Did REWIND prove dulaglutide prevents heart attacks?

Not on its own. The nonfatal MI component showed a non-significant HR of 0.96. The composite MACE reduction was driven primarily by a 24% reduction in nonfatal stroke. Dulaglutide reduced cardiovascular events as a group, but the MI-specific evidence from REWIND alone is not definitive.

Is REWIND relevant to patients without diabetes?

No. All REWIND participants had type 2 diabetes. For cardiovascular risk reduction in patients without diabetes, the SELECT trial of semaglutide 2.4 mg is the relevant dataset, though that trial required obesity and established cardiovascular disease.

Why did REWIND take longer than other GLP-1 cardiovascular trials?

Because the enrolled population had lower baseline cardiovascular risk. Fewer events per year means more time needed to accumulate enough events for statistical power. Median follow-up was 5.4 years compared to 3.8 years for LEADER and 2.1 years for SUSTAIN-6.

Does REWIND mean dulaglutide is better than liraglutide for the heart?

No. The composite MACE hazard ratios were nearly identical (REWIND HR 0.88 vs LEADER HR 0.87). The populations differed substantially, making direct comparison inappropriate. Liraglutide showed a stronger cardiovascular death signal; dulaglutide showed a stronger stroke signal.

What dose of dulaglutide was used in REWIND?

Only the 1.5 mg once-weekly dose was tested. Higher doses (3.0 mg, 4.5 mg) now available for glycemic control were not studied for cardiovascular outcomes. Whether dose escalation affects cardiovascular risk is unknown.

Did REWIND change the FDA label for Trulicity?

Yes. In 2020, the FDA updated the Trulicity label to include a cardiovascular risk reduction indication covering both patients with established cardiovascular disease and those with multiple cardiovascular risk factors, reflecting REWIND's primary prevention cohort.

Were women adequately represented in REWIND?

Better than in most CVOTs. Women comprised 46.3% of REWIND participants, compared to roughly 23% in LEADER and 39% in SUSTAIN-6. No significant sex-based interaction was detected for the primary endpoint.

Does REWIND support using dulaglutide purely for weight loss?

No. REWIND was a cardiovascular outcomes trial in type 2 diabetes. Mean weight loss was modest (approximately 1.5 kg difference vs placebo at the end of the trial). For weight management, higher-dose semaglutide or tirzepatide have stronger evidence.

How does REWIND compare to SGLT2 inhibitor cardiovascular trials?

SGLT2 inhibitor trials like EMPA-REG OUTCOME and CANVAS showed cardiovascular benefit driven more by heart failure hospitalization reductions and renal protection. REWIND's benefit was atherosclerotic (stroke reduction). The mechanisms are complementary, and current guidelines support combining both classes in appropriate patients.

What REWIND Actually Changes in Clinical Practice

Q: Should all patients with type 2 diabetes now be on a GLP-1 receptor agonist?

Guidelines do not recommend universal GLP-1 RA use. The recommendation applies to patients with established cardiovascular disease or multiple cardiovascular risk factors. Cost, insurance coverage, injection tolerance, and individual risk profiles still drive the decision.

By HealthRX Medical Team

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

At a glance

Trial name: REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes)
N: 9,901 participants across 24 countries
Intervention: Dulaglutide 1.5 mg subcutaneous injection once weekly
Comparator: Matched placebo
Median follow-up: 5.4 years
Primary endpoint: First occurrence of 3-point MACE (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke)
Key result: HR 0.88 (95% CI 0.79, 0.99; p = 0.026), a 12% relative risk reduction

Why REWIND Was Different Before a Single Pill Was Swallowed

Earlier GLP-1 receptor agonist cardiovascular outcomes trials (CVOTs), including LEADER (liraglutide) and SUSTAIN-6 (semaglutide), enrolled populations dominated by patients who already had atherosclerotic cardiovascular disease. REWIND deliberately cast a wider net. Eligibility required type 2 diabetes with either established cardiovascular disease or cardiovascular risk factors such as hypertension, dyslipidemia, smoking, or albuminuria. The result: only 31.5% of enrolled participants had prior cardiovascular events.

