Accelerated cognitive decline in type 2 diabetes

Abstract

Globally, the prevalence of type 2 diabetes is high and rising. Improvements in diabetes treatment have led to increased longevity and, thus, a prolonged disease duration for people with type 2 diabetes. Comorbidities and complications are common, particularly in older adults. Cognitive impairment is increasingly recognized as an important complication of type 2 diabetes. However, this co-existence is often unrecognized, leading to underdiagnosing cognitive impairment in type 2 diabetes. This is unfortunate, since cognitive impairment can negatively impact diabetes self-management and increases the risk of treatment-related complications such as hypoglycemic events. In this thesis, we investigated accelerated cognitive decline in type 2 diabetes across three parts:

Part 1: Risk factors of accelerated cognitive decline in patients with type 2 diabetes Understanding the mechanisms behind accelerated cognitive decline is crucial for developing effective prevention strategies. Our research showed that females with type 2 diabetes had a higher risk of cognitive decline compared to males. We investigated numerous risk factors, however within the scope of our research, only depressive symptoms explained part of this sex-related risk difference. We also explored the role of chronic kidney disease in cognitive dysfunction in type 2 diabetes. Our findings revealed associations between impaired kidney function, kidney damage, and cognition. However, the impact of chronic kidney disease on cognition was limited.

Part 2: Prediction and detection of cognitive impairment in patients with type 2 diabetes Only recently, clinical guidelines in diabetes have begun to emphasize the importance of cognitive impairment in diabetes. Prediction models like the diabetes-specific dementia risk score (DSDRS) can detect who has a high risk of developing dementia in the future. We found that the DSDRS could also predict who is at high risk for concurrent cognitive dysfunction (i.e. at the moment of risk assessment) and 2.5 years later. It was also able to detect more subtle forms of cognitive impairment. This predictive ability could facilitate the identification of patients at risk of cognitive decline, offering valuable support for future prevention strategies and clinical trials.

Part 3: Prevention of accelerated cognitive decline with DPP-4 inhibitors in patients with type 2 diabetes The DPP-4 inhibitor belongs to a class of incretin-based anti-diabetic drugs that may have possible non-glycemic effect on the brain. There have been few randomized controlled trials (RCTs) designed to investigate the non-glycemic effects of pharmacological interventions on cognition in type 2 diabetes. The CARMELINA (NCT01897532) and CAROLINA (NCT01243424) cognition substudies were designed to evaluate the effect of linagliptin, a DPP-4 inhibitor, versus placebo or glimepiride, on the occurance of accelerated cognitive decline in patients with type 2 diabetes at high cardiovascular risk. For this, a novel quantitative cognitive outcome was used. Both studies found no evidence that linagliptin could prevent accelerated cognitive decline in these patients.