Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes

A Long-term, Randomised, Double-blind, Placebo-controlled, Multinational, Multi-centre Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN™ 6 - Long-term Outcomes)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01720446

Acronym

SUSTAIN™ 6

Enrollment

3297

Registered

2012-11-02

Start date

2013-02-21

Completion date

2016-03-15

Last updated

2019-06-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes, Diabetes Mellitus, Type 2

Brief summary

This trial is conducted globally. The aim of the trial is to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes. The trial is event-driven, i.e. the maximum trial duration (up to max. 148 weeks) will depend on the accrual of major adverse cardiovascular events (MACE) in this trial and the remaining research programme. The incidence of MACE will be monitored throughout the trial which will be terminated according to plan when pre-specified stopping criteria are met.

Interventions

DRUGsemaglutide

Once weekly doses of 0.5 mg semaglutide after an initial dose escalation step of 0.25 mg as an add-on to the standard-of-care treatment. Administered subcutaneously (s.c., under the skin)

DRUGplacebo

Once weekly doses volume-matched placebo, as an add-on to the standard-of-care treatment. Administered subcutaneously (s.c., under the skin).

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

Inclusion criteria

- Men and women with type 2 diabetes mellitus - Age above or equal to 50 years at screening and clinical evidence of cardiovascular disease or age above or equal to 60 years at screening and subclinical evidence of cardiovascular disease - Anti-diabetic drug naïve, or treated with one or two oral antidiabetic drug (OADs), or treated with human Neutral Protamin Hagedorn (NPH) insulin or long-acting insulin analogue or pre-mixed insulin, both types of insulin either alone or in combination with one or two OADs - HbA1c above or equal to 7.0% at screening

Exclusion criteria

- Type 1 diabetes mellitus - Use of glucagon-like peptide-1 (GLP-1) receptor agonist (exenatide, liraglutide, or other) or pramlintide within 90 days prior to screening - Use of any dipeptidyl peptidase 4 (DPP-IV) inhibitor within 30 days prior to screening - Treatment with insulin other than basal and pre-mixed insulin within 90 days prior to screening - except for short-term use in connection with intercurrent illness - Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (eg diabetes ketoacidosis) within 90 days prior to screening - History of chronic pancreatitis or idiopathic acute pancreatitis - Acute coronary or cerebro-vascular event within 90 days prior to randomisation - Currently planned coronary, carotid or peripheral artery revascularisation - Chronic heart failure New York Heart Association (NYHA) class IV - Personal or family history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma - Personal history of non-familial medullary thyroid carcinoma - Screening calcitonin above or equal to 50 ng/L

Design outcomes

Primary

Measure	Time frame	Description
Time From Randomisation to First Occurrence of a MACE, Defined as Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke	Time from randomisation up to end of follow-up (scheduled at week 109)	Percentage of subjects experiencing a first event of a major adverse cardiovascular event (MACE), defined as cardiovascular (CV) death, non-fatal myocardial infarction (MI), or non-fatal stroke.