That enrollment strategy changed the clinical question from "does this drug help sick patients stay alive longer?" to "does this drug prevent events in patients who haven't had one yet?"

Other design features that set REWIND apart:

Mean age 66.2 years, roughly 3 to 5 years older than LEADER or SUSTAIN-6 populations.
46.3% women, far exceeding the 20 to 35% female representation typical of prior GLP-1 CVOTs.
Median baseline HbA1c of 7.3%, meaning participants had relatively well-controlled glucose at entry. This was not a trial of people in glycemic crisis.
Median follow-up of 5.4 years, the longest of any completed GLP-1 receptor agonist CVOT at publication.

These four features, lower risk, older age, more women, longer observation, make REWIND's positive result harder to dismiss as driven by a single high-risk subgroup.

The Primary Endpoint Result in Context

The 12% reduction in 3-point MACE (HR 0.88 to 95% CI 0.79, 0.99) reached statistical significance with a p-value of 0.026. The individual components broke down as follows:

HealthRX MACE Component Breakdown: REWIND vs Prior GLP-1 CVOTs

| Component | REWIND HR (95% CI) | LEADER HR (95% CI) | SUSTAIN-6 HR (95% CI) | |---|---|---|---| | Cardiovascular death | 0.91 (0.78, 1.06) | 0.78 (0.66, 0.93) | 0.98 (0.65, 1.48) | | Nonfatal MI | 0.96 (0.79, 1.16) | 0.88 (0.75, 1.03) | 0.74 (0.51, 1.08) | | Nonfatal stroke | 0.76 (0.61, 0.95) | 0.89 (0.72, 1.11) | 0.61 (0.38, 0.99) | | Composite MACE | 0.88 (0.79, 0.99) | 0.87 (0.78, 0.97) | 0.74 (0.58, 0.95) |

Two patterns stand out. First, REWIND's composite result was driven primarily by stroke reduction (HR 0.76), not cardiovascular death. This differs from LEADER, where cardiovascular mortality drove the composite. Second, the individual component point estimates for cardiovascular death and nonfatal MI in REWIND did not reach significance on their own. The composite held because stroke reduction was strong enough to carry it.

Clinically this means dulaglutide's cardiovascular story is more about atherothrombotic event prevention than about mortality reduction, at least within the 5.4-year observation window.

The Primary Prevention Subgroup: The Finding That Changed Guidelines

A prespecified subgroup analysis compared participants with prior cardiovascular disease (n = 3,114) against those without (n = 6,787). The interaction p-value was 0.97, meaning the treatment effect did not differ between the two groups. The hazard ratio in the primary prevention subgroup was 0.87 (95% CI 0.74, 1.02), and in the secondary prevention subgroup it was 0.87 (95% CI 0.74, 1.02).

Neither subgroup reached individual significance, but the consistency of effect across both groups, combined with the non-significant interaction test, was enough for major guideline bodies to act.

What the Guidelines Actually Said

The 2022 ADA Standards of Care expanded the recommendation for GLP-1 receptor agonists with proven cardiovascular benefit beyond patients with established atherosclerotic cardiovascular disease. The updated language recommended considering these agents for patients with "indicators of high cardiovascular risk," explicitly citing REWIND as supporting evidence.

The 2023 ESC Guidelines for managing cardiovascular disease in patients with diabetes gave a Class I recommendation for GLP-1 receptor agonists in T2D patients with atherosclerotic cardiovascular disease and extended a Class IIa recommendation for patients with T2D and multiple risk factors but no established cardiovascular disease.

Before REWIND, these recommendations applied only to secondary prevention. REWIND was the key trial that expanded the indication upstream.

What the FDA Label Does and Does Not Say

The Trulicity (dulaglutide) prescribing information was updated in 2020 to include a cardiovascular risk reduction indication: "to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors."

That phrase, "or multiple cardiovascular risk factors," is the REWIND-derived expansion. Liraglutide's label, by contrast, is restricted to "established cardiovascular disease." The FDA's willingness to include primary prevention language for dulaglutide but not for liraglutide reflects a regulatory judgment that REWIND's enrollment design provided sufficient evidence for the broader population.

