Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted globally. The aim of the trial is to investigate the cardiovascular safety of oral semaglutide in subjects with type 2 diabetes.
Interventions
DRUGsemaglutide
For oral use once daily.
DRUGplacebo
For oral use once daily.
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female diagnosed with type 2 diabetes * Age at least 50 years at screening and presence of cardiovascular disease, or age at least 60 years at screening and presence of at least one cardiovascular risk factor
Exclusion criteria
* Current or previous (within 90 days prior to screening) treatment with any GLP-1 (glucagon-like peptide-1) receptor agonist, DPP-4 (dipeptidyl peptidase-4) inhibitor or pramlintide * Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid carcinoma (MTC) * History of pancreatitis (acute or chronic) * History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery) * Subjects presently classified as being in New York Heart Association (NYHA) Class IV heart failure * Planned coronary, carotid or peripheral artery revascularisation known on the day of screening * Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 60 days prior to screening * Chronic or intermittent hemodialysis or peritoneal dialysis or severe renal impairment (corresponding to eGFR (glomerular filtration rate, estimated) below 30 mL/min/1.73 m\^2) * History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and carcinoma in situ)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | Number of participants experiencing a first event of a MACE, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | Participants experiencing an event onset for each individual component of the expanded composite cardiovascular outcomes (defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring hospitalisation or heart failure requiring hospitalisation) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. |
| Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | Participants experiencing first occurrence of a composite CV endpoint (defined as all-cause death, non-fatal myocardial infarction or nonfatal stroke) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. |
| Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | Number of participants experiencing a first event of a fatal or non-fatal myocardial infarction are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. |
| Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | Number of participants experiencing a first event of a fatal or non-fatal stroke are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. |
| Time From Randomisation to All-cause Death | Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 5 weeks of follow-up period. | Number of all-cause deaths in the study are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. |
| Time to First AE Leading to Permanent Trial Product Discontinuation | Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window. | Number of participants who permanently discontinued trial product in ths study are presented. Results are based on the on-treatment observation period which starts at the date of first dose on trial product; ends on last date on trial product +38 days (ascertainment window). |
| Number of Serious Adverse Events | Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window. | Number of serious adverse events were recorded from week 0 to week 87 in the study. Results are based on the on-treatment observation period which started at the date of first dose on trial product and ended on last date on trial product +38 days (ascertainment window). |
| Change in Eye Examination Category | Week -3, End of treatment | Participants with eye examination findings, normal, abnormal non clinically significant (NCS) and abnormal clinically significant (CS) at baseline (week -3) and end of treatment visit (week 83) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. |
| 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 | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | Participants experiencing first occurrence of an expanded composite CV endpoint \[defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, UAP (unstable angina pectoris) requiring hospitalisation or heart failure requiring hospitalisation\] are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. |
| Change in Systolic and Diastolic Blood Pressure | Week 0, End of treatment | Change from baseline (week 0) in systolic and diastolic blood pressure measured at the end of treatment visit (week 83) is reported. Results are based on the on-treatment observation period which started at the date of first dose on trial product, ended on last date on trial product +38 days (ascertainment window). |
| Change in LDL-cholesterol - Ratio to Baseline | Week 0, End of treatment | 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. |
| Change in Glycosylated Haemoglobin (HbA1c) | Week 0, End of treatment | 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. |
| Change in Body Weight | Week 0, End of treatment | 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. |
| Change in Total Cholesterol - Ratio to Baseline | Week 0, End of treatment | 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. |
