What does REWIND stand for?

REWIND stands for Researching Cardiovascular Events with a Weekly Incretin in Diabetes. It was a randomized, double-blind, placebo-controlled trial designed to test whether dulaglutide reduced cardiovascular events in adults with type 2 diabetes.

How is dulaglutide different from semaglutide or liraglutide?

All three are GLP-1 receptor agonists, but they differ in molecular structure, dosing frequency, and available doses. Dulaglutide (Trulicity) is given once weekly at 0.75 to 4.5 mg. Liraglutide (Victoza) is a daily injection. Semaglutide is available as a weekly injection (Ozempic) or oral tablet (Rybelsus). Each has its own cardiovascular outcomes trial with distinct patient populations and results.

Did REWIND show that dulaglutide prevents heart attacks?

Not definitively. The composite endpoint (cardiovascular death, heart attack, or stroke) was significantly reduced, but non-fatal myocardial infarction alone was not significantly reduced (HR 0.96, p = NS). The strongest individual signal was for non-fatal stroke reduction.

Were most REWIND participants already diagnosed with heart disease?

No. About 69% of participants did not have established cardiovascular disease at enrollment. They qualified based on having cardiovascular risk factors such as hypertension, dyslipidemia, tobacco use, or abdominal obesity. This is a key distinction from trials like LEADER and SUSTAIN-6.

How long did the REWIND trial last?

The median follow-up was 5.4 years, which is roughly twice as long as most other GLP-1 receptor agonist cardiovascular outcomes trials. This longer duration provided more events and statistical power for a lower-risk population.

What dose of dulaglutide was used in REWIND?

Only the 1.5 mg once-weekly dose was tested. The prescribing information lists doses from 0.75 mg to 4.5 mg for glycemic control, but cardiovascular outcome data exist only for the 1.5 mg dose studied in REWIND.

Is dulaglutide approved for reducing cardiovascular risk?

Yes. Based on REWIND data, the FDA updated the dulaglutide label to include an indication for reducing MACE in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors.

What were the main side effects in REWIND?

Gastrointestinal symptoms (nausea, diarrhea, vomiting) were the most common side effects and the leading cause of treatment discontinuation. Rates of pancreatitis were numerically higher with dulaglutide (23 vs. 13 adjudicated cases), though absolute numbers were small. No medullary thyroid cancers were reported.

How does REWIND compare to the LEADER trial?

Both showed cardiovascular benefit with a GLP-1 receptor agonist. LEADER tested daily liraglutide in a population where 81% had established cardiovascular disease, with a 13% MACE reduction over 3.8 years. REWIND tested weekly dulaglutide in a population where only 31% had established cardiovascular disease, with a 12% MACE reduction over 5.4 years. REWIND's broader population is its distinguishing feature.

Should someone without heart disease take dulaglutide based on REWIND?

REWIND supports the use of dulaglutide in patients with type 2 diabetes and cardiovascular risk factors, even without prior events. Current ADA guidelines reflect this. However, the absolute risk reduction is modest (about 1.4 percentage points over 5 years), so the decision should factor in individual risk profile, cost, side effect tolerance, and alternative treatment options.

REWIND Trial: A Plain-English Overview of What It Established

By HealthRX Medical Team

Published May 25, 2026Updated May 25, 2026Last reviewed May 25, 2026

At a glance

| Detail | Value | |---|---| | Full title | 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 | | Median follow-up | 5.4 years | | Primary endpoint | First occurrence of 3-point MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) | | Key result | HR 0.88 (95% CI 0.79, 0.99; p = 0.026) | | Population | Adults ≥50 with T2D and either established CV disease or CV risk factors |

The Question REWIND Asked

By 2016, regulatory agencies required every new diabetes drug to prove it does not increase cardiovascular risk. Several GLP-1 receptor agonist trials had already reported results: LEADER (liraglutide) and SUSTAIN-6 (semaglutide) showed cardiovascular benefit, while ELIXA (lixisenatide) and EXSCEL (exenatide) did not. But those trials enrolled populations dominated by patients who already had established cardiovascular disease, typically 70 to 85% of participants.

REWIND asked a different question. Could a GLP-1 receptor agonist reduce heart attacks, strokes, and cardiovascular deaths in a broader group of people with type 2 diabetes, including those who had risk factors but no prior cardiovascular event? This distinction matters because most people living with type 2 diabetes fall into that lower-risk category. A trial that only proves benefit in people who have already had a heart attack leaves the majority of patients without clear evidence.

The primary publication in The Lancet reported results in June 2019.

