Cardiovascular effectiveness and safety of SGLT2 inhibitors vs DPP4 inhibitors by dementia status: a cohort study of older adults with diabetes
- 08-11-2025
- Dementia
- Article
Published in:
- Authors
- Che-Yuan Wu
- Abhinav Sharma
- Jodi D. Edwards
- Peter P. Liu
- Moira K. Kapral
- Nathan Herrmann
- C. Fangyun Wu
- Sho Podolsky
- Walter Swardfager
- Baiju R. Shah
- Published in
- Diabetologia | Issue 2/2026
Abstract
Aims/hypothesis
People with dementia are at a higher risk of inappropriate medication use; however, limited data inform clinical outcomes of sodium–glucose cotransporter 2 inhibitor (SGLT2i) use in people with diabetes and comorbid dementia. We aim to investigate cardiovascular effectiveness and safety of SGLT2i vs dipeptidyl peptidase-4 inhibitors (DPP4i) in older community-dwelling adults with diabetes by dementia status.
Methods
This population-based, target trial emulation cohort study used linkable administrative datasets of residents of Ontario, Canada. Eligible initiators of SGLT2i or DPP4i with diabetes aged ≥66 years (2016–2022) were stratified by dementia status and matched 1:1 on propensity score. The primary cardiovascular effectiveness outcome was composite of all-cause mortality or hospitalisation for ischaemic stroke, myocardial infarction or heart failure. We also investigated eight safety outcomes potentially related to SGLT2i. Incidence rate differences (IRDs) per 1000 person-years and the 95% CIs were estimated. Homogeneity in IRDs between strata was assessed using the Cochran’s Q statistic. One year number needed to treat (NNT) or harm (NNH) was also estimated using the Aalen-Johansen estimator with death as a competing risk.
Results
We analysed 2481 pairs with dementia and 52,196 pairs without dementia. The absolute reduction in the composite effectiveness endpoint with SGLT2i vs DPP4i initiation was greater among those with dementia (IRD [95% CI] −61.1 [−78.2, −43.9]; NNT: 20), compared to no dementia (IRD −21.7 [−23.7, −19.7]; NNT: 43; homogeneity: p<0.001). Across the individual effectiveness endpoints, SGLT2i vs DPP4i initiation in people with dementia was associated with reduced all-cause mortality (IRD −51.2 [−65.7, −36.7]; NNT: 25) and hospitalisation for heart failure (IRD −16.4 [−24.6, −8.2]; NNT: 99). For safety outcomes, SGLT2i vs DPP4i initiators with dementia showed less acute kidney injury (IRD −39.7 [−55.0, −24.4]; NNT: 76) and increased genital infection (IRD 9.7 [3.7, 15.6]; NNH: 64). The absolute increase in diabetic ketoacidosis (IRD 1.1 [0.7, 1.6] vs 5.9 [2.1, 9.8]; NNH: 785 vs 109; homogeneity: p=0.015) with SGLT2i was greater among those with dementia vs no dementia.
Conclusions/interpretation
While SGLT2i might provide cardiorenal protection among those with dementia, closer monitoring may be warranted due to greater susceptibility to diabetic ketoacidosis.
Graphical Abstract
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- Title
- Cardiovascular effectiveness and safety of SGLT2 inhibitors vs DPP4 inhibitors by dementia status: a cohort study of older adults with diabetes
- Authors
-
Che-Yuan Wu
Abhinav Sharma
Jodi D. Edwards
Peter P. Liu
Moira K. Kapral
Nathan Herrmann
C. Fangyun Wu
Sho Podolsky
Walter Swardfager
Baiju R. Shah
- Publication date
- 08-11-2025
- Publisher
- Springer Berlin Heidelberg
- Published in
-
Diabetologia / Issue 2/2026
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428 - DOI
- https://doi.org/10.1007/s00125-025-06595-0
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