| Change in HDL-cholesterol - Ratio to Baseline | Week 0, End of treatment | 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. |
| Change in Triglycerides - Ratio to Baseline | Week 0, End of treatment | 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. |
| Change in Pulse Rate | Week 0, End of treatment | Change from baseline (week 0) in pulse rate measured at the end of treatment visit (week 83) is reported. Results are based on the on-treatment observation period which started at the date of first dose on trial product, ended on last date on trial product +38 days (ascertainment window). |
Countries
Algeria, Argentina, Brazil, Canada, Denmark, Germany, India, Israel, Italy, Malaysia, Mexico, Netherlands, Poland, Romania, South Africa, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Oral Semaglutide 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. | 1,591 |
| Placebo Participants were to take oral semaglutide placebo tablets once-daily for a period of upto 82 weeks. | 1,592 |
| Total | 3,183 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 5 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Oral Semaglutide | Total |
|---|---|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 7 | 66 years STANDARD_DEVIATION 7 | 66 years STANDARD_DEVIATION 7 |
| Baseline cardiovasular disease (CVD)/chronic kidney disease (CKD) risk details Established CVD and/or CKD, age ≥ 50 years | 1345 Participants | 1350 Participants | 2695 Participants |
| Baseline cardiovasular disease (CVD)/chronic kidney disease (CKD) risk details Evidence of CV risk factors, age ≥ 60 years | 247 Participants | 241 Participants | 488 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 261 Participants | 253 Participants | 514 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1331 Participants | 1338 Participants | 2669 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska native | 15 Participants | 14 Participants | 29 Participants |
| Race/Ethnicity, Customized Asian | 306 Participants | 324 Participants | 630 Participants |
| Race/Ethnicity, Customized Black or African American | 103 Participants | 89 Participants | 192 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 5 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 15 Participants | 11 Participants | 26 Participants |
| Race/Ethnicity, Customized White | 1152 Participants | 1148 Participants | 2300 Participants |
| Sex: Female, Male Female | 500 Participants | 507 Participants | 1007 Participants |
| Sex: Female, Male Male | 1092 Participants | 1084 Participants | 2176 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 23 / 1,591 | 45 / 1,591 |
| other Total, other adverse events | 0 / 1,591 | 0 / 1,591 |
| serious Total, serious adverse events | 301 / 1,591 | 358 / 1,591 |
Outcome results
Primary
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
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.
Population: Overall number of participants analyzed = full analysis set (FAS) which comprised all randomised participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | 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 | 61 Participants |
| Placebo | 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 | 76 Participants |
Comparison: 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.p-value: <0.000195% CI: [0.57, 1.11]Regression, Cox
Comparison: 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.p-value: =0.174995% CI: [0.57, 1.11]Regression, Cox
Secondary
Change in Body Weight
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
Population: Overall number of participants analyzed = number of participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Semaglutide | Change in Body Weight | -4.2 Kg | Standard Deviation 5.7 |
| Placebo | Change in Body Weight | -0.8 Kg | Standard Deviation 4.5 |
Secondary
Change in Eye Examination Category
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
Population: Overall number of participants analyzed = FAS which comprised all randomised participants. Number Analyzed = number of participants with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Oral Semaglutide | Change in Eye Examination Category | Right eye fundoscopy (week -3): Normal | 845 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Left eye fundoscopy (week -3): Normal | 848 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Left eye fundoscopy (week -3): Abnormal NCS | 657 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Left eye fundoscopy (week -3): Abnormal CS | 86 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Right eye fundoscopy (week -3): Abnormal NCS | 659 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Right eye fundoscopy (week -3): Abnormal CS | 86 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Left eye fundoscopy (EOT): Normal | 783 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Left eye fundoscopy (EOT): Abnormal NCS | 599 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Left eye fundoscopy (EOT): Abnormal CS | 83 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Right eye fundoscopy (EOT): Normal | 780 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Right eye fundoscopy (EOT): Abnormal NCS | 601 Participants |
