Diabetes is a major, growing health problem worldwide: in 2015, 415 million adults worldwide were estimated to have diabetes, with the figure projected to reach 642 million by 2040. As people live longer with diabetes, their risk of developing dementia increases compared to the general population. It is not clear exactly why this is, although problems with control of blood sugar, and other co-existing health conditions may play a role. Some research suggests that being on metformin a medication to lower blood sugar seems to protect against the risk of developing dementia. However, not all studies fully account for differences between people prescribed different antidiabetic medications, which may explain peoples different risks of developing dementia. In this study, we will use UK healthcare data to follow older individuals with newly diagnosed diabetes to investigate whether being on metformin compared to other oral antidiabetic medications is associated with lower risks of dementia and mild cognitive impairment, while controlling for other factors linked to dementia. If we see a reduction in dementia risk with metformin, we will investigate whether this is due to effects on lowering blood sugar or to other effects such as reducing infections. Our study will provide evidence for any relative benefits of metformin compared to other antidiabetic medications among people who are at higher risk of dementia. It will also help to inform the design of future studies into dementia prevention.
Globally, diabetes prevalence is expected to rise from 415 million in 2015 to 642 million by 2040. Gains in life expectancy have contributed to a diversification of diabetes-related morbidity, including effects on cognition and dementia. A systematic review and meta-analysis of 14 cohort studies showed that people with type 2 diabetes had a 60% greater risk of developing dementia those without diabetes. Dementia risk in people with diabetes is likely to be mediated through multiple mechanisms including hyperinsulinaemia, chronic hyperglycaemia and systemic inflammation. This can lead to pro-inflammatory microglial activation and accumulation of the beta amyloid and tau pathologies characteristic of Alzheimers disease and other dementias. While some evidence suggests a potential protective effect of the oral hypoglycaemic agent metformin on dementia risk, existing studies show varying results and may be limited by inadequate control for confounding.
In this cohort study, we will use routinely collected primary and secondary care data to investigate the effect of metformin versus other oral antidiabetic agents newly prescribed to older individuals with incident type 2 diabetes on rates of incident dementia and mild cognitive impairment in a new user active comparator design. We will use multivariable Cox proportional hazards regression to adjust for potential confounding factors and will undertake a range of sensitivity analyses to test the validity of our assumptions. We will also explore whether any effect of metformin is mediated through its glucose-lowering actions or through effects on immunomodulation.
While NICE recommends metformin use as the initial treatment for adults with type 2 diabetes, it may be less frequently used among older people or in particular ethnic groups or settings. This study will provide evidence to guide prescribing of antidiabetic medications among individuals at higher risk of dementia, and will inform further research into dementia prevention strategies.
Primary outcome
1. Incident all-cause dementia
Secondary outcomes
2. Incident mild cognitive impairment
3. Incident dementia by subtype (vascular dementia, Alzheimer?s disease, other specified cause of dementia, mixed/ unspecified dementia)
Charlotte Warren-Gash - Chief Investigator - London School of Hygiene & Tropical Medicine ( LSHTM )
Louis Tunnicliffe - Corresponding Applicant - London School of Hygiene & Tropical Medicine ( LSHTM )
Carol Brayne - Collaborator - University of Cambridge
Christopher Rentsch - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Dylan Williams - Collaborator - University College London ( UCL )
Krishnan Bhaskaran - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Liam Smeeth - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Louis Tunnicliffe - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Nishi Chaturvedi - Collaborator - University College London ( UCL )
Rohini Mathur - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Rutendo Muzambi - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Sophie Eastwood - Collaborator - University College London ( UCL )
Susanna Dunachie - Collaborator - University of Oxford
William Doran - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Carol Brayne - Collaborator - University of Cambridge
Christopher Rentsch - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Dylan Williams - Collaborator - University College London ( UCL )
Krishnan Bhaskaran - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Liam Smeeth - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Louis Tunnicliffe - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Nishi Chaturvedi - Collaborator - University College London ( UCL )
Rohini Mathur - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Rutendo Muzambi - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
Sophie Eastwood - Collaborator - University College London ( UCL )
Susanna Dunachie - Collaborator - University of Oxford
William Doran - Collaborator - London School of Hygiene & Tropical Medicine ( LSHTM )
HES Admitted Patient Care;ONS Death Registration Data;Patient Level Index of Multiple Deprivation;Practice Level Index of Multiple Deprivation