Trial Outcomes & Findings for A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes (NCT NCT03914326)

Last Updated: 2025-12-11

Results Overview

Number of participants with first occurrence of EAC (event adjudication committee) confirmed major adverse cardiovascular event (MACE), a composite end-point. i.e., from time of randomization to first occurrence of cardiovascular (CV) death, non-fatal myocardial infarction and non-fatal stroke combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

9651 participants

Primary outcome timeframe

From randomisation (week 0) up to week 265

Results posted on

2025-12-11

Participant Flow

The trial was conducted at 446 sites in 34 countries.

A total of 9,651 participants were enrolled/randomized (1:1) to treatment with oral semaglutide (4,825 participants) or placebo (4,826 participants). One participant was randomised twice in the trial. Thus, the FAS comprised 9,650 participants (4,825 participants in the oral semaglutide group and 4,825 participants in the placebo group).

Participant milestones

Participant milestones
Measure	Oral Semaglutide Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Overall Study STARTED	4825	4826
Overall Study Full Analysis Set	4825	4825
Overall Study Exposed	4814	4816
Overall Study COMPLETED	4755	4740
Overall Study NOT COMPLETED	70	86

Reasons for withdrawal

Reasons for withdrawal
Measure	Oral Semaglutide Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Overall Study Withdrawal by Subject	27	34
Overall Study Lost to Follow-up	43	51
Overall Study Randomised more than once	0	1

Baseline Characteristics

A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).	Total n=9650 Participants Total of all reporting groups
Age, Continuous	66.1 Years STANDARD_DEVIATION 7.6 • n=237 Participants	66.1 Years STANDARD_DEVIATION 7.5 • n=243 Participants	66.1 Years STANDARD_DEVIATION 7.6 • n=480 Participants
Sex: Female, Male Female	1376 Participants n=237 Participants	1414 Participants n=243 Participants	2790 Participants n=480 Participants
Sex: Female, Male Male	3449 Participants n=237 Participants	3411 Participants n=243 Participants	6860 Participants n=480 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	674 Participants n=237 Participants	706 Participants n=243 Participants	1380 Participants n=480 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4106 Participants n=237 Participants	4072 Participants n=243 Participants	8178 Participants n=480 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	45 Participants n=237 Participants	47 Participants n=243 Participants	92 Participants n=480 Participants
Race (NIH/OMB) American Indian or Alaska Native	7 Participants n=237 Participants	12 Participants n=243 Participants	19 Participants n=480 Participants
Race (NIH/OMB) Asian	1134 Participants n=237 Participants	1121 Participants n=243 Participants	2255 Participants n=480 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	4 Participants n=237 Participants	5 Participants n=243 Participants	9 Participants n=480 Participants
Race (NIH/OMB) Black or African American	124 Participants n=237 Participants	128 Participants n=243 Participants	252 Participants n=480 Participants
Race (NIH/OMB) White	3327 Participants n=237 Participants	3321 Participants n=243 Participants	6648 Participants n=480 Participants
Race (NIH/OMB) More than one race	185 Participants n=237 Participants	192 Participants n=243 Participants	377 Participants n=480 Participants
Race (NIH/OMB) Unknown or Not Reported	44 Participants n=237 Participants	46 Participants n=243 Participants	90 Participants n=480 Participants

PRIMARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomization to First Occurrence of a Major Adverse Cardiovascular Event (MACE), a Composite Endpoint Consisting of: Cardiovascular (CV) Death/Non-fatal Myocardial Infarction/Non-fatal Stroke	579 Participants	668 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

Number of participants with first occurrence of a composite endpoint. i.e., from time of randomization to first occurrence of CV death, renal death, onset of persistent greater than or equal to (≥) 50% reduction in estimated glomerular filtration rate (eGFR) (chronic kidney disease epidemiology collaboration CKD-EPI), onset of persistent eGFR (CKD-EPI) less than (\<)15 milliliters per minute per 1.73 square meters (mL/min/1.73 m\^2), initiation of chronic renal replacement therapy (dialysis or kidney transplantation) combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomization to First Occurrence of CV Death;Renal Death;Onset of Persistent≥50% Reduction in eGFR(CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73m^2;Initiation of Chronic Renal Replacement Therapy	403 Participants	435 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