| Oral Semaglutide | Change in Eye Examination Category | Right eye fundoscopy (EOT): Abnormal CS | 81 Participants |
| Placebo | Change in Eye Examination Category | Right eye fundoscopy (week -3): Abnormal CS | 72 Participants |
| Placebo | Change in Eye Examination Category | Right eye fundoscopy (week -3): Normal | 858 Participants |
| Placebo | Change in Eye Examination Category | Right eye fundoscopy (EOT): Abnormal CS | 64 Participants |
| Placebo | Change in Eye Examination Category | Left eye fundoscopy (EOT): Abnormal CS | 62 Participants |
| Placebo | Change in Eye Examination Category | Left eye fundoscopy (week -3): Normal | 843 Participants |
| Placebo | Change in Eye Examination Category | Left eye fundoscopy (EOT): Normal | 790 Participants |
| Placebo | Change in Eye Examination Category | Left eye fundoscopy (week -3): Abnormal NCS | 673 Participants |
| Placebo | Change in Eye Examination Category | Right eye fundoscopy (EOT): Abnormal NCS | 599 Participants |
| Placebo | Change in Eye Examination Category | Left eye fundoscopy (week -3): Abnormal CS | 74 Participants |
| Placebo | Change in Eye Examination Category | Left eye fundoscopy (EOT): Abnormal NCS | 597 Participants |
| Placebo | Change in Eye Examination Category | Right eye fundoscopy (week -3): Abnormal NCS | 661 Participants |
| Placebo | Change in Eye Examination Category | Right eye fundoscopy (EOT): Normal | 787 Participants |
Secondary
Change in Glycosylated Haemoglobin (HbA1c)
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
Population: Overall number of participants analyzed = number of participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Semaglutide | Change in Glycosylated Haemoglobin (HbA1c) | -1.0 Percentage of HbA1c | Standard Deviation 1.4 |
| Placebo | Change in Glycosylated Haemoglobin (HbA1c) | -0.3 Percentage of HbA1c | Standard Deviation 1.3 |
Secondary
Change in HDL-cholesterol - Ratio to Baseline
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
Population: Overall number of participants analyzed = number of participants with available data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Oral Semaglutide | Change in HDL-cholesterol - Ratio to Baseline | 1.05 Ratio of HDL-cholesterol | Geometric Coefficient of Variation 16.9 |
| Placebo | Change in HDL-cholesterol - Ratio to Baseline | 1.02 Ratio of HDL-cholesterol | Geometric Coefficient of Variation 15.9 |
Secondary
Change in LDL-cholesterol - Ratio to Baseline
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
Population: Overall number of participants analyzed = number of participants with available data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Oral Semaglutide | Change in LDL-cholesterol - Ratio to Baseline | 0.96 Ratio of LDL-cholesterol | Geometric Coefficient of Variation 36.6 |
| Placebo | Change in LDL-cholesterol - Ratio to Baseline | 0.97 Ratio of LDL-cholesterol | Geometric Coefficient of Variation 34.5 |
Secondary
Change in Pulse Rate
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
Population: Overall number of participants analyzed = number of participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Semaglutide | Change in Pulse Rate | 4 Beats/minute | Standard Deviation 11 |
| Placebo | Change in Pulse Rate | -0 Beats/minute | Standard Deviation 11 |
Secondary
Change in Systolic and Diastolic Blood Pressure
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
Population: Overall number of participants analyzed = number of participants with available data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oral Semaglutide | Change in Systolic and Diastolic Blood Pressure | Systolic blood pressure | -5 mmHg | Standard Deviation 18 |
| Oral Semaglutide | Change in Systolic and Diastolic Blood Pressure | Diastolic blood pressure | -1 mmHg | Standard Deviation 11 |
| Placebo | Change in Systolic and Diastolic Blood Pressure | Systolic blood pressure | -2 mmHg | Standard Deviation 18 |
| Placebo | Change in Systolic and Diastolic Blood Pressure | Diastolic blood pressure | -2 mmHg | Standard Deviation 10 |
Secondary
Change in Total Cholesterol - Ratio to Baseline
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
Population: Overall number of participants analyzed = number of participants with available data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Oral Semaglutide | Change in Total Cholesterol - Ratio to Baseline | 0.97 Ratio of total cholesterol | Geometric Coefficient of Variation 21.9 |
| Placebo | Change in Total Cholesterol - Ratio to Baseline | 0.98 Ratio of total cholesterol | Geometric Coefficient of Variation 21.1 |
Secondary
Change in Triglycerides - Ratio to Baseline
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
Population: Overall number of participants analyzed = number of participants with available data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Oral Semaglutide | Change in Triglycerides - Ratio to Baseline | 0.92 Ratio of triglycerides | Geometric Coefficient of Variation 41.8 |
| Placebo | Change in Triglycerides - Ratio to Baseline | 0.97 Ratio of triglycerides | Geometric Coefficient of Variation 39.8 |
Secondary
Number of Serious Adverse Events
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.
