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Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial

Published on Jul 1, 2019in The Lancet59.102
· DOI :10.1016/S0140-6736(19)31149-3
Hertzel C. Gerstein93
Estimated H-index: 93
(Population Health Research Institute),
Helen M. Colhoun50
Estimated H-index: 50
(Edin.: University of Edinburgh)
+ 1453 AuthorsWilliam Zigrang2
Estimated H-index: 2
Sources
Abstract
Summary Background Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A 1c (HbA 1c ) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. Methods This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01394952 . Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA 1c 7·2% [IQR 6·6–8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). 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 (hazard ratio [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). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p Interpretation Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. Funding Eli Lilly and Company.
  • References (32)
  • Citations (52)
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References32
Newest
#1Hertzel C. Gerstein (Population Health Research Institute)H-Index: 93
#2Helen M. Colhoun (Edin.: University of Edinburgh)H-Index: 50
Last. William ZigrangH-Index: 2
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Summary Background Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. Methods REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at leas...
18 CitationsSource
Abstract Background Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium...
158 CitationsSource
#1Kristina S. Boye (Eli Lilly and Company)H-Index: 24
#2Matthew C. Riddle (OHSU: Oregon Health & Science University)H-Index: 54
Last. Mark Lakshmanan (Eli Lilly and Company)H-Index: 12
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#1Thomas A. Zelniker (Brigham and Women's Hospital)H-Index: 12
#2Stephen D. Wiviott (Brigham and Women's Hospital)H-Index: 67
Last. Marc S. Sabatine (Brigham and Women's Hospital)H-Index: 90
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Background: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose contransporter-2 inhibitors (SGLT2i) have emerged as two new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease (ASCVD) for different outcomes with these classes of drugs remain undefined. Methods: We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovas...
38 CitationsSource
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#2Moses Elisaf (UoI: University of Ioannina)H-Index: 63
Last. Haralampos J. Milionis (UoI: University of Ioannina)H-Index: 38
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#2Stephen D. Wiviott (Brigham and Women's Hospital)H-Index: 67
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Summary Background The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined. Methods We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were compl...
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Abstract Glucagon-like peptide-1 receptor (GLP-1R) agonists augment insulin secretion and are thus used clinically to improve glycemia in subjects with type 2 diabetes (T2D). As recent data reveal marked improvements in cardiovascular outcomes in T2D subjects treated with the GLP-1R agonists liraglutide and semaglutide in the LEADER and SUSTAIN-6 clinical trials respectively, there is growing interest in delineating the mechanism(s) of action for GLP-1R agonist-induced cardioprotection. Of impor...
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Patients with type 2 diabetes (T2DM) have a substantial risk of developing cardiovascular disease. The strong connection between the severity of hyperglycaemia, metabolic changes secondary to T2DM and vascular damage increases the risk of macrovascular complications. There is a challenging demand for the development of drugs that control hyperglycaemia and influence other metabolic risk factors to improve cardiovascular outcomes such as cardiovascular death, nonfatal myocardial infarction, nonfa...
9 CitationsSource
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Last. Trisha MandalH-Index: 1
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Summary Background Many antihyperglycaemic drugs, including insulin, are primarily cleared by the kidneys, restricting treatment options for patients with kidney disease. Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys, and confers a lower risk of hypoglycaemia than does insulin. We assessed the efficacy and safety of dulaglutide in patients with type 2 diabetes and moderate-to-severe chronic kidney disease. Methods AWARD-7 was a multicent...
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Patienten mit Diabetes mellitus Typ 2 haben ein deutliches erhohtes Risiko fur die Entwicklung kardiovaskularer Erkrankungen wie Myokardinfarkt, Schlaganfall oder Herzinsuffizienz. Die Ergebnisse groser kardiovaskularer Endpunktstudien mit neuen blutzuckersenkenden Substanzen wie DPP(Dipeptidylpeptidase)-4-Inhibitoren, SGLT2(„sodium-glucose linked transporter 2“) Inhibitoren und GLP(„glucagon-like peptide“)-1-Rezeptor-Agonisten haben in den letzten Jahren zu neuen evidenzbasierten Strategien der...
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25 years ago, the future of treating obesity and diabetes focused on end organs known to be involved in energy balance and glucose regulation, including the brain, muscle, adipose tissue, and pancreas. Today, the most effective therapies are focused around the gut. This includes surgical options, such as vertical sleeve gastrectomy and Roux-en-Y gastric bypass, that can produce sustained weight loss and diabetes remission but also extends to pharmacological treatments that simulate or amplify va...
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