Effect of thiazolidinediones compared to other antidiabetic medications on incident dementia in people with type 2 diabetes: A target trial emulation study

Summary Background People with Type 2 diabetes mellitus (T2DM) are at increased risk of developing dementia. Evidence suggests that thiazolidinediones (TZDs) may be protective for dementia onset including Alzheimer's disease and vascular dementia, compared to other second-line antidiabetic medications (SAMs). However, causality remains uncertain due to methodological limitations. We examined the effect of TZD on the risk of vascular dementia and all-cause dementia in T2DM, compared to other second-line treatments. Methods We emulated a pragmatic randomised trial using UK primary care data, Clinical Practice Research Datalink Aurum, between 2003 and 2023 to estimate the comparative effectiveness of initiating a TZD, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, or sulfonylurea (SU) against incident dementia in T2DM adults on metformin therapy. Patients were followed for up to 5 years from 180 days after their first SAM prescription. We used overlap weighting to adjust for baseline confounding and fitted double robust Cox models to estimate adjusted hazard ratios (aHRs). Findings This study included 124,311 participants (mean age 63 years, 61% males, and 20% whites), of whom 595 developed vascular dementia and 1,678 developed all-cause dementia during follow-up. On top of metformin, 8,669 initiated TZD, 30,216 initiated DPP-4 inhibitors, 55,997 initiated SU and 29,429 initiated SGLT2 inhibitors. TZD were associated with a similar risk of vascular dementia compared with DPP-4 inhibitors (aHR 0.89;95% CI 0.36-2.23) and SU (0.58;0.24-1.42). SGLT2 inhibitors were associated with a lower risk of vascular dementia than TZD (0.29;0.09-0.94), DPP-4 inhibitors (0.25;0.10-0.64), and SU (0.17;0.07-0.40). Most patterns persisted in all-cause dementia: SGLT2 inhibitors vs DPP-4 inhibitors (0.51;0.26-0.99) and SGLT2 inhibitors vs SU (0.35;0.18-0.67), with no difference observed between SGLT2 inhibitors and TZDs. Interpretation Dementia risk was similar for TZDs, DPP-4 inhibitors and SUs but was significantly lower for SGLT2 inhibitors, a finding that warrants further investigation. Considering potential cognitive effects when selecting therapies for T2DM is important in an ageing population.