REWIND
(2019)Objective
Dulaglutide - To evaluate the effect of weekly dulaglutide on major cardiovascular events, including stroke, in patients with type 2 diabetes.
Study Summary
• 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.
Inclusion Criteria
Type 2 diabetes patients ≥50 years old with prior cardiovascular disease or ≥1 CV risk factor. Median HbA1c 7.2%.
Study Design
Arms: Dulaglutide 1.5 mg weekly vs. Placebo
Patients per Arm: Dulaglutide: 4949; Placebo: 4952
Outcome
↳ ARR: 1.37%; NNT: 73
• Non-fatal stroke: 2.73% vs. 3.53%; HR 0.76 (95% CI 0.61–0.95); P=0.017
↳ ARR: 0.81%; NNT: 125
• Vascular death: 6.41% vs. 6.99%; HR 0.91 (95% CI 0.78–1.06); P=0.21
• Non-fatal MI: 4.14% vs. 4.28%; HR 0.96 (95% CI 0.79–1.16); P=0.65
• All-cause mortality: 10.8% vs. 12.0%; HR 0.90 (95% CI 0.80–1.01); P=0.067
• Mean HbA1c difference: -0.61% favoring dulaglutide; P<0.001
• Subgroup (with/without CVD): HR 0.87 (95% CI 0.74–1.02) for both groups
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)
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, multicenter, superiority trial
- Randomization
- Yes
- Blinding
- Double-blind with identical-appearing syringes
- Sample Size
- 9901
- Follow-up
- Median 5.4 years (IQR 5.1-5.9)
- Centers
- 371
- Countries
- 24 countries globally
Primary Outcome
Definition: First occurrence of composite endpoint: non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 663/4952 (13.4%) - 2.66 per 100 person-years | 594/4949 (12.0%) - 2.35 per 100 person-years | 0.88 (0.79-0.99) | 0.026 |
Limitations & 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
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.