NCT01720446: SUSTAIN™ 6

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

Completed Phase 3 Results posted Last updated 27 June 2019

What this trial tests

Phase 3 trial testing semaglutide in Diabetes in 3,297 participants. Completed in 15 March 2016.

Timeline

21 February 2013

Primary endpoint
15 March 2016

15 March 2016

Quick facts

Lead sponsor	Novo Nordisk A/S
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	3,297
Start date	21 February 2013
Primary completion	15 March 2016
Estimated completion	15 March 2016
Sites	253 locations across Italy, Malaysia, Taiwan, Poland, Denmark, Russia, Mexico, Thailand

Drugs / interventions tested

• semaglutide (semaglutide) — full drug profile →
• semaglutide (semaglutide) — full drug profile →
• placebo

Conditions studied

• Diabetes — all drugs for Diabetes →
• Diabetes Mellitus, Type 2 — all drugs for Diabetes Mellitus, Type 2 →

Sponsor

Novo Nordisk A/S — full company profile →

Who can join

50 and older, any sex, with Diabetes or Diabetes Mellitus, Type 2. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

Group	Value	95% CI
Semaglutide	6.6
Placebo	8.9

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

Group	Value	95% CI
Semaglutide	12.1
Placebo	16.0

Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome Secondary · 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).

Cardiovascular death

Group	Value	95% CI
Semaglutide	1.6
Placebo	1.9

Non-fatal MI

Group	Value	95% CI
Semaglutide	2.5
Placebo	3.7

Non-fatal Stroke

Group	Value	95% CI
Semaglutide	1.5
Placebo	2.5

Revascularisation

Group	Value	95% CI
Semaglutide	2.6
Placebo	4.2

UAP requiring hospitalisation

Group	Value	95% CI
Semaglutide	1.1
Placebo	1.3

Hospitalisation for heart failure

Group	Value	95% CI
Semaglutide	2.7
Placebo	2.4

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

Group	Value	95% CI
Semaglutide	7.4
Placebo	9.6

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

Group	Value	95% CI
Semaglutide 0.5 mg	-1.09	± 0.05
Semaglutide 1.0 mg	-1.41	± 0.05
Placebo 0.5 mg	-0.44	± 0.05
Placebo 1.0 mg	-0.36	± 0.05

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

Group	Value	95% CI
Semaglutide 0.5 mg	-1.75	± 0.12
Semaglutide 1.0 mg	-2.11	± 0.12
Placebo 0.5 mg	-1.02	± 0.12
Placebo 1.0 mg	-0.88	± 0.12

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Body Weight Secondary · Week 0, up to week 104

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

Group	Value	95% CI
Semaglutide 0.5 mg	-3.57	± 0.21
Semaglutide 1.0 mg	-4.88	± 0.22
Placebo	-0.62	± 0.15

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile Secondary · 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).

Total cholesterol (mg/dL)

Group	Value	95% CI
Semaglutide 0.5 mg	0.97	± 0.01
Semaglutide 1.0 mg	0.97	± 0.01
Placebo 0.5 mg	1.00	± 0.01
Placebo 1.0 mg	0.99	± 0.01

HDL-cholesterol (mg/dL)

Group	Value	95% CI
Semaglutide 0.5 mg	0.99	± 0.01
Semaglutide 1.0 mg	1.01	± 0.01
Placebo 0.5 mg	0.99	± 0.01
Placebo 1.0 mg	0.97	± 0.01

LDL-cholesterol (mg/dL)

Group	Value	95% CI
Semaglutide 0.5 mg	0.97	± 0.01
Semaglutide 1.0 mg	0.98	± 0.01
Placebo 0.5 mg	1.01	± 0.01
Placebo 1.0 mg	0.99	± 0.01

Triglycerides (mg/dL)

Group	Value	95% CI
Semaglutide 0.5 mg	0.93	± 0.01
Semaglutide 1.0 mg	0.92	± 0.01
Placebo 0.5 mg	0.96	± 0.01
Placebo 1.0 mg	0.98	± 0.01

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Urinary Albumin to Creatinine Ratio Secondary · Week 0, up to week 104

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

Group	Value	95% CI
Semaglutide 0.5 mg	1.02	± 0.05
Semaglutide 1.0 mg	0.91	± 0.05
Placebo 0.5 mg	1.32	± 0.07
Placebo 1.0 mg	1.29	± 0.06

Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs Secondary · 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).

Diastolic blood pressure (mmHg)

Group	Value	95% CI
Semaglutide 0.5 mg	-1.37	± 0.32
Semaglutide 1.0 mg	-1.57	± 0.32
Placebo 0.5 mg	-1.42	± 0.32
Placebo 1.0 mg	-1.71	± 0.32

Systolic blood pressure (mmHg)

Group	Value	95% CI
Semaglutide 0.5 mg	-3.44	± 0.54
Semaglutide 1.0 mg	-5.37	± 0.54
Placebo 0.5 mg	-2.17	± 0.54
Placebo 1.0 mg	-2.78	± 0.54

Incidence During the Trial in Other Treatment Outcomes: Hypoglycaemic Events Secondary · 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.

