NCT01394952: REWIND

Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND)

Completed Phase 3 Results posted Last updated 8 October 2019

What this trial tests

Phase 3 trial testing Dulaglutide in Cardiovascular Disease in 9,901 participants. Completed in 21 August 2018.

Timeline

22 July 2011

Primary endpoint
21 August 2018

21 August 2018

Quick facts

Lead sponsor	Eli Lilly and Company
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	9,901
Start date	22 July 2011
Primary completion	21 August 2018
Estimated completion	21 August 2018
Sites	300 locations across Colombia, Taiwan, Poland, South Korea, New Zealand, Russia, Sweden, Mexico

Drugs / interventions tested

• Dulaglutide (DULAGLUTIDE) — full drug profile →
• Placebo

Conditions studied

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

Sponsor

Eli Lilly and Company — full company profile →

Who can join

50 and older, any sex, with Cardiovascular Disease 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.

Number of Participants Who Experienced an Event For Time, From Randomization to First Occurrence of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke (a Composite Cardiovascular Outcome) Primary · From randomization to first occurrence or death from any cause or study completion (Median Follow-Up of 5.4 Years)

The time from randomization to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite endpoint) was evaluated using time-to-event analysis. The primary analysis model was a Cox proportional hazards regression model for the time to the first occurrence of a primary endpoint event, with treatment as a fixed effect using the intent-to-treat population. The number of participants who experienced a primary cardiovascular (CV) endpoint event is presented.

Group	Value	95% CI
Placebo	663
Dulaglutide	594

Number of Participants Who Experienced an Event for Time to First Occurrence After Randomization of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke, Individually Secondary · From randomization to first occurrence or study completion (Median Follow-Up of 5.4 Years)

The time from randomization to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (individually) was evaluated using time-to-event analysis via the Cox proportional hazards regression model where response equals treatment. Death from CV causes is defined as a death resulting from an acute myocardial infarction (MI), sudden cardiac death, death due to heart failure, death due to stroke, or death due to other CV causes. The number of participants who experienced an event is presented.

Death from CV causes

Group	Value	95% CI
Placebo	346
Dulaglutide	317

Nonfatal MI

Group	Value	95% CI
Placebo	212
Dulaglutide	205

Nonfatal stroke

Group	Value	95% CI
Placebo	175
Dulaglutide	135

Number of Participants Who Experienced an Event for Time to All-cause Mortality Secondary · From randomization to study completion (Median Follow-Up of 5.4 Years)

The time to all-cause mortality was evaluated using time-to-event analysis via the Cox proportional hazards regression model where response equals treatment. The number of participants who experienced an event is presented.

Group	Value	95% CI
Placebo	592
Dulaglutide	536

Number of Participants Who Experienced an Event for Time to First Occurrence After Randomization of the Composite Microvascular Endpoint Secondary · From randomization to first occurrence or study completion (Median Follow-Up of 5.4 Years)

The time from randomization to first occurrence of the composite microvascular endpoint was evaluated using time-to-event analysis via the Cox proportional hazards regression model where response equals treatment. The composite microvascular endpoint is defined as diabetic retinopathy requiring laser therapy, vitrectomy, or anti-vascular endothelial growth factor therapy (VEGF), clinical proteinuria, a greater than equal ≥ 30% decline in estimated glomerular filtration rate, or need for chronic renal replacement therapy. The number of participants who experienced the composite microvascular en

Group	Value	95% CI
Placebo	1241
Dulaglutide	1099

Number of Participants Who Experienced An Event for Time to First Occurrence After Randomization of Heart Failure Requiring Hospitalization or an Urgent Heart Failure Clinic Visit Secondary · From randomization to first occurrence or study completion (Median Follow-Up of 5.4 Years)

The time to first occurrence after randomization of heart failure requiring hospitalization or an urgent heart failure clinic visit was evaluated using time-to-event analysis via the Cox proportional hazards regression model where response equals treatment. The number of participants who experienced an event is presented.

