Series: Landmark Trials in Endocrinology & Metabolism | Study #10
Category: GLP-1 Receptor Agonists · Cardiovascular Outcomes | Design: Multicentre, double-blind, placebo-controlled RCT | n: 9,901 | Follow-up: 5.4 years (median)
📋 Summary
Authors: Gerstein HC et al., for the REWIND Investigators
Journal: Lancet 2019;394:121–130 | DOI: 10.1016/S0140-6736(19)31149-3
REWIND enrolled 9,901 patients with type 2 diabetes mellitus, making it the largest GLP-1 receptor agonist CVOT at the time of publication. Critically, the trial was designed with a more inclusive population than preceding CVOTs: 69% of participants did not have established atherosclerotic cardiovascular disease and were enrolled on the basis of cardiovascular risk factors alone, including age 50 years or older with a prior cardiovascular event, or age 55 years or older (men) or 60 years or older (women) with two or more cardiovascular risk factors. The mean HbA1c at baseline was 7.3%, lower than most CVOT populations. Patients were randomly assigned to dulaglutide 1.5 mg once weekly or placebo. Over a median follow-up of 5.4 years, the primary 3-point MACE outcome occurred in 12.0% in the dulaglutide group versus 13.4% in the placebo group (HR 0.88; 95% CI 0.79 to 0.99; p=0.026). Among the individual components, nonfatal stroke was significantly reduced (HR 0.76; 95% CI 0.61 to 0.95; p=0.017), while nonfatal MI (HR 0.96; 95% CI 0.79 to 1.16) and cardiovascular death (HR 0.91; 95% CI 0.78 to 1.06) did not reach significance individually. A prespecified composite renal outcome was also significantly reduced with dulaglutide (HR 0.85; 95% CI 0.77 to 0.93; p<0.001), driven by reduction in new macroalbuminuria.
📊 Key Findings
| Outcome | Dulaglutide | Placebo | Effect Size |
|---|---|---|---|
| 3-point MACE (CV death, MI, stroke) | 12.0% | 13.4% | HR 0.88 (0.79–0.99) · p=0.026 |
| Nonfatal stroke | — | — | HR 0.76 (0.61–0.95) · p=0.017 |
| Nonfatal MI | — | — | HR 0.96 (0.79–1.16) · NS |
| Cardiovascular death | — | — | HR 0.91 (0.78–1.06) · NS |
| Renal composite (new macroalbuminuria, ≥30% eGFR decline, ESKD) | — | — | HR 0.85 (0.77–0.93) · p<0.001 |
| Body weight change | −1.5 kg | +0.4 kg | Difference −1.9 kg |
| HbA1c change | −0.61% | — | Modest glycaemic benefit |
| Absolute risk reduction (MACE) | ~1.4% over 5.4 years | NNT approximately 71 | |
💬 Expert Commentary
REWIND occupies a unique position in the GLP-1 receptor agonist CVOT literature because of its population. With 69% of participants free of established cardiovascular disease at baseline and a mean HbA1c well below the threshold of most preceding CVOTs, REWIND most closely approximates the real-world type 2 diabetes population managed in endocrine and primary care practice. The demonstration of cardiovascular benefit in this lower-risk, better-controlled population extends the evidence for the class beyond secondary prevention and into a setting where absolute event rates are lower, meaning the NNT of approximately 71 over 5.4 years is lower in absolute terms than in LEADER, though the relative risk reduction is comparable. The stroke benefit, consistently the most prominent cardiovascular component finding across GLP-1 receptor agonist CVOTs, was again the individually significant element, and the magnitude of stroke reduction (24%) is clinically meaningful.
The renal composite finding in REWIND, driven primarily by attenuation of macroalbuminuria progression, is consistent with the renal signal observed with other members of the class, including liraglutide in LEADER. GLP-1 receptor agonists appear to exert a modest but consistent nephroprotective effect, likely mediated through haemodynamic and anti-inflammatory mechanisms distinct from but complementary to SGLT2 inhibition. REWIND was also notable for the absence of safety signals for amputation, bone fracture, or pancreatitis, reinforcing the favourable tolerability profile of once-weekly dulaglutide. The 5.4-year median follow-up is among the longest in the GLP-1 receptor agonist CVOT literature and provides greater confidence in the durability of the cardiovascular benefit and the safety of long-term exposure.
Limitations: The relatively modest absolute risk reduction and NNT of 71 reflect the lower-risk population enrolled. Cardiovascular death and MI were not individually reduced at statistical significance. The HbA1c differential between groups was small, suggesting that glycaemic differences alone do not explain the benefit. The study was industry-sponsored by Eli Lilly.
🔑 BOTTOM LINE
REWIND demonstrated that dulaglutide reduces 3-point MACE in a broad type 2 diabetes population that includes the majority without established cardiovascular disease, with a significant 24% reduction in nonfatal stroke and a concurrent renal benefit, extending the cardiovascular indication for GLP-1 receptor agonists into a primary prevention context for the first time within this drug class.
⭐ Clinical Impact Rating: ●●●●○ Practice-changing in broader population
Next in the series: Study #11 STEP 1: Once-Weekly Semaglutide 2.4 mg for Obesity Without Diabetes
