Perspective

REWIND: Dulaglutide reduces CV risk in type 2 diabetes without CVD

Compared with placebo, the once-weekly GLP-1 receptor agonist dulaglutide reduced major adverse cardiovascular events in adults with type 2 diabetes with and without established cardiovascular disease, making the agent the first type 2 diabetes agent to demonstrate CV superiority in a broad type 2 diabetes population, Eli Lilly announced in a press release.

In the REWIND CV outcomes trial, dulaglutide (Trulicity) was associated with significantly reduced major adverse cardiovascular events, a composite endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke, meeting the primary efficacy objective, according to the release.

The REWIND trial is distinct from other CV outcome trials due to the limited number of people with established CV disease who participated in the trial, according to Lilly. Of the 9,901 REWIND participants, only 31% had established CVD. Additionally, 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, according to the release.

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

REWIND is a multicenter, randomized, double-blind, placebo-controlled trial designed to assess the effect of weekly dulaglutide 1.5 mg, both added to standard of care, on CV events in adults with type 2 diabetes. The primary CV outcome was the first occurrence of major adverse cardiovascular events. Secondary outcomes included each component of the primary composite CV outcome; a composite clinical microvascular outcome of retinal or renal disease; hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit; and all-cause mortality.

The cohort included 9,901 participants from 24 countries with mean diabetes duration of 10 years and mean baseline HbA1c 7.3%.

"The broad range of people with type 2 diabetes studied in REWIND, including those with and without cardiovascular disease, underscores the importance of these findings in this precedent-setting trial," Enrique Conterno, president of Lilly Diabetes and Lilly USA, said in the release. "Millions of people with type 2 diabetes face a high risk for cardiovascular disease. These data further validate Trulicity as a well-established option for people with type 2 diabetes."

The safety profile of dulaglutide in REWIND was generally consistent with the GLP-1 receptor agonist class, according to Lilly.

The findings follow positive results for dulaglutide demonstrated in the AWARD-7 clinical trial, published in July in Lancet Diabetes & Endocrinology. As Endocrine Today reported, people with type 2 diabetes and mild to moderate chronic kidney disease assigned to dulaglutide combined with insulin lispro experienced a similar reduction in HbA1c vs. similar patients assigned insulin glargine combined with insulin lispro, along with a lower rate of hypoglycemia and a slower decline in renal function.

“To our knowledge, this is the first clinical trial in patients with type 2 diabetes and moderate to severe chronic kidney disease that has shown clear effects of a GLP-1 receptor agonist to preserve eGFR,” Katherine R. Tuttle, MD, FASN, FACP, executive director for research at Providence Health Care in Spokane, Washington, and a clinical professor of medicine in the nephrology division at the University of Washington School of Medicine, told Endocrine Today in an interview at the time.

The findings also follow an Oct. 25 FDA advisory committee meeting reported by Endocrine Today that included a vote on whether to continue supporting agency-recommended CV outcomes trials to demonstrate safety for all type 2 diabetes drugs. In their 10-9 vote in favor of continuing with such trials, the members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) called for modifications to the 2008 FDA-issued guidance, including broadening the population recruited for such trials to include people without established CVD, and the inclusion of endpoints beyond three-point major adverse cardiac events.

The full findings from REWIND will be presented at the American Diabetes Association Scientific Sessions in 2019. – by Regina Schaffer

Disclosures: Conterno is president of Lilly Diabetes and Lilly USA. Gerstein reports he serves as an adviser for, receives research support from or has a financial relationship with Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi. Tuttle reports she is a consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Gilead Sciences.

Compared with placebo, the once-weekly GLP-1 receptor agonist dulaglutide reduced major adverse cardiovascular events in adults with type 2 diabetes with and without established cardiovascular disease, making the agent the first type 2 diabetes agent to demonstrate CV superiority in a broad type 2 diabetes population, Eli Lilly announced in a press release.

In the REWIND CV outcomes trial, dulaglutide (Trulicity) was associated with significantly reduced major adverse cardiovascular events, a composite endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke, meeting the primary efficacy objective, according to the release.