Population: Overall number of participants analyzed = FAS which comprised all randomised participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Semaglutide | Number of Serious Adverse Events | 545 Events |
| Placebo | Number of Serious Adverse Events | 618 Events |
Secondary
Time From Randomisation to All-cause Death
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.
Population: Overall number of participants analyzed = FAS which comprised all randomised participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Time From Randomisation to All-cause Death | 23 Participants |
| Placebo | Time From Randomisation to All-cause Death | 45 Participants |
Comparison: 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.p-value: 0.007895% CI: [0.31, 0.84]Regression, Cox
Secondary
Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke
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.
Population: Overall number of participants analyzed = FAS which comprised all randomised participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke | 69 Participants |
| Placebo | Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke | 89 Participants |
Comparison: 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.p-value: =0.095295% CI: [0.56, 1.05]Regression, Cox
Secondary
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
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.
Population: Overall number of participants analyzed = FAS which comprised all randomised participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | 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 | 83 Participants |
| Placebo | 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 | 100 Participants |
Comparison: 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.p-value: =0.182795% CI: [0.61, 1.1]Regression, Cox
Secondary
Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint
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.
Population: Overall number of participants analyzed = FAS which comprised all randomised participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Oral Semaglutide | Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Non-fatal myocardial infarction | 37 Participants |
| Oral Semaglutide | Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Unstable angina requiring hospitalisation | 11 Participants |
| Oral Semaglutide | Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Non-fatal stroke | 12 Participants |
| Oral Semaglutide | Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Heart failure requiring hospitalisation | 21 Participants |
| Oral Semaglutide | Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Cardiovascular death | 15 Participants |
| Placebo | Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Heart failure requiring hospitalisation | 24 Participants |
| Placebo | Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Cardiovascular death | 30 Participants |
| Placebo | Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Non-fatal myocardial infarction | 31 Participants |
| Placebo | Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Non-fatal stroke | 16 Participants |
| Placebo | Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Unstable angina requiring hospitalisation | 7 Participants |
Comparison: 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.p-value: =0.026195% CI: [0.27, 0.92]Regression, Cox
Comparison: 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.p-value: =0.504495% CI: [0.73, 1.9]Regression, Cox
Comparison: 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.p-value: =0.43595% CI: [0.35, 1.57]Regression, Cox
Comparison: 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.p-value: =0.360595% CI: [0.6, 4.01]Regression, Cox
Comparison: 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.p-value: =0.622795% CI: [0.48, 1.55]Regression, Cox
Secondary
Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction
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.
Population: Overall number of participants analyzed = FAS which comprised all randomised participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction | 37 Participants |
| Placebo | Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction | 35 Participants |
Comparison: 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.p-value: 0.858395% CI: [0.66, 1.66]Regression, Cox
Secondary
Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke
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.
Population: Overall number of participants analyzed = FAS which comprised all randomised participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke | 13 Participants |
| Placebo | Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke | 17 Participants |
Comparison: 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.p-value: 0.448595% CI: [0.37, 1.56]Regression, Cox
Secondary
Time to First AE Leading to Permanent Trial Product Discontinuation
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.
Population: Overall number of participants analyzed = FAS which comprised all randomised participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Semaglutide | Time to First AE Leading to Permanent Trial Product Discontinuation | 184 Participants |
| Placebo | Time to First AE Leading to Permanent Trial Product Discontinuation | 104 Participants |
Comparison: 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.p-value: <0.000195% CI: [1.42, 2.3]Regression, Cox