REWIND: Once-Weekly GLP-1 Agonist Cuts CVD in Type 2 Diabetes

The once-weekly injectable glucagon-like peptide 1 (GLP-1) agonist dulaglutide (Trulicity, Lilly) for the treatment of type 2 diabetes has significantly reduced the risk of major adverse cardiovascular events (MACE) in the REWIND trial, Lilly has announced, revealing the top-line results of the study today.

REWIND is the cardiovascular (CV) outcomes trial for dulaglutide and the first such study to include a majority of patients who did not have established cardiovascular disease (CVD) at baseline, the company says in a press release.

The MACE endpoint was a composite of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke. The study compared the effect of once-weekly dulaglutide 1.5 mg, delivered subcutaneously, to placebo when added to standard of care in type 2 diabetes.

Full details of the REWIND study will be reported at the American Diabetes Association Scientific Sessions in San Francisco in 2019, the company says.

"The REWIND study was ambitious, assessing whether Trulicity could protect people with type 2 diabetes from experiencing an initial CV event and prevent future events in those who have established CVD," said REWIND study chair Hertzel Gerstein, MD, professor of medicine and deputy director of the Population Health Institute at McMaster University and Hamilton Health Sciences, Ontario, Canada.

"The MACE reduction demonstrated by Trulicity across a broad range of people with type 2 diabetes is compelling and we look forward to analyzing and reporting all of the data," he added in the press release.

A Fantastic Step Forward: Only 30% of REWIND Participants Had Prior CVD

A US Food and Drug Administration (FDA) panel recently voted to retain CV outcomes studies for new type 2 diabetes drugs as a condition of US marketing. The original 2008 FDA guidance arose out of concerns about CV harm arising from older studies of type 2 diabetes medications.

But thus far, none of the eight completed mandated CV outcomes trials have identified excess CV risk from the drugs in question, and three have actually shown benefit.

These three studies included two studies of oral sodium glucose cotransporter-2 (SGLT2) inhibitors, the EMPA-REG OUTCOMES trial with empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) and CANVAS with canagliflozin (Invokana, Janssen). In both studies, all patients had type 2 diabetes and existing CVD or were at high risk for CVD.

Likewise, in the third study, LEADER, with the injectable once-daily GLP-1 agonist liraglutide (Victoza, Novo Nordisk), all of the patients with type 2 diabetes had established CVD or chronic renal failure, or were aged 60 years and older with CVD risk factors.

In contrast, only 31% of REWIND participants had established CVD, Lilly notes.

Asked for his thoughts by Medscape Medical News, Darren McGuire, MD, a cardiologist from UT Southwestern Medical Center, Dallas, Texas, who specializes in the treatment of diabetes, said: "This is another fantastic step forward for patients with diabetes."

"Of course, will have to see the actual data to draw firm conclusions, but achieving superiority in a population dominated by high-risk primary prevention is intriguing in that benefit may extend into that population."

"This was not evident from prior trials of GLP-1 receptor agonists...And to have available a once-weekly formulation is another clear advantage here."

McGuire has participated in some of the CV outcomes trials for type 2 diabetes drugs but was not involved in the REWIND trial.

Most recently, positive top-line results with another SGLT2 inhibitor, dapagliflozin (Farxiga/Forxiga, AstraZeneca) were reported from the DECLARE-TIMI 58 study; full details of this trial are to be reported this weekend at the American Heart Association (AHA) Scientific Sessions 2018 in Chicago.

About REWIND...Results Directly Applicable to Typical T2D Patient?

REWIND (Researching Cardiovascular Events With a Weekly Incretin in Diabetes) was a multicenter, randomized, double-blind, placebo-controlled trial designed to assess the effect of dulaglutide 1.5 mg once-weekly compared with placebo, both added standard care, on CV events in adults with type 2 diabetes.

The primary CV outcome was the first occurrence of MACE (the composite of CV death or nonfatal MI or nonfatal stroke).

Secondary outcomes included each component of the primary composite CV outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization, or an urgent heart failure visit, and all-cause mortality.

The 9901 participants from 24 countries had a mean duration of diabetes of 10 years and a mean baseline HbA_1c of 7.3%.

And just under a third of participants had established CVD at baseline.

Established CVD in REWIND was defined as prior MI, ischemic stroke, unstable angina, revascularization (coronary, carotid, or peripheral), hospitalization for ischemia-related events (unstable angina or myocardial ischemia on imaging or need for percutaneous coronary intervention), or documented myocardial ischemia.

And importantly, says the company, REWIND had a median follow-up period of more than 5 years, the longest for a CV outcome trial in the GLP-1 receptor agonist class.

"The REWIND trial's international scope, high proportion of women, high proportion of people without established CVD, and inclusion of participants with a lower mean baseline HbA_1c suggest that the findings will be directly relevant to the typical type 2 diabetes patient seen in general practice throughout the world," says Lilly.

McGuire has reported providing clinical trial leadership for AstraZeneca, sanofi aventis, Janssen, Boehringer Ingelheim, Merck, Pfizer, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline, Esperion, and Akebia , and consultancy for AstraZeneca, sanofi aventis, Eli Lilly, Boehringer Ingelheim, Merck, Pfizer, Novo Nordisk, Metavant, and Applied Therapeutics.

Follow Lisa Nainggolan on Twitter: @lisanainggolan1. For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

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