Comparative Effects of SGLT2 Inhibitors, Pioglitazone, DPP-4 Inhibitors, and Sulfonylureas on Dementia Risk in Type 2 Diabetes - 24/10/26

Doi : 10.1016/j.tjpad.2026.100691

Yu-Hsin Yen ^a,^{^{#
Yu-Hsin Yen and Fu-Shun Yen contributed equally in this work.}} , James Cheng-Chung Wei ^b,^c,^d , Yao-Min Hung ^r,^s,^t,^u , Shih-Yi Lin ^e , Fu-Shun Yen ^f,^{^{#
Yu-Hsin Yen and Fu-Shun Yen contributed equally in this work.}} , Heng-Jun Lin ^g,^h , Yu-Han Huang ^g,^h , Der-Yang Cho ^i,^j,^k , Chii-Min Hwu ^l,^m,^⁎ , Chih-Cheng Hsu ^n,^o,^p,^q,^⁎

^a Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore

^b Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Rd., South District, Taichung City 40201, Taiwan

^c Institute of Medicine, Chung Shan Medical University, Taichung City 40201, Taiwan

^d Graduate Institute of Integrated Medicine, China Medical University, Taichung 40402, Taiwan

^e Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, 160, Sec. 3, Taichung-Kang Road, Taichung 407, Taiwan

^f Dr. Yen’s Clinic, No. 15, Shanying Road, Gueishan District, Taoyuan 33354, Taiwan

^g Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan

^h College of Medicine, China Medical University, Taichung, Taiwan

ⁱ Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung, 404327, Taiwan

^j Department of Neurosurgery, China Medical University Hospital, Taichung, 404327, Taiwan

^k Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404327, Taiwan

^l Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, No.155, Sec.2, Linong Street, Taipei 11221, Taiwan

^m Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Road, Beitou District, Taipei 11217, Taiwan

ⁿ Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan

^o Department of Health Services Administration, China Medical University, Taichung 40402, Taiwan

^p Department of Family Medicine, Min-Sheng General Hospital, 168 ChingKuo Road, Taoyuan 33044, Taiwan

^q National Center for Geriatrics and Welfare Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan

^r Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

^s College of Health and Nursing, Meiho University, Pingtung, Taiwan

^t Master Program in Biomedicine, College of Science and Engineering, National Taitung University, Taitung, Taiwan

^u Fooyin University College of Nursing, Kaohsiung, Taiwan

^⁎ Corresponding authors at: Chih-Cheng Hsu, Institute of Population Health Sciences, National Health Research Institutes Institute of Population Health Sciences National Health Research Institutes ^⁎⁎ Corresponding authors at: Chii-Min Hwu, Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital Section of Endocrinology and Metabolism Department of Medicine Taipei Veterans General Hospital

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Abstract

INTRODUCTION

Dementia risk is significantly amplified by type 2 diabetes (T2D). This study compares the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2is) against pioglitazone, dipeptidyl peptidase-4 inhibitors (DPP-4is), and sulfonylureas on dementia risk.

METHODS

Using Taiwan’s National Health Insurance Research Database (2000–2021), researchers emulated target trials with propensity-score matching. Cox proportional-hazards and Kaplan-Meier analyses estimated adjusted hazard ratios (aHRs) for dementia subtypes.

RESULTS

Over a mean follow-up of 2.9 years, SGLT2i users had significantly lower cumulative incidences of all-cause and vascular dementia (all log-rank p < 0.05). Compared to pioglitazone, SGLT2i use was associated with lower risks of all-cause dementia (aHR 0.78, 95% CI 0.73–0.83) and vascular dementia (aHR 0.83, 95% CI 0.69–0.99). Alzheimer's risk reductions were not statistically significant.

DISCUSSION

In these nationwide emulated trials, SGLT2is were associated with lower risks of all-cause and vascular dementia compared with pioglitazone, DPP-4is, and sulfonylureas.

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Key words : all-cause dementia, Alzheimer’s disease, vascular dementia, sodium–glucose cotransporter-2 inhibitors, pioglitazone, dipeptidyl peptidase-4 inhibitors, sulfonylureas, type 2 diabetes

Abbreviations : T2D, SGLT2is, DPP-4is, GLP-1 RAs, ACEI, ARB