Diabetes Mellitus, Type 2
Conditions
Brief summary
The researchers are doing this study to look whether the type 2 diabetes medicine, semaglutide, has a positive effect on heart disease. Participants will either get semaglutide tablets or placebo tablets (dummy medicine) - which treatment is decided by chance. Participants must take one tablet with water every morning on an empty stomach and not eat or drink anything for at least 30 minutes. The study will last for about 3.5-5 years. Participants will have up to 25 clinic visits and 1 phone call with the study doctor. Women cannot be in the study if pregnant, breast-feeding or if they plan to become pregnant during the study period.
Interventions
DRUGSemaglutide
Increasing doses (3 mg/7 mg/14 mg) of semaglutide tablets to be taken with water at the same time every morning in a fasting state
DRUGPlacebo (semaglutide)
Placebo tablets to be taken with water at the same time every morning in a fasting state
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Sponsor staff involved in the clinical trial is masked according to company standard procedures
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, age equal to or above 50 years at the time of signing informed consent * Diagnosed with type 2 diabetes mellitus * HbA1c 6.5% - 10.0% (47 - 86 mmol/mol) (both inclusive) (latest available and no more than 30 days old local laboratory assessment based on medical records or point of care measurement) * At least one of the below conditions (a-d): a) Coronary heart disease defined as at least one of the following: i. Prior myocardial infarction ii. Prior coronary revascularisation procedure iii. 50% or above stenosis in coronary artery documented by cardiac catheterisation, computerized tomography coronary angiography iv. Coronary heart disease with ischaemia documented by stress test with any imaging modality b) Cerebrovascular disease defined as at least one of the following: i. Prior stroke ii. Prior carotid artery revascularisation procedure iii.50% or above stenosis in carotid artery documented by X-ray angiography, magnetic resonance angiography, computerized tomography angiography or Doppler ultrasound c) Symptomatic peripheral artery disease (PAD) defined as at least one of the following: i. Intermittent claudication with an Ankle-brachial index (ABI) below 0.85 at rest ii. Intermittent claudication with a 50% or above stenosis in peripheral artery (excluding carotid) documented by X-ray angiography, magnetic resonance angiography, computerized tomography angiography or Doppler ultrasound iii. Prior peripheral artery (excluding carotid) revascularization procedure iv. Lower extremity amputation at or above ankle due to atherosclerotic disease (excluding e.g. trauma or osteomyelitis) d) Chronic kidney disease defined as: i. eGFR below 60 mL/min/1.73 m\^2 (based on medical records using latest available and no more than 6 months old assessment)
Exclusion criteria
* Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening * Planned coronary, carotid or peripheral artery revascularisation known on the day of screening * Heart failure presently classified as being in New York Heart Association Class IV * Treatment with any glucagon-like peptide-1 receptor agonist within 30 days before screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants From Randomization to First Occurrence of a Major Adverse Cardiovascular Event (MACE), a Composite Endpoint Consisting of: Cardiovascular (CV) Death/Non-fatal Myocardial Infarction/Non-fatal Stroke | From randomisation (week 0) up to week 265 | Number of participants with first occurrence of EAC (event adjudication committee) confirmed major adverse cardiovascular event (MACE), a composite end-point. i.e., from time of randomization to first occurrence of cardiovascular (CV) death, non-fatal myocardial infarction and non-fatal stroke combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants From Randomization to Time of Occurrence of CV Death | From randomisation (week 0) up to week 265 | Number of participants from time of randomization to time to occurrence of EAC confirmed CV death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomization to First Occurrence of Major Adverse Limb Events (MALE), a Composite Endpoint Consisting of: Acute Limb Ischemia Hospitalisation/Chronic Limb Ischemia Hospitalisation | From randomisation (week 0) up to week 265 | Number of participants from randomization to first occurrence of EAC confirmed major adverse limb events (MALE), a composite endpoint consisting of: acute limb ischemia hospitalisation/chronic limb ischemia hospitalisation combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of an Expanded MACE Composite Endpoint Consisting of: CV Death/Non-fatal Myocardial Infarction/ Non-fatal Stroke/Coronary Revascularisation/Unstable Angina Pectoris Requiring Hospitalisation | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of an expanded MACE composite endpoint consisting of: CV death/non-fatal myocardial infarction/ non-fatal stroke/coronary revascularisation/unstable angina pectoris requiring hospitalisation combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of a Composite Endpoint Consisting of : All-cause Death/ Non-fatal MI/ Non-fatal Stroke | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of EAC confirmed composite endpoint consisting of : all-cause death/ non-fatal MI/ non-fatal stroke combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of a Composite Heart Failure Endpoint Consisting of: CV Death/Heart Failure Requiring Hospitalisation/Urgent Heart Failure Visit | From randomisation (week 0) up to week 265 | Number of participants from randomisation to first occurrence of EAC confirmed composite heart failure endpoint consisting of: CV death/heart failure requiring hospitalisation/urgent heart failure visit combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death |
