Once-Weekly Dulaglutide and Major Cardiovascular Events—Results of the REWIND Trial
Gilles R. Dagenais, MD
Université Laval, Québec, QC, Canada Rafael Diaz, MD
ECLA (EstudiosClínicos Latino América), Rosario, Argentina Matthew C. Riddle, MD
Oregon Health & Science University, Portland, OR, USA Hertzel C. Gerstein, MD, MSc
McMaster University & Hamilton Health Sciences, Hamilton, ON, Canada Helen Colhoun, MD
University of Edinburgh, Edinburgh, UK Jeffrey L. Probstfield, MD
University of Washington, Seattle, Washington, USA Lars Rydén, MD, PhD
Three different GLP-1 RAs have been shown to reduce CV outcomes in people with type 2 diabetes at high CV risk with elevated HbA1c levels.
The REWIND trial assessed the effect of dulaglutide on major adverse CV events when added to the existing antihyperglycemic regimens in individuals with type 2 diabetes with and without previous CV disease and a wide range of glycemic control.
Dulaglutide is a GLP-1 receptor agonist (GLP-1 RA) approved for the management of hyperglycemia in people with type 2 diabetes. The available evidence has shown that it reduces blood glucose, blood pressure, weight, and albuminuria, and may have other actions suggesting possible cardiovascular (CV) benefits. Moreover, the fact that the CV effects of other GLP-1 RAs have been tested in middle-aged people with high HbA1c levels and a 4% or higher annual risk of CV events highlights the need to test the effect of dulaglutide on CV events in people with a broader CV risk and a wider range of glycemic control.
The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial was designed to assess whether the addition of dulaglutide to the diabetes medication regimen of middle-aged and older people with type 2 diabetes safely reduces the incidence of CV outcomes vs. placebo.
The long-term effects of dulaglutide on renal outcomes were also assessed in an exploratory analysis.
Multicenter, randomized, double-blind, placebo-controlled trial at 371 sites in 24 countries.
9,901 participants at least 50 years with type 2 diabetes who had either a previous CV event or CV risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (n=4,949; 1.5 mg) or placebo (n=4,952).
Key inclusion criteria included HbA1C ≤9.5%, BMI >23 kg/m2, and age-related criteria (age ≥50 and vascular disease, age ≥55 and subclinical vascular disease, age ≥ 60 and 2 CV risk factors).
The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction (MI), non-fatal stroke, or death from CV causes (including unknown causes).
The renal component of the composite microvascular outcome was defined as the first occurrence of new macroalbuminuria (UACR (urine albumin/creatinine ratio) >33.9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy.
During a median follow-up of 5.4 years (IQR 5.1–5.9), the primary composite outcome occurred in 594 (12.0%) participants at an incidence rate of 2.4 per 100 person-years in the dulaglutide group and in 663 (13.4%) participants at an incidence rate of 2.7 per 100 person-years in the placebo group (HR 0.88, 95% CI 0.79–0.99; P=0.026).
All-cause mortality did not differ between groups (536 (10.8%) in the dulaglutide group vs. 592 (12.0%) in the placebo group; HR 0.90, 95% CI 0.80–1.01; P=0.067) (Figure).
2,347 (47.4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1,687 (34.1%) participants assigned to placebo (P <0.0001).
Exploratory renal analyses
At baseline, 791 (7.9%) had macroalbuminuria and mean eGFR was 76.9 mL/min/1.73 m² (SD 22.7).
During a median follow-up of 5.4 years (IQR 5.1–5.9) comprising 51,820 person-years, the renal outcome developed in 848 (17.1%) participants at an incidence rate of 3.5 per 100 person-years in the dulaglutide group and in 970 (19.6%) participants at an incidence rate of 4.1 per 100 person-years in the placebo group (HR 0.85, 95% CI 0.77–0.93; p=0.0004).
The clearest effect was for new macroalbuminuria (HR 0.77, 95% CI 0.68–0.87; P <0.0001), with HRs of 0.89 (0.78–1.01; P=0.066) for sustained decline in eGFR of 30% or more and 0.75 (0.39–1.44; P=0.39) for chronic renal replacement therapy.
This long-duration randomized controlled trial of people with type 2 diabetes and only a 31.5% prevalence of previous CV disease showed that dulaglutide reduced the risk of CV outcomes compared with placebo.
Long-term use of dulaglutide was associated with reduced composite renal outcomes in patients with type 2 diabetes.
Key Messages/Clinical Perspectives
The addition of dulaglutide might be considered for both primary and secondary CV prevention in middle-aged patients with type 2 diabetes and CV risk factors.
Future large prospective trials of the effects of dulaglutide on prespecified renal outcomes should be performed to better understand its effects on renal function in patients with preserved and reduced baseline renal function.
Present disclosure: G.R. Dagenais, R. Diaz: the presenters has reported that no relationships exist relevant to the contents of this presentation. M.C. Riddle: Consultant; Self; ADOCIA, DalCor Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline plc., Theracos, Inc.. Research Support; Self; AstraZeneca. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Sanofi. H. Colhoun: Advisory Panel; Self; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Sanofi-Aventis. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. J.L. Probstfield: Other Relationship; Self; Bayer US, Eli Lilly and Company. L. Rydén: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; Bayer AG. Other Relationship; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S.
Jose C. Florez, MD, PhD
Chair, ADA Scientific Sessions Meeting Planning Committee
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