Articles

Dulaglutide and cardiovascular outcomes in type 2 diabetes

(REWIND): a double-blind, randomised placebo-controlled
trial
Hertzel C Gerstein, Helen M Colhoun, Gilles R Dagenais, Rafael Diaz, Mark Lakshmanan, Prem Pais, Jeffrey Probstfield, Jeffrey S Riesmeyer,
Matthew C Riddle, Lars Rydén, Denis Xavier, Charles Messan Atisso, Leanne Dyal, Stephanie Hall, Purnima Rao-Melacini, Gloria Wong,
Alvaro Avezum, Jan Basile, Namsik Chung, Ignacio Conget, William C Cushman, Edward Franek, Nicolae Hancu, Markolf Hanefeld, Shaun Holt,
Petr Jansky, Matyas Keltai, Fernando Lanas, Lawrence A Leiter, Patricio Lopez-Jaramillo, Ernesto German Cardona Munoz, Valdis Pirags,
Nana Pogosova, Peter J Raubenheimer, Jonathan E Shaw, Wayne H-H Sheu, Theodora Temelkova-Kurktschiev, for the REWIND Investigators*

Summary
Background Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in Lancet 2019; 394: 121–30
people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. Published Online
We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added June 10, 2019
http://dx.doi.org/10.1016/
to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous
S0140-6736(19)31149-3
cardiovascular disease and a wide range of glycaemic control.
See Comment page 95
*Investigators listed in the
Methods This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men appendix
and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular
Population Health Research
risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Institute, McMaster University
Randomisation was done by a computer-generated random code with stratification by site. All investigators and and Hamilton Health Sciences,
participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident Hamilton, ON, Canada
(Prof H C Gerstein MD,
cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite L Dyal MSc, S Hall BA,
endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown P Rao-Melacini MSc,
causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, G Wong BSc); University of
number NCT01394952. Edinburgh, Edinburgh, UK
(Prof H M Colhoun MD); Institut
Universitaire de Cardiologie et
Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c Pneumologie, Université Laval,
7·2% [IQR 6·6–8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or Québec City, QC, Canada
placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred (Prof G R Dagenais MD); ECLA,
Estudios Clínicos
in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in Latinoamérica, Rosario,
663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, Argentina (R Diaz MD); Eli Lilly
95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group and Company, Indianapolis, IN,
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 USA (M Lakshmanan MD,
J S Riesmeyer, C M Atisso PhD);
dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants St John’s Research Institute,
assigned to placebo (p<0·0001). Bangalore, India (Prof P Pais MD,
Prof D Xavier MD); Department
Interpretation Dulaglutide could be considered for the management of glycaemic control in middle-aged and older of Medicine, University of
Washington, Seattle, WA, USA
people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. (Prof J Probstfield MD);
Department of Medicine,
Funding Eli Lilly and Company. Oregon Health & Science
University Portland, OR, USA
(Prof M C Riddle MD);
Copyright © 2019 Elsevier Ltd. All rights reserved. Department of Medicine K2,
Karolinska Institutet,
Introduction co-transporter-2 (SGLT2) inhibitors9,10 reduce cardio­ ­ Stockholm, Sweden
(Prof L Rydén MD); Instituto
Despite the widespread use of many proven cardio­ vascular events in middle-aged and older (≥50 years)
Dante Pazzanese de Cardiologia
protective therapies and a concomitant fall in risk of people with type 2 diabetes and mean glycated haemo­ and University Santo Amaro,
cardiovascular events1 during the past 20 years, diabetes globin A1c (HbA1c) concentrations of 8·0% or more has São Paulo, Brazil
continues to increase the risk of death and cardiovascular changed clinical practice guidelines11,12 and fuelled debate (Prof A Avezum MD); Medical
University of South Carolina,
events by 1·5–2 times.2,3 Although reasons for this higher regarding mechanisms linking diabetes to cardiovascular
Charleston, SC, USA
incidence are debated, the importance of knowing disease. (Prof J Basile MD); Yonsei
whether glucose-lowering drugs alter these outcomes Dulaglutide is a GLP-1 receptor agonist approved University Health System,
has justified many large cardiovascular trials in this for the management of hyperglycaemia in people Seoul, South Korea
(Prof N Chung MD);
population.4 Evidence that three glucagon-like peptide-1 with type 2 diabetes in many countries. It comprises
Endocrinology and Nutrition
(GLP-1) receptor agonists5–8 and three sodium-glucose two modi­fied human GLP-1 molecules covalently linked

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Department, Hospital Clínic i

