REWIND Results in Detail: Numbers, Subgroups, and Time Course

By
Published Updated Last reviewed
GLP-1 medication and metabolic health image for REWIND Results in Detail: Numbers, Subgroups, and Time Course

At a glance

| Field | Detail | |---|---| | Trial name | REWIND (Researching Cardiovascular Events With a Weekly Incretin in Diabetes) | | N | 9,901 | | Intervention | Dulaglutide 1.5 mg subcutaneous injection once weekly | | Comparator | Matching placebo (once weekly injection) | | Median follow-up | 5.4 years | | Primary endpoint | First occurrence of three-point MACE (cardiovascular death, non-fatal MI, non-fatal stroke) | | Key result | HR 0.88 to 95% CI 0.79, 0.99, p = 0.026 |

Why REWIND's Numbers Deserve a Closer Look

Most GLP-1 receptor agonist cardiovascular outcome trials (CVOTs) enrolled patients at very high cardiovascular risk, with the majority having established atherosclerotic disease. REWIND broke from that pattern. Only 31.5% of its participants had established cardiovascular disease at baseline. The remaining 68.5% qualified through cardiovascular risk factors alone: age 55 or older with at least two of hypertension, dyslipidemia, smoking, or albuminuria. This design choice means the results speak to a broader type 2 diabetes population than prior CVOTs like LEADER or SUSTAIN-6.

The trial also ran longer than most peers, with a median follow-up of 5.4 years compared to the 2.1 years of SUSTAIN-6 or 3.8 years of LEADER. That duration matters because it permits a clearer view of whether cardiovascular benefits grow, plateau, or fade over time.

Primary Endpoint: Three-Point MACE

The primary composite endpoint was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Results from the primary publication:

| Component | Dulaglutide (n = 4,949) | Placebo (n = 4,952) | HR (95% CI) | |---|---|---|---| | Composite MACE | 594 (12.0%) | 663 (13.4%) | 0.88 (0.79, 0.99) | | CV death | 317 (6.4%) | 346 (7.0%) | 0.91 (0.78, 1.06) | | Non-fatal MI | 205 (4.1%) | 212 (4.3%) | 0.96 (0.79, 1.16) | | Non-fatal stroke | 135 (2.7%) | 175 (3.5%) | 0.76 (0.61, 0.95) |

Several patterns stand out from these component-level results:

Stroke drove the signal. Non-fatal stroke showed a statistically significant 24% relative risk reduction (HR 0.76 to 95% CI 0.61, 0.95). Neither cardiovascular death nor non-fatal MI reached individual significance. This stroke finding aligns with observations from other GLP-1 agonist CVOTs, where stroke reductions tend to appear more consistently than MI reductions, though it warrants cautious interpretation given the trial was powered for the composite.

Absolute risk reduction was modest but clinically relevant. The absolute MACE difference was 1.4 percentage points over 5.4 years, yielding an NNT of approximately 71 per year. For a primary prevention-heavy population with baseline annualized MACE rates near 2.5%, this is in line with what statin trials have delivered in comparable risk strata.

All-cause mortality did not differ. Deaths from any cause occurred in 536 (10.8%) dulaglutide patients versus 592 (12.0%) placebo patients (HR 0.90 to 95% CI 0.80, 1.01, p = 0.067). The trend favored dulaglutide, but the trial was not powered for mortality and the confidence interval crossed 1.0.

Time Course of Benefit

Kaplan-Meier curves for the primary endpoint began separating early, within the first year, and continued diverging through the full follow-up period. This progressive separation is notable. Some cardiovascular interventions show early separation that plateaus (common with antiplatelet agents), while others take years to separate (as seen with some lipid-lowering therapies).

The steady divergence in REWIND suggests the mechanism of benefit is not purely driven by an early anti-thrombotic or hemodynamic effect. The consistent, gradual separation is more compatible with anti-atherosclerotic or anti-inflammatory mechanisms that accumulate over time. Whether this reflects plaque stabilization, weight loss, blood pressure reduction, or direct vascular effects of GLP-1 receptor agonism remains an open question.

Landmark analyses were not formally reported in the primary paper, but the Kaplan-Meier data indicate no attenuation of benefit in later years. The hazard ratio appeared, if anything, stronger in the second half of follow-up than the first, though formal interaction tests for time-varying effects were not published.

Subgroup Analyses

REWIND pre-specified subgroup analyses addressed the central question of whether cardiovascular benefit extended to patients without prior cardiovascular events. The primary publication reported the following key interactions:

| Subgroup | HR (95% CI) | p for interaction | |---|---|---| | Prior CV disease (n = 3,114) | 0.87 (0.74, 1.02) | 0.97 | | No prior CV disease (n = 6,787) | 0.87 (0.74, 1.02) |, | | Age <66 years | 0.86 (0.74, 1.01) | 0.80 | | Age ≥66 years | 0.90 (0.78, 1.04) |, | | Male | 0.90 (0.79, 1.04) | 0.45 | | Female | 0.85 (0.71, 1.03) |, | | HbA1c <7.2% | 0.86 (0.73, 1.02) | 0.72 | | HbA1c ≥7.2% | 0.89 (0.78, 1.03) |, | | BMI <32 kg/m² | 0.86 (0.73, 1.00) | 0.77 | | BMI ≥32 kg/m² | 0.90 (0.78, 1.05) |, |

No subgroup interaction reached significance. The point estimates clustered tightly around 0.87, 0.90 regardless of baseline cardiovascular history, sex, age, glycemic control, or BMI.