| Number of Participants From Randomization to First Occurrence of CKD Endpoint:Renal Death;Onset of Persistent≥50% Reduction in eGFR (CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73 m^2;Initiation of Chronic Renal Replacement Therapy | From randomisation (week 0) up to week 265 | The number of participants from randomization to first occurrence of CKD endpoint:renal death;onset of persistent≥50% reduction in eGFR (CKD-EPI);onset of persistent eGFR(CKD-EPI)\<15 mL/min/1.73 m\^2;initiation of chronic renal replacement therapy combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to Time to Occurrence of All-cause Death | From randomisation (week 0) up to week 265 | The number of participants from randomisation to time to occurrence of EAC confirmed all-cause death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of Non-fatal Myocardial Infarction (MI) | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of EAC confirmed non-fatal MI during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of Non-fatal Stroke | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of EAC confirmed non-fatal stroke during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of Heart Failure Requiring Hospitalisation or Urgent Heart Failure Visit | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of EAC confirmed heart failure requiring hospitalisation or urgent heart failure visit during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of Coronary Revascularisation | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of coronary revascularisation during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomization to First Occurrence of CV Death;Renal Death;Onset of Persistent≥50% Reduction in eGFR(CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73m^2;Initiation of Chronic Renal Replacement Therapy | From randomisation (week 0) up to week 265 | Number of participants with first occurrence of a composite endpoint. i.e., from time of randomization to first occurrence of CV death, renal death, onset of persistent greater than or equal to (≥) 50% reduction in estimated glomerular filtration rate (eGFR) (chronic kidney disease epidemiology collaboration CKD-EPI), onset of persistent eGFR (CKD-EPI) less than (\<)15 milliliters per minute per 1.73 square meters (mL/min/1.73 m\^2), initiation of chronic renal replacement therapy (dialysis or kidney transplantation) combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to Time to Occurrence of Renal Death | From randomisation (week 0) up to week 265 | The number of participants from randomisation to time to occurrence of EAC confirmed renal death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of Onset of Persistent 50% or More Reduction in eGFR | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of onset of persistent 50% or more reduction in eGFR during in-trial period were observed. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of Onset of Persistent eGFR (CKD-EPI) Below 15 mL/Min/1.73 m^2 | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of onset of persistent eGFR (CKD-EPI) below 15 mL/min/1.73 m\^2 during in-trial period were observed. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of Initiation of Chronic Renal Replacement Therapy (Dialysis or Kidney Transplantation) | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of EAC confirmed initiation of chronic renal replacement therapy (dialysis or kidney transplantation) during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of Acute Limb Ischemia | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of EAC confirmed acute limb ischaemia hospitalization during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of Chronic Limb Ischemia Hospitalisation | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of EAC confirmed chronic limb ischaemia hospitalization during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Annual Rate of Change in eGFR (CKD-EPI) (Total eGFR Slope) | From randomisation (week 0) up to week 260 | Annual rate of change in eGFR in terms of chronic kidney disease CKD-EPI were reported during in trial period. eGFR was calculated using the CKD-EPI formula. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Change From Baseline in Glycosylated Haemoglobin (HbA1c) | Baseline (Week 0), Week 104 | Change in HbA1c from baseline (Week 0) up to Week 104 during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Change From Baseline in Body Weight | Baseline (Week 0), Week 104 | Change in body weight from baseline (Week 0) up to Week 104 during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Severe Hypoglycaemic Episodes | From randomisation (week 0) up to week 265 | The number of severe hypoglycaemic episodes (such as the seriousness of hypoglycaemia, contributing factors, seizures, and unconsciousness; classified by American Diabetes Association) observed during the in-trial period were reported in this endpoint. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of a Severe Hypoglycaemic Episode | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of severe hypoglycaemic episodes (such as the seriousness of hypoglycaemia, contributing factors, seizures, and unconsciousness; classified by American Diabetes Association) during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
| Number of Participants From Randomisation to First Occurrence of Unstable Angina Requiring Hospitalisation | From randomisation (week 0) up to week 265 | The number of participants from randomisation to first occurrence of EAC confirmed unstable angina requiring hospitalisation during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death. |
Countries
Algeria, Argentina, Austria, Belgium, Brazil, Canada, China, Colombia, Croatia, Czechia, Denmark, France, Germany, Hong Kong, India, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 446 sites in 34 countries.
