Exploring the Associations Between Newer Glucose-Lowering Drugs Use and Cognitive Function Decline in Adults With Diabetes: A Target Trial Emulation
Author(s)
Piaopiao Li, MS1, Qiaochu Xue, PhD2, Jieun Lee, PhD2, Elizabeth Staton, PhD student2, Young-Rock Hong, PhD2, Hui Shao, MHA, PhD, MD2.
1PhD candidate, University of Florida, Gainesville, FL, USA, 2Emory University, Atlanta, GA, USA.
1PhD candidate, University of Florida, Gainesville, FL, USA, 2Emory University, Atlanta, GA, USA.
OBJECTIVES: Type 2 diabetes (T2D) increases the risk of cognitive function decline (CFD). Emerging evidence suggests potential cognitive benefits from newer glucose-lowering drugs (GLDs), specifically glucagon-like peptide-1 receptor agonist (GLP-1RA), sodium-glucose transport protein 2 inhibitors (SGLT2i). However, real-world evidence about their effects is limited and inconsistent. We aimed to investigate the associations between these newer GLD and CFD among adults with T2D.
METHODS: In this retrospective cohort study using target trial emulation analytical framework, we identified adults with T2D from All-of-Us database (01/01/2005-07/01/2022) using the SUPREME-DM algorithm. We used RxNorm to identify the three medication groups: (1) dipeptidyl peptidase 4 inhibitors (DPP4i) new users, (2) SGLT2i new users, and (3) GLP-1RA new users. CFD outcomes, including mild cognitive impairment and Alzheimer's disease and related dementias, were measured by ICD codes. Using DPP4i users as reference group, we compared the outcomes with SGLT2i and GLP-1RA groups respectively. The comparison cohorts were matched by 1:1 propensity score algorithm based on age, sex, socioeconomic status, comorbidities (cardiovascular diseases), and clinical measurements (A1c, BMI). In matched cohorts, hazard ratio (HRs) with 95% CI was estimated using Cox proportional hazard model.
RESULTS: We included 6,527 individuals in the GLP-1RA vs. DPP4i cohort, the CFD incidence was 8.48 and 9.59 per 1000 person-years, respectively (p <.01). 4,905 individuals were included in the SGLT2i vs. DPP4i cohort, the CFD incidence was 9.76 and 12.58 per 1000 person-years respectively (p <.01). In the Cox model, the GLP-1RA group was associated with a significantly lower risk of incident CFD (HR 0.77 [95% CI 0.63-0.94]) than the DPP4i group. The SGLT2i group was associated with a significantly lower risk of incident CFD (HR 0.67 [95% CI 0.52-0.87]) than the DPP4i group.
CONCLUSIONS: In conclusion, compared to DPP4i, SGLT2i and GLP-1RAs were associated with significantly reduced risk of indecent CFD in real-world populations with T2D.
METHODS: In this retrospective cohort study using target trial emulation analytical framework, we identified adults with T2D from All-of-Us database (01/01/2005-07/01/2022) using the SUPREME-DM algorithm. We used RxNorm to identify the three medication groups: (1) dipeptidyl peptidase 4 inhibitors (DPP4i) new users, (2) SGLT2i new users, and (3) GLP-1RA new users. CFD outcomes, including mild cognitive impairment and Alzheimer's disease and related dementias, were measured by ICD codes. Using DPP4i users as reference group, we compared the outcomes with SGLT2i and GLP-1RA groups respectively. The comparison cohorts were matched by 1:1 propensity score algorithm based on age, sex, socioeconomic status, comorbidities (cardiovascular diseases), and clinical measurements (A1c, BMI). In matched cohorts, hazard ratio (HRs) with 95% CI was estimated using Cox proportional hazard model.
RESULTS: We included 6,527 individuals in the GLP-1RA vs. DPP4i cohort, the CFD incidence was 8.48 and 9.59 per 1000 person-years, respectively (p <.01). 4,905 individuals were included in the SGLT2i vs. DPP4i cohort, the CFD incidence was 9.76 and 12.58 per 1000 person-years respectively (p <.01). In the Cox model, the GLP-1RA group was associated with a significantly lower risk of incident CFD (HR 0.77 [95% CI 0.63-0.94]) than the DPP4i group. The SGLT2i group was associated with a significantly lower risk of incident CFD (HR 0.67 [95% CI 0.52-0.87]) than the DPP4i group.
CONCLUSIONS: In conclusion, compared to DPP4i, SGLT2i and GLP-1RAs were associated with significantly reduced risk of indecent CFD in real-world populations with T2D.
Conference/Value in Health Info
2025-09, ISPOR Real-World Evidence Summit 2025, Tokyo, Japan
Value in Health Regional, Volume 49S (September 2025)
Code
RWD276
Topic Subcategory
Health & Insurance Records Systems
Disease
SDC: Diabetes/Endocrine/Metabolic Disorders (including obesity)