Universitari, Barcelona, Spain Research in context
(I Conget MD); Memphis
Veterans Affairs Medical Center, Evidence before this study myocardial infarction or stroke, or death from cardiovascular
Memphis, TN, USA We searched PubMed for reports published in English between causes were LEADER (HR 0·87, 95% CI 0·78–0·97), SUSTAIN-6
(W C Cushman MD); Jan 1, 2010, and March 31, 2019, of double-blind, randomised, (HR 0·74, 0·58–0·95), and Harmony Outcomes (HR 0·78,
Mossakowski Medical Research
Centre, Polish Academy of
placebo-controlled trials that were designed to test the effect of 0·68–0·90). These five trials suggested that GLP-1 receptor
Sciences and Central Clinical glucagon-like peptide-1 (GLP-1) receptor agonists on incident agonists might only reduce cardiovascular outcomes in people
Hospital MSWiA, Warsaw, cardiovascular events in people with type 2 diabetes. with previous cardiovascular disease. They also were unable to
Poland (Prof E Franek MD); Iuliu Search terms were “type 2 diabetes”, “GLP1-RA”, “glucagon-like determine the cardiovascular effects of GLP-1 receptor agonists
Hatieganu University of
Medicine and Pharmacy,
peptide receptor 1 agonist”, “glucagon-like peptide receptor 1 across a wide range of glycaemic control.
Cluj Napoca, Romania analogue”, “lixisenatide”, “liraglutide”, “semaglutide”,
Added value of this study
(Prof N Hancu MD); Department “taspoglutide”, “albiglutide”, “dulaglutide”, “cardiovascular
of Internal Medicine, Dresden The REWIND trial of 9901 people had a long median follow-up
disease”, and “randomized controlled trial”. This search
Technical University, Dresden, period of 5·4 years, recruited a low proportion of people (31·5%)
Germany (Prof M Hanefeld PhD); identified five trials that assessed the effects of lixisenatide
with previous cardiovascular disease, a high proportion of
Victoria University of (ELIXA; n=6068), albiglutide (Harmony Outcomes; n=9463),
women (46·3%), and followed people with a mean HbA1c of 7·3%.
Wellington, Wellington, liraglutide (LEADER; n=9340), semaglutide (SUSTAIN-6;
New Zealand Findings showed that weekly injections of the GLP-1 receptor
n=3297), or long-acting exenatide (EXSCEL; n=14 752) versus
(S Holt MBChB [Hons]); agonist dulaglutide reduced cardiovascular outcomes in both
University Hospital Motol, placebo on incident cardiovascular outcomes in people with
men and women with or without previous cardiovascular disease,
Prague, Czech Republic type 2 diabetes whose mean age ranged from 54 years to
and had an effect size similar to that observed in the other GLP-1
(P Jansky MD); Semmelweis 64 years and mean glycated haemoglobin A1c (HbA1c) ranged
University, Hungarian Institute receptor agonist cardiovascular outcomes trials.
from 7·7% to 8·8%. The trials were done in people with previous
of Cardiology, Budapest,
Hungary (Prof M Keltai MD); cardiovascular disease (ELIXA and Harmony Outcomes), or with Implications of all the available evidence
Universidad de La Frontera, a prevalence of cardiovascular disease ranging from 73% to 83% GLP-1 receptor agonists that have been shown to reduce
Temuco, Chile (Prof F Lanas PhD); (LEADER, SUSTAIN-6, and EXSCEL). Median follow-up cardiovascular outcomes should be considered for the
Li Ka Shing Knowledge
durations ranged from 1·6 years to 3·8 years. Trials that management of glycaemic control in people with type 2 diabetes
Institute, St Michael’s Hospital,
University of Toronto, Toronto, reported a reduced hazard ratio (HR) for the primary composite with either previous cardiovascular disease or cardiovascular
ON, Canada (Prof L A Leiter MD); cardiovascular outcome of the first occurrence of non-fatal risk factors.
Research Institute, FOSCAL and
Medical School, Universidad
de Santander UDES,
Bucaramanga, Colombia
to an IgG4 heavy chain molecule, has a half-life of detected type 2 diabetes whose HbA1c was 9·5% or less
(Prof P Lopez-Jaramillo PhD); 5 days, and is administered subcutaneously at weekly (with no lower limit) on stable doses of up to two oral
Universidad de Guadalajara doses of 0·75 mg or 1·5 mg.13 Evidence that it safely glucose-lowering drugs with or without basal insulin
Centro Universitario de Ciencias reduces glucose con­centration, blood pressure, weight,14 therapy were eligible if their body-mass index (BMI) was
de la Salud, Guadalajara, Mexico
(E G Cardona Munoz MD);
and albuminuria,15 and has other actions suggesting at least 23 kg/m². Additionally, patients aged 50 years or
Latvijas Universitate, Riga, possible cardiovascular benefits16 supported its testing older had to have vascular disease (ie, a previous myo­
Latvia (Prof V Pirags MD); in a large cardiovascular superiority trial. Moreover, the cardial infarction, ischaemic stroke, revascularisation,
National Medical Research fact that the cardiovascular effects of other GLP-1 hospital admission for unstable angina, or imaging
Center of Cardiology, Moscow,
Russia (Prof N Pogosova MD);
receptor agonists were being tested in middle-aged evidence of myocardial ischaemia); those aged 55 years
University of Cape Town, people with high HbA1c concentrations and a 4% or or older had to have myocardial ischaemia, coronary,
Cape Town, South Africa higher annual risk of cardiovascular events highlighted carotid, or lower extremity artery stenosis exceeding
(P J Raubenheimer MBBCh); the need to test the effect of dulaglutide on cardiovas­ 50%, left ventricular hypertrophy, estimated glomerular
Baker Heart and Diabetes
Institute, Melbourne, VIC,
cular events in people with a broader cardio­vascular risk filtration rate (eGFR) less than 60 mL/min per 1·73 m²,
Australia (Prof J E Shaw MD); and a wider range of glycaemic control. Thus, the or albuminuria; and those aged 60 years or older had to
Taichung Veterans General Researching Cardiovascular Events with a Weekly have at least two of tobacco use, dys­lipidaemia, hyper­
Hospital, Taichung, Taiwan Incretin in Diabetes (REWIND) trial was designed to tension, or abdominal obesity. Key exclusion criteria
(Prof W H-H Sheu MD);
and Robert Koch Medical
assess whether the addition of dulaglutide to the were an eGFR18 less than 15 mL/min per 1·73 m²,
Centre, Sofia, Bulgaria (Prof diabetes medication regimen of middle-aged and older cancer in the previous 5 years, severe hypoglycaemia in
T Temelkova-Kurktschiev PhD) people with type 2 diabetes safely reduces the incidence the previous year, life expectancy less than 1 year, a
Correspondence to: of cardiovascular outcomes compared with placebo. coronary or cerebrovascular event within the previous
Prof Hertzel C Gerstein, 2 months, and plans for revas­cularisation. A complete
Population Health Research
Institute, McMaster University
Methods list of trial inclusion and exclusion criteria is given in the
and Hamilton Health Sciences, Study design and participants appendix (pp 151–55). The REWIND protocol was
Hamilton, ON, L8S 4K1, Canada REWIND was a multicentre, randomised, double-blind, approved by research ethics boards for all sites and all
gerstein@mcmaster.ca placebo-controlled trial done at 371 sites in 24 countries. participants provided written informed consent. The trial
See Online for appendix Details of the study design and baseline characteristics was carefully monitored by members of an independent
of participants have been published previously.17 Men data monitoring committee who reviewed accruing and
and women (aged ≥50 years) with established or newly unblinded data every 6 months.

