Background Diabetes is an independent risk factor for cognitive impairment. We aimed
to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor
agonist dulaglutide and cognitive impairment as an exploratory analysis within the
Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial.
Methods REWIND is a randomised, double-blind placebo-controlled trial at 371 sites
in 24 countries. We included men and women (aged >= 50 years) with either established
or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated
haemoglobin of up to 9.5% (80 mmol/mol) on a maximum of two oral glucose-lowering
drugs with or without basal insulin, and a body-mass index of at least 23 kg/m(2).
Participants were randomly assigned (1:1) subcutaneous injections once a week of either
dulaglutide (1.5 mg) or an equal volume of matching placebo. Randomisation was done
using a computer-generated code with stratification by site. Participants and all
study personnel were masked to treatment allocation until the database was locked.
Participants were followed up at least every 6 months for the composite primary outcome
of stroke, myocardial infarction, or death from cardiovascular or unknown causes.
Cognitive function was assessed at baseline and during follow-up using the Montreal
Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present
here the exploratory primary cognitive outcome, which was the first occurrence of
a follow-up score on MoCA or DSST that was 1.5 S Ds or more below the baseline mean
score in the participant's country. All analyses were done using an intention-to-treat
approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952. Findings
Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to
either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5.4 (IQR
5.1-5.9) years, 8828 participants provided a baseline and one or more follow-up MoCA
or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo.
The cognitive outcome occurred in 4.05 per 100 patient-years in participants assigned
dulaglutide and 4.35 per 100 patient-years in people assigned placebo (hazard ratio
[HR] 0.93, 95% CI 0.85-1.02; p=0.11). After post-hoc adjustment for individual standardised
baseline scores, the hazard of substantive cognitive impairment was reduced by 14%
in those assigned dulaglutide (HR 0.86, 95% CI 0.79-0.95; p=0.0018). Interpretation
Long-term treatment with dulaglutide might reduce cognitive impairment in people with
type 2 diabetes. Further studies of this drug focused on brain health and cognitive
function are clearly indicated.
