hyperglycaemic hyperosmolar nonketotic syndrome † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Hyperkalaemia † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Hypervolaemia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Hypoglycaemia † 1  5/1591 (0.31%)  5 4/1591 (0.25%)  4
Hypokalaemia † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Hyponatraemia † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Hypovolaemia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Lactic acidosis † 1  3/1591 (0.19%)  3 2/1591 (0.13%)  2
Latent autoimmune diabetes in adults † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Musculoskeletal and connective tissue disorders     
Arthritis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Arthropathy † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Back pain † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Bursitis † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Intervertebral disc protrusion † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Lumbar spinal stenosis † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Muscular weakness † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Musculoskeletal chest pain † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Neck pain † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Osteoarthritis † 1  6/1591 (0.38%)  6 10/1591 (0.63%)  10
Pain in extremity † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pathological fracture † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Polymyalgia rheumatica † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Rhabdomyolysis † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Rotator cuff syndrome † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Sacroiliitis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Spinal column stenosis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Spinal osteoarthritis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Trigger finger † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Adenocarcinoma gastric † 1  1/1591 (0.06%)  1 2/1591 (0.13%)  2
Adenocarcinoma of colon † 1  4/1591 (0.25%)  4 1/1591 (0.06%)  1
Adenocarcinoma pancreas † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
B-cell lymphoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Basal cell carcinoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  2
Bladder cancer † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Bladder transitional cell carcinoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Breast cancer † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Carcinoid tumour of the appendix † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cholangiocarcinoma † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Choroid melanoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Chronic myelomonocytic leukaemia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Colon cancer † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Diffuse large B-cell lymphoma † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Endometrial adenocarcinoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Haemangioma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Hepatic cancer † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Hepatocellular carcinoma † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Light chain disease † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Lip squamous cell carcinoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Lung adenocarcinoma † 1  2/1591 (0.13%)  2 0/1591 (0.00%)  0
Lung cancer metastatic † 1  2/1591 (0.13%)  2 0/1591 (0.00%)  0
Lymphoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Malignant peritoneal neoplasm † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Medullary thyroid cancer † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Mesothelioma malignant † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Metastases to liver † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Metastases to lung † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Metastatic malignant melanoma † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Non-Hodgkin's lymphoma † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Pancreatic carcinoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pancreatic carcinoma metastatic † 1  2/1591 (0.13%)  2 1/1591 (0.06%)  1
Pancreatic neuroendocrine tumour metastatic † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Papillary renal cell carcinoma † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Penile squamous cell carcinoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pituitary tumour benign † 1  2/1591 (0.13%)  2 0/1591 (0.00%)  0
Plasma cell myeloma † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Polycythaemia vera † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Prostate cancer † 1  0/1591 (0.00%)  0 4/1591 (0.25%)  4
Prostate cancer metastatic † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Prostate cancer stage III † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Prostate cancer stage IV † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Rectal adenocarcinoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Renal neoplasm † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Small cell carcinoma † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Squamous cell carcinoma of lung † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Squamous cell carcinoma of the tongue † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Thyroid cancer metastatic † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Nervous system disorders     
Carotid artery occlusion † 1  2/1591 (0.13%)  2 0/1591 (0.00%)  0
Carotid artery stenosis † 1  4/1591 (0.25%)  4 4/1591 (0.25%)  5
Cerebellar infarction † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cerebral infarction † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Cerebral ischaemia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Cerebrovascular accident † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Dementia with Lewy bodies † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Diabetic neuropathy † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Dizziness † 1  2/1591 (0.13%)  2 2/1591 (0.13%)  2
Dyspraxia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Encephalopathy † 1  2/1591 (0.13%)  2 0/1591 (0.00%)  0
Headache † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Hemiparesis † 1  2/1591 (0.13%)  3 0/1591 (0.00%)  0
Hypoaesthesia † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Hypoglycaemic seizure † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Hypoglycaemic unconsciousness † 1  9/1591 (0.57%)  11 6/1591 (0.38%)  8
Ischaemic cerebral infarction † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Ischaemic stroke † 1  9/1591 (0.57%)  9 11/1591 (0.69%)  12
Lacunar infarction † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Lacunar stroke † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Lumbosacral plexopathy † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Migraine † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Myasthenia gravis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Neuritis † 1  1/1591 (0.06%)  2 0/1591 (0.00%)  0
Neurotoxicity † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Optic neuritis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Parkinsonism † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Seizure † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Spondylitic myelopathy † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Syncope † 1  7/1591 (0.44%)  7 4/1591 (0.25%)  4
Transient ischaemic attack † 1  3/1591 (0.19%)  3 6/1591 (0.38%)  6
VIth nerve paralysis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Vascular dementia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Product Issues     
Device malfunction † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Psychiatric disorders     