Pre-assignment details
A total of 9,651 participants were enrolled/randomized (1:1) to treatment with oral semaglutide (4,825 participants) or placebo (4,826 participants). One participant was randomised twice in the trial. Thus, the FAS comprised 9,650 participants (4,825 participants in the oral semaglutide group and 4,825 participants in the placebo group).
Participants by arm
| Arm | Count |
|---|---|
| Oral Semaglutide Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260). | 4,825 |
| Placebo Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260). | 4,825 |
| Total | 9,650 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 43 | 51 |
| Overall Study | Randomised more than once | 0 | 1 |
| Overall Study | Withdrawal by Subject | 27 | 34 |
Baseline characteristics
| Characteristic | Placebo | Total | Oral Semaglutide |
|---|---|---|---|
| Age, Continuous | 66.1 Years STANDARD_DEVIATION 7.5 | 66.1 Years STANDARD_DEVIATION 7.6 | 66.1 Years STANDARD_DEVIATION 7.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 706 Participants | 1380 Participants | 674 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4072 Participants | 8178 Participants | 4106 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 47 Participants | 92 Participants | 45 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 12 Participants | 19 Participants | 7 Participants |
| Race (NIH/OMB) Asian | 1121 Participants | 2255 Participants | 1134 Participants |
| Race (NIH/OMB) Black or African American | 128 Participants | 252 Participants | 124 Participants |
| Race (NIH/OMB) More than one race | 192 Participants | 377 Participants | 185 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 5 Participants | 9 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 46 Participants | 90 Participants | 44 Participants |
| Race (NIH/OMB) White | 3321 Participants | 6648 Participants | 3327 Participants |
| Sex: Female, Male Female | 1414 Participants | 2790 Participants | 1376 Participants |
| Sex: Female, Male Male | 3411 Participants | 6860 Participants | 3449 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 528 / 4,825 | 579 / 4,825 |
| other Total, other adverse events | 1,761 / 4,825 | 1,599 / 4,825 |
| serious Total, serious adverse events | 2,312 / 4,825 | 2,427 / 4,825 |
Outcome results
Primary
Number of Participants From Randomization to First Occurrence of a Major Adverse Cardiovascular Event (MACE), a Composite Endpoint Consisting of: Cardiovascular (CV) Death/Non-fatal Myocardial Infarction/Non-fatal Stroke
Number of participants with first occurrence of EAC (event adjudication committee) confirmed major adverse cardiovascular event (MACE), a composite end-point. i.e., from time of randomization to first occurrence of cardiovascular (CV) death, non-fatal myocardial infarction and non-fatal stroke combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomization to First Occurrence of a Major Adverse Cardiovascular Event (MACE), a Composite Endpoint Consisting of: Cardiovascular (CV) Death/Non-fatal Myocardial Infarction/Non-fatal Stroke | 579 Participants |
| Placebo | Number of Participants From Randomization to First Occurrence of a Major Adverse Cardiovascular Event (MACE), a Composite Endpoint Consisting of: Cardiovascular (CV) Death/Non-fatal Myocardial Infarction/Non-fatal Stroke | 668 Participants |
p-value: 0.002895% CI: [0.77, 0.96]Regression, Cox
Secondary
Annual Rate of Change in eGFR (CKD-EPI) (Total eGFR Slope)
Annual rate of change in eGFR in terms of chronic kidney disease CKD-EPI were reported during in trial period. eGFR was calculated using the CKD-EPI formula. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 260
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization. Here 'overall number of participants analyzed' signifies number of participants evaluable for this outcome measure also.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Semaglutide | Annual Rate of Change in eGFR (CKD-EPI) (Total eGFR Slope) | -1.67 ml/min/1.73 m^2 per year | Standard Error 0 |
| Placebo | Annual Rate of Change in eGFR (CKD-EPI) (Total eGFR Slope) | -2.06 ml/min/1.73 m^2 per year | Standard Error 0 |
Secondary
Change From Baseline in Body Weight
Change in body weight from baseline (Week 0) up to Week 104 during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: Baseline (Week 0), Week 104
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization. Here 'overall number of participants analyzed' signifies number of participants evaluable for this outcome measure also.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Semaglutide | Change From Baseline in Body Weight | -4.21 Kilograms | Standard Deviation 5.85 |