This does not mean dulaglutide has stronger cardiovascular data than liraglutide. LEADER's composite MACE result (HR 0.87) was nearly identical to REWIND's. The difference is trial design: LEADER enrolled a higher-risk population, so its label reflects that population.

Limitations That Matter for Practice

Event-driven power in a lower-risk cohort. REWIND needed 5.4 years to accumulate enough events for significance, compared to roughly 3.8 years for LEADER. Longer trials introduce more confounders: background therapy changes, new drug introductions, crossover effects. The investigators reported that HbA1c separation between groups narrowed over time as standard-of-care intensified in the placebo arm.

Single dose tested. REWIND used only dulaglutide 1.5 mg weekly. The 3.0 mg and 4.5 mg doses now available for glycemic control were not tested. Whether higher doses would produce a stronger cardiovascular signal is unknown, though the relationship between GLP-1 receptor agonist dose and cardiovascular benefit remains unclear across the class.

Stroke drove the composite. The cardiovascular death and nonfatal MI components did not individually reach significance. For a patient whose primary concern is mortality risk, the data supporting liraglutide remain stronger.

Background statin and antihypertensive use was high. Approximately 66% of REWIND participants were on statins and 82% on antihypertensives at baseline. The incremental benefit of dulaglutide was therefore on top of already optimized risk factor management. In patients with poorly managed lipids or blood pressure, fixing those first may yield larger absolute risk reductions.

HbA1c was well controlled at baseline. Participants entered with a median HbA1c of 7.3%. Patients with much higher baseline HbA1c may experience different cardiovascular effect magnitudes, though no significant interaction by baseline HbA1c was detected.

What This Means for Prescribing Decisions Today

Three practical shifts flow from REWIND.

First, GLP-1 receptor agonists are no longer a second-line afterthought reserved for patients who have already had a heart attack. For patients with T2D and multiple cardiovascular risk factors (age over 55, hypertension, dyslipidemia, smoking, albuminuria), the ADA and ESC guidelines now support early use of agents with proven cardiovascular benefit. Dulaglutide's label explicitly covers this group.

Second, REWIND supports prioritizing GLP-1 receptor agonists over DPP-4 inhibitors or sulfonylureas in patients at cardiovascular risk. The CAROLINA trial showed that the DPP-4 inhibitor linagliptin was non-inferior to glimepiride for MACE but demonstrated no cardiovascular benefit. For patients who need an add-on to metformin and have cardiovascular risk factors, the REWIND data provide a reason to choose dulaglutide (or another GLP-1 RA with CVOT evidence) over a neutral alternative.

Third, REWIND does not resolve the GLP-1 RA head-to-head question. Semaglutide's SELECT trial later showed a 20% MACE reduction in patients with obesity and cardiovascular disease but without diabetes. REWIND studied a different population (T2D required, lower cardiovascular risk, no obesity requirement). Choosing between dulaglutide and semaglutide for a given patient requires weighing cost, insurance coverage, dosing convenience, and weight loss goals rather than cross-trial MACE comparisons.

Secondary Outcomes Worth Noting

REWIND also reported a significant reduction in the composite microvascular outcome (HR 0.87 to 95% CI 0.79, 0.95), driven primarily by a reduction in new macroalbuminuria. This renal signal is consistent with findings from AWARD-7 and from the AMPLITUDE-O trial of efpeglenatide, suggesting a class-wide renal protective effect for GLP-1 receptor agonists.

All-cause mortality showed a non-significant trend favoring dulaglutide (HR 0.90 to 95% CI 0.80, 1.01, p = 0.067). This near-miss is worth acknowledging: with 5.4 years of follow-up and over 9,900 participants, the trial was not powered for all-cause mortality as a standalone endpoint.

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
Trulicity (dulaglutide) prescribing information. Eli Lilly and Company. Revised 2020. FDA Label
American Diabetes Association Professional Practice Committee. Standards of Medical Care in Diabetes, 2022. Diabetes Care. 2022;45(Suppl 1). PubMed
Marx N, Federici M, Schütt K, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023;44(39):4043-4140. PubMed
Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019;139(17):2022-2031. PubMed
Gerstein HC, Sattar N, Engberg S, 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