medwireNews: Lower levels of glycated hemoglobin (HbA1c), but not the choice of second-line glucose-lowering treatment, are associated with better medium-term cognitive performance in people with type 2 diabetes of short duration, show results from the GRADE trial.
The study included 3721 participants (mean age 57 years, 62% men) who had been diagnosed with type 2 diabetes less than 10 years prior to baseline (mean duration 4.3 years), were taking at least 1000 mg of metformin daily, and had an HbA1c level of 6.8–8.5% (51–69 mmol/mol).
They were randomly assigned to receive second-line treatment with the long-acting insulin glargine, the sulfonylurea glimepiride, the glucagon-like peptide (GLP)-1 receptor agonist liraglutide, or the dipeptidyl peptidase-4 inhibitor sitagliptin.
After a median of 4.1 years of follow-up, José Luchsinger (The George Washington University Biostatistics Center, Rockville, Maryland, USA) and co-investigators found no significant difference in baseline-adjusted Digit Symbol Substitution Test (DSST) scores, a measure of frontal executive ability, among each of the second-line treatment groups.
Moreover, there were no significant between-group differences in the Spanish English Verbal Learning Test (SEVLT) or in animal and letter fluency tests (FTs), which all measure memory.
Initial, unadjusted analyses of the link between time-weighted HbA1c levels and cognitive outcomes also showed no significant association.
However, after adjustment for age, sex, race, ethnicity, education, and duration of diabetes, the researchers found that higher time-weighted HbA1c levels were significantly related to worse scores in the DSST, SEVLT immediate and delayed recall, and animal FT.
Specifically, each percentage point increase in time-weighted HbA1c level was associated with a significant mean 0.94-point reduction in DSST score, a 0.27-point reduction in the immediate recall SEVLT score, and a 0.28-point reduction in the animal FT.
Although the association between HbA1c and cognitive performance was statistically significant, the researchers describe the magnitude of the effect as “modest” and say that the “clinical significance of this difference is unclear.”
They conclude: “The results of this randomized clinical trial suggest that choice of second-line glucose-lowering medication class added to metformin is not associated with change in cognitive performance in persons with early [type 2 diabetes].”
They add: “Worse glycemic control is associated with modestly worse cognitive performance.”
In an accompanying editor’s note, Timothy Anderson (University of Pittsburgh, Pennsylvania, USA) and Deborah Grady (University of California, San Francisco, USA) say that the “findings provide important data for clinicians, particularly in light of recent lay press and scientific enthusiasm about GLP-1 agonists for dementia prevention.”
They remark: “Future and ongoing clinical trials may provide insights into whether GLP-1s may be useful in reducing the risk of dementia, whether through a unique medication class effect or their impact on blood glucose and blood pressure, but for the time being, the findings of Luchsinger et al provide the best evidence available that diabetes medication class selection should not be driven by concerns about lowering dementia risk.”
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JAMA Intern Med 2025; doi:10.1001/jamainternmed.2025.1189
JAMA Intern Med 2025; doi:10.1001/jamainternmed.2025.1199
