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Can a glucagon-like peptide-1 (GLP-1) receptor agonist lower cognitive decline in type 2 diabetes? An exploratory analysis of the dulaglutide (Trulicity) cardiovascular outcome trial suggests so.

In a weekly injection of 1.5 mg of dulaglutide helped reduce major adverse cardiovascular events by 12% over a median of 5.4 years. This was driven mainly by a drop in stroke, which showed a 24% risk reduction vs placebo (HR 0.76, 95% CI 0.61-0.95; P=0.017).

Now, a secondary analysis from Hertzel Gerstein, MD, of McMaster University in Hamilton, Ontario, and coauthors writing in suggests dulaglutide also might help reduce the occurrence of accelerated cognitive decline by as much as 14%.

Fewer participants treated with dulaglutide than placebo met the primary cognitive outcome of substantive cognitive impairment (4.05 vs 4.35 per 100 patient-years; HR 0.86, 95% CI 0.79-0.95, P=0.0018). This outcome was defined as the first occurrence of a follow-up score on one of two different cognitive tests -- the Montreal Cognitive Assessment () or the Digit Symbol Substitution Test () -- that was 1.5 standard deviations or more below the mean baseline score in the participant's country.

Does lower stroke risk explain this cognitive outcome? "That is certainly one hypothesis," Gerstein told 番茄社区.

But in their analysis, the researchers showed that after accounting for dulaglutide's benefit on stroke, cognitive impairment still was lower. "That finding does not support the hypothesis that stroke was the reason for the effect on cognitive impairment -- but it does not rule it out -- and suggests that other mechanisms may be at play," Gerstein said.

"However, a benefit on both cognitive impairment and stroke suggests that perhaps the therapy has some neuroprotective effects," he added.

Type 2 diabetes is a for cognitive impairment and dementia. The first large cardiovascular outcome trial to report cognitive results didn't show a benefit for the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (Tradjenta) over placebo: in the substudy of people with type 2 diabetes and cardiorenal disease, linagliptin did not modulate cognitive decline over 2.5 years.

Cardiovascular outcome trials are mostly event-driven, observed Geert Jan Biessels, MD, PhD, of Utrecht University Medical Center in the Netherlands, in an . Thousand of participants, predominantly those at high cardiovascular risk, are recruited and followed for several years, he noted.

"Another feature of these trials is that they are designed to maintain glycemic equipoise between treatment groups to minimize potentially confounding effects of differences in glycemic control," he wrote.

In the REWIND analysis -- supported by dulaglutide drugmaker Eli Lilly & Co. -- Gerstein and collaborators looked at 8,828 type 2 diabetes patients who had cognitive assessments in the trial. Participants were 50 or older, had HbA1c of 9.5% or less, were on no more than two oral glucose lowering agents with or without basal insulin, and had body-mass index values of 23 or greater. They also had previous myocardial infarction, ischemic stroke, revascularization, unstable angina requiring hospital admission, or image-proven myocardial ischemia.

Individuals were randomized to weekly dulaglutide (4,456 people) or placebo (4,372 people) between August 2011 and August 2013. Each group had a mean age of 65.5 and 53% were men. Cardiovascular followup was at least every 6 months. MoCA and DSST were administered at baseline and at regular intervals during more than 5 years of follow-up. Analyses were intention-to-treat.

"Although [the cognitive] result is from an exploratory secondary analysis, this finding is nevertheless important," Biessels wrote. "If some classes of anti-diabetes drugs are superior than others in preventing dementia, this finding has clinical implications."

The effect persisted after accounting for baseline variations in age, education, and ethnic origin. Adjusting for incident stroke did not change the finding (adjusted HR 0.86, 95% CI 0.78–0.94; P=0.0008).

The analyses support the hypothesis that dulaglutide, and possibly GLP-1 receptor agonists in general, may be effective against cognitive decline, Gerstein said. "The effect of this drug class on dementia and related diseases in people with diabetes and those without diabetes urgently needs to be studied," he stated.

The study had several limitations, the researchers noted. Only two cognitive tests were used across a wide variety of settings and cultures. Although country-standardized scores and the 1.5 standard deviation threshold were prespecified before unmasking, adjustment for every individual's baseline scores was included later. MoCA and DSST also might not assess all cognitive domains affected by diabetes. Also, the study was limited to diabetic individuals with serious cardiovascular disease, and included a host of other inclusion and exclusion criteria.

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