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REWIND trial deep-dive: dulaglutide cuts MACE 12% in T2D, mostly primary prevention

Last verified 2026-05-28 · Phase 3 · Completed; primary results published July 13, 2019 · NCT01394952 ↗

By Eli Marsden · Founding Editor
Editorially reviewed (not clinically reviewed) · How we verify contentLast reviewed

REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) was a multicenter, randomized, double-blind, placebo-controlled trial sponsored by Eli Lilly to evaluate whether once-weekly subcutaneous dulaglutide 1.5 mg reduced major adverse cardiovascular events in adults with type 2 diabetes across a broad cardiovascular-risk spectrum. The trial enrolled 9,901 participants aged 50 or older with T2D and either established cardiovascular disease (31% of the cohort) or multiple cardiovascular risk factors (69%), randomizing them 1:1 to dulaglutide or placebo on top of standard care. Median follow-up was 5.4 years — the longest of any GLP-1 cardiovascular outcomes trial — and the primary endpoint was the time to first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Primary results were published by Gerstein and colleagues in the Lancet on July 13, 2019.

Enrollment
9,901
Duration
Median follow-up 5.4 years (longest GLP-1 cardiovascular outcomes trial)
Drug
Dulaglutide 1.5 mg (Trulicity)
Population
Adults aged 50 or older with type 2 diabetes (HbA1c ≤9.5%) and either prior cardiovascular disease (31% of participants — prior MI, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging, or coronary/carotid/peripheral revascularization) or cardiovascular risk factors (69% — age 55+ with documented myocardial ischemia, coronary stenosis ≥50%, ankle-brachial index <0.9, LVH, eGFR <60, or albuminuria, or age 60+ with two or more risk factors). Mean baseline age 66.2 years, 46.3% female, mean HbA1c 7.3%, mean BMI 32.3 kg/m², mean diabetes duration 10.5 years.

Primary endpoint

Time to first occurrence of three-point MACE: nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death

Treatment arm

594 of 4,949 (12.0%); 2.4 per 100 person-years

Comparator

663 of 4,952 (13.4%); 2.7 per 100 person-years

Treatment difference: Hazard ratio 0.88 (95% CI 0.79-0.99); P=0.026 for superiority

12% relative reduction in MACE with dulaglutide vs placebo over a median 5.4 years. Absolute risk reduction 1.4 percentage points, number needed to treat ≈72 over 5.4 years. The benefit emerged after roughly 2 years of separation between Kaplan-Meier curves.

Secondary endpoints

EndpointTreatmentComparatorDifference
Nonfatal myocardial infarction (component of MACE)

No meaningful reduction in nonfatal MI — a notable contrast with LEADER and SELECT, where MI drove much of the MACE benefit.

205 of 4,949 (4.1%); 0.8 per 100 person-years212 of 4,952 (4.3%); 0.8 per 100 person-yearsHazard ratio 0.96 (95% CI 0.79-1.16); P=0.65
Nonfatal stroke (component of MACE)

24% relative reduction in nonfatal stroke — the dominant driver of the MACE result in REWIND, the opposite pattern of most other GLP-1 CVOTs.

135 of 4,949 (2.7%); 0.5 per 100 person-years175 of 4,952 (3.5%); 0.7 per 100 person-yearsHazard ratio 0.76 (95% CI 0.61-0.95); P=0.017
Death from cardiovascular causes (component of MACE)

Numerical reduction in CV death; confidence interval crossed 1.0.

317 of 4,949 (6.4%); 1.3 per 100 person-years346 of 4,952 (7.0%); 1.4 per 100 person-yearsHazard ratio 0.91 (95% CI 0.78-1.06); P=0.21
Death from any cause (all-cause mortality)

Numerical 10% reduction in all-cause death; did not reach formal statistical significance.