Secondary

Measure	Time frame	Description
Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Time from randomisation up to end of follow-up (scheduled at week 109)	Percentage of subjects experiencing an event onset for each individual component of the expanded composite cardiovascular outcomes (defined as either MACE, revascularisation \[coronary and peripheral\], unstable angina requiring hospitalisation or hospitalisation for heart failure).
Time From Randomisation to First Occurrence of All-cause Death, Non-fatal MI, or Non-fatal Stroke	Time from randomisation up to end of follow-up (scheduled at week 109)	Percentage of subjects experiencing a first occurrence of all-cause death, non-fatal MI, or non-fatal stroke.
Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Glycosylated Haemoglobin (HbA1c)	Week 0, up to week 104	Estimated mean change from baseline in glycosylated haemoglobin (HbA1c) to last assessment in the trial during the treatment period.
Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Fasting Plasma Glucose	Week 0, up to week 104	Estimated mean change from baseline to last assessment in fasting plasma glucose in the trial during the treatment period.
Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Body Weight	Week 0, up to week 104	Estimated mean change from baseline to last assessment in body weight in the trial during the treatment period.
Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	Week 0, up to week 104	Estimated ratio to baseline at week 104 during the treatment period in lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides).
Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Urinary Albumin to Creatinine Ratio	Week 0, up to week 104	Estimated ratio to baseline in urinary albumin to creatinine ratio at week 104 during the treatment period.
Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Outcome	Time from randomisation up to end of follow-up (scheduled at week 109)	Percentage of subjects experiencing first occurrence of an expanded composite CV outcome (defined as either MACE, revascularisation \[coronary and peripheral\], unstable angina requiring hospitalisation or hospitalisation for heart failure)
Incidence During the Trial in Other Treatment Outcomes: Hypoglycaemic Events	Week 0 - 109	Rates (event rate per 100 exposure years) of severe or blood glucose confirmed symptomatic hypoglycaemia defned as an episode that was severe according to the American diabetic association (ADA) classification or blood glucose (BG) confirmed by a PG value \<3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Incidence During the Trial in Other Treatment Outcomes: Adverse Events	Weeks 0-109	Rates (event rate per 100 years of exposure) of treatment emergent adverse events.
Occurrence During the Trial in Other Treatment Outcomes: Anti-semaglutide Antibodies	Weeks 0-109	The percentage of subjects that tested positive for anti-semaglutide antibodies at any time point post-baseline during the trial, from week 0 to week 109.
Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Week 0, up to week 104	Estimated mean change from baseline to last assessment in the trial in patient reported outcomes (PRO). PRO questionnaire (SF-36v2TM) measured the individual overall health related quality of life namely bodily pain, general health, mental component summary, mental health, physical component summary, physical functioning, role-emotional, role-physical, social functioning and vitality. The PRO scores were transformed to a 0-100 scale with higher scores indicating greater health related quality of life.
Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile (Free Fatty Acids)	Week 0, up to week 104	Estimated ratio to baseline at week 104 during the treatment period in lipid profile (free fatty acids).
Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs (Pulse Rate)	Week 0, up to week 104	Estimated mean change from baseline to last assessment in the trial during the treatment period in vital signs (pulse rate).
Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs	Week 0, up to week 104	Estimated mean change from baseline to last assessment in the trial during the treatment period in vital signs (diastolic blood pressure and systolic blood pressure).

Countries

Algeria, Argentina, Australia, Brazil, Bulgaria, Canada, Denmark, Germany, India, Israel, Italy, Malaysia, Mexico, Poland, Russia, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States

Participant flow

Recruitment details

The trial was conducted at 229 sites in 20 countries. Country (sites): Algeria (4), Argentina (7), Australia (8), Brazil (8), Bulgaria (5), Canada (13), Denmark (5), Germany (7), Israel (6), Italy (6), Malaysia (6), Mexico (9), Poland (5), Russia (11), Spain (6), Taiwan (4), Thailand (5), Turkey (10), United Kingdom (8) and United States (96).

Pre-assignment details

Subjects could be anti-glycaemic drug naïve, or treated with 1 or 2 oral anti diabetic drugs (OADs), or treated with human NPH insulin or long-acting insulin analogue or pre-mixed insulin, alone or in combination with 1 or 2 OAD(s).

Participants by arm

Arm	Count
Semaglutide 0.5 mg Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.	826
Semaglutide 1.0 mg Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.	822
Placebo 0.5 mg Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.	824
Placebo 1.0 mg Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.	825
Total	3,297

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Lost to Follow-up	12	6	16	16
Overall Study	Withdrawal by Subject	2	5	4	4

