GLP-1RA might reduce cognitive impairment in T2DM

Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial

Literature - Cukierman-Yaffe T, Gerstein HC, Colhoun HM et al. - Lancet Neurol 2020; 19: 582–90

Introduction and methods

Diabetes patients have a 1.5-2.0 fold increased risk of cognitive decline, cognitive impairment or dementia compared to those without diabetes [1,2]. Prevalence of cognitieve dysfunction is 13% in diabetes patients 65-74 years and 24% in patients ≥75 years [3]. As there is link between CVD and cognitive dysfunction and risk factors for these conditions overlap, it is hypothesized that therapies that reduce CVD in diabetes patients might also have beneficial cognitive effects.

The REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial demonstrated that the GLP-1RA dulaglutide reduced a composite of CV events, including stroke, in T2DM patients. This analysis examined the effect of dulaglutide on cognitive impairment, as measured by the two tests MoCA and DSST.

REWIND is an international, multicenter, randomized, double-blind, placebo-controlled trial enrolling adults ≥50 years with established or newly diagnosed T2DM with additional CV risk factors and previous CVD (history of MI, ischemic stroke, revascularization, unstable angina requiring hospital admission, or image proven myocardial ischemia). 9901 Participants were randomized to subcutaneous injections every week of either dulaglutide or placebo. Prespecified assessments of cognitive status were performed at baseline, 2-year, 5-year and end-of-study visit. Two validated measures of cognitive status were applied: the Montreal Cognitive Assessment (MoCA) test and the Digit Symbol Substitution Test (DSST). MoCA is a cognitive screening test validated in the setting of mild cognitive impairment. DSST is a subtest, and assesses a wide array of cognitive domains, including visual-motor speed and coordination. Test results were available for 8828 participants (89%).

The exploratory primary cognitive outcome was country-standardized substantive cognitive impairment (SCI), defined as first occurrence of a post-randomization country-standardized MoCA or DSST score of -1.5 SD or less. Median follow-up was 5.4 (5.1-5.9) years.

Main results

  • Incidence of the primary cognitive outcome in participants assigned to dulaglutide was 4.05 per 100 patient-years (PYs) and in those assigned to placebo this was 4.35 per 100 PYs (HR 0.93, 95%CI: 0.85-1.02, P=0.11). A greater effect of dulaglutide was seen in participants with lowest baseline scores for MoCA and DSST. Therefore, subsequent analyses were adjusted for individual baseline scores.
  • After adjustment for baseline MoCA and DSST standardized scores, participants assigned to dulaglutide had a 14% lower risk of SCI than placebo-treated participants (HR 0.86, 95%CI: 0.79-0.95, P=0.018). Using a discrete time proportional odds logistic model OR was 0.87 (95%CI: 0.78-0.96, P=0.005).
  • Adjusting for age, sex, education or ethnicity and including SCI within various composite outcomes did not affect the primary outcome, nor did adjusting for first incident stroke (adjusted HR 0.86, 95%CI: 0.78-0.94, P=0.0008).
  • Subgroup analysis showed similar treatment effects across subgroups, except for men vs. women (P-interaction=0.032) with a larger benefit in men.


In an exploratory analysis of the REWIND trial, therapy with the GLP-1RA dulaglutide reduced the outcome of cognitive impairment compared to placebo in T2DM patients ≥50 years.


1. Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J Diabetes Investig 2013; 4: 640–50.

2 Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes-systematic overview of prospective observational studies. Diabetologia 2005; 48: 2460–69.

3. Feil DG, Rajan M, Soroka O, Tseng CL, Miller DR, Pogach LM. Risk of hypoglycemia in older veterans with dementia and cognitive impairment: implications for practice and policy. J Am Geriatr Soc 2011; 59: 2263–72.

Find this article online at The Lancet Neurology

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