536 of 4,949 (10.8%); 2.1 per 100 person-years592 of 4,952 (12.0%); 2.4 per 100 person-yearsHazard ratio 0.90 (95% CI 0.80-1.01); P=0.067
Hospitalization for heart failure

No meaningful reduction in heart-failure hospitalizations — consistent with the broader GLP-1 class signal that these drugs do not move heart-failure outcomes the way SGLT2 inhibitors do.

213 of 4,949 (4.3%); 0.9 per 100 person-years226 of 4,952 (4.6%); 0.9 per 100 person-yearsHazard ratio 0.93 (95% CI 0.77-1.12); P=0.46
Composite renal outcome (new macroalbuminuria, sustained ≥30% eGFR decline, or chronic renal replacement therapy)

15% relative reduction in the composite renal endpoint, driven mainly by new macroalbuminuria; reported in the companion renal-outcomes paper.

848 of 4,949 (17.1%); 3.5 per 100 person-years970 of 4,952 (19.6%); 4.1 per 100 person-yearsHazard ratio 0.85 (95% CI 0.77-0.93); P=0.0004
HbA1c change at study end (least-squares mean difference)

Modest but durable HbA1c improvement over 5.4 years despite both arms receiving standard glycemic care with rescue medications allowed.

7.3% baseline; sustained reduction throughout follow-up7.3% baseline; less sustained reductionLeast-squares mean difference -0.61 percentage points (95% CI -0.65 to -0.58) favoring dulaglutide
Body weight change at study end (least-squares mean difference)

Modest absolute weight difference at the 1.5 mg dose — far smaller than the 14-21% weight loss seen in dedicated obesity trials of semaglutide 2.4 mg or tirzepatide. Dulaglutide is dosed for glycemic control, not weight loss.

32.3 kg/m² baseline BMI32.3 kg/m² baseline BMILeast-squares mean difference -1.46 kg (95% CI -1.61 to -1.31) favoring dulaglutide
New or worsening retinopathy (prespecified microvascular outcome)

Unlike SUSTAIN-6, where semaglutide showed an excess of retinopathy complications, REWIND did not show a retinopathy signal with dulaglutide.

Numerically similar to placeboReferenceNo significant difference between arms
Discontinuation of study drug due to adverse events470 of 4,949 (9.5%)295 of 4,952 (6.0%)Higher on dulaglutide, driven mainly by gastrointestinal events

Adverse events

EventTreatment rateComparator rate
Any gastrointestinal adverse event

Most common AE category on dulaglutide, predominantly nausea, diarrhoea, vomiting, and abdominal pain.

47.4% (2,347/4,949)34.1% (1,687/4,952)
Nausea16.9% (839/4,949)8.4% (415/4,952)
Diarrhoea15.7% (779/4,949)9.7% (482/4,952)
Vomiting9.0% (446/4,949)4.3% (213/4,952)
Pancreatitis (acute)

No statistically significant difference; rates similar to those reported in other GLP-1 CVOTs.

0.5% (27/4,949)0.4% (21/4,952)
Pancreatic cancer

Small numerical excess; not statistically significant.

0.4% (21/4,949)0.3% (16/4,952)
Medullary thyroid cancer

No cases observed in either arm over 5.4-year median follow-up.

0 events0 events
Severe hypoglycaemia

No excess hypoglycaemia with dulaglutide, consistent with GLP-1 mechanism.

1.3% (64/4,949)1.5% (75/4,952)
Permanent discontinuation due to adverse event

Higher on dulaglutide, driven mainly by GI intolerance.

9.5% (470/4,949)6.0% (295/4,952)

Subgroup analyses

  • Primary-prevention cohort (no prior CVD at baseline, n=6,838, 69% of trial): Hazard ratio for MACE 0.87 (95% CI 0.74-1.02)

    Effect direction and magnitude consistent with the overall result; REWIND is the only major GLP-1 CVOT in which most participants had no prior CVD, making this the most cited subgroup in the trial.

  • Secondary-prevention cohort (prior CVD at baseline, n=3,114, 31% of trial): Hazard ratio for MACE 0.87 (95% CI 0.74-1.02)

    Effect size essentially identical to the primary-prevention subgroup — a key argument that GLP-1 cardiovascular benefit is not confined to high-risk secondary-prevention populations.