Who Was Enrolled

REWIND recruited 9,901 participants from 371 sites across 24 countries. Eligibility required age 50 or older, type 2 diabetes with an HbA1c of 9.5% or less, and either prior cardiovascular disease or at least two additional cardiovascular risk factors (tobacco use, dyslipidemia, hypertension, or abdominal obesity).

The resulting population looked markedly different from earlier GLP-1 cardiovascular outcomes trials:

| Characteristic | REWIND | LEADER | SUSTAIN-6 | |---|---|---|---| | Prior CV disease | 31.5% | 81.3% | 83.0% | | Mean age (years) | 66.2 | 64.3 | 64.6 | | Mean HbA1c (%) | 7.3 | 8.7 | 8.7 | | Mean diabetes duration (years) | 9.5 | 12.8 | 13.9 | | Female (%) | 46.3 | 35.7 | 39.3 |

Several features stand out. Nearly 70% of REWIND participants had no history of cardiovascular events. The average HbA1c was only 7.3%, meaning most participants had reasonably controlled blood sugar at baseline. Women made up 46% of enrollment, a higher proportion than most diabetes cardiovascular trials. And median follow-up was 5.4 years, roughly twice as long as LEADER or SUSTAIN-6.

These design choices were deliberate. The investigators wanted a population that looked like the broader type 2 diabetes clinic, not just the highest-risk subset.

What Was Given

Participants received either dulaglutide 1.5 mg or matching placebo by subcutaneous injection once weekly, added to their existing diabetes medications. The dulaglutide prescribing information lists 0.75 mg and 1.5 mg as available doses. REWIND used only the higher dose.

Investigators could adjust other diabetes medications throughout the trial to maintain glycemic control, but they were asked to avoid open-label GLP-1 receptor agonists. This pragmatic design meant background therapy changed over time, which reflects real clinical practice but also means glycemic differences between groups were modest (about 0.6% HbA1c separation at the end of the trial).

What Was Measured

The primary endpoint was the first occurrence of the composite known as 3-point MACE: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. All suspected events were adjudicated by an independent committee blinded to treatment assignment.

Pre-specified secondary endpoints included each component of MACE individually, all-cause mortality, a composite microvascular outcome (retinal or renal), and HbA1c change. The trial also tracked hospitalizations for heart failure and a broad set of safety outcomes.

The REWIND Results Broken Down

Primary Composite Endpoint

The headline finding: dulaglutide reduced 3-point MACE by 12% compared to placebo.

| Outcome | Dulaglutide (n = 4,949) | Placebo (n = 4,952) | HR (95% CI) | p-value | |---|---|---|---|---| | 3-point MACE | 594 (12.0%) | 663 (13.4%) | 0.88 (0.79, 0.99) | 0.026 | | CV death | 317 (6.4%) | 346 (7.0%) | 0.91 (0.78, 1.06) | NS | | Non-fatal MI | 205 (4.1%) | 212 (4.3%) | 0.96 (0.79, 1.16) | NS | | Non-fatal stroke | 135 (2.7%) | 175 (3.5%) | 0.76 (0.61, 0.95) | 0.017 | | All-cause mortality | 536 (10.8%) | 592 (12.0%) | 0.90 (0.80, 1.01) | 0.067 |

The composite result was statistically significant. When broken into individual components, only non-fatal stroke reached significance on its own, with a 24% relative reduction. Cardiovascular death and non-fatal myocardial infarction each trended favorably but did not cross the significance threshold individually.

All-cause mortality missed statistical significance narrowly (HR 0.90, p = 0.067). The trial was not powered to detect differences in individual components, so these sub-results should be interpreted cautiously.

Subgroup Findings

A critical finding from REWIND: the cardiovascular benefit appeared consistent regardless of whether participants had prior cardiovascular disease. The primary publication reported that the hazard ratio for MACE was similar in participants with established cardiovascular disease (HR 0.87 to 95% CI 0.74, 1.02) and those without (HR 0.87 to 95% CI 0.74, 1.02). The interaction p-value was not significant, meaning there was no statistical evidence that the treatment effect differed between these groups.

This consistency across primary and secondary prevention populations is what distinguishes REWIND from earlier GLP-1 cardiovascular outcomes trials.

Microvascular and Renal Outcomes

The composite microvascular endpoint also favored dulaglutide (HR 0.87 to 95% CI 0.79, 0.95; p = 0.002), driven primarily by a reduction in new macroalbuminuria. A subsequent renal sub-analysis published in The Lancet showed that dulaglutide reduced the composite renal outcome by 15%, with the benefit coming from reduced development of macroalbuminuria rather than changes in eGFR decline or renal replacement therapy.