The REWIND trial is distinct from other CV outcome trials due to the limited number of people with established CV disease who participated in the trial, according to Lilly. Of the 9,901 REWIND participants, only 31% had established CVD. Additionally, 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, according to the release.

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

REWIND is a multicenter, randomized, double-blind, placebo-controlled trial designed to assess the effect of weekly dulaglutide 1.5 mg, both added to standard of care, on CV events in adults with type 2 diabetes. The primary CV outcome was the first occurrence of major adverse cardiovascular events. Secondary outcomes included each component of the primary composite CV outcome; a composite clinical microvascular outcome of retinal or renal disease; hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit; and all-cause mortality.

The cohort included 9,901 participants from 24 countries with mean diabetes duration of 10 years and mean baseline HbA1c 7.3%.

"The broad range of people with type 2 diabetes studied in REWIND, including those with and without cardiovascular disease, underscores the importance of these findings in this precedent-setting trial," Enrique Conterno, president of Lilly Diabetes and Lilly USA, said in the release. "Millions of people with type 2 diabetes face a high risk for cardiovascular disease. These data further validate Trulicity as a well-established option for people with type 2 diabetes."

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The safety profile of dulaglutide in REWIND was generally consistent with the GLP-1 receptor agonist class, according to Lilly.

The findings follow positive results for dulaglutide demonstrated in the AWARD-7 clinical trial, published in July in Lancet Diabetes & Endocrinology. As Endocrine Today reported, people with type 2 diabetes and mild to moderate chronic kidney disease assigned to dulaglutide combined with insulin lispro experienced a similar reduction in HbA1c vs. similar patients assigned insulin glargine combined with insulin lispro, along with a lower rate of hypoglycemia and a slower decline in renal function.

“To our knowledge, this is the first clinical trial in patients with type 2 diabetes and moderate to severe chronic kidney disease that has shown clear effects of a GLP-1 receptor agonist to preserve eGFR,” Katherine R. Tuttle, MD, FASN, FACP, executive director for research at Providence Health Care in Spokane, Washington, and a clinical professor of medicine in the nephrology division at the University of Washington School of Medicine, told Endocrine Today in an interview at the time.

The findings also follow an Oct. 25 FDA advisory committee meeting reported by Endocrine Today that included a vote on whether to continue supporting agency-recommended CV outcomes trials to demonstrate safety for all type 2 diabetes drugs. In their 10-9 vote in favor of continuing with such trials, the members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) called for modifications to the 2008 FDA-issued guidance, including broadening the population recruited for such trials to include people without established CVD, and the inclusion of endpoints beyond three-point major adverse cardiac events.

The full findings from REWIND will be presented at the American Diabetes Association Scientific Sessions in 2019. – by Regina Schaffer

Disclosures: Conterno is president of Lilly Diabetes and Lilly USA. Gerstein reports he serves as an adviser for, receives research support from or has a financial relationship with Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi. Tuttle reports she is a consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Gilead Sciences.

    Perspective
    Alan Garber

    Alan Garber

    These findings are a matter of population recruitment. The LEADER trial, for example, was conducted with very high-risk people, mostly with coronary artery disease, and mostly because they wanted to enrich the CV event rate. We don’t know, for all these other agents, whether they would be as effective in so-called primary prevention, but you have to remember, if people with diabetes have such high underlying risk for cardiovascular disease, and even if they are event-free, the likelihood of them not having disease is pretty low.

    Things are very interesting in the field overall. Early studies on glycemic control and cardiovascular disease were largely negative, but they used agents against diabetes that often resulted in hypoglycemia and weight gain as side effects, namely, insulin and sulfonylureas. Maybe, these positive study findings — and this is at best speculation — are less about the unique mechanisms of the agents and more about the avoidance of negative aspects of the older antidiabetic medications.

    • Alan Garber, MD, PhD, MACE
    • Chief Medical Editor, Endocrine Today Professor, Departments of Medicine, Biochemistry and Cell and Molecular Biology Baylor College of Medicine

    Disclosures: Garber reports he is a consultant for Intarcia and Novo Nordisk.