  • Female participants (n=4,589, 46.3%): Hazard ratio for MACE 0.81 (95% CI 0.66-0.99)

    Numerically larger benefit in women than in men; REWIND enrolled the highest proportion of women of any GLP-1 CVOT.

  • Participants with baseline HbA1c below 7.2% (median): Hazard ratio for MACE consistent with overall effect

    Benefit independent of baseline glycemic control, consistent with the framing that GLP-1 cardiovascular benefit is not driven by HbA1c reduction alone.

Clinical significance

REWIND is the GLP-1 cardiovascular outcomes trial that broke the trial-population mold. Before REWIND, the major GLP-1 CVOTs — LEADER, SUSTAIN-6, EXSCEL, ELIXA, Harmony Outcomes — had enrolled mostly secondary-prevention populations with established cardiovascular disease, leaving open whether GLP-1 agonism prevented first events or only blunted recurrent ones. REWIND answered that question by enrolling 69% primary prevention and showing nearly identical MACE benefit in both subgroups. The result moved dulaglutide from a glycemic-control drug into the cardioprotection conversation for the broader T2D population and underpinned the February 2020 FDA label expansion of Trulicity to reduce major adverse cardiovascular events in adults with type 2 diabetes who have either established cardiovascular disease or multiple cardiovascular risk factors. The 12% relative MACE reduction was smaller than LEADER's 13% or SUSTAIN-6's 26% — likely reflecting REWIND's lower-risk population, where absolute event rates were lower and ceiling for relative reduction was harder to reach.

Frequently asked questions

Does REWIND apply to non-diabetic obesity patients?

Not directly. REWIND enrolled adults with type 2 diabetes — HbA1c ≤9.5% at entry, mean baseline HbA1c 7.3%, mean diabetes duration 10.5 years — and tested dulaglutide 1.5 mg, a dose optimized for glycemic control rather than weight loss. The cardiovascular benefit shown in REWIND has not been formally tested in non-diabetic populations with obesity. The closest analog for non-diabetic patients is the SELECT trial of semaglutide 2.4 mg in adults with overweight or obesity and prior cardiovascular disease (Lincoff 2023, NEJM), which showed a 20% MACE reduction in that population. SELECT, not REWIND, is the citation to use when counseling a non-diabetic obesity patient about cardiovascular benefits of GLP-1 therapy.

Why was the MACE effect smaller than LEADER or SUSTAIN-6?

REWIND's 12% relative MACE reduction was smaller than LEADER's 13% (liraglutide) and considerably smaller than SUSTAIN-6's 26% (injectable semaglutide), and the most likely explanation is the population. LEADER and SUSTAIN-6 enrolled mostly secondary-prevention participants with prior cardiovascular events, where baseline event rates are higher and there is more room for a relative reduction. REWIND's mostly primary-prevention cohort had lower baseline event rates, which mechanically compresses the achievable relative effect even when the underlying biology is similar. Dose differences matter too — dulaglutide 1.5 mg is a glycemic-control dose, smaller than the semaglutide doses used in the obesity-focused SELECT trial. The point of REWIND was not to maximize relative effect size but to show that cardiovascular benefit extended to lower-risk T2D patients, and it did.

Did REWIND show cardiovascular benefit in primary prevention (patients without prior CVD)?

Yes. This is REWIND's defining contribution to the GLP-1 cardiovascular literature. 69% of REWIND participants (n=6,838) had no established cardiovascular disease at baseline, only risk factors. In the prespecified primary-prevention subgroup analysis, the hazard ratio for MACE was 0.87 (95% CI 0.74-1.02) — essentially identical to the 0.87 (95% CI 0.74-1.02) seen in the secondary-prevention subgroup. The effect-size consistency across the two subgroups, with confidence intervals that overlapped substantially, supported the inference that GLP-1 cardiovascular benefit is not confined to patients with prior events. This finding underpinned the broader FDA label that allows Trulicity to be prescribed for cardiovascular risk reduction in T2D patients who have either established CVD or multiple CV risk factors.