Weight and Glycemic Effects

HbA1c was approximately 0.6% lower in the dulaglutide group at 5 years. Body weight was about 1.5 kg lower. These differences are modest, which reinforces the interpretation that the cardiovascular benefit is not purely a consequence of better glucose control or weight loss.

Safety Profile in REWIND

Gastrointestinal side effects were the most common reason for treatment discontinuation, consistent with the GLP-1 receptor agonist class. Nausea, vomiting, and diarrhea occurred more frequently with dulaglutide than placebo, though rates were lower than in shorter trials, possibly because the 5.4-year median follow-up dilutes early gastrointestinal symptoms.

| Safety event | Dulaglutide | Placebo | |---|---|---| | Any serious adverse event | 2,347 (47.4%) | 2,405 (48.6%) | | Gastrointestinal events (total) | 2,347 (47.4%) | 1,687 (34.1%) | | Pancreatitis (adjudicated) | 23 (0.5%) | 13 (0.3%) | | Pancreatic cancer | 9 (0.2%) | 15 (0.3%) | | Medullary thyroid cancer | 0 | 0 |

There was a numerically higher rate of adjudicated pancreatitis with dulaglutide (23 vs. 13 events), though the absolute numbers were small. No cases of medullary thyroid carcinoma were reported in either group. The overall serious adverse event rate was similar between groups.

Limitations Worth Knowing

The composite endpoint effect was modest. A 12% relative risk reduction translates to an absolute risk reduction of about 1.4 percentage points over 5.4 years. The number needed to treat (NNT) to prevent one MACE event was approximately 71 over the trial duration. For individual patients, the absolute benefit is small.

Individual components did not all reach significance. Cardiovascular death and non-fatal MI did not show significant reductions on their own. The composite was largely driven by the stroke signal. Whether dulaglutide specifically protects against stroke or whether the composite result reflects a diffuse small benefit across all three components cannot be definitively determined.

The 1.5 mg dose was the only dose tested. The lower 0.75 mg dose was not studied in REWIND. Whether it provides similar cardiovascular protection is unknown.

Background therapy changed over time. As expected in a long trial, investigators adjusted medications to maintain glycemic targets. This is pragmatically appropriate but limits the ability to attribute outcomes purely to dulaglutide vs. placebo. The relatively small HbA1c separation at 5 years (0.6%) partly reflects this.

SGLT2 inhibitors were underrepresented. REWIND enrolled participants before SGLT2 inhibitor cardiovascular benefits were widely known. Only about 3% of participants used an SGLT2 inhibitor. Whether dulaglutide provides additive cardiovascular benefit on top of SGLT2 inhibitor therapy remains an open question addressed only by indirect evidence.

Where REWIND Fits in the Broader Evidence

The 2019 ADA/EASD consensus report and subsequent updates elevated GLP-1 receptor agonists with proven cardiovascular benefit (liraglutide, semaglutide, dulaglutide) to preferred second-line agents after metformin in patients with established atherosclerotic cardiovascular disease. REWIND's contribution was extending that evidence base to a primary prevention population, which broadened the clinical scenarios where guideline panels felt comfortable recommending GLP-1 receptor agonists.

The 2024 ADA Standards of Care now recommend GLP-1 receptor agonists with demonstrated cardiovascular benefit for adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors. REWIND's enrollment of a majority primary-prevention population is one reason that second category exists in current guidelines.

Compared to the SELECT trial (semaglutide 2.4 mg in obesity without diabetes), which showed a 20% MACE reduction, REWIND's 12% reduction is smaller. But the populations, doses, and drug formulations differ enough that direct comparison is misleading. REWIND tested a standard diabetes dose of a different GLP-1 receptor agonist in people with type 2 diabetes.

The Bottom Line

REWIND showed that dulaglutide 1.5 mg once weekly reduces the risk of major cardiovascular events in a broad population of adults with type 2 diabetes, including those without prior heart disease. The effect was statistically significant but modest in absolute terms. The stroke reduction was the most prominent individual finding. The trial's long follow-up, high proportion of women, and inclusion of primary prevention patients make it a unique data point in the GLP-1 cardiovascular evidence base.

For clinicians, REWIND supports using dulaglutide in patients with type 2 diabetes and cardiovascular risk factors, not only those who have already had a cardiovascular event. For patients, the practical message is that a weekly injection prescribed for blood sugar management may also provide a small but real reduction in cardiovascular risk.

Frequently asked questions

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References

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
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
Dulaglutide (Trulicity) prescribing information. Eli Lilly and Company. FDA Label
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
American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes, 2024. Diabetes Care. 2024;47(Suppl 1). PubMed