It is estimated that the number of individuals affected by dementia, a general term for loss of memory, language, problem-solving and other thinking abilities that are severe enough to interfere with daily life, worldwide was about 57 million in 2019, which is expected to reach 153 million by 2050. Diabetes, a condition that has trouble regulating the amount of sugar in the blood, has been associated with an approximately 2-fold increase in the relative risk of cognitive decline and dementia later in life, while younger age at the onset of diabetes mellitus, worse glucose control and a history of severe hypoglycaemia (a low blood sugar level) episodes have been reported as contributing factors. It appears that the use of two different glucose-lowering drugs, Sodium-glucose Cotransporter-2 (SGLT-2) Inhibitors and Glucagon-like Peptide-1 (GLP-1) Receptor Agonists, might be associated with a neuroprotective potential in the context of diabetes. If this is confirmed, it might have important clinical and public health implications for everyday practice, considering the prevalence and associated-ramifications of dementia-related disorders. Therefore, we plan to perform a population-based cohort study in CPRD Aurum to compare the risk of all-cause dementia, Alzheimer’s disease, and vascular dementia between (i) SGLT2 inhibitors and (ii) GLP-1 receptor agonists against Dipeptidyl Peptidase IV (DPP-4) inhibitors, another glucose-lowering drug, among people with type 2 diabetes.
Aims:
To investigate whether the use of SGLT2 inhibitors or GLP1 receptor agonists is associated with the risk of dementia, compared to DPP4 inhibitors.
Methods:
We will perform two cohort studies using a new-user design to investigate the effects of SGLT2 inhibitors or GLP1 receptor agonists separately. Propensity score fine stratification weighting will be applied to create a pseudo-comparator group with similar characteristics as the exposed group. Competing risk Cox proportional hazard regression models will be used to calculate crude hazard ratios (crude HRs) and adjusted hazard ratios (adjusted HRs), together with their corresponding 95% CIs. Death during the follow-up period will be treated as a competing event.
Outcomes:
The primary outcome is all-cause dementia. The secondary outcomes are the two main subtypes of dementia, Alzheimer’s disease and vascular dementia.
Exposure and comparator:
SGLT2 inhibitors users will be compared to DPP4 inhibitors users in SGLT2 Cohort, while GLP1 receptor agonists users will be compared to DPP4 inhibitors users in GLP1 Cohort.
Participants:
Individuals with a diagnosis of type 2 diabetes aged 40 years and over who received SGLT2, GLP1 receptor agonists, or DPP4 will be eligible for this study. Those with a record of CKD stage 5 will be excluded from this study. All participants must have been registered with the general practice for at least one year before the index date (start of follow-up).
Covariates:
Sociodemographic characteristics, behavioural risk factors, diabetes-related characteristics, comorbidities, biomarkers, and drug prescriptions will be adjusted to account for residual confounding.
Intended public health benefits:
If the neuroprotective effect of SGLT2 inhibitors and GLP1 agonists is confirmed, it might have important clinical and public health implications for everyday practice, considering the prevalence and associated ramifications of dementia-related disorders. Conversely, it means that all three medicines are safe to prescribe in practice.
The primary outcome is all-cause dementia. The secondary outcomes are the two main subtypes of dementia, Alzheimer’s disease and vascular dementia. Outcome events have to occur after the onset of diabetes. Individuals with a record of target outcome event in each cohort will be excluded from analyses.
Krishnarajah Nirantharakumar - Chief Investigator - University of Birmingham
Jingya Wang - Corresponding Applicant - University of Birmingham
Konstantinos Toulis - Collaborator - University of Birmingham
Krishna Gokhale - Collaborator - University of Birmingham
Nicola Adderley - Collaborator - University of Birmingham
Practice Level Index of Multiple Deprivation