Baseline characteristics

Characteristic	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo 0.5 mg	Placebo 1.0 mg	Total
Age, Customized 50-64 years	440 participants	415 participants	419 participants	425 participants	1699 participants
Age, Customized 65-74 years	312 participants	324 participants	324 participants	317 participants	1277 participants
Age, Customized 75-84 years	71 participants	76 participants	75 participants	79 participants	301 participants
Age, Customized 85 and over	3 participants	7 participants	6 participants	4 participants	20 participants
Body weight	91.80 kg STANDARD_DEVIATION 20.25	92.86 kg STANDARD_DEVIATION 21.05	91.83 kg STANDARD_DEVIATION 20.35	91.90 kg STANDARD_DEVIATION 20.75	92.09 kg STANDARD_DEVIATION 20.6
Diastolic BP	77.10 mmHg STANDARD_DEVIATION 9.78	76.88 mmHg STANDARD_DEVIATION 10.21	77.54 mmHg STANDARD_DEVIATION 9.85	76.66 mmHg STANDARD_DEVIATION 10.21	77.05 mmHg STANDARD_DEVIATION 10.02
Fasting plasma glucose	185.4 mg/dL STANDARD_DEVIATION 66.09	182.9 mg/dL STANDARD_DEVIATION 68.04	185.8 mg/dL STANDARD_DEVIATION 68.23	184.6 mg/dL STANDARD_DEVIATION 63.08	184.7 mg/dL STANDARD_DEVIATION 66.37
Free fatty acids	0.83 mmol/L	0.80 mmol/L	0.83 mmol/L	0.81 mmol/L	0.82 mmol/L
Glycosylated haemoglobin	8.67 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.39	8.73 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.51	8.70 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.49	8.70 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.45	8.70 percentage of glycosylated haemoglobin STANDARD_DEVIATION 1.46
HDL-cholesterol	45.92 mg/dL STANDARD_DEVIATION 13	44.97 mg/dL STANDARD_DEVIATION 12.42	45.82 mg/dL STANDARD_DEVIATION 12.92	44.61 mg/dL STANDARD_DEVIATION 12.26	45.33 mg/dL STANDARD_DEVIATION 12.66
LDL-cholesterol	89.62 mg/dL STANDARD_DEVIATION 39.08	89.72 mg/dL STANDARD_DEVIATION 34.49	89.01 mg/dL STANDARD_DEVIATION 38.35	91.14 mg/dL STANDARD_DEVIATION 37.9	89.87 mg/dL STANDARD_DEVIATION 37.49
Pulse rate	72.69 beats/min STANDARD_DEVIATION 11.22	71.53 beats/min STANDARD_DEVIATION 10.86	72.01 beats/min STANDARD_DEVIATION 10.62	71.95 beats/min STANDARD_DEVIATION 10.92	72.05 beats/min STANDARD_DEVIATION 10.91
Sex: Female, Male Female	331 Participants	304 Participants	342 Participants	318 Participants	1295 Participants
Sex: Female, Male Male	495 Participants	518 Participants	482 Participants	507 Participants	2002 Participants
Systolic BP	136.1 mmHg STANDARD_DEVIATION 17.97	135.8 mmHg STANDARD_DEVIATION 16.96	135.8 mmHg STANDARD_DEVIATION 16.16	134.8 mmHg STANDARD_DEVIATION 17.45	135.6 mmHg STANDARD_DEVIATION 17.15
Total cholesterol	165.38 mg/dL	164.96 mg/dL	164.38 mg/dL	165.97 mg/dL	165.17 mg/dL
Triglycerides	163.66 mg/dL	158.93 mg/dL	162.30 mg/dL	163.00 mg/dL	161.96 mg/dL

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	573 / 826	587 / 822	547 / 824	524 / 825
serious Total, serious adverse events	289 / 826	276 / 822	329 / 824	298 / 825

Outcome results

Primary

Time From Randomisation to First Occurrence of a MACE, Defined as Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke

Percentage of subjects experiencing a first event of a major adverse cardiovascular event (MACE), defined as cardiovascular (CV) death, non-fatal myocardial infarction (MI), or non-fatal stroke.

Time frame: Time from randomisation up to end of follow-up (scheduled at week 109)

Population: Full analysis set included all the randomised subjects. As specified in the protocol, the two semaglutide dose arms (semaglutide 0.5 mg + semaglutide 1.0 mg) and the two placebo dose arms (placebo 0.5 mg + placebo 1.0 mg) were pooled for the analysis of this endpoint.