| Placebo | Change From Baseline in Body Weight | -1.28 Kilograms | Standard Deviation 4.9 |
Secondary
Change From Baseline in Glycosylated Haemoglobin (HbA1c)
Change in HbA1c from baseline (Week 0) up to Week 104 during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: Baseline (Week 0), Week 104
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization. Here 'overall number of participants analyzed' signifies number of participants evaluable for this outcome measure also.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Semaglutide | Change From Baseline in Glycosylated Haemoglobin (HbA1c) | -0.71 Percentage of HbA1c | Standard Deviation 1.22 |
| Placebo | Change From Baseline in Glycosylated Haemoglobin (HbA1c) | -0.15 Percentage of HbA1c | Standard Deviation 1.19 |
Secondary
Number of Participants From Randomisation to First Occurrence of a Composite Endpoint Consisting of : All-cause Death/ Non-fatal MI/ Non-fatal Stroke
The number of participants from randomisation to first occurrence of EAC confirmed composite endpoint consisting of : all-cause death/ non-fatal MI/ non-fatal stroke combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of a Composite Endpoint Consisting of : All-cause Death/ Non-fatal MI/ Non-fatal Stroke | 779 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of a Composite Endpoint Consisting of : All-cause Death/ Non-fatal MI/ Non-fatal Stroke | 902 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of a Composite Heart Failure Endpoint Consisting of: CV Death/Heart Failure Requiring Hospitalisation/Urgent Heart Failure Visit
Number of participants from randomisation to first occurrence of EAC confirmed composite heart failure endpoint consisting of: CV death/heart failure requiring hospitalisation/urgent heart failure visit combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of a Composite Heart Failure Endpoint Consisting of: CV Death/Heart Failure Requiring Hospitalisation/Urgent Heart Failure Visit | 405 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of a Composite Heart Failure Endpoint Consisting of: CV Death/Heart Failure Requiring Hospitalisation/Urgent Heart Failure Visit | 443 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of Acute Limb Ischemia
The number of participants from randomisation to first occurrence of EAC confirmed acute limb ischaemia hospitalization during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of Acute Limb Ischemia | 16 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of Acute Limb Ischemia | 17 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of an Expanded MACE Composite Endpoint Consisting of: CV Death/Non-fatal Myocardial Infarction/ Non-fatal Stroke/Coronary Revascularisation/Unstable Angina Pectoris Requiring Hospitalisation
The number of participants from randomisation to first occurrence of an expanded MACE composite endpoint consisting of: CV death/non-fatal myocardial infarction/ non-fatal stroke/coronary revascularisation/unstable angina pectoris requiring hospitalisation combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of an Expanded MACE Composite Endpoint Consisting of: CV Death/Non-fatal Myocardial Infarction/ Non-fatal Stroke/Coronary Revascularisation/Unstable Angina Pectoris Requiring Hospitalisation | 670 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of an Expanded MACE Composite Endpoint Consisting of: CV Death/Non-fatal Myocardial Infarction/ Non-fatal Stroke/Coronary Revascularisation/Unstable Angina Pectoris Requiring Hospitalisation | 777 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of a Severe Hypoglycaemic Episode
The number of participants from randomisation to first occurrence of severe hypoglycaemic episodes (such as the seriousness of hypoglycaemia, contributing factors, seizures, and unconsciousness; classified by American Diabetes Association) during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of a Severe Hypoglycaemic Episode | 76 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of a Severe Hypoglycaemic Episode | 84 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of Chronic Limb Ischemia Hospitalisation
The number of participants from randomisation to first occurrence of EAC confirmed chronic limb ischaemia hospitalization during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of Chronic Limb Ischemia Hospitalisation | 63 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of Chronic Limb Ischemia Hospitalisation | 88 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of Coronary Revascularisation
