Effect of randomised blood pressure lowering treatment and intensive glucose control on dementia and cognitive decline according to baseline cognitive function and other subpopulations of individuals with type 2 diabetes: Results from the ADVANCE trial.

Background and aims: Accumulating evidence indicates that reducing high blood pressure (BP) prevents dementia and mild cognitive impairment (MCI). Furthermore, although diabetes is a risk factor for dementia and MCI, there is uncertainty of the effect of intensive glucose control on these endpoints. This study aimed to determine the effects of BP-lowering (vs placebo) and intensive glucose-lowering (vs standard control) treatments according to baseline cognition and other characteristics on dementia and cognitive decline (CD) in people with type 2 diabetes mellitus (T2DM). Methods: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial involved 11,140 individuals with T2DM. The effects of BP-lowering and intensive glucose-lowering treatments were explored in subgroups of baseline Mini-Mental State Examination (MMSE), categorised as cognitively normal (scores ≥28) and cognitive impairment (scores <28). The primary outcome was a composite of dementia/CD that accounted for the competing risk of death. Multinomial regression models, adjusted for common cardiovascular risk factors, were used to estimate odds ratios (OR) with 95 % confidence intervals (CI) of the effects of the treatments on dementia/CD. Homogeneity of effects by subgroups were evaluated using interaction terms in the models. A two-sided p value <0.05 was regarded as statistically significant. Results: BP-lowering treatment (vs. placebo) was associated with a lower odds of dementia/CD in participants with cognitive impairment (OR 0.76, 95 % CI (0.59-0.99)) but not in those cognitively normal (OR 1.05, 95 % CI (0.92-1.21); p for interaction 0.03). Those with a history of cardio-renal-metabolic syndrome did not experience a benefit of active BP lowering treatment compared with placebo on dementia/CD. There were no further subgroup effects of BP-lowering treatment. The effect of intensive glucose lowering (vs standard control) on the odds of dementia/CD did not vary by baseline cognition subgroup. However, it did vary by level of blood glucose at baseline (<7.9 mmol/L OR 1.12, 95 % CI (0.96-1.30) vs ≥ 7.9 mmol/L 0.87 (0.75-1.00); p for interaction 0.02) and duration of T2DM (<10 years OR 0.92 (0.81-1.05) vs ≥10 years 1.16 (0.97-1.38); p for interaction 0.04). Conclusions: This study suggests greater effects of BP-lowering treatment in those with early loss of cognitive function than in those cognitively normal. There were also differential effects of intensive glucose-lowering on dementia and CD according to levels of blood glucose and duration of diabetes in people with T2DM. Clinical trial registration: ADVANCE is registered with ClinicalTrials.gov: number NCT00145925.