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The study consisted of two phases: a run-in period seven secondary outcomes were a composite clinical micro­
and a treatment period. During the 3-week single-blind vascular outcome comprising diabetic retinopathy (defined
placebo run-in period, all patients received placebo and as photocoagulation, anti-vascular endothelial growth
were instructed on how to inject study drug. Patients factor therapy, or vitrectomy) or renal disease (defined
were instructed to remain on their anti­hyperglycaemic as development of a urinary albumin-to-creatinine ratio
therapy with the exception of patients taking a dipeptidyl >33·9 mg/mmol in those with a lower baseline con­
peptidase-4 (DPP-4) inhibitor or GLP-1 receptor agonist at centration, a sustained 30% or greater decline in eGFR
screening, who discontinued these therapies at the start [ie, based on two con­secutive eGFR concen­trations], or
of the run-in period. chronic renal replacement therapy); hospital admission for
unstable angina; each component of the primary composite
Randomisation and masking cardio­vas­cular outcome; death; and heart failure requiring
Participants who were 100% adherent to weekly placebo either hospital admission or an urgent visit requiring
injections during the single-blind run-in period and therapy. Potential cardiovascular outcomes, all deaths, and
who still met eligibility criteria were randomly assigned pancreatic and thyroid safety outcomes were adjudicated by
to weekly subcutaneous injections of either masked an independent clinical endpoint committee that was
dulaglutide 1·5 mg or the same volume of masked placebo masked to treatment assignment. Criteria for adjudication
(containing the same excipients but without dulaglutide) of clinical events are listed in the appendix (pp 12–27).
using a preloaded syringe. Syringes containing dulaglutide
and placebo were identical in appearance. Randomisation
was done by a com­ puter-generated random code with 12 133 patients screened
an interactive web response system with stratification by
site. All investigators and participants were masked to
1216 excluded
treatment allocation. The independent data monitoring 974 ineligible
committee and the statisticians supporting the com­ 186 withdrew consent
49 physician decision
mittee’s activities were the only people with access to 6 sponsor decision
unblinded data. 1 adverse event

Procedures
10 917 entered run-in period
During the treatment period, participants in both groups
were instructed to inject study drug on the same day at
approximately the same time, each week. Participants
1016 excluded
were seen at 2 weeks, 3 months, and 6 months and then 566 ineligible
every 3 months for drug dispensing and every 6 months 376 withdrew consent
for detailed assessments until 1200 confirmed primary 54 physician decision
11 sponsor decision
outcomes had accrued. Assessments included cardio­ 9 adverse event
vascular events, adverse events, vital signs, and periodic
questionnaires, laboratory tests, and electrocardiograms
9901 randomly assigned
(ECGs). Investigators were advised to promote a healthy
lifestyle and to manage glucose concentrations according
to local guidelines and were free to add any glucose-
lowering drug apart from another GLP-1 receptor ago­ 4949 assigned to dulaglutide 4952 assigned to placebo
nist or pramlintide. Management of blood pressure,
lipids, other cardiovascular risk factors, and medical
conditions was at the discretion of either the study 4932 final status known 4935 final status known
17 final status unknown 17 final status unknown
investigator or the patient’s usual physician(s) as 5 lost to follow-up 2 physician decision
informed by current country guidelines. Unless consent 5 participant decision 10 participant decision
7 sponsor decision 5 sponsor decision
was explicitly withdrawn, all randomly assigned par­
ticipants were followed up until the end of the trial,
irrespective of adherence to study medication. Those 4817 final visit, primary outcome, 4793 final visit, primary outcome,
or non-cardiovascular death or non-cardiovascular death
who stopped study medication were encouraged to 132 no final visit and no primary 159 no final visit and no primary
restart it unless there was a clear contraindication. outcome or death outcome or death
115 vital status known 142 vital status known
17 vital status unknown 17 vital status unknown
Outcomes
The primary endpoint was the first occurrence of any
component of the composite outcome, which comprised 4949 analysed 4952 analysed
non-fatal myocardial infarction, non-fatal stroke, and
death from cardiovascular causes or unknown causes. The Figure 1: Trial profile

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Prespecified and all other adverse events were reported C-cell hyperplasia; serious hepatic, gastrointestinal,
by investigators on case report forms. They included renal, or urinary events; immune reactions; supra­
study drug discontinuation; acute pancreatitis; cancer; ventricular tachycardia; conduction disorders; or severe
hypoglycaemia.

Dulaglutide (n=4949) Placebo (n=4952) Statistical analysis

Age (years) 66·2 (6·5) 66·2 (6·5) Assuming a primary outcome rate of 2% per year in the
Sex placebo group, a two-sided significance level of 5%, a
Female 2306 (46·6%) 2283 (46·1%) 3-year recruitment period, and an annual dropout rate of
Male 2643 (53·4%) 2669 (53·9%) 0·15%, follow-up of at least 9600 people for a maximum
Race of 8 years, and accrual of 1200 unique primary outcomes
White 3754 (75·9%) 3744 (75·6%) was estimated to provide at least 90% power to detect
Current tobacco use 694 (14·0%) 713 (14·4%) a hazard ratio (HR) of 0·82 or lower for the primary
Cardiovascular disease* 1560 (31·5%) 1554 (31·4%) outcome and 80% power to detect an HR of 0·85 or
Cardiovascular event† 1028 (20·8%) 1007 (20·3%) lower. The independent data monitoring committee did a
Hypertension 4605 (93·0%) 4619 (93·3%) formal interim analysis for superiority after 756 unique
Previous heart failure 421 (8·5%) 432 (8·7%) primary outcomes had occurred, after which continuation
Diabetes of the trial was recommended.
Duration of diabetes (years)‡ 10·5 (7·3); 9·5 (5·5–14·5) 10·6 (7·2); 9·5 (5·5–14·5) All efficacy and safety analyses were done according
Diabetic retinopathy 448 (9·1%) 443 (8·9%)
to an intention-to-treat approach that included all ran­
HbA1c (%)‡ 7·3% (1·1); 7·2% (6·6–8·1) 7·4% (1·1); 7·2% (6·6–8·1)
domly assigned participants irrespective of adherence, as
eGFR <60 mL/min per 1·73 m² 1081 (21·8%) 1118 (22·6%)
described in the protocol and prespecified statistical
Albuminuria§ 1707 (34·5%) 1760 (35·5%)
analysis plan (appendix pp 42–319). Participants were
censored at the time of the last known follow-up date.
Antidiabetic medications
Continuous data were summarised as either means
Metformin 4022 (81·3%) 4015 (81·1%)
and SDs or medians and IQRs, and count data were
Sulfonylurea 2270 (45·9%) 2282 (46·1%)
summarised as numbers and percentages.
Insulin 1189 (24·0%) 1174 (23·7%)
All outcomes occurring on or after randomisation were
DPP-4 inhibitor 266 (5·4%) 298 (6·0%)
included in the analysis. Incidence rates were estimated
Thiazolidinedione 100 (2·0%) 68 (1·4%)
as the number of first events per 100 person-years of
Other glucose-lowering drugs 14 (0·3%) 18 (0·4%)
outcome-specific follow-up (ie, time from randomisation
Cardiovascular
until either the first occurrence of the outcome or the
Body-mass index (kg/m²) 32·3 (5·7) 32·3 (5·8)
last follow-up with no outcome). Kaplan-Meier estimates
Systolic blood pressure (mm Hg) 137·1 (16·6) 137·3 (17·0)
were used to generate cumulative risks and Cox propor­
Diastolic blood pressure (mm Hg) 78·4 (9.8) 78·5 (9.9) tional hazards models were used to determine the effect
Heart rate (beats per min) 71·4 (10·7) 71·6 (11·0) of the intervention on the outcome and to estimate HRs
Serum creatinine (µmol/L) 83·7 (27·4) 84·5 (27·3) and 95% CIs. The assumptions of the Cox models were
eGFR (mL/min per 1·73 m²) 75·3 (61·6–91·8) 74·7 (61·2–90·6) verified by plotting the log of negative log of the survival
UACR (mg/mmol) 1·80 (0·70–6·60) 1·88 (0·70–7·38) function against the log of time, and consistency of the
Cholesterol (mmol/L) 4·52 (1·16) 4·52 (1·16) effect across the three components of the composite
LDL cholesterol (mmol/L) 2·56 (0·98) 2·56 (0·98) outcome was assessed by a composite treatment hetero­
HDL cholesterol (mmol/L) 1·18 (0·33) 1·18 (0·36) geneity test.19 All reported p values are two-sided. To
Triglycerides (mmol/L) 1·60 (1·15–2·20) 1·60 (1·20–2·25) account for the significance level of 0·009 used for the
Cardiovascular medications interim analysis and maintain an overall type I error
ACE inhibitor or ARB 4009 (81·0%) 4059 (82·0%) of 0·05, the final adjusted p value for declaring superiority
β blocker 2237 (45·2%) 2274 (45·9%) for the primary outcome was 0·0467.20 To address multi­
Other blood pressure drug 2767 (55·9%) 2833 (57·2%) plicity related to testing the effect of allocation on the
Statin 3279 (66·3%) 3268 (66·0%) secondary outcomes, a predetermined, graphical approach
Fibrate 452 (9·1%) 446 (9·0%) for multiple comparisons was used to strongly control the
Antiplatelet 2662 (53·8%) 2680 (54·1%) overall type I error.21–23
Data are mean (SD), n (%), or median (IQR), unless otherwise stated. HbA1c=glycated haemoglobin A1c. eGFR=estimated
The effect of the intervention on the primary outcome
glomerular filtration rate. DPP-4=dipeptidyl peptidase-4. UACR=urinary albumin-to-creatinine ratio. was tested in seven predefined subgroups (ie, age,
ACE=angiotensin-converting enzyme. ARB=angiotensin-receptor blocker. *Myocardial infarction, ischaemic stroke, sex, BMI, duration of diabetes, baseline HbA1c, history
unstable angina with electrocardiogram changes, myocardial ischaemia on imaging or stress test, or coronary, carotid,
or peripheral revascularisation. †Myocardial infarction or ischaemic stroke. ‡Data are mean (SD); median (IQR).
of cardiovascular disease, and geographical region) by
§UACR 3·39 mg/mmol or more. including the subgroup and interaction term in the
Cox model. Tests for nominally significant interactions
Table 1: Baseline characteristics
between treatment and the seven prespecified subgroups