The number of participants from randomisation to first occurrence of coronary revascularisation during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of Coronary Revascularisation | 200 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of Coronary Revascularisation | 263 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of Heart Failure Requiring Hospitalisation or Urgent Heart Failure Visit
The number of participants from randomisation to first occurrence of EAC confirmed heart failure requiring hospitalisation or urgent heart failure visit during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of Heart Failure Requiring Hospitalisation or Urgent Heart Failure Visit | 146 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of Heart Failure Requiring Hospitalisation or Urgent Heart Failure Visit | 167 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of Initiation of Chronic Renal Replacement Therapy (Dialysis or Kidney Transplantation)
The number of participants from randomisation to first occurrence of EAC confirmed initiation of chronic renal replacement therapy (dialysis or kidney transplantation) during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of Initiation of Chronic Renal Replacement Therapy (Dialysis or Kidney Transplantation) | 40 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of Initiation of Chronic Renal Replacement Therapy (Dialysis or Kidney Transplantation) | 48 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of Non-fatal Myocardial Infarction (MI)
The number of participants from randomisation to first occurrence of EAC confirmed non-fatal MI during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of Non-fatal Myocardial Infarction (MI) | 191 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of Non-fatal Myocardial Infarction (MI) | 253 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of Non-fatal Stroke
The number of participants from randomisation to first occurrence of EAC confirmed non-fatal stroke during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of Non-fatal Stroke | 144 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of Non-fatal Stroke | 161 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of Onset of Persistent 50% or More Reduction in eGFR
The number of participants from randomisation to first occurrence of onset of persistent 50% or more reduction in eGFR during in-trial period were observed. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of Onset of Persistent 50% or More Reduction in eGFR | 71 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of Onset of Persistent 50% or More Reduction in eGFR | 86 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of Onset of Persistent eGFR (CKD-EPI) Below 15 mL/Min/1.73 m^2
The number of participants from randomisation to first occurrence of onset of persistent eGFR (CKD-EPI) below 15 mL/min/1.73 m\^2 during in-trial period were observed. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of Onset of Persistent eGFR (CKD-EPI) Below 15 mL/Min/1.73 m^2 | 23 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of Onset of Persistent eGFR (CKD-EPI) Below 15 mL/Min/1.73 m^2 | 33 Participants |
Secondary
Number of Participants From Randomisation to First Occurrence of Unstable Angina Requiring Hospitalisation
The number of participants from randomisation to first occurrence of EAC confirmed unstable angina requiring hospitalisation during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to First Occurrence of Unstable Angina Requiring Hospitalisation | 74 Participants |
| Placebo | Number of Participants From Randomisation to First Occurrence of Unstable Angina Requiring Hospitalisation | 80 Participants |
Secondary
Number of Participants From Randomisation to Time to Occurrence of All-cause Death
The number of participants from randomisation to time to occurrence of EAC confirmed all-cause death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to Time to Occurrence of All-cause Death | 528 Participants |
| Placebo | Number of Participants From Randomisation to Time to Occurrence of All-cause Death | 577 Participants |
Secondary
Number of Participants From Randomisation to Time to Occurrence of Renal Death
The number of participants from randomisation to time to occurrence of EAC confirmed renal death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomisation to Time to Occurrence of Renal Death | 1 Participants |
