Title: People living with Diabetes Mellitus and Intermediate Hyperglycaemia: risk of infections, and effects of average level and variability of glycated haemoglobin (HbA1c) on this risk, in people of different ethnic groups
Funder: Department of Health and Social Care

Abstract: Background: Infections are common in people with diabetes and can substantially affect quality of life. Previous studies have evaluated infections but mostly among older people with type 2 diabetes (T2DM). Further data on absolute risks of infection by characteristics such as age, sex, ethnicity or clinical factors could help target intervention development to those at highest risk and inform policy decisions e.g. for shielding in any future pandemic. Improved characterisation of how glycated haemoglobin (HbA1c) is associated with poor infection outcomes (e.g. average and variability in HbA1c) could also be used to develop prognostic scores and guide management. Using a large, extensive dataset, we now intend to estimate i) risks of infections in specific patient groups (T2DM, T1DM and those with pre-diabetes or &ldquo;intermediate hyperglycaemia&quot;; IH), and how these risks vary by ethnicity and other characteristics among people with T1DM, T2DM and IH); ii) how long-term glycaemic control and fluctuations in control (HbA1c) affect these risks. Methods: We plan to use the Clinical Practice Research Datalink (CPRD) primary care database, linking to Hospital Episode Statistics (HES) and Office of National Statistics (ONS) Mortality. We will obtain 3 separate cohorts of people with diagnosed diabetes (T1DM, T2DM) or evidence of IH, age-sex matched to people without DM or IH from the same practice (control cohort). The primary cohort will include patients who were actively registered as of 1/1/2015, followed to the end of 2019 (before the COVID-19 pandemic). A secondary cohort actively registered as of 1/1/2020 will be created to study COVID-19. We will use Read codes to identify people with diabetes, and also measurements of HbA1c or fasting blood glucose to identify those with IH. Our main outcomes will be infections identified by Read codes accompanied by a relevant prescription. We will investigate risk of hospitalisation for infection, and infection-related mortality through linkage to HES and ONS. We will estimate event rates for specific infections and infections overall during 2015-2019 (2020-2021 for COVID-19) using Poisson regression to adjust for confounders. Where possible multiplicative statistical interaction will be explored by adding cross-product terms to models and comparing models with and without these terms. To investigate associations with glycaemic control, we will estimate both average (mean) and variability (covariance) in HbA1c primarily focused on recordings made during the last 4 years among eligible patients, including these estimates in multivariable models. We will stratify all results by age and sex. Dissemination, Impact and Public Patient Involvement (PPI): Patients helped develop our proposal and we have established a Patient Study Advisory Group to inform our analyses and develop dissemination plans. We will use our networks, local/national diabetes groups, and NIHR South London Applied Research Consortium to disseminate our findings. Our work could refine targets for glycaemic control to include a focus on reducing instability in HbA1c, and help target future interventions to those patients at highest risk. Finally, better understanding of infection risks in people with diabetes from different ethnic groups could inform responses to future waves of COVID-19 and other pandemics (potentially influenza).

Lay abstract: Most people living with diabetes (PLWD) and their doctors worry about developing conditions like heart attacks, strokes, or eye and kidney damage. Improvements in diabetes care by keeping blood sugar levels lower, and using drugs to help prevent heart attacks and strokes (like statins, aspirin, and blood pressure lowering drugs) are reducing these problems. However, PLWD are more likely to get infections, especially bacterial and fungal infections. Some