Arm	Measure	Value (NUMBER)
Semaglutide	Time From Randomisation to First Occurrence of a MACE, Defined as Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke	6.6 percentage of subjects
Placebo	Time From Randomisation to First Occurrence of a MACE, Defined as Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke	8.9 percentage of subjects

Comparison: The primary endpoint was analysed using a stratified Cox proportional hazards model with treatment group (semaglutide, placebo) as fixed factor. Assuming the same population MACE risk for the semaglutide and placebo groups (i.e., the population hazards ratio \[HR\] equals 1), a total minimum of 122 events were needed in order to have at least 90% power to ascertain that the upper two-sided 95% confidence limit for the HR was less than 1.8.p-value: <0.000195% CI: [0.58, 0.95]Regression, Cox

Comparison: A post hoc analysis of superiority of semaglutide versus placebo was performed based on the pre-specified Cox proportional hazard analysis using the two-sided Wald test of no difference, with treatment (semaglutide, placebo) as fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).p-value: 0.016795% CI: [0.58, 0.95]Regression, Cox

Secondary

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Body Weight

Estimated mean change from baseline to last assessment in body weight in the trial during the treatment period.

Time frame: Week 0, up to week 104

Population: Full analysis set included all the randomised subjects. As specified in the protocol, the two placebo dose arms (placebo 0.5 mg + placebo 1.0 mg) were pooled for the analysis of this endpoint.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Body Weight	-3.57 kg	Standard Error 0.21
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Body Weight	-4.88 kg	Standard Error 0.22
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Body Weight	-0.62 kg	Standard Error 0.15

Comparison: Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: <0.000195% CI: [-3.47, -2.44]Mixed Models Analysis

Secondary

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Fasting Plasma Glucose

Estimated mean change from baseline to last assessment in fasting plasma glucose in the trial during the treatment period.

Time frame: Week 0, up to week 104

Population: Full analysis set included all the randomised subjects.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Fasting Plasma Glucose	-1.75 mmol/L	Standard Error 0.12
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Fasting Plasma Glucose	-2.11 mmol/L	Standard Error 0.12
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Fasting Plasma Glucose	-1.02 mmol/L	Standard Error 0.12
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Fasting Plasma Glucose	-0.88 mmol/L	Standard Error 0.12

Secondary

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Glycosylated Haemoglobin (HbA1c)

Estimated mean change from baseline in glycosylated haemoglobin (HbA1c) to last assessment in the trial during the treatment period.

Time frame: Week 0, up to week 104

Population: Full analysis set included all the randomised subjects

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Glycosylated Haemoglobin (HbA1c)	-1.09 percentage of glycosylated haemoglobin	Standard Error 0.05
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Glycosylated Haemoglobin (HbA1c)	-1.41 percentage of glycosylated haemoglobin	Standard Error 0.05
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Glycosylated Haemoglobin (HbA1c)	-0.44 percentage of glycosylated haemoglobin	Standard Error 0.05
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Glycosylated Haemoglobin (HbA1c)	-0.36 percentage of glycosylated haemoglobin	Standard Error 0.05

Secondary

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile

Estimated ratio to baseline at week 104 during the treatment period in lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides).

Time frame: Week 0, up to week 104

Population: Full analysis set included all randomised subjects.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	Total cholesterol (mg/dL)	0.97 mg/dL	Standard Error 0.01
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	HDL-cholesterol (mg/dL)	0.99 mg/dL	Standard Error 0.01
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	LDL-cholesterol (mg/dL)	0.97 mg/dL	Standard Error 0.01
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	Triglycerides (mg/dL)	0.93 mg/dL	Standard Error 0.01
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	HDL-cholesterol (mg/dL)	1.01 mg/dL	Standard Error 0.01
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	LDL-cholesterol (mg/dL)	0.98 mg/dL	Standard Error 0.01
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	Triglycerides (mg/dL)	0.92 mg/dL	Standard Error 0.01
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	Total cholesterol (mg/dL)	0.97 mg/dL	Standard Error 0.01
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	LDL-cholesterol (mg/dL)	1.01 mg/dL	Standard Error 0.01
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	HDL-cholesterol (mg/dL)	0.99 mg/dL	Standard Error 0.01
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	Triglycerides (mg/dL)	0.96 mg/dL	Standard Error 0.01
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	Total cholesterol (mg/dL)	1.00 mg/dL	Standard Error 0.01
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	Triglycerides (mg/dL)	0.98 mg/dL	Standard Error 0.01
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	HDL-cholesterol (mg/dL)	0.97 mg/dL	Standard Error 0.01
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	Total cholesterol (mg/dL)	0.99 mg/dL	Standard Error 0.01
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile	LDL-cholesterol (mg/dL)	0.99 mg/dL	Standard Error 0.01