The lack of interaction between prior CV disease status (p = 0.97) is the most consequential finding for clinical practice. While LEADER and SUSTAIN-6 primarily demonstrated benefit in secondary prevention populations, REWIND's consistency across primary and secondary prevention supports a broader indication. This informed the 2019 ADA/EASD consensus and subsequent ADA Standards of Care recommendations to consider GLP-1 agonists in type 2 diabetes patients with cardiovascular risk factors, not only those with established disease.

Secondary and Exploratory Endpoints

Beyond MACE, REWIND assessed several outcomes that round out the clinical picture:

Glycemic control. Mean HbA1c separation between groups was approximately 0.6 percentage points at 1 year, narrowing to roughly 0.3 percentage points by end of follow-up as investigators titrated background medications per protocol. Despite this attenuation, the cardiovascular effect persisted, consistent with the hypothesis that GLP-1 agonist cardioprotection operates partly through non-glycemic pathways.

Body weight. Dulaglutide produced sustained weight loss. The between-group difference was approximately 1.5 kg by end of study. While modest by current GLP-1 agonist standards (tirzepatide and semaglutide 2.4 mg achieve far greater weight loss), this reduction contributed to the overall cardiometabolic profile.

Renal outcomes. A composite renal endpoint (new macroalbuminuria, sustained ≥30% decline in eGFR, or chronic renal replacement) favored dulaglutide (HR 0.85 to 95% CI 0.77, 0.93). The benefit was driven primarily by macroalbuminuria reduction. This finding was further explored in the REWIND renal sub-study, which confirmed that the renal effect was largely albuminuria-mediated rather than eGFR-mediated.

Hospitalizations. Heart failure hospitalization showed no significant difference (HR 0.93 to 95% CI 0.77, 1.12), consistent with other GLP-1 agonist CVOTs that generally show neutral effects on heart failure.

Safety Signals and Tolerability

Gastrointestinal adverse events were the primary tolerability concern. Nausea occurred in 15.4% of dulaglutide patients versus 7.1% on placebo. Diarrhea (12.6% vs 8.4%) and vomiting (7.3% vs 3.6%) were also more common. These rates are typical for the GLP-1 agonist class and generally diminished over time.

Pancreatitis occurred at low and similar rates in both groups. Pancreatic cancer showed no imbalance. Thyroid C-cell concerns, which prompted a boxed warning on the dulaglutide FDA label, were not borne out in clinical events during the trial.

Serious adverse events were balanced (33.0% dulaglutide vs 31.2% placebo). Study drug discontinuation due to adverse events was modestly higher with dulaglutide (7.8% vs 5.5%), primarily driven by GI intolerance in the first year.

Key Limitations

The authors themselves noted several constraints:

  1. Effect size was modest. A 12% relative risk reduction with a confidence interval nearly touching 1.0 (upper bound 0.99) means the result, while statistically significant, carries less certainty than trials with wider margins like LEADER (HR 0.87 to 95% CI 0.78, 0.97).

  2. Single dose tested. Only the 1.5 mg dose was studied. Whether lower or higher doses would produce different cardiovascular effects is unknown. The Trulicity prescribing information includes doses of 0.75 mg through 4.5 mg, but cardiovascular evidence exists only for 1.5 mg.

  3. Population composition limits generalizability in one direction. While the inclusion of primary prevention patients is a strength, the population was relatively older (mean age 66.2 years) and had long diabetes duration (mean 9.5 years). Whether the results extend to younger patients with shorter diabetes duration is uncertain.

  4. Background therapy evolved during the trial. The trial ran from 2011 to 2018. During that period, SGLT2 inhibitor use increased in both arms. The protocol permitted open-label glucose-lowering medication, meaning background therapy was not static. This is realistic but introduces noise.

  5. Component-level results. No individual MACE component reached significance except non-fatal stroke. This is expected given sample size constraints, but it means we cannot confidently attribute the composite benefit to any single pathway.

Placing REWIND Among GLP-1 CVOTs

| Trial | Drug | N | Median f/u | % with prior CVD | MACE HR (95% CI) | |---|---|---|---|---|---| | LEADER | Liraglutide | 9,340 | 3.8 yr | 81% | 0.87 (0.78, 0.97) | | SUSTAIN-6 | Semaglutide SC | 3,297 | 2.1 yr | 83% | 0.74 (0.58, 0.95) | | REWIND | Dulaglutide | 9,901 | 5.4 yr | 31% | 0.88 (0.79, 0.99) | | HARMONY | Albiglutide | 9,463 | 1.6 yr | 100% | 0.78 (0.68, 0.90) | | AMPLITUDE-O | Efpeglenatide | 4,076 | 1.8 yr | 90% | 0.73 (0.58, 0.92) |

REWIND's effect size is in line with the GLP-1 agonist class. Its unique contribution is the inclusion of a large primary prevention cohort, the longest follow-up duration among GLP-1 CVOTs, and the demonstration that benefit was not contingent on established atherosclerotic disease.

Frequently asked questions

›
›
›
›
›
›
›
›
›
›

References

  1. 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. PubMed
  2. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019;394(10193):131-138. PubMed
  3. Trulicity (dulaglutide) prescribing information. Eli Lilly and Company. Revised 2022. FDA Label
  4. Marso SP, Daniels GH, Tanaka K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes (LEADER). N Engl J Med. 2016;375(4):311-322. PubMed
  5. American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes, 2023. Diabetes Care. 2023;46(Suppl 1). PubMed
  6. Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the ADA and EASD. Diabetes Care. 2018;41(12):2669-2701. PubMed