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were not adjusted for multiple testing. The change from 82·2% of the follow-up time from randomisation until
baseline in continuous variables was analysed using either a primary outcome event or final follow-up,
linear mixed models with baseline value as a covariate, compared with 83·1% of the follow-up time for patients
participant as a random effect, and fixed effects for assigned to placebo. Study drug was well tolerated;
treatment, visit, and treatment–visit interaction, and 451 (9·1%) participants assigned to dulaglutide and
reported as the least-squares mean (LSM) value.24 A set 310 (6·3%) assigned to placebo permanently stopped
of plausible ranges for laboratory tests were defined study drug during follow-up because of an adverse
before unblinding (appendix p 34) and tests with values event. There were no between-group differences in use
outside these ranges were excluded from the analyses. of other medications at baseline (table 1), but fewer
The proportion of participants in each group who had participants in the dulaglutide group than in the placebo
prespecified adverse events of special interest were group were taking a GLP-1 receptor agonist, SGLT2
compared using log-rank tests, and the proportion inhibitor, metformin, sulfonylurea, insulin, or angioten­
who had serious adverse events and adverse events sin-converting enzyme inhibitor or angiotensin-receptor
were compared using χ² tests. Data were analysed with blocker at the last visit (appendix p 36).
SAS software (version 9.4). This trial is registered with The primary composite outcome occurred in
ClinicalTrials.gov, number NCT01394952. 594 (12·0%) par­ ticipants (2·4 per 100 person-years)
assigned to dulaglutide and 663 (13·4%) participants
Role of the funding source (2·7 per 100 person-years) assigned to placebo (HR 0·88,
The trial was sponsored and funded by Eli Lilly and 95% CI 0·79–0·99; p=0·026; figure 2, table 2). Consistent
Company led by an international steering committee effects were observed for all three compo­nents of the
coordinated by the Population Health Research Institute composite primary outcome (pheterogeneity=0·89),19 with HRs
in Hamilton, Canada, which also did all data analyses. of 0·91 (95% CI 0·78–1·06; p=0·21) for cardiovascular
Site management and data collection were provided by death, 0·96 (0·79–1·16; p=0·65) for non-fatal myocardial
ICON Clinical Research. Scientists employed by the infarction, and 0·76 (0·61–0·95; p=0·017) for non-fatal
funder were on the steering committee and contributed stroke (figure 2, table 2).
to trial design, trial implementation, and data inter­ When assessed within subgroups, the HR of the
pretation. All authors and the sponsor jointly made the intervention on the primary outcome was similar in
decision to submit for publication. The corresponding participants with and without previous cardiovascular
author had full access to all the data in the study and
had final responsibility for the decision to submit for A Composite cardiovascular outcome B Cardiovascular death
publication. 18 Placebo HR=0·91 (95% CI 0·78–1·06)
Dulaglutide p=0·21
15
Results
Cumulative risk (%)

Between Aug 18, 2011, and Aug 14, 2013, 12 133 patients 12

were screened at 371 sites in 24 countries. 10 917 eligible 9

patients began the 3-week run-in period, of whom 6
9901 were randomly assigned to treatment group
3 HR 0·88 (95% CI 0·79–0·99)
(dulaglutide, n=4949; placebo, n=4952; figure 1). Follow- p=0·026
up ended on Aug 21, 2018. 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Mean age of participants was 66·2 years [SD 6·5], and Number at risk
Placebo 4952 4791 4625 4437 4275 3575 742 4952 4854 4748 4617 4499 3813 802
4589 [46·3%] were female (table 1, appendix p 35).17 At Dulaglutide 4949 4815 4670 4521 4369 3686 741 4949 4866 4773 4663 4556 3887 807
baseline, 3114 (31·5%) participants reported previous
cardiovascular disease and 2199 (22·2%) had a baseline C Non-fatal myocardial infarction D Non-fatal stroke
eGFR less than 60 mL/min per 1·73 m². The median 18 HR 0·96 (95% CI 0·79–1·16) HR 0·76 (95% CI 0·61–0·95)
p=0·65 p=0·017
duration of diabetes was 9·5 years (IQR 5·5–14·5), 15
median HbA1c was 7·2% (IQR 6·6–8·1), and median
Cumulative risk (%)