Group	Value	95% CI
Placebo	226
Dulaglutide	213

Number of Participants Who Experienced an Event for Time to First Occurrence After Randomization of First Hospitalization for Unstable Angina Secondary · From randomization to first occurrence or study completion (Median Follow-Up of 5.4 Years)

Time to first occurrence after randomization of first hospitalization for unstable angina was evaluated using time-to-event analysis via the Cox proportional hazards regression model where response equals treatment. The number of participants who experienced an event is presented.

Group	Value	95% CI
Placebo	77
Dulaglutide	88

Adverse events — posted to ClinicalTrials.gov

Time frame: From Randomization to Study Completion (Up to 7 Years). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 2044/4949 (41%)

Deaths: 592/4949

Dulaglutide

Serious: 1991/4943 (40%)

Deaths: 536/4943

Serious adverse events (1416 terms)

Reaction	System	Placebo	Dulaglutide
Pneumonia	Infections and infestations	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—
Fall	Injury, poisoning and procedural complications	—	—
Cardiac failure	Cardiac disorders	—	—
Atrial fibrillation	Cardiac disorders	—	—
Hypoglycaemia	Metabolism and nutrition disorders	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Angina pectoris	Cardiac disorders	—	—
Coronary artery disease	Cardiac disorders	—	—
Angina unstable	Cardiac disorders	—	—
Acute myocardial infarction	Cardiac disorders	—	—
Cholelithiasis	Hepatobiliary disorders	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Acute coronary syndrome	Cardiac disorders	—	—
Cellulitis	Infections and infestations	—	—
Non-cardiac chest pain	General disorders	—	—
Syncope	Nervous system disorders	—	—
Myocardial infarction	Cardiac disorders	—	—
Sepsis	Infections and infestations	—	—
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Cerebrovascular accident	Nervous system disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—

Other adverse events (24 terms — click to expand)

Reaction	System	Placebo	Dulaglutide
Nausea	Gastrointestinal disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Urinary tract infection	Infections and infestations	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Hypertension	Vascular disorders	—	—
Bronchitis	Infections and infestations	—	—
Hypoglycaemia	Metabolism and nutrition disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Influenza	Infections and infestations	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Cataract	Eye disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Headache	Nervous system disorders	—	—
Dizziness	Nervous system disorders	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Microalbuminuria	Renal and urinary disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Benign prostatic hyperplasia	Reproductive system and breast disorders	—	—

Most-reported serious reactions: Pneumonia, Osteoarthritis, Fall, Cardiac failure, Atrial fibrillation, Hypoglycaemia, Hyperglycaemia, Acute kidney injury.

Data from ClinicalTrials.gov NCT01394952 adverse events section.

Sponsor's own description

The purpose of this trial is to assess whether dulaglutide can reduce major cardiovascular events and other serious outcomes in persons with type 2 diabetes, when added to their anti-hyperglycemic regimen.

Publications & conference data

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

1. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
   Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, et al · · 2019 · cited 2083× · PMID 31189511 · DOI 10.1016/s0140-6736(19)31149-3
2. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.
   Kahn SE, Cooper ME, Del Prato S. · · 2014 · cited 1100× · PMID 24315620 · DOI 10.1016/s0140-6736(13)62154-6
3. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention.
   Kong P, Cui ZY, Huang XF, Zhang DD, et al · · 2022 · cited 749× · PMID 35459215 · DOI 10.1038/s41392-022-00955-7
4. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
   Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, et al · · 2019 · cited 438× · PMID 31189509 · DOI 10.1016/s0140-6736(19)31150-x
5. 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
6. Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes.
   Hinnen D. · · 2017 · cited 262× · PMID 28848315 · DOI 10.2337/ds16-0026
7. Macrophage functions in lean and obese adipose tissue.
   Thomas D, Apovian C. · · 2017 · cited 231× · PMID 28641779 · DOI 10.1016/j.metabol.2017.04.005
8. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial.
   Cukierman-Yaffe T, Gerstein HC, Colhoun HM, Diaz R, et al · · 2020 · cited 223× · PMID 32562683 · DOI 10.1016/s1474-4422(20)30173-3