A recent exploratory analysis of the REWIND trial evaluated a potential additive cognitive benefit to using a once-weekly GLP-1 RA, Dulaglutide.
Previous studies have found diabetes to be an independent risk factor for the development of cognitive dysfunction. Though this relationship’s specific cause has not been fully described, a recent study suggests new treatment strategies could come from analyzing the existing link and shared risk factors between cardiovascular disease and cognitive impairment. Due to this connection, researchers sought to evaluate whether a diabetes medication that was found to reduce composite CV outcomes (including stroke) in the REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) study would decrease the risk of cognitive impairment in these patients. Investigators conducted an exploratory analysis of the REWIND trial to evaluate the effect of dulaglutide, a GLP-1 RA, on cognitive impairment.
The REWIND trial was a double-blind, randomized controlled trial that included patients 50 years or older with type 2 diabetes and other CV conditions. Only patients whose A1C was 9.5% or lower, who were on up to two diabetes medications, and who had a BMI of 23 kg/m2 or more were included. Participants who were previously receiving DPP-4 inhibitors or other GLP-1 RA discontinued these medications before the trial. This study used two cognitive tests, the Montreal Cognitive Assessment and the Digit Symbol Substitution Test, which were administered at baseline, at two years, five years, and at the end of the study. To be included in the analysis, at least one baseline and one follow-up assessment of the same type had to be available during the median follow-up of 5.4 years. Of the 9901 participants included in the REWIND trial, 8828 of those had available cognitive test results and were included in this intention to treat analysis. Of these, a total of 4456 participants were assigned to once-weekly dulaglutide 1.5 mg, and 4372 to placebo. This exploratory study’s primary outcome was the substantive cognitive impairment (SCI), which they defined as the first incidence of a cognitive test score of 1.5 standard deviations or more below the mean baseline score, which was standardized based on the participant’s country.
Baseline characteristics among the two groups included in the cognitive analysis were similar. Participants in both groups had a mean age of 65.5 years, a higher number were men, 31% had CVD, most had hypertension (93%) and a lower level of education, and a smaller number of participants had a previous stroke or atrial fibrillation (9% and 6%, respectively in the treatment group). Researchers reported that a lower number of participants in the dulaglutide group developed SCI’s primary outcome compared to the placebo group (4.05 per 100 patient-years and 4.35 per 100 patient-years, respectively).
Further analyses were adjusted for each participant’s baseline cognitive test scores since this was found to affect the results. After post-hoc adjustment for baseline scores, the risk of cognitive impairment was 14% lower in those receiving dulaglutide (HR=0.86, 95% CI 0.79-0.95, p=0.0018). Similar results were seen when adjusting for age, sex, education, and ethnicity. Researchers additionally noted that although stroke is associated with cognitive decline, adjusting for the occurrence of a stroke before the outcome of SCI happened did not affect dulaglutide’s reduction in risk (aHR=0.86, 95% CI 0.78-0.94).
Researchers determined that, based on the results obtained from these analyses, treatment with once-weekly injections of dulaglutide for more than five years may reduce the risk of cognitive dysfunction in patients 50 years or older with diabetes compared to placebo. If this effect is further proven significant in future studies, treatment with dulaglutide could offer a convenient way for patients with diabetes to treat this condition and improve their quality of life by preventing cognitive impairment and CV comorbidities. This study was funded by the manufacturer of dulaglutide and had several limitations due to its experimental design. One of the main ones was that it only obtained results from two cognitive tests, and the areas measured by these may not have included all cognitive domains that can be affected by diabetes. On the other hand, since it extrapolated results from a large randomized controlled trial with a long follow up period, these results could be used to guide future research. Further studies should include a more thorough assessment of how GLP-1 RA can affect brain function and how this compares to other medications available.
- The risk of cognitive impairment was reduced by 14% in participants receiving once-weekly treatment with dulaglutide.
- The reduction in cognitive impairment risk in those treated with dulaglutide remained after adjusting for stroke occurrence.
- More studies are needed to evaluate further dulaglutide’s and other GLP-1 RA’s long-term effects on brain function.
Cuckierman-Yaffe, et al. “Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial” The Lancet, vol 19, issue 7, 2020, p 582-590. doi: 10.1016/S1474-4422(20)30173-3.
Leyany Feijoo Ramos, PharmD. Candidate, LECOM School of Pharmacy