12
eGFR was 74·9 mL/min per 1·73 m² (IQR 61·4–91·1).
9
During a median follow-up of 5·4 years (IQR 5·1–5·9)
comprising 51 820 person-years, the primary composite 6
outcome status was known in 9610 (97·1%) participants 3
(figure 1). 2092 (42·3%) of 4949 participants assigned 0
to dulaglutide and 2171 (43·8%) of 4952 participants 0 1 2 3 4 5 6 0 1 2 3 4 5 6
assigned to placebo had at least one discontinuation Number at risk
Time since randomisation (years) Time since randomisation (years)
of study drug during follow-up, whereas 3621 (73·2%) Placebo 4952 4819 4680 4518 4372 3672 766 4952 4826 4692 4534 4396 3710 777
Dulaglutide 4949 4833 4705 4574 4443 3772 767 4949 4847 4736 4606 4476 3796 776
assigned to dulaglutide and 3520 (71·1%) assigned
to placebo were taking study drug at the last visit. Par­ Figure 2: Cumulative incidence of cardiovascular outcomes
ticipants assigned to dulaglutide took study drug for HR=hazard ratio. HbA1c=glycated haemoglobin A1c.

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Dulaglutide (n=4949) Placebo (n=4952) Hazard ratio (95% CI) p value

Number of Incidence rate Number of Incidence rate
patients (%) (number of patients (%) (number of
events per 100 events per 100
person-years) person-years)
Primary composite outcome 594 (12·0%) 2·35 663 (13·4%) 2·66 0·88 (0·79–0·99)* 0·026
Myocardial infarction 223 (4·5%) 0·87 231 (4·7%) 0·91 0·96 (0·79–1·15) 0·63
Non-fatal myocardial infarction 205 (4·1%) 0·80 212 (4·3%) 0·84 0·96 (0·79–1·16) 0·65
Fatal myocardial infarction 26 (0·5%) 0·10 20 (0·4%) 0·08 1·29 (0·72–2·30) 0·40
Stroke 158 (3·2%) 0·61 205 (4·1%) 0·81 0·76 (0·62–0·94) 0·010
Non-fatal stroke 135 (2·7%) 0·52 175 (3·5%) 0·69 0·76 (0·61–0·95) 0·017
Fatal stroke 26 (0·5%) 0·10 33 (0·7%) 0·13 0·78 (0·47–1·30) 0·34
Cardiovascular death† 317 (6·4%) 1·22 346 (7·0%) 1·34 0·91 (0·78–1·06) 0·21
Non-cardiovascular death 219 (4·4%) 0·84 246 (5·0%) 0·95 0·88 (0·73–1·06) 0·18
All-cause death 536 (10·8%) 2·06 592 (12·0%) 2·29 0·90 (0·80–1·01) 0·067
Hospital admission for heart failure or 213 (4·3%) 0·83 226 (4·6%) 0·89 0·93 (0·77–1·12) 0·46
urgent visit
Hospital admission for unstable angina 88 (1·8%) 0·34 77 (1·6%) 0·30 1·14 (0·84–1·54) 0·41
Composite microvascular outcome (eye or 910 (18·4%) 3·76 1019 (20·6%) 4·31 0·87 (0·79–0·95) 0·0020
renal outcome)
Eye outcome‡ 95 (1·9%) 0·37 76 (1·5%) 0·30 1·24 (0·92–1·68) 0·16
Renal outcome§ 848 (17·1%) 3·47 970 (19·6%) 4·07 0·85 (0·77–0·93) 0·0004
All hazard ratios (HRs) were estimated with Cox proportional hazards models and p values are two-sided. *After accounting for α=0·009 spent on the primary outcome for
the interim analysis, the α for the final analysis is 0·0467, and the HR is 0·88 (95·33% CI 0·79–0·99). †Includes deaths of unknown cause. ‡Photocoagulation, anti-vascular
endothelial growth factor therapy, or vitrectomy. §New macroalbuminuria, a sustained decline in estimated glomerular filtration rate of 30% or more from baseline,
or chronic renal replacement therapy.

Table 2: Primary and secondary outcomes

disease (pinteraction=0·97), in participants whose HbA1c had a 0·61% (95% CI 0·58–0·65) lower LSM HbA1c
was less than 7·2% or greater-than or equal to 7·2% (p<0·0001), 1·46 kg (1·25–1·67) lower LSM bodyweight
(pinteraction=0·75), and in participants analysed according to (p<0·0001), 0·53 kg/m² (0·46–0·61) lower LSM
age, sex, duration of diabetes, and BMI (figure 3). There BMI (p<0·0001), 1·70 mm Hg (1·33–2·07) lower LSM
was nominally significant heterogeneity with respect to systolic blood pressure (p<0·0001), 0·49 mm Hg
geographical region (pinteraction=0·0080). Similar HRs were (0·25–0·73) lower LSM mean arterial blood pressure,
also noted when the effect of dulaglutide was explored 1·82 mm Hg (1·53–2·12) lower LSM pulse pressure,
in post-hoc subgroups based on a previous cardio­ 1·87 beats per min (1·62–2·11) higher LSM heart rate
vascular event (ie, myocardial infarction or ischaemic (p<0·0001), 0·07 mmol/L (0·03–0·10) lower LSM total
stroke), different HbA1c or BMI categories, or ethnicity cholesterol, 0·05 mmol/L (0·02–0·08) lower LSM LDL
(appendix p 37). cholesterol, and a lower ratio of waist-to-hip circumference
The incidence of the composite microvascular out­ in men and women (figure 4, appendix pp 32, 39).
come was lower in participants assigned to dulaglutide Frequencies of prespecified adverse events of special
than in those assigned to placebo (3·8 per 100 person- interest, including first study drug discontinuation,
years vs 4·3 per 100 person-years, respectively; HR 0·87, serious gastrointestinal events, severe hypoglycaemia,
95% CI 0·79–0·95; table 2, appendix p 30). This cancers, or pancreatitis, did not differ significantly
difference was char­acterised by fewer composite renal between the dulaglutide and placebo groups (table 3).
outcomes in the dulaglutide group than in the placebo The numbers of serious adverse events did not differ
group (3·5 per 100 person-years vs 4·1 per 100 person- significantly between groups (appendix p 40). However,
years, respectively; HR 0·85, 95% CI 0·77–0·93). 2347 (47·4%) par­­ ticipants assigned to dulaglutide
Dulaglutide did not significantly affect the incidence of reported a gastrointestinal adverse event during follow-
all-cause mortality, heart failure, revascularisation, up compared with 1687 (34·1%) participants assigned to
hospital admissions, fractures, or cholelithiasis (table 2; placebo (p<0·0001; appendix p 41).
appendix p 31, 38).
During follow-up, differences from baseline were Discussion
greater in the dulaglutide group than in the placebo group This long-duration randomised controlled trial of people
for several measurements. Compared with participants in with type 2 diabetes and only a 31·5% prevalence of
the placebo group, participants assigned to dulaglutide previous cardiovascular disease showed that a weekly