Comparison: Analysis for total cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit. The response and its baseline value were log-transformed before analysis.p-value: 0.014995% CI: [0.95, 1]Mixed Models Analysis

Comparison: Analysis for HDL-cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.810695% CI: [0.99, 1.02]Mixed Models Analysis

Comparison: Analysis for LDL-cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.018595% CI: [0.93, 0.99]Mixed Models Analysis

Comparison: Analysis for triglycerides was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.183395% CI: [0.93, 1.01]Mixed Models Analysis

Secondary

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile (Free Fatty Acids)

Estimated ratio to baseline at week 104 during the treatment period in lipid profile (free fatty acids).

Time frame: Week 0, up to week 104

Population: Full analysis set included all randomised subjects.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile (Free Fatty Acids)	0.95 mmol/L	Standard Error 0.02
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile (Free Fatty Acids)	0.91 mmol/L	Standard Error 0.01
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile (Free Fatty Acids)	0.96 mmol/L	Standard Error 0.02
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile (Free Fatty Acids)	0.99 mmol/L	Standard Error 0.02

Comparison: Analysis for free fatty acids was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.779695% CI: [0.95, 1.04]Mixed Models Analysis

Secondary

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)

Estimated mean change from baseline to last assessment in the trial in patient reported outcomes (PRO). PRO questionnaire (SF-36v2TM) measured the individual overall health related quality of life namely bodily pain, general health, mental component summary, mental health, physical component summary, physical functioning, role-emotional, role-physical, social functioning and vitality. The PRO scores were transformed to a 0-100 scale with higher scores indicating greater health related quality of life.

Time frame: Week 0, up to week 104

Population: Full analysis set included all randomised subjects.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	General health	1.66 Scores on a scale	Standard Error 0.29
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Mental component summary	0.0 Scores on a scale	Standard Error 0.35
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Mental health	0.48 Scores on a scale	Standard Error 0.33
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Physical component summary	0.76 Scores on a scale	Standard Error 0.28
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Bodily pain	0.66 Scores on a scale	Standard Error 0.35
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Physical functioning	0.42 Scores on a scale	Standard Error 0.32
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Role-emotional	0.17 Scores on a scale	Standard Error 0.42
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Role-physical	0.39 Scores on a scale	Standard Error 0.34
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Social functioning	-0.25 Scores on a scale	Standard Error 0.35
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Vitality	0.29 Scores on a scale	Standard Error 0.31
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Social functioning	0.97 Scores on a scale	Standard Error 0.35
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Bodily pain	1.82 Scores on a scale	Standard Error 0.35
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Physical component summary	1.74 Scores on a scale	Standard Error 0.28
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Physical functioning	1.12 Scores on a scale	Standard Error 0.32
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Role-emotional	0.89 Scores on a scale	Standard Error 0.42
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Vitality	1.55 Scores on a scale	Standard Error 0.31
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Role-physical	1.18 Scores on a scale	Standard Error 0.35
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	General health	2.55 Scores on a scale	Standard Error 0.29
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Mental component summary	0.86 Scores on a scale	Standard Error 0.35
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Mental health	1.08 Scores on a scale	Standard Error 0.33
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Role-physical	-0.33 Scores on a scale	Standard Error 0.35
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Social functioning	-0.20 Scores on a scale	Standard Error 0.36
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Bodily pain	0.16 Scores on a scale	Standard Error 0.35
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Role-emotional	-0.36 Scores on a scale	Standard Error 0.42
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Physical functioning	-0.38 Scores on a scale	Standard Error 0.32
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Mental component summary	-0.17 Scores on a scale	Standard Error 0.35
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Mental health	-0.14 Scores on a scale	Standard Error 0.33
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	General health	0.78 Scores on a scale	Standard Error 0.29
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Physical component summary	0.07 Scores on a scale	Standard Error 0.28
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Vitality	-0.04 Scores on a scale	Standard Error 0.31
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Physical component summary	0.35 Scores on a scale	Standard Error 0.28
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Role-physical	0.03 Scores on a scale	Standard Error 0.35
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Physical functioning	-0.37 Scores on a scale	Standard Error 0.33
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Vitality	0.35 Scores on a scale	Standard Error 0.31
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Role-emotional	-0.05 Scores on a scale	Standard Error 0.42
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Mental component summary	-0.11 Scores on a scale	Standard Error 0.35
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Bodily pain	0.35 Scores on a scale	Standard Error 0.35
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	General health	1.13 Scores on a scale	Standard Error 0.3
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Mental health	-0.31 Scores on a scale	Standard Error 0.33
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)	Social functioning	-0.17 Scores on a scale	Standard Error 0.36

