Differences in neurocognitive outcomes among patients with type 2 diabetes mellitus (T2DM) receiving incretin-based therapies remain unclear in routine clinical practice. A retrospective, population-based cohort study published in the Journal of Diabetes and Its Complications evaluated incident neurocognitive outcomes in patients initiating tirzepatide compared with semaglutide.

The analysis used de-identified electronic health records from the TriNetX network and included adults with T2DM who initiated either therapy. Propensity score matching (1:1) balanced baseline characteristics, including age, sex, race, and cardiometabolic and psychiatric comorbidities. Incident diagnoses of mild cognitive impairment (MCI), dementia, and Alzheimer's disease (AD) were assessed at least 12 months after treatment initiation using risk ratios and Kaplan-Meier analysis. A total of 290,606 patients initiated semaglutide, and 44,471 initiated tirzepatide, with 44,470 patients per group after matching.

The analysis showed that tirzepatide initiation was associated with a lower risk of MCI (RR 0.12; 95% CI 0.06-0.22), dementia (RR 0.15; 95% CI 0.09-0.26), and AD (RR 0.48; 95% CI 0.22-1.01) compared with semaglutide. Absolute risks were low across outcomes. Kaplan-Meier analysis showed more consistent separation for MCI than for dementia or AD.

These findings indicate that tirzepatide initiation was associated with a lower incidence of MCI, while differences in dementia and AD outcomes were less consistent. The observational design and reliance on electronic health record data require cautious interpretation, and these findings remain hypothesis-generating pending confirmation in prospective trials.