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Dulaglutide Placebo Hazard ratio (95% CI) pinteraction

Events/patients Incidence Events/patients Incidence

(%) (per 100 person–years) (%) (per 100 person–years)

Age (years) 0·57

≥66 331/2314 (14·3%) 2·9 384/2350 (16·3%) 3·3 0·86 (0·74–1·00)
<66 263/2635 (10·0%) 1·9 279/2602 (10·7%) 2·1 0·92 (0·78–1·09)
Sex 0·60
Female 218/2306 (9·5%) 1·8 249/2283 (10·9%) 2·1 0·85 (0·71–1·02)
Male 376/2643 (14·2%) 2·8 414/2669 (15·5%) 3·1 0·90 (0·79–1·04)
Duration of diabetes (years) 0·88
<5 128/1227 (10·4%) 2·0 146/1192 (12·2%) 2·4 0·84 (0·66–1·06)
5–10 174/1446 (12·0%) 2·3 196/1476 (13·3%) 2·6 0·89 (0·73–1·09)
≥10 292/2276 (12·8%) 2·5 321/2284 (14·1%) 2·8 0·90 (0·77–1·06)
History of cardiovascular disease* 0·97
Yes 280/1560 (17·9%) 3·7 315/1554 (20·3%) 4·2 0·87 (0·74–1·02)
No 277/3093 (8·9%) 1·7 317/3128 (10·1%) 2·0 0·87 (0·74–1·02)
Baseline HbA1c* 0·75
≥7·2% 328/2610 (12·6%) 2·5 373/2603 (14·3%) 2·9 0·86 (0·74–1·00)
<7·2% 263/2329 (11·3%) 2·2 289/2334 (12·4%) 2·4 0·90 (0·76–1·06)
BMI (kg/m2) 0·21
≥32 254/2281 (11·1%) 2·1 308/2302 (13·4%) 2·6 0·82 (0·69–0·96)
<32 340/2667 (12·7%) 2·5 355/2650 (13·4%) 2·7 0·94 (0·81–1·09)
Region 0·0080
Europe 248/2174 (11·4%) 2·2 315/2165 (14·5%) 2·9 0·77 (0·65–0·90)
Latin America 191/1511 (12·6%) 2·6 190/1510 (12·6%) 2·6 0·99 (0·81–1·21)
USA and Canada 132/1032 (12·8%) 2·4 117/1039 (11·3%) 2·1 1·14 (0·89–1·47)
Asia Pacific 23/232 (9·9%) 1·9 41/238 (17·2%) 3·5 0·54 (0·32–0·89)
Overall 594/4949 (12·0%) 2·4 663/4952 (13·4%) 2·7 0·88 (0·79–0·99) NA

0·5 1·0 2·0

Figure 3: Subgroup analyses for the primary cardiovascular outcome

The size of each box is proportional to the number of events. BMI=body-mass index. NA=not applicable. *Participants were not included in a category if the criteria or
test result needed to assign them to a category were unknown or missing.

injection of 1·5 mg dulaglutide reduced the risk of events, whereas REWIND prospectively tested the
cardio­vascular outcomes compared with placebo, with hypothesis that dulaglutide was superior. Second, most
the Kaplan-Meier curves starting to diverge within the of the participants in REWIND did not have previous
first year. Across the three components of the composite cardiovascular disease or a previous cardiovascular event.
primary outcome, the greatest between-group difference Thus, the average cardiovascular incidence of participants
was seen in the number of non-fatal strokes. In this assigned to placebo was 2·7%, which was lower than the
population of people with a mean duration of type 2 annual placebo incidence rates for the same composite
diabetes of 10 years, in whom 25% had a base­line HbA1c outcome of 3·9% or higher in the other trials.5 Moreover,
less than 6·6% and 25% had a level more than 8·1%, the broad inclusion criteria, high proportion of women,
dulaglutide durably reduced HbA1c by a mean absolute and the representativeness of the recruited participants25
amount of 0·6% more than placebo while not increasing in REWIND suggest that dulaglutide might be effective
hypoglycaemia. It also modestly reduced weight, LDL for both primary and secondary cardiovascular prevention
cholesterol, and systolic blood pressure, modestly in a high proportion of people with type 2 diabetes.
increased heart rate, and was well tolerated with high Third, the 5·4-year median follow-up was much longer
adherence. For every 60 people with type 2 diabetes and than that in the other cardiovascular outcomes trials,
additional cardiovascular risk factors who were treated in which median follow-up ranged from 1·5 years to
with dulaglutide for a median of 5·4 years versus placebo, 3·8 years,5,7 showing that the cardiovascular benefits of
one cardiovascular event was prevented. The number GLP-1 receptor agonists extend much longer than
needed to treat is 18 for people with a previous cardio­ previously reported. Fourth, our trial shows the durability
vascular event. and safety of the effect of dulaglutide on glucose, blood
The REWIND trial differs from previous cardiovascular pressure, and weight, and represents the longest trial
outcomes trials with GLP-1 receptor agonists7,8 in several of the effect of a GLP-1 receptor agonist on these
ways. First, the other trials were designed to show non- measures. Finally, our findings show that dulaglutide
inferiority to placebo with respect to cardiovascular reduces cardiovascular events in people with HbA1c

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similar to those in the other trials with higher baseline

A HbA1c B Weight
8·00 94 Overall LSM difference
HbA1c concentrations.5–7,26,27
Placebo
7·75 Dulaglutide –1·46 (95% CI –1·67 to –1·25) Several possibilities could account for the salutary
92 p<0·0001
7·50
effects of dulaglutide and other GLP-1 receptor agonists
on cardiovascular outcomes. These include the reduction
Mean weight (kg)
90
Mean HbA1c (%)