Number of participants from time of randomization to time to occurrence of EAC confirmed CV death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomization to Time of Occurrence of CV Death	301 Participants	320 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

Number of participants from randomization to first occurrence of EAC confirmed major adverse limb events (MALE), a composite endpoint consisting of: acute limb ischemia hospitalisation/chronic limb ischemia hospitalisation combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomization to First Occurrence of Major Adverse Limb Events (MALE), a Composite Endpoint Consisting of: Acute Limb Ischemia Hospitalisation/Chronic Limb Ischemia Hospitalisation	71 Participants	99 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of an expanded MACE composite endpoint consisting of: CV death/non-fatal myocardial infarction/ non-fatal stroke/coronary revascularisation/unstable angina pectoris requiring hospitalisation combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of an Expanded MACE Composite Endpoint Consisting of: CV Death/Non-fatal Myocardial Infarction/ Non-fatal Stroke/Coronary Revascularisation/Unstable Angina Pectoris Requiring Hospitalisation	670 Participants	777 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of EAC confirmed composite endpoint consisting of : all-cause death/ non-fatal MI/ non-fatal stroke combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of a Composite Endpoint Consisting of : All-cause Death/ Non-fatal MI/ Non-fatal Stroke	779 Participants	902 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

Number of participants from randomisation to first occurrence of EAC confirmed composite heart failure endpoint consisting of: CV death/heart failure requiring hospitalisation/urgent heart failure visit combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of a Composite Heart Failure Endpoint Consisting of: CV Death/Heart Failure Requiring Hospitalisation/Urgent Heart Failure Visit	405 Participants	443 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomization to first occurrence of CKD endpoint:renal death;onset of persistent≥50% reduction in eGFR (CKD-EPI);onset of persistent eGFR(CKD-EPI)\<15 mL/min/1.73 m\^2;initiation of chronic renal replacement therapy combined data during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomization to First Occurrence of CKD Endpoint:Renal Death;Onset of Persistent≥50% Reduction in eGFR (CKD-EPI);Onset of Persistent eGFR(CKD-EPI)<15 mL/Min/1.73 m^2;Initiation of Chronic Renal Replacement Therapy	112 Participants	129 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to time to occurrence of EAC confirmed all-cause death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to Time to Occurrence of All-cause Death	528 Participants	577 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of EAC confirmed non-fatal MI during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of Non-fatal Myocardial Infarction (MI)	191 Participants	253 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of EAC confirmed non-fatal stroke during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of Non-fatal Stroke	144 Participants	161 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of EAC confirmed heart failure requiring hospitalisation or urgent heart failure visit during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of Heart Failure Requiring Hospitalisation or Urgent Heart Failure Visit	146 Participants	167 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of coronary revascularisation during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of Coronary Revascularisation	200 Participants	263 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of EAC confirmed unstable angina requiring hospitalisation during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of Unstable Angina Requiring Hospitalisation	74 Participants	80 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to time to occurrence of EAC confirmed renal death during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to Time to Occurrence of Renal Death	1 Participants	7 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of onset of persistent 50% or more reduction in eGFR during in-trial period were observed. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of Onset of Persistent 50% or More Reduction in eGFR	71 Participants	86 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of onset of persistent eGFR (CKD-EPI) below 15 mL/min/1.73 m\^2 during in-trial period were observed. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of Onset of Persistent eGFR (CKD-EPI) Below 15 mL/Min/1.73 m^2	23 Participants	33 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of EAC confirmed initiation of chronic renal replacement therapy (dialysis or kidney transplantation) during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of Initiation of Chronic Renal Replacement Therapy (Dialysis or Kidney Transplantation)	40 Participants	48 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of EAC confirmed acute limb ischaemia hospitalization during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of Acute Limb Ischemia	16 Participants	17 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of EAC confirmed chronic limb ischaemia hospitalization during in-trial period were presented. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of Chronic Limb Ischemia Hospitalisation	63 Participants	88 Participants

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 260

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization. Here 'overall number of participants analyzed' signifies number of participants evaluable for this outcome measure" also.