Alcoholism † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Bipolar disorder † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Confusional state † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Depression † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Drug dependence † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Mania † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Mental status changes † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Renal and urinary disorders     
Acute kidney injury † 1  13/1591 (0.82%)  14 14/1591 (0.88%)  18
Acute prerenal failure † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Azotaemia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Bladder prolapse † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Chronic kidney disease † 1  1/1591 (0.06%)  1 5/1591 (0.31%)  5
Diabetic nephropathy † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Haematuria † 1  2/1591 (0.13%)  2 2/1591 (0.13%)  2
Hydronephrosis † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
IgA nephropathy † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Nephrolithiasis † 1  2/1591 (0.13%)  2 2/1591 (0.13%)  2
Renal failure † 1  1/1591 (0.06%)  1 2/1591 (0.13%)  2
Renal impairment † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Ureterolithiasis † 1  3/1591 (0.19%)  3 2/1591 (0.13%)  2
Urethral stenosis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Urinary incontinence † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Reproductive system and breast disorders     
Benign prostatic hyperplasia † 1  3/1591 (0.19%)  3 2/1591 (0.13%)  2
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Acute respiratory failure † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  3
Aspiration † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Asthma † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Bronchial hyperreactivity † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Bronchospasm † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Chronic obstructive pulmonary disease † 1  8/1591 (0.50%)  11 4/1591 (0.25%)  4
Dyspnoea † 1  1/1591 (0.06%)  2 2/1591 (0.13%)  2
Haemothorax † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Hypoxia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Idiopathic pulmonary fibrosis † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Lung disorder † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Obstructive airways disorder † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Organising pneumonia † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pharyngeal oedema † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Pleural effusion † 1  1/1591 (0.06%)  2 1/1591 (0.06%)  1
Pneumonitis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Pulmonary embolism † 1  2/1591 (0.13%)  2 2/1591 (0.13%)  2
Pulmonary oedema † 1  2/1591 (0.13%)  2 0/1591 (0.00%)  0
Respiratory failure † 1  2/1591 (0.13%)  2 2/1591 (0.13%)  2
Sleep apnoea syndrome † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Skin and subcutaneous tissue disorders     
Angioedema † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Dermatomyositis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Diabetic foot † 1  2/1591 (0.13%)  2 6/1591 (0.38%)  7
Skin ulcer † 1  1/1591 (0.06%)  1 4/1591 (0.25%)  4
Vasculitic ulcer † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Surgical and medical procedures     
Aortic aneurysm repair † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cardiac pacemaker insertion † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Cataract operation † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Cholecystectomy † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Finger repair operation † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Gastric bypass † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Glaucoma surgery † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Hip arthroplasty † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Implantable defibrillator insertion † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Joint arthroplasty † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Knee arthroplasty † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Spinal fusion surgery † 1  0/1591 (0.00%)  0 2/1591 (0.13%)  2
Subdural haematoma evacuation † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Transurethral prostatectomy † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Trapeziectomy † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Vascular disorders     
Aortic aneurysm † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Aortic dissection † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Aortic stenosis † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Arteriosclerosis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Deep vein thrombosis † 1  3/1591 (0.19%)  3 1/1591 (0.06%)  1
Hypertension † 1  1/1591 (0.06%)  1 1/1591 (0.06%)  1
Hypertensive crisis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Hypertensive emergency † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
Hypotension † 1  5/1591 (0.31%)  5 3/1591 (0.19%)  3
Malignant hypertension † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Orthostatic hypotension † 1  1/1591 (0.06%)  1 3/1591 (0.19%)  3
Peripheral arterial occlusive disease † 1  2/1591 (0.13%)  2 7/1591 (0.44%)  7
Peripheral artery dissection † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Peripheral artery occlusion † 1  1/1591 (0.06%)  1 0/1591 (0.00%)  0
Peripheral artery stenosis † 1  3/1591 (0.19%)  3 1/1591 (0.06%)  1
Peripheral ischaemia † 1  1/1591 (0.06%)  1 3/1591 (0.19%)  3
Peripheral vascular disorder † 1  3/1591 (0.19%)  3 2/1591 (0.13%)  2
Thrombosis † 1  0/1591 (0.00%)  0 1/1591 (0.06%)  1
1
Term from vocabulary, MedDRA 20
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Oral Semaglutide Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/1591 (0.00%)      0/1591 (0.00%)    
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Reporting Anchor and Disclosure (1452)
Organization: Novo Nordisk A/S
Phone: (+1) 866-867-7178
EMail: clinicaltrials@novonordisk.com
Publications of Results:
Cefalu 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.
Bain SC, Mosenzon O, Arechavaleta R, Bogdanski P, Comlekci A, Consoli A, Deerochanawong C, Dungan K, Faingold MC, Farkouh ME, Franco DR, Gram J, Guja C, Joshi P, Malek R, Merino-Torres JF, Nauck MA, Pedersen SD, Sheu WH, Silver RJ, Tack CJ, Tandon N, Jeppesen OK, Strange M, Thomsen M, Husain M. Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial. Diabetes Obes Metab. 2019 Mar;21(3):499-508. doi: 10.1111/dom.13553. Epub 2018 Nov 11.
Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O, Pedersen SD, Tack CJ, Thomsen M, Vilsboll T, Warren ML, Bain SC; PIONEER 6 Investigators. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019 Aug 29;381(9):841-851. doi: 10.1056/NEJMoa1901118. Epub 2019 Jun 11.
Evans LM, Mellbin L, Johansen P, Lawson J, Paine A, Sandberg A. 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. Endocrinol Diabetes Metab. 2021 May 15;4(3):e00259. doi: 10.1002/edm2.259. eCollection 2021 Jul.
Husain M, Consoli A, De Remigis A, Pettersson Meyer AS, Rasmussen S, Bain S. Semaglutide reduces cardiovascular events regardless of metformin use: a post hoc subgroup analysis of SUSTAIN 6 and PIONEER 6. Cardiovasc Diabetol. 2022 Apr 28;21(1):64. doi: 10.1186/s12933-022-01489-6.
Aroda VR, Bauer R, Christiansen E, Haluzik M, Kallenbach K, Montanya E, Rosenstock J, Meier JJ. Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Diabetes Obes Metab. 2022 Jul;24(7):1338-1350. doi: 10.1111/dom.14710. Epub 2022 May 9.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT02692716    
Other Study ID Numbers: NN9924-4221
2015-003563-10 ( EudraCT Number )
U1111-1173-0750 ( Other Identifier: WHO )
NL56580.091.16 ( Other Identifier: CCMO )
First Submitted: February 23, 2016
First Posted: February 26, 2016
Results First Submitted: October 15, 2019
Results First Posted: February 27, 2020
Last Update Posted: July 20, 2022