7·25
7·00 88 in HbA1c, LDL cholesterol, blood pressure, and weight.
6·75 Emerging evidence also suggests that these drugs might
86
6·50 Overall LSM difference independently improve endothelial function, endothelial
6·25
–0·61 (95% CI –0·65 to –0·58) 84 cell responses to ischaemia, and platelet function, and
p<0·0001
6·00 82 might have direct neuroprotective effects.28 These drugs
0 3 1 2 3 4 5 0 1 2 3 4 5 might also attenuate progression of atherosclerosis,
months
vascular inflammation, and vasoconstriction.29
C Systolic blood pressure D Heart rate Irrespective of the mechanism, the unique features of
140 Overall LSM difference 79 Overall LSM difference this trial add to a growing body of literature describing
Mean systolic blood pressure (mm Hg)

139 –1·70 (95% CI –2·07 to –1·33) 78 1·87 (95% CI 1·62 to 2·11)

the cardiovascular effects of GLP-1 receptor agonists,8
Mean heart rate (beats per min)

p<0·0001 p<0·0001
138 77
76
and suggest that most middle-aged and older people with
137
136 75 type 2 diabetes can achieve cardiovascular benefits with
135 74 GLP-1 receptor agonists such as dulaglutide. Consistent
134 73 with the findings from three cardiovascular outcomes
133 72 trials of other GLP-1 receptor agonists,5,6,27,30 the REWIND
132 71 trial raises the possibility of a greater effect on stroke
131 70
than on myocardial infarction. Although it also raises the
130 69
0 1 2 3 4 5 0 1 2 3 4 5 possibility of some geographical variation of effect, this
Study visit (year) Study visit (year) variation loses statistical significance after accounting for
the seven subgroups that were assessed (for which the
Figure 4: Continuous measures during follow-up Bonferroni-corrected p value for significance is <0·05/7
LSM=least-square means. HbA1c=glycated haemoglobin A1c.
or 0·007), and might therefore be a spurious finding.
Finally, the suggestion of a protective effect of dulaglutide
Dulaglutide (n=4949) Placebo (n=4952) Log-rank test on renal outcomes is consistent with the other trials in
p value which renal outcomes were reported,5,6,27 and supports
First study drug discontinuation 2092 (42·3%) 2171 (43·8%) 0·38 further analyses of these effects. The long-term effect of
Acute pancreatitis* 23 (0·5%) 13 (0·3%) 0·11 dulaglutide on renal outcomes has been assessed in an
Imaging and enzymes† 4 (0·1%) 3 (0·1%) 0·71 exploratory analysis, published elsewhere.31
Imaging, enzymes, and symptoms‡ 4 (0·1%) 3 (0·1%) 0·71 Strengths of these findings include the trial’s broad and
Any cancer§ 351 (7·1%) 348 (7·0%) 0·98 representative inclusion criteria and recruited partici­
Medullary thyroid carcinoma or C-cell 1 (<0·1%) 0 0·32 pants,25 long follow-up, high retention, measurement of
hyperplasia¶ clinically relevant outcomes, and investigator freedom to
Thyroid cancer 7 (0·1%) 3 (0·1%) 0·21 use any non-GLP-1 receptor agonist drug. Although less
Pancreatic cancer 19 (0·4%) 12 (0·2%) 0·22 than a third of participants had previous cardiovascular
Serious hepatic event 25 (0·5%) 40 (0·8%) 0·057 disease, the observed cardiovascular effect size is similar
Serious renal or urinary event|| 84 (1·7%) 93 (1·9%) 0·46 to the HR of 0·87 from a meta-analysis of outcome trials
Immune reactions 8 (0·2%) 20 (0·4%) 0·022 of other GLP-1 receptor agonists in mainly secondary
Serious gastrointestinal event 120 (2·4%) 117 (2·4%) 0·87 prevention populations.32 This observation, and the fact
Supraventricular tachycardia or 216 (4·4%) 192 (3·9%) 0·26 that there was a numerically greater use of proven
cardiovascular conduction disorders cardioprotective drugs in the placebo group (which might
Severe hypoglycaemia 64 (1·3%) 74 (1·5%) 0·38 have diminished the effect size of dulaglutide) further
*Based on the first occurrence of acute pancreatitis, diagnosed on the basis of at least two of the three diagnostic support these findings. The major limitation is the
criteria (symptoms, elevated pancreatic enzymes, or an abnormal pancreatic image). †The subset of participants with observation that more than 25% of participants were not
first acute pancreatitis who had both elevated pancreatic enzymes and an abnormal pancreatic image. ‡The subset of taking study drug at the time of their last visit. Although
participants with first acute pancreatitis who had all three of elevated pancreatic enzymes, an abnormal pancreatic
image, and symptoms. §Excluding non-melanoma skin cancers. ¶There were no cases of medullary thyroid carcinoma.
this might have also diminished the benefit of allocation
||Based on a search of the REWIND database for any reported adverse event linked to acute renal failure. to dulaglutide, the observation that participants took
study drug for more than 80% of the follow-up time is
Table 3: Prespecified adverse events of special interest reported during the trial
reassuring.
Our findings show that the addition of dulaglutide to
concentrations both within and higher than guideline- the medical regimen of people with type 2 diabetes and a
recommended targets, without increasing weight or the broad range of glycaemic control reduced a composite of
risk of hypoglycaemia, and has effect sizes that are cardiovascular outcomes over a 5 year period. Moreover,