Comparison: Analysis for bodily pain was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.317195% CI: [-0.48, 1.47]Mixed Models Analysis

Comparison: Analysis for general health was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.03595% CI: [0.06, 1.69]Mixed Models Analysis

Comparison: Analysis for mental component summary was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.727795% CI: [-0.79, 1.13]Mixed Models Analysis

Comparison: Analysis for mental health was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.18695% CI: [-0.3, 1.53]Mixed Models Analysis

Comparison: Analysis for physical component summary was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.083395% CI: [-0.09, 1.45]Mixed Models Analysis

Comparison: Analysis for physical functioning was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.079995% CI: [-0.1, 1.69]Mixed Models Analysis

Comparison: Analysis for role emotional was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.371795% CI: [-0.63, 1.68]Mixed Models Analysis

Comparison: Analysis for role physical was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.143195% CI: [-0.24, 1.67]Mixed Models Analysis

Comparison: Analysis for social functioning was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.922395% CI: [-1.03, 0.93]Mixed Models Analysis

Comparison: Analysis for vitality was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.452395% CI: [-0.53, 1.19]Mixed Models Analysis

Secondary

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Urinary Albumin to Creatinine Ratio

Estimated ratio to baseline in urinary albumin to creatinine ratio at week 104 during the treatment period.

Time frame: Week 0, up to week 104

Population: Full analysis set included all the randomised subjects

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Urinary Albumin to Creatinine Ratio	1.02 mg/g	Standard Error 0.05
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Urinary Albumin to Creatinine Ratio	0.91 mg/g	Standard Error 0.05
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Urinary Albumin to Creatinine Ratio	1.32 mg/g	Standard Error 0.07
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Urinary Albumin to Creatinine Ratio	1.29 mg/g	Standard Error 0.06

Comparison: Analysis for urinary albumin to creatinine ration was donne using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit. The response and its baseline value were log-transformed before analysis.p-value: 0.000395% CI: [0.68, 0.89]Mixed Models Analysis

Comparison: Analysis for urinary albumin to creatinine ration was donne using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: <0.000195% CI: [0.62, 0.81]Mixed Models Analysis

Secondary

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs

Estimated mean change from baseline to last assessment in the trial during the treatment period in vital signs (diastolic blood pressure and systolic blood pressure).

Time frame: Week 0, up to week 104

Population: Full analysis set included all the randomised subjects.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs	Diastolic blood pressure (mmHg)	-1.37 mmHg	Standard Error 0.32
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs	Systolic blood pressure (mmHg)	-3.44 mmHg	Standard Error 0.54
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs	Systolic blood pressure (mmHg)	-5.37 mmHg	Standard Error 0.54
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs	Diastolic blood pressure (mmHg)	-1.57 mmHg	Standard Error 0.32
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs	Diastolic blood pressure (mmHg)	-1.42 mmHg	Standard Error 0.32
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs	Systolic blood pressure (mmHg)	-2.17 mmHg	Standard Error 0.54
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs	Diastolic blood pressure (mmHg)	-1.71 mmHg	Standard Error 0.32
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs	Systolic blood pressure (mmHg)	-2.78 mmHg	Standard Error 0.54

