REWIND
Researching Cardiovascular Events with a Weekly Incretin in Diabetes: Dulaglutide and cardiovascular outcomes in type 2 diabetes
Year of Publication: 2019
Authors: Hertzel C Gerstein, Helen M Colhoun, Gilles R Dagenais, ..., Theodora Temelkova-Kurktschiev
Journal: The Lancet
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.
Link: http://dx.doi.org/10.1016/S0140-6736(19)31149-3
PDF: https://www.researchgate.net/profile/Gus...saWNhdGlvbiJ9fQ
PDF: 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?
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
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Mean age | 66.2 (6.5) years | 66.2 (6.5) years |
| Female | 46.1% | 46.6% |
| Previous cardiovascular disease | 31.4% | 31.5% |
| Previous cardiovascular event | 20.3% | 20.8% |
| Median diabetes duration | 9.5 (5.5-14.5) years | 9.5 (5.5-14.5) years |
| Median HbA1c | 7.2% (6.6-8.1) | 7.2% (6.6-8.1) |
| Mean BMI | 32.3 (5.8) kg/m² | 32.3 (5.7) kg/m² |
| Hypertension | 93.3% | 93.0% |
| eGFR <60 mL/min per 1.73 m² | 22.6% | 21.8% |
| Albuminuria | 35.5% | 34.5% |
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 | 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 | Secondary | 1019/4952 (20.6%) | 910/4949 (18.4%) | 0.87 | 0.0020 |
| Gastrointestinal adverse events | Adverse | 1687/4952 (34.1%) | 2347/4949 (47.4%) | <0.0001 | |
| 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 |
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 discontinuation rates in dulaglutide group due to gastrointestinal side effects
- Significant increase in gastrointestinal adverse events with dulaglutide
- Post-hoc finding of geographical variation in treatment effect may be spurious
- 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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