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. 2024 Aug;20(8):5528-5539.
doi: 10.1002/alz.14048. Epub 2024 Jul 3.

Heterogeneous treatment effects of sodium-glucose cotransporter 2 inhibitors on risk of dementia in people with type 2 diabetes: A population-based cohort study

Huilin Tang  1 , William T Donahoo  2 , Mikael Svensson  1   3 , C Elizabeth Shaaban  4   5 , Glenn Smith  6   7 , Michael S Jaffee  7   8 , Yu Huang  9 , Xia Hu  10 , Ying Lu  1 , Ramzi G Salloum  9 , Steven T DeKosky  7   8 , Jiang Bian  9 , Jingchuan Guo  1   3
Affiliations

Heterogeneous treatment effects of sodium-glucose cotransporter 2 inhibitors on risk of dementia in people with type 2 diabetes: A population-based cohort study

Huilin Tang et al. Alzheimers Dement. 2024 Aug.

Abstract

Introduction: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exhibit potential benefits in reducing dementia risk, yet the optimal beneficiary subgroups remain uncertain.

Methods: Individuals with type 2 diabetes (T2D) initiating either SGLT2 inhibitor or sulfonylurea were identified from OneFlorida+ Clinical Research Network (2016-2022). A doubly robust learning was deployed to estimate risk difference (RD) and 95% confidence interval (CI) of all-cause dementia.

Results: Among 35,458 individuals with T2D, 1.8% in the SGLT2 inhibitor group and 4.7% in the sulfonylurea group developed all-cause dementia over a 3.2-year follow-up, yielding a lower risk for SGLT2 inhibitors (RD, -2.5%; 95% CI, -3.0% to -2.1%). Hispanic ethnicity and chronic kidney disease were identified as the two important variables to define four subgroups in which RD ranged from -4.3% (-5.5 to -3.2) to -0.9% (-1.9 to 0.2).

Discussion: Compared to sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of all-cause dementia, but the association varied among different subgroups.

Highlights: New users of sodium-glucose cotransporter 2 (SGLT2) inhibitors were significantly associated with a lower risk of all-cause dementia as compared to those of sulfonylureas. The association varied among different subgroups defined by Hispanic ethnicity and chronic kidney disease. A significantly lower risk of Alzheimer's disease and vascular dementia was observed among new users of SGLT2 inhibitors compared to those of sulfonylureas.

Keywords: Alzheimer's disease; SGLT2 inhibitors; dementia; heterogeneous treatment effects; sulfonylureas; type 2 diabetes.

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Conflict of interest statement

H.T. is supported by the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation Predoctoral Fellowship and American Foundation for Pharmaceutical Education (AFPE) Predoctoral Fellowship. C.E.S. reports that she is funded by National Institute on Aging (NIA; K01AG071849) and she is also the Chair of the ISTAART Professional Interest Area to Elevate Early Career Researchers and Co‐Chair of the ISTAART Sex and Gender Interest Group, Diversity and Disparities Professional Interest Area. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. S.T.D. received royalty from UpToDate and consulting fee from Brainstorm Cell Therapeutics; he also participated on the Acumen Pharmaceuticals Medical Advisory Board, Biogen Data Safety Monitoring Board (DSMB), Cognition Therapeutics Medical Advisory Board, Prevail Pharmaceuticals DSMB, and Vaccinex Medical Advisory Board; they are outside of the current work. J.B. is supported by NIA (1R01AG076234) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK133465). J.G. is supported by NIDDK (R01DK133465). She received consulting fees from Pfizer Inc. (outside the current work). All other authors declare no conflict of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Flowchart of patient selection. SGLT2 inhibitor, sodium‐glucose cotransporter 2 inhibitor.
FIGURE 2
FIGURE 2
A single decision tree was developed to identify the absolute risk change in risk of all‐cause dementia associated with sodium‐glucose cotransporter 2 (SGLT2) inhibitors versus sulfonylureas in people with type 2 diabetes, based on baseline characteristics of patients in the OneFlorida+ (N = 35,458). Negative values indicate reduced absolute risk of all‐cause dementia (benefit from SGLT2 inhibitors), whereas positive values indicate increased absolute risk of all‐cause dementia (harm from SGLT2 inhibitors). CKD, chronic kidney disease.
FIGURE 3
FIGURE 3
Predicted individualized treatment effect (ITE, treatment effect on person level) of sodium‐glucose cotransporter 2 (SGLT2) inhibitors versus sulfonylureas on the risk of developing all‐cause dementia. The predicted ITE is presented as risk difference in the risk of all‐cause dementia between SGLT2 inhibitors versus sulfonylureas (Y‐axis). The predicted ITE is stratified into deciles (X‐axis). A total of 33,212 (93.7%) individuals had negative predicted ITE (benefit from SGLT2 inhibitors).
FIGURE 4
FIGURE 4
Sensitivity analyses of absolute risk difference for all‐cause dementia for sodium‐glucose cotransporter 2 (SGLT2) (inhibitors versus sulfonylureas in the overall population and subgroups identified using a single decision tree model. CI, confidence interval; CKD, chronic kidney disease; CeVD, cerebrovascular disease.
FIGURE 5
FIGURE 5
A summary of results of conditional average treatment effects from a single decision tree model regarding the absolute risk change in risk of Alzheimer's disease and vascular dementia associated with sodium‐glucose cotransporter 2 (SGLT2) inhibitors versus sulfonylureas in people with type 2 diabetes. Negative values indicate reduced absolute risk of vascular dementia (benefit from SGLT2 inhibitors), whereas positive values indicate increased absolute risk of vascular dementia (harm from SGLT2 inhibitors). SGLT2i, SGLT2 inhibitors; SU, sulfonylureas.
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References

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