Comparison: Analysis for diastolic blood pressure was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.920595% CI: [-0.83, 0.92]Mixed Models Analysis

Comparison: Analysis for systolic blood pressure was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: 0.097695% CI: [-2.77, 0.23]Mixed Models Analysis

Secondary

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs (Pulse Rate)

Estimated mean change from baseline to last assessment in the trial during the treatment period in vital signs (pulse rate).

Time frame: Week 0, up to week 104

Population: Full analysis set included all the randomised subjects.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Semaglutide	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs (Pulse Rate)	2.12 beats/min	Standard Error 0.34
Placebo	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs (Pulse Rate)	2.41 beats/min	Standard Error 0.34
Placebo 0.5 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs (Pulse Rate)	0.09 beats/min	Standard Error 0.34
Placebo 1.0 mg	Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs (Pulse Rate)	-0.07 beats/min	Standard Error 0.34

Comparison: Analysis for pulse rate was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.p-value: <0.000195% CI: [1.07, 2.98]Mixed Models Analysis

Secondary

Incidence During the Trial in Other Treatment Outcomes: Adverse Events

Rates (event rate per 100 years of exposure) of treatment emergent adverse events.

Time frame: Weeks 0-109

Population: Full analysis set included all randomised subjects.

Arm	Measure	Value (NUMBER)
Semaglutide	Incidence During the Trial in Other Treatment Outcomes: Adverse Events	330.5 Event rate per 100 years of exposure
Placebo	Incidence During the Trial in Other Treatment Outcomes: Adverse Events	337.0 Event rate per 100 years of exposure
Placebo 0.5 mg	Incidence During the Trial in Other Treatment Outcomes: Adverse Events	317.4 Event rate per 100 years of exposure
Placebo 1.0 mg	Incidence During the Trial in Other Treatment Outcomes: Adverse Events	298.3 Event rate per 100 years of exposure

Secondary

Incidence During the Trial in Other Treatment Outcomes: Hypoglycaemic Events

Rates (event rate per 100 exposure years) of severe or blood glucose confirmed symptomatic hypoglycaemia defned as an episode that was severe according to the American diabetic association (ADA) classification or blood glucose (BG) confirmed by a PG value \<3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.

Time frame: Week 0 - 109

Population: Full analysis set included all randomised subjects.

Arm	Measure	Value (NUMBER)
Semaglutide	Incidence During the Trial in Other Treatment Outcomes: Hypoglycaemic Events	37.5 Event rate per 100 exposure years
Placebo	Incidence During the Trial in Other Treatment Outcomes: Hypoglycaemic Events	36.2 Event rate per 100 exposure years
Placebo 0.5 mg	Incidence During the Trial in Other Treatment Outcomes: Hypoglycaemic Events	35.3 Event rate per 100 exposure years
Placebo 1.0 mg	Incidence During the Trial in Other Treatment Outcomes: Hypoglycaemic Events	39.7 Event rate per 100 exposure years

Secondary

Occurrence During the Trial in Other Treatment Outcomes: Anti-semaglutide Antibodies

The percentage of subjects that tested positive for anti-semaglutide antibodies at any time point post-baseline during the trial, from week 0 to week 109.

Time frame: Weeks 0-109

Population: Full analysis set included all randomised subjects

Arm	Measure	Value (NUMBER)
Semaglutide	Occurrence During the Trial in Other Treatment Outcomes: Anti-semaglutide Antibodies	1.4 Percentage of subjects
Placebo	Occurrence During the Trial in Other Treatment Outcomes: Anti-semaglutide Antibodies	2.3 Percentage of subjects

Secondary

Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome

Percentage of subjects experiencing an event onset for each individual component of the expanded composite cardiovascular outcomes (defined as either MACE, revascularisation \[coronary and peripheral\], unstable angina requiring hospitalisation or hospitalisation for heart failure).

