Risk of dementia after initiation of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in adults aged 40-69 years with type 2 diabetes: population based cohort study

• Published in: BMJ (Online) 2024-08, Vol.386, p.e079475
• Main Authors: Shin, Anna, Koo, Bo Kyung, Lee, Jun Young, Kang, Eun Ha
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alzheimer's disease; Arthritis; Cardiovascular diseases; Clinical trials; Codes; Cognitive ability; Cohort analysis; Cohort Studies; Comorbidity; Dementia; Dementia - epidemiology; Dementia disorders; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - epidemiology; Dipeptidyl-Peptidase IV Inhibitors - adverse effects; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Disease; Drugs; Emergency medical care; Eye surgery; Female; Glucose; Health care policy; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - therapeutic use; Incidence; Male; Metformin; Middle Aged; National health insurance; Neurodegenerative diseases; Observational studies; Osteoarthritis; Population studies; Propensity Score; Proportional Hazards Models; Ratios; Republic of Korea - epidemiology; Risk Factors; Sodium-glucose cotransporter; Sodium-Glucose Transporter 2 Inhibitors - adverse effects; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Surgery; Vascular dementia
• ISSN: 1756-1833; 0959-8138; 1756-1833
• DOI: 10.1136/bmj-2024-079475

AbstractObjectiveTo compare the risk of dementia associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors in adults aged 40-69 years with type 2 diabetes.DesignPopulation based cohort study.SettingKorean National Health Insurance Service data, 2013-21.Participants110 885 propensity score matched pairs of adults with type 2 diabetes aged 40-69 years who were initiators of either an SGLT-2 inhibitor or a DPP-4 inhibitor.Main outcome measuresThe primary outcome was new onset dementia. Secondary outcomes were dementia requiring drug treatment and individual types of dementia, including Alzheimer’s disease and vascular dementia. Control outcomes were genital infections (positive), and osteoarthritis related clinical encounters and cataract surgery (negative). Hazard ratios and 95% confidence intervals (CIs) were estimated using Cox models. Follow-up time stratified analyses (>2 years and ≤2 years) and subgroup analyses by age, sex, concomitant use of metformin, and baseline cardiovascular risk were performed.Results110 885 propensity score matched pairs of initiators of an SGLT-2 inhibitor or a DPP-4 inhibitor were followed-up for a mean 670 (standard deviation 650) days, generating 1172 people with newly diagnosed dementia: incidence rate 0.22 per 100 person years in initiators of SGLT-2 inhibitors and 0.35 per 100 person years in initiators of DPP-4 inhibitors, with hazard ratios of 0.65 (95% CI 0.58 to 0.73) for dementia, 0.54 (0.46 to 0.63) for dementia requiring drugs, 0.61 (0.53 to 0.69) for Alzheimer’s disease, and 0.48 (0.33 to 0.70) for vascular dementia. The hazard ratios for the control outcomes were 2.67 (2.57 to 2.77) for genital infections, 0.97 (0.95 to 0.98) for osteoarthritis related encounters, and 0.92 (0.89 to 0.96) for cataract surgery. When calibrated for residual confounding measured by cataract surgery, the hazard ratio for dementia was 0.70 (0.62 to 0.80). The association was greater for more than two years of treatment (hazard ratio of dementia 0.57, 95% CI 0.46 to 0.70) than for two years or less (0.52, 0.41 to 0.66) and persisted across subgroups.ConclusionSGLT-2 inhibitors might prevent dementia, providing greater benefits with longer treatment. As this study was observational and therefore prone to residual confounding and informative censoring, the effect size could have been overestimated. Randomised controlled trials are needed to confirm these findings.