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our results suggest that dulaglutide could be added to 2 Emerging Risk Factors Collaboration, Di Angelantonio E,
the management of people with diabetes and additional Kaptoge S, et al. Association of cardiometabolic multimorbidity
with mortality. JAMA 2015; 314: 52–60.
cardiovascular risk factors to reduce glucose concen­ 3 Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and
trations, minimise hypoglycaemia, reduce weight and incidence of cardiovascular diseases: a cohort study in 1·9 million
blood pressure, and reduce cardiovascular events. people. Lancet Diabetes Endocrinol 2015; 3: 105–13.
4 Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular outcomes
Contributors trials in type 2 diabetes: where do we go from here? Reflections
HCG (REWIND Chair) prepared the first draft of the report, from a Diabetes Care Editors’ Expert Forum. Diabetes Care 2018;
and together with HMC, GRD, RD, ML, PP, JP, JSR, MCR, LR, and DX 41: 14–31.
reviewed the literature, provided overall trial leadership, and interpreted 5 Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and
the data. LD, PR-M, GW, and CMA did or confirmed the statistical cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;
analyses, and LD and PR-M prepared the figures. All other authors led 375: 311–22.
the trial overall or in their respective countries and all authors critically 6 Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular
reviewed and revised the report before submission. outcomes in patients with type 2 diabetes. N Engl J Med 2016;
375: 1834–44.
Declaration of interests
7 Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and
HCG holds the McMaster-Sanofi Population Health Institute Chair in cardiovascular outcomes in patients with type 2 diabetes and
Diabetes Research and Care. He reports research grants from Eli Lilly, cardiovascular disease (Harmony Outcomes): a double-blind,
AstraZeneca, Merck, Novo Nordisk, and Sanofi; honoraria for speaking randomised placebo-controlled trial. Lancet 2018; 392: 1519–29.
from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, 8 Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes
and Sanofi; and consulting fees from Abbott, AstraZeneca, Boehringer with glucagon-like peptide-1 receptor agonists in patients with
Ingelheim, Eli Lilly, Merck, Novo Nordisk, Janssen, Sanofi, Kowa, type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol 2018;
and Cirius. HMC reports research grants from Eli Lilly, AstraZeneca, 6: 105–13.
Regeneron, Pfizer, Roche, Sanofi, and Novo Nordisk; honoraria for 9 Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary
speaking from Eli Lilly and Regeneron; consulting fees from Eli Lilly, and secondary prevention of cardiovascular and renal outcomes in
Novartis, Regeneron, Sanofi, and Novo Nordisk; and shares in Bayer and type 2 diabetes: a systematic review and meta-analysis of
Roche. RD reports research grants from the Population Health Research cardiovascular outcome trials. Lancet 2019; 393: 31–39.
Institute, Duke Clinical Research Institute, Montreal Health Innovations 10 Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal
Coordinating Center, CPC Clinical Research, DalCor, Amgen, Lepetit, outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;
and Cirius; honoraria for speaking from Sanofi; and consulting fees from published online April 14. DOI:10.1056/NEJMoa1811744.
Sanofi and Cirius. MCR reports grants to his institution from Eli Lilly, 11 Diabetes Canada Clinical Practice Guidelines Expert Committee,
AstraZeneca, and Novo Nordisk; honoraria for consulting from Adocia, Lipscombe L, Booth G, et al. Pharmacologic glycemic management of
DalCor, GlaxoSmithKline, and Theracos; and honoraria for speaking from type 2 diabetes in adults. Can J Diabetes 2018; 42 (suppl 1): S88–103.
Sanofi. LR reports grants from the Swedish Heart Lung Foundation, 12 American Diabetes Association. 9. Pharmacologic approaches to
glycemic treatment: standards of medical care in diabetes-2019.
Stockholms Läns Landsting, and Boehringer Ingelheim, and fees for
Diabetes Care 2019; 42 (suppl 1): S90–102.
consulting and speaking from Boehringer Ingelheim, Novo Nordisk,
13 Jendle J, Grunberger G, Blevins T, Giorgino F, Hietpas RT,
Eli Lilly, Merck, and Bayer. ML is employed by Eli Lilly, owns stock,
Botros FT. Efficacy and safety of dulaglutide in the treatment of
and has a patent pending, JSR is employed by Eli Lilly and has a patent
type 2 diabetes: a comprehensive review of the dulaglutide clinical
pending. CMA is employed by Eli Lilly and owns stock. DX reports grants data focusing on the AWARD phase 3 clinical trial program.
from Cadila, Boehringer Ingelheim, AstraZeneca, Sanofi-Aventis, Pfizer, Diabetes Metab Res Rev 2016; 32: 776–90.
Bristol-Myers Squibb, the UK Medical Research Council, and the 14 Zhang L, Zhang M, Zhang Y, Tong N. Efficacy and safety of
Wellcome Trust. JB reports consulting fees from Eli Lilly, ReCor, dulaglutide in patients with type 2 diabetes: a meta-analysis and
and Medtronic. WCC reports grants from Eli Lilly. EF reports consulting systematic review. Sci Rep 2016; 6: 18904.
and speaking fees from AstraZeneca, Boehringer Ingelheim, Bioton, 15 Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus
Mundipharma, MSD, Novartis, Novo Nordisk, and Servier. MH reports insulin glargine in patients with type 2 diabetes and
honoraria for speaking from Sanofi, Novo Nordisk, Amgen, MSD, and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre,
AstraZeneca. FL reports grants from the Population Health Research open-label, randomised trial. Lancet Diabetes Endocrinol 2018;
Institute. LAL reports grants from Eli Lilly, AstraZeneca, Boehringer 6: 605–17.
Ingelheim, Janssen, Novo Nordisk, Sanofi, and GSK; honoraria for 16 Almutairi M, Al Batran R, Ussher JR. Glucagon-like peptide-1
speaking from Eli Lilly, AstraZeneca, Boehringer Ingelheim, Janssen, receptor action in the vasculature. Peptides 2019; 111: 26–32.
Merck, Novo Nordisk, and Sanofi; and consulting fees from Eli Lilly, 17 Gerstein HC, Colhoun HM, Dagenais GR, et al. Design and
AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, baseline characteristics of participants in the Researching
Sanofi, and Servier. JES reports grants from Eli Lilly, and consulting fees Cardiovascular Events with a Weekly Incretin in Diabetes
or speaking honoraria from AstraZeneca, Eli Lilly, Novo Nordisk, Sanofi, (REWIND) trial on the cardiovascular effects of dulaglutide.
Mylan, Boehringer Ingelheim, Merck Sharp and Dohme, and Abbott. Diabetes Obes Metab 2018; 20: 42–49.
TT-K reports consulting fees from Bayer, AstraZeneca, and Hamilton 18 Levey AS, Coresh J, Greene T, et al. Using standardized serum
creatinine values in the modification of diet in renal disease study
Health Sciences. All other authors declare no competing interests.
equation for estimating glomerular filtration rate. Ann Intern Med
Data sharing 2006; 145: 247–54.
The data sharing policy is described in the appendix (pp 28–29). 19 Pogue J, Devereaux PJ, Thabane L, Yusuf S. Designing and
analyzing clinical trials with composite outcomes: consideration of
Acknowledgments possible treatment differences between the individual outcomes.
The trial was funded by Eli Lilly and Company. We gratefully PLoS One 2012; 7: e34785.
acknowledge the contribution of all participants. The names of the 20 Jennison C, Turnbull BW. Group sequential methods with
REWIND investigators, coordinators, committee members, and staff are applications to clinical trials. Boca Raton: Chapman & Hall/CRC,
listed in the appendix (pp 2–11). Their contributions, as well as those of 2000.
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