Time frame: Time from randomisation up to end of follow-up (scheduled at week 109)

Arm	Measure	Group	Value (NUMBER)
Semaglutide	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Cardiovascular death	1.6 percentage of subjects
Semaglutide	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Non-fatal MI	2.5 percentage of subjects
Semaglutide	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Non-fatal Stroke	1.5 percentage of subjects
Semaglutide	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Revascularisation	2.6 percentage of subjects
Semaglutide	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	UAP requiring hospitalisation	1.1 percentage of subjects
Semaglutide	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Hospitalisation for heart failure	2.7 percentage of subjects
Placebo	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	UAP requiring hospitalisation	1.3 percentage of subjects
Placebo	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Cardiovascular death	1.9 percentage of subjects
Placebo	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Revascularisation	4.2 percentage of subjects
Placebo	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Non-fatal MI	3.7 percentage of subjects
Placebo	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Hospitalisation for heart failure	2.4 percentage of subjects
Placebo	Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome	Non-fatal Stroke	2.5 percentage of subjects

Comparison: Analysis for CV death was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).p-value: 0.918195% CI: [0.65, 1.48]Regression, Cox

Comparison: Analysis for non-fatal myocardial infarction was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).p-value: 0.119495% CI: [0.51, 1.08]Regression, Cox

Comparison: Analysis for non-fatal stroke was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).p-value: 0.043895% CI: [0.38, 0.99]Regression, Cox

Comparison: Analysis for revascularisation was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).p-value: 0.002795% CI: [0.5, 0.86]Regression, Cox

Comparison: Analysis for 'unstable angina requiring hospitalisation' was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).p-value: 0.491495% CI: [0.47, 1.44]Regression, Cox

Comparison: Analysis for hospitalisation for heart failure was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).p-value: 0.573595% CI: [0.77, 1.61]Regression, Cox

Secondary

Time From Randomisation to First Occurrence of All-cause Death, Non-fatal MI, or Non-fatal Stroke

Percentage of subjects experiencing a first occurrence of all-cause death, non-fatal MI, or non-fatal stroke.

Time frame: Time from randomisation up to end of follow-up (scheduled at week 109)

Arm	Measure	Value (NUMBER)
Semaglutide	Time From Randomisation to First Occurrence of All-cause Death, Non-fatal MI, or Non-fatal Stroke	7.4 percentage of subjects
Placebo	Time From Randomisation to First Occurrence of All-cause Death, Non-fatal MI, or Non-fatal Stroke	9.6 percentage of subjects

Comparison: Analysis for all-cause death, non-fatal MI or non-fatal stroke was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).p-value: 0.029295% CI: [0.61, 0.97]Regression, Cox

Secondary

Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Outcome

Percentage of subjects experiencing first occurrence of an expanded composite CV outcome (defined as either MACE, revascularisation \[coronary and peripheral\], unstable angina requiring hospitalisation or hospitalisation for heart failure)

Time frame: Time from randomisation up to end of follow-up (scheduled at week 109)

Arm	Measure	Value (NUMBER)
Semaglutide	Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Outcome	12.1 percentage of subjects
Placebo	Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Outcome	16.0 percentage of subjects

Comparison: Analysis was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).p-value: 0.001695% CI: [0.62, 0.89]Regression, Cox

Source: ClinicalTrials.gov · Data processed: Jun 7, 2026

Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes

Conditions

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Time From Randomisation to First Occurrence of a MACE, Defined as Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Body Weight

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Fasting Plasma Glucose

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Glycosylated Haemoglobin (HbA1c)

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile (Free Fatty Acids)

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Urinary Albumin to Creatinine Ratio

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs (Pulse Rate)

Incidence During the Trial in Other Treatment Outcomes: Adverse Events

Incidence During the Trial in Other Treatment Outcomes: Hypoglycaemic Events

Occurrence During the Trial in Other Treatment Outcomes: Anti-semaglutide Antibodies

Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome

Time From Randomisation to First Occurrence of All-cause Death, Non-fatal MI, or Non-fatal Stroke

Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Outcome