Annual rate of change in eGFR in terms of chronic kidney disease CKD-EPI were reported during in trial period. eGFR was calculated using the CKD-EPI formula. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4819 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4822 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Annual Rate of Change in eGFR (CKD-EPI) (Total eGFR Slope)	-1.67 ml/min/1.73 m^2 per year Standard Error 0.0	-2.06 ml/min/1.73 m^2 per year Standard Error 0.0

SECONDARY outcome

Timeframe: Baseline (Week 0), Week 104

Change in HbA1c from baseline (Week 0) up to Week 104 during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4076 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4004 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Change From Baseline in Glycosylated Haemoglobin (HbA1c)	-0.71 Percentage of HbA1c Standard Deviation 1.22	-0.15 Percentage of HbA1c Standard Deviation 1.19

SECONDARY outcome

Timeframe: Baseline (Week 0), Week 104

Change in body weight from baseline (Week 0) up to Week 104 during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4251 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4155 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Change From Baseline in Body Weight	-4.21 Kilograms Standard Deviation 5.85	-1.28 Kilograms Standard Deviation 4.90

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of severe hypoglycaemic episodes (such as the seriousness of hypoglycaemia, contributing factors, seizures, and unconsciousness; classified by American Diabetes Association) observed during the in-trial period were reported in this endpoint. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Severe Hypoglycaemic Episodes	88 Episodes	121 Episodes

SECONDARY outcome

Timeframe: From randomisation (week 0) up to week 265

Population: FAS included all unique randomized participants who were grouped according to the treatment assigned at randomization.

The number of participants from randomisation to first occurrence of severe hypoglycaemic episodes (such as the seriousness of hypoglycaemia, contributing factors, seizures, and unconsciousness; classified by American Diabetes Association) during in-trial period were reported. In-trial observation period was defined as the period from date of randomization to the first of (both inclusive): date of follow-up visit, date when participant withdrew consent, date of last contact with participant (for participant lost to follow-up), and date of death.

Outcome measures

Outcome measures
Measure	Oral Semaglutide n=4825 Participants Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 Participants Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Number of Participants From Randomisation to First Occurrence of a Severe Hypoglycaemic Episode	76 Participants	84 Participants

Adverse Events

Oral Semaglutide

Serious events: 2312 serious events

Other events: 1761 other events

Deaths: 528 deaths

Placebo

Serious events: 2427 serious events

Other events: 1599 other events

Deaths: 579 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Oral Semaglutide n=4825 participants at risk Participants were to receive once daily semaglutide tablets with a dose escalation every 4 weeks in doses 3 mg (week 0 to week 4), 7 mg (week 4 to week 8) until maintenance dose of 14 mg was reached and maintained till the end of treatment visit (up to week 260).	Placebo n=4825 participants at risk Participants were to receive once daily placebo matching oral semaglutide until end of the treatment visit (up to week 260).
Infections and infestations COVID-19	15.7% 756/4825 • Number of events 838 • From Week 0 up to Week 265 The safety evaluation data as reported by the investigator was based on the Full Analysis Set.	16.1% 777/4825 • Number of events 836 • From Week 0 up to Week 265 The safety evaluation data as reported by the investigator was based on the Full Analysis Set.
Eye disorders Diabetic retinopathy	19.5% 943/4825 • Number of events 1122 • From Week 0 up to Week 265 The safety evaluation data as reported by the investigator was based on the Full Analysis Set.	19.3% 932/4825 • Number of events 1116 • From Week 0 up to Week 265 The safety evaluation data as reported by the investigator was based on the Full Analysis Set.
Gastrointestinal disorders Nausea	7.1% 344/4825 • Number of events 442 • From Week 0 up to Week 265 The safety evaluation data as reported by the investigator was based on the Full Analysis Set.	1.3% 62/4825 • Number of events 66 • From Week 0 up to Week 265 The safety evaluation data as reported by the investigator was based on the Full Analysis Set.

Additional Information

Clinical Reporting Office (2834)

Novo Nordisk A/S

Phone: (+1) 866-867-7178

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee At the end of the trial, one or more scientific publications may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.
Publication restrictions are in place

Restriction type: OTHER