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Peer-reviewedCC BY 4.0Frontiers in Endocrinology

Distinct temporal neuropsychiatric outcomes associated with GLP-1 receptor agonists versus SGLT2 inhibitors after acute kidney disease in type 2 diabetes

  • Yu-Chen Cheng1,2
  • Yuahn-Sieh Huang3
  • Jui-Yi Chen4,5,6
  • Vin-Cent Wu7,8
  • Ruei-Ming Chen9,10,11
  • Kuo-Cheng Lu12
  • Ko-Lin Kuo12,13,14
  • Chien-Lin Lu1,15
  • Cai-Mei Zheng16,17
  • Yi-Chou Hou1,18
18 affiliations
  1. 1School of Medicine, College of Medicine, Fu Jen Catholic University
  2. 2Department of Neurology, Fu Jen Catholic University Hospital, Fu Jen Catholic University
  3. 3Department of Biology and Anatomy, National Defense Medical Center
  4. 4Division of Nephrology, Department of Internal Medicine, Chi Mei Medical Center
  5. 5Department of Health and Nutrition, Chia Nan University of Pharmacy and Science
  6. 6Department of Public Health, College of Medicine, National Cheng Kung University
  7. 7Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital
  8. 8NSARF (National Taiwan University Hospital Study Group of Acute Renal Failure) and Taiwan Consortium for Acute Kidney Injury and Renal Diseases (CAKS)
  9. 9Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University
  10. 10Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University
  11. 11Department of Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei Medical University
  12. 12Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation
  13. 13School of Medicine, Tzu Chi University
  14. 14School of Post-Baccalaureate Chinese Medicine, Tzu Chi University
  15. 15Division of Nephrology, Department of Internal Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University
  16. 16Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University
  17. 17TMU Research Center of Urology and Kidney, Taipei Medical University
  18. 18Division of Nephrology, Department of Internal Medicine, Cardinal Tien Hospital
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Abstract

Background: Neurological and neuropsychiatric complications may persist after acute kidney disease (AKD), particularly among patients with type 2 diabetes mellitus (T2DM). Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) provide established cardiorenal benefits, their associations with neurological outcomes after AKD remain uncertain.

Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adults with T2DM and dialysis-requiring AKD receiving GLP-1RAs or SGLT2is were identified and balanced using 1:1 propensity score matching, yielding 3,398 patients in each group. Incident delirium and other neuropsychiatric outcomes were evaluated. The 90–365-day period was the primary analysis, with 90–180- and 90–720-day windows used to assess temporal patterns. Kaplan–Meier and multivariable Cox regression analyses were performed.

Results: During 90–365 days, GLP-1RA use was associated with better delirium-free survival than SGLT2i use (118/3,032 vs. 155/2,982 events; log-rank P = 0.009). This association remained significant after multivariable adjustment (adjusted hazard ratio [HR], 0.668; 95% CI, 0.488–0.914; P = 0.012). Statin use was independently associated with lower delirium risk (adjusted HR, 0.674; 95% CI, 0.492–0.924; P = 0.014), while exploratory analyses suggested a distinct association between LDL cholesterol of 100–129.9 mg/dL and delirium risk. In contrast, SGLT2i use showed a favorable association with depression during early follow-up, which attenuated over time. The GLP-1RA–delirium association was also attenuated by 90–720 days. Exploratory sensitivity analyses using non-overlapping follow-up intervals showed outcome-specific associations: adjusted differences in delirium were not significant, whereas depression and overall neurological complications were more frequent with GLP-1RA than with SGLT2i.

Conclusions: Among patients with dialysis-requiring AKD and T2DM, GLP-1RA and SGLT2i use showed outcome-specific associations with subsequent neuropsychiatric events. Although the primary analysis suggested a lower delirium risk with GLP-1RA, this association was not consistently observed in adjusted time-stratified analyses. These findings should be considered exploratory and require prospective validation.

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Cite

BibTeXRIS
BibTeX
@article{cheng2026distinct,
  title = {{Distinct temporal neuropsychiatric outcomes associated with GLP-1 receptor agonists versus SGLT2 inhibitors after acute kidney disease in type 2 diabetes}},
  author = {Yu-Chen Cheng and Yuahn-Sieh Huang and Jui-Yi Chen and Vin-Cent Wu and Ruei-Ming Chen and Kuo-Cheng Lu and Ko-Lin Kuo and Chien-Lin Lu and Cai-Mei Zheng and Yi-Chou Hou},
  journal = {Frontiers in Endocrinology},
  year = {2026},
  month = oct,
  doi = {10.3389/fendo.2026.1963944},
  url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1963944/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Distinct temporal neuropsychiatric outcomes associated with GLP-1 receptor agonists versus SGLT2 inhibitors after acute kidney disease in type 2 diabetes
AU  - Yu-Chen Cheng
AU  - Yuahn-Sieh Huang
AU  - Jui-Yi Chen
AU  - Vin-Cent Wu
AU  - Ruei-Ming Chen
AU  - Kuo-Cheng Lu
AU  - Ko-Lin Kuo
AU  - Chien-Lin Lu
AU  - Cai-Mei Zheng
AU  - Yi-Chou Hou
PY  - 2026
DA  - 2026/10/27
JO  - Frontiers in Endocrinology
DO  - 10.3389/fendo.2026.1963944
UR  - https://www.frontiersin.org/articles/10.3389/fendo.2026.1963944/full
AB  - Background: Neurological and neuropsychiatric complications may persist after acute kidney disease (AKD), particularly among patients with type 2 diabetes mellitus (T2DM). Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) provide established cardiorenal benefits, their associations with neurological outcomes after AKD remain uncertain.  Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adults with T2DM and dialysis-requiring AKD receiving GLP-1RAs or SGLT2is were identified and balanced using 1:1 propensity score matching, yielding 3,398 patients in each group. Incident delirium and other neuropsychiatric outcomes were evaluated. The 90–365-day period was the primary analysis, with 90–180- and 90–720-day windows used to assess temporal patterns. Kaplan–Meier and multivariable Cox regression analyses were performed.  Results: During 90–365 days, GLP-1RA use was associated with better delirium-free survival than SGLT2i use (118/3,032 vs. 155/2,982 events; log-rank P = 0.009). This association remained significant after multivariable adjustment (adjusted hazard ratio [HR], 0.668; 95% CI, 0.488–0.914; P = 0.012). Statin use was independently associated with lower delirium risk (adjusted HR, 0.674; 95% CI, 0.492–0.924; P = 0.014), while exploratory analyses suggested a distinct association between LDL cholesterol of 100–129.9 mg/dL and delirium risk. In contrast, SGLT2i use showed a favorable association with depression during early follow-up, which attenuated over time. The GLP-1RA–delirium association was also attenuated by 90–720 days. Exploratory sensitivity analyses using non-overlapping follow-up intervals showed outcome-specific associations: adjusted differences in delirium were not significant, whereas depression and overall neurological complications were more frequent with GLP-1RA than with SGLT2i.  Conclusions: Among patients with dialysis-requiring AKD and T2DM, GLP-1RA and SGLT2i use showed outcome-specific associations with subsequent neuropsychiatric events. Although the primary analysis suggested a lower delirium risk with GLP-1RA, this association was not consistently observed in adjusted time-stratified analyses. These findings should be considered exploratory and require prospective validation.
SN  - 1664-2392
ER  -