Group	Value	95% CI
Semaglutide 0.5 mg	37.5
Semaglutide 1.0 mg	36.2
Placebo 0.5 mg	35.3
Placebo 1.0 mg	39.7

Incidence During the Trial in Other Treatment Outcomes: Adverse Events Secondary · Weeks 0-109

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

Group	Value	95% CI
Semaglutide 0.5 mg	330.5
Semaglutide 1.0 mg	337.0
Placebo 0.5 mg	317.4
Placebo 1.0 mg	298.3

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events from the first trial-related activity after the subject had signed the informed consent (week -2) until the end of the posttreatment follow-up period (week 109).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Semaglutide 0.5 mg

Serious: 289/826 (35%)

Deaths: —

Semaglutide 1.0 mg

Serious: 276/822 (34%)

Deaths: —

Placebo 0.5 mg

Serious: 329/824 (40%)

Deaths: —

Placebo 1.0 mg

Serious: 298/825 (36%)

Deaths: —

Serious adverse events (714 terms)

Reaction	System	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo 0.5 mg	Placebo 1.0 mg
Acute myocardial infarction	Cardiac disorders	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—
Angina unstable	Cardiac disorders	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—
Cardiac failure congestive	Cardiac disorders	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—
Coronary arterial stent insertion	Surgical and medical procedures	—	—	—	—
Angina pectoris	Cardiac disorders	—	—	—	—
Ischaemic stroke	Nervous system disorders	—	—	—	—
Coronary revascularisation	Surgical and medical procedures	—	—	—	—
Chronic kidney disease	Renal and urinary disorders	—	—	—	—
Coronary artery bypass	Surgical and medical procedures	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—
Coronary artery disease	Cardiac disorders	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—
Cardiac failure	Cardiac disorders	—	—	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—	—	—
Transient ischaemic attack	Nervous system disorders	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—
Cellulitis	Infections and infestations	—	—	—	—
Peripheral revascularisation	Surgical and medical procedures	—	—	—	—
Cardiac failure chronic	Cardiac disorders	—	—	—	—
Non-cardiac chest pain	General disorders	—	—	—	—
Ventricular tachycardia	Cardiac disorders	—	—	—	—
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—	—	—

Other adverse events (26 terms — click to expand)

Reaction	System	Semaglutide 0.5 mg	Semaglutide 1.0 mg	Placebo 0.5 mg	Placebo 1.0 mg
Nausea	Gastrointestinal disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Lipase increased	Investigations	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—
Diabetic retinopathy	Eye disorders	—	—	—	—
Cataract	Eye disorders	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—
Influenza	Infections and infestations	—	—	—	—
Amylase increased	Investigations	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Microalbuminuria	Renal and urinary disorders	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—
Fatigue	General disorders	—	—	—	—

Most-reported serious reactions: Acute myocardial infarction, Acute kidney injury, Angina unstable, Pneumonia, Cardiac failure congestive, Atrial fibrillation, Coronary arterial stent insertion, Angina pectoris.

Data from ClinicalTrials.gov NCT01720446 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
   Marso SP, Bain SC, Consoli A, Eliaschewitz FG, et al · · 2016 · cited 4533× · PMID 27633186 · DOI 10.1056/nejmoa1607141
2. Diabetic vascular diseases: molecular mechanisms and therapeutic strategies.
   Li Y, Liu Y, Liu S, Gao M, et al · · 2023 · cited 392× · PMID 37037849 · DOI 10.1038/s41392-023-01400-z
3. Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease.
   Mitrofanova A, Merscher S, Fornoni A. · · 2023 · cited 248× · PMID 37500941 · DOI 10.1038/s41581-023-00741-w
4. Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy.
   Rayego-Mateos S, Morgado-Pascual JL, Opazo-Ríos L, Guerrero-Hue M, et al · · 2020 · cited 237× · PMID 32471207 · DOI 10.3390/ijms21113798
5. Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: Pooled Analysis of SUSTAIN 6 and LEADER.
   Shaman AM, Bain SC, Bakris GL, Buse JB, et al · · 2022 · cited 189× · PMID 34903039 · DOI 10.1161/circulationaha.121.055459
6. GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential.
   Ma X, Liu Z, Ilyas I, Little PJ, et al · · 2021 · cited 189× · PMID 34131405 · DOI 10.7150/ijbs.59965
7. Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control.
   Borghetti G, von Lewinski D, Eaton DM, Sourij H, et al · · 2018 · cited 166× · PMID 30425649 · DOI 10.3389/fphys.2018.01514
8. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk.
   Husain M, Bain SC, Jeppesen OK, Lingvay I, et al · · 2020 · cited 144× · PMID 31903692 · DOI 10.1111/dom.13955