| Placebo | Number of Participants From Randomisation to Time to Occurrence of Renal Death | 7 Participants |
Secondary
Number of Participants From Randomization to First Occurrence of CKD Endpoint:Renal Death;Onset of Persistent≥50% Reduction in eGFR (CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73 m^2;Initiation of Chronic Renal Replacement Therapy
The number of participants from randomization to first occurrence of CKD endpoint:renal death;onset of persistent≥50% reduction in eGFR (CKD-EPI);onset of persistent eGFR(CKD-EPI)\<15 mL/min/1.73 m\^2;initiation of chronic renal replacement therapy combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomization to First Occurrence of CKD Endpoint:Renal Death;Onset of Persistent≥50% Reduction in eGFR (CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73 m^2;Initiation of Chronic Renal Replacement Therapy | 112 Participants |
| Placebo | Number of Participants From Randomization to First Occurrence of CKD Endpoint:Renal Death;Onset of Persistent≥50% Reduction in eGFR (CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73 m^2;Initiation of Chronic Renal Replacement Therapy | 129 Participants |
Secondary
Number of Participants From Randomization to First Occurrence of CV Death;Renal Death;Onset of Persistent≥50% Reduction in eGFR(CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73m^2;Initiation of Chronic Renal Replacement Therapy
Number of participants with first occurrence of a composite endpoint. i.e., from time of randomization to first occurrence of CV death, renal death, onset of persistent greater than or equal to (≥) 50% reduction in estimated glomerular filtration rate (eGFR) (chronic kidney disease epidemiology collaboration CKD-EPI), onset of persistent eGFR (CKD-EPI) less than (\<)15 milliliters per minute per 1.73 square meters (mL/min/1.73 m\^2), initiation of chronic renal replacement therapy (dialysis or kidney transplantation) combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomization to First Occurrence of CV Death;Renal Death;Onset of Persistent≥50% Reduction in eGFR(CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73m^2;Initiation of Chronic Renal Replacement Therapy | 403 Participants |
| Placebo | Number of Participants From Randomization to First Occurrence of CV Death;Renal Death;Onset of Persistent≥50% Reduction in eGFR(CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73m^2;Initiation of Chronic Renal Replacement Therapy | 435 Participants |
Secondary
Number of Participants From Randomization to First Occurrence of Major Adverse Limb Events (MALE), a Composite Endpoint Consisting of: Acute Limb Ischemia Hospitalisation/Chronic Limb Ischemia Hospitalisation
Number of participants from randomization to first occurrence of EAC confirmed major adverse limb events (MALE), a composite endpoint consisting of: acute limb ischemia hospitalisation/chronic limb ischemia hospitalisation combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomization to First Occurrence of Major Adverse Limb Events (MALE), a Composite Endpoint Consisting of: Acute Limb Ischemia Hospitalisation/Chronic Limb Ischemia Hospitalisation | 71 Participants |
| Placebo | Number of Participants From Randomization to First Occurrence of Major Adverse Limb Events (MALE), a Composite Endpoint Consisting of: Acute Limb Ischemia Hospitalisation/Chronic Limb Ischemia Hospitalisation | 99 Participants |
Secondary
Number of Participants From Randomization to Time of Occurrence of CV Death
Number of participants from time of randomization to time to occurrence of EAC confirmed CV death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Number of Participants From Randomization to Time of Occurrence of CV Death | 301 Participants |
| Placebo | Number of Participants From Randomization to Time of Occurrence of CV Death | 320 Participants |
Secondary
Number of Severe Hypoglycaemic Episodes
The number of severe hypoglycaemic episodes (such as the seriousness of hypoglycaemia, contributing factors, seizures, and unconsciousness; classified by American Diabetes Association) observed during the in-trial period were reported in this endpoint. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.
Time frame: From randomisation (week 0) up to week 265
Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Semaglutide | Number of Severe Hypoglycaemic Episodes | 88 Episodes |
| Placebo | Number of Severe Hypoglycaemic Episodes | 121 Episodes |