Why is Trulicity used less for weight loss than Wegovy or Zepbound?

Three reasons. First, dulaglutide is not FDA-approved for chronic weight management — only for type 2 diabetes and, since 2020, for cardiovascular risk reduction in T2D. Wegovy (semaglutide 2.4 mg) and Zepbound (tirzepatide) carry explicit obesity-treatment indications. Second, the dulaglutide weight effect at the doses tested in REWIND was modest — about 1.5 kg placebo-subtracted at 1.5 mg over 5.4 years — versus 14.9% for semaglutide 2.4 mg in STEP-1 and 20.9% for tirzepatide 15 mg in SURMOUNT-1. Higher dulaglutide doses (3 mg and 4.5 mg) tested in the AWARD-11 diabetes trial produced larger weight loss but are still indicated for glycemic control, not obesity. Third, insurance coverage and step-therapy protocols increasingly steer patients toward agents with the obesity-specific label, particularly when prior authorization requires evidence of an FDA-approved weight-management indication.

How does REWIND compare to FLOW (kidney) and the upcoming SURPASS-CVOT?

REWIND's renal companion paper (Gerstein 2019, PMID 31189509) showed a 15% reduction in a composite renal endpoint driven mainly by new macroalbuminuria, but the trial was not designed as a kidney outcomes trial. FLOW (Perkovic 2024, NEJM) was the dedicated semaglutide kidney trial — 3,533 adults with T2D and chronic kidney disease, hard renal endpoint, 24% reduction in major kidney events — and produced the regulatory case for using semaglutide specifically to slow CKD progression in T2D. SURPASS-CVOT is the in-progress head-to-head cardiovascular outcomes trial of tirzepatide vs dulaglutide in T2D adults with established cardiovascular disease (NCT04255433, ~13,000 participants, primary completion expected 2024-2025). When SURPASS-CVOT reads out, it will provide the first direct head-to-head GLP-1 vs dual GIP/GLP-1 cardiovascular comparison and clarify whether tirzepatide's metabolic advantages translate to incremental cardiovascular benefit over the dulaglutide platform REWIND established.

What FDA approval did REWIND support?

On February 21, 2020, the FDA expanded the Trulicity (dulaglutide) label to include the reduction of major adverse cardiovascular events in adults with type 2 diabetes who have either established cardiovascular disease or multiple cardiovascular risk factors. REWIND was the principal pivotal trial. The expanded indication made dulaglutide the first GLP-1 receptor agonist approved for cardiovascular risk reduction in a broad T2D population — including those without established cardiovascular disease — based on the primary-prevention subgroup signal. Earlier GLP-1 cardiovascular indications, including liraglutide's, had been restricted to T2D adults with established cardiovascular disease.

References

  1. 1.Gerstein HC, Colhoun HM, Dagenais GR, et al.; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019. PMID: 31189511.
  2. 2.Gerstein HC, Colhoun HM, Dagenais GR, et al.; REWIND Investigators. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019. PMID: 31189509.
  3. 3.Eli Lilly and Company. Researching Cardiovascular Events With a Weekly INcretin in Diabetes (REWIND, NCT01394952) — Study Record. ClinicalTrials.gov. 2019. https://clinicaltrials.gov/study/NCT01394952
  4. 4.U.S. Food and Drug Administration. FDA Approves Trulicity (dulaglutide) for the Reduction of Major Adverse Cardiovascular Events in Adults With Type 2 Diabetes. FDA Drug Approval Announcement, February 21, 2020. 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-trulicity-cardiovascular-risk-reduction
  5. 5.Riddle MC, Gerstein HC, Xavier D, et al. HbA1c Reduction in Dulaglutide-Treated Patients Irrespective of Duration of Diabetes, Microvascular Disease, and BMI: A Post Hoc Analysis From the REWIND Trial. Diabetes Care. 2022. PMID: 35043140.

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