REWIND
Researching Cardiovascular Events with a Weekly Incretin in Diabetes: Dulaglutide and cardiovascular outcomes in type 2 diabetes
Clinical Question
Does dulaglutide reduce major adverse cardiovascular events when added to existing antihyperglycemic regimens in people with type 2 diabetes with and without previous cardiovascular disease across a wide range of glycemic control?
Study Overview
Objective
Dulaglutide - To evaluate the effect of weekly dulaglutide on major cardiovascular events, including stroke, in patients with type 2 diabetes.
Study Summary
- Dulaglutide reduced major adverse cardiovascular events (MACE).
- Stroke risk reduction was statistically significant with modest absolute benefit.
- Benefits observed regardless of cardiovascular disease history.
Intervention
Multinational, randomized, double-blind, placebo-controlled trial at 371 sites across 24 countries. Adults ≥50 with type 2 diabetes and either prior cardiovascular disease or risk factors were assigned to dulaglutide 1.5 mg weekly or placebo. Median follow-up was 5.4 years.
Patients per Arm
Dulaglutide: 4949; Placebo: 4952
Bottom Line
Dulaglutide significantly reduced the primary composite cardiovascular outcome (12.0% vs 13.4%; HR 0.88, 95% CI 0.79-0.99) in people with type 2 diabetes, with the greatest benefit seen in stroke reduction, across a broad population including those without established cardiovascular disease.
Major Points
- Large international cardiovascular outcomes trial with 9901 participants followed for median 5.4 years
- First GLP-1 receptor agonist trial designed for superiority testing rather than non-inferiority
- Broad inclusion criteria: only 31.5% had previous cardiovascular disease, 46.3% were women
- Primary composite outcome reduced by 12% (HR 0.88, 95% CI 0.79-0.99; p=0.026)
- Greatest benefit seen in non-fatal stroke reduction (HR 0.76, 95% CI 0.61-0.95)
- Consistent effects across subgroups including those with and without prior cardiovascular disease
- Significant reductions in HbA1c (-0.61%), weight (-1.46 kg), and systolic BP (-1.70 mmHg)
Design
Study Type: Randomized, double-blind, placebo-controlled, multicenter, superiority trial
Randomization: 1
Blinding: Double-blind with identical-appearing syringes
Enrollment Period: August 18, 2011 to August 14, 2013
Follow-up Duration: Median 5.4 years (IQR 5.1-5.9)
Centers: 371
Countries: 24 countries globally
Sample Size: 9901
Analysis: Intention-to-treat analysis using Cox proportional hazards models with covariates, formal interim analysis after 756 events
Inclusion Criteria
- Men and women aged ≥50 years with type 2 diabetes
- HbA1c ≤9.5% with no lower limit
- Stable doses of up to two oral glucose-lowering drugs ± basal insulin
- BMI ≥23 kg/m²
- Age 50-54: previous vascular disease required
- Age 55-59: vascular disease or specific risk factors required
- Age ≥60: at least two cardiovascular risk factors required
Exclusion Criteria
- eGFR <15 mL/min per 1.73 m²
- Cancer in previous 5 years
- Severe hypoglycemia in previous year
- Life expectancy <1 year
- Coronary or cerebrovascular event within 2 months
- Plans for revascularization
Arms
| Field | Dulaglutide | Control |
|---|---|---|
| Intervention | Dulaglutide 1.5 mg subcutaneous injection weekly | Matching placebo subcutaneous injection weekly |
| Duration | Median 5.4 years | Median 5.4 years |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| First occurrence of composite endpoint: non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes) | Primary | 663/4952 (13.4%) - 2.66 per 100 person-years | 594/4949 (12.0%) - 2.35 per 100 person-years | 0.88 | 0.026 |
| Non-fatal myocardial infarction | Secondary | 212/4952 (4.3%) | 205/4949 (4.1%) | 0.96 | 0.65 |
| Non-fatal stroke | Secondary | 175/4952 (3.5%) | 135/4949 (2.7%) | 0.76 | 0.017 |
| Cardiovascular death (includes deaths of unknown cause) | Secondary | 346/4952 (7.0%) | 317/4949 (6.4%) | 0.91 | 0.21 |
| All-cause mortality | Secondary | 592/4952 (12.0%) | 536/4949 (10.8%) | 0.9 | 0.067 |
| Composite microvascular outcome (eye or renal) | Secondary | 1019/4952 (20.6%) | 910/4949 (18.4%) | 0.87 | 0.0020 |
| Hospital admission for heart failure or urgent visit | Secondary | 226/4952 (4.6%) | 213/4949 (4.3%) | 0.93 | 0.46 |
| Hospital admission for unstable angina | Secondary | 77/4952 (1.6%) | 88/4949 (1.8%) | 1.14 | 0.41 |
| Gastrointestinal adverse events (any) | Adverse | 1687/4952 (34.1%) | 2347/4949 (47.4%) | <0.0001 | |
| First study drug discontinuation (any reason) | Adverse | 2171/4952 (43.8%) | 2092/4949 (42.3%) | 0.38 | |
| Study drug discontinuation due to adverse events | Adverse | 310/4952 (6.3%) | 451/4949 (9.1%) | ||
| Acute pancreatitis | Adverse | 13/4952 (0.3%) | 23/4949 (0.5%) | 0.11 | |
| Any cancer | Adverse | 348/4952 (7.0%) | 351/4949 (7.1%) | 0.98 | |
| Medullary thyroid carcinoma or C-cell hyperplasia | Adverse | 0/4952 (0%) | 1/4949 (<0.1%) | 0.32 | |
| Thyroid cancer | Adverse | 3/4952 (0.1%) | 7/4949 (0.1%) | 0.21 | |
| Pancreatic cancer | Adverse | 12/4952 (0.2%) | 19/4949 (0.4%) | 0.22 | |
| Serious hepatic event | Adverse | 40/4952 (0.8%) | 25/4949 (0.5%) | 0.057 | |
| Serious renal or urinary event | Adverse | 93/4952 (1.9%) | 84/4949 (1.7%) | 0.46 | |
| Immune reactions | Adverse | 20/4952 (0.4%) | 8/4949 (0.2%) | 0.022 | |
| Serious gastrointestinal event | Adverse | 117/4952 (2.4%) | 120/4949 (2.4%) | 0.87 | |
| Supraventricular tachycardia or conduction disorders | Adverse | 192/4952 (3.9%) | 216/4949 (4.4%) | 0.26 | |
| Severe hypoglycemia | Adverse | 74/4952 (1.5%) | 64/4949 (1.3%) | 0.38 |
Subgroup Analysis
Consistent effects across all prespecified subgroups including age, sex, BMI, diabetes duration, baseline HbA1c, and history of cardiovascular disease. Nominally significant heterogeneity by geographical region (p=0.0080) but loses significance after multiple testing correction.
Criticisms
- Industry-sponsored trial with potential bias
- More than 25% of participants not taking study drug at final visit
- Higher study-drug discontinuation due to adverse events in dulaglutide group (9.1% vs 6.3%)
- Significant increase in gastrointestinal adverse events with dulaglutide (47.4% vs 34.1%)
- Nominally significant geographical variation in treatment effect (p=0.008) among seven prespecified subgroups, but loses significance after correction for multiple testing
- Relatively low baseline cardiovascular risk population
Funding
Eli Lilly and Company
Based on: REWIND (The Lancet, 2019)
Authors: Hertzel C Gerstein, Helen M Colhoun, Gilles R Dagenais, ..., Theodora Temelkova-Kurktschiev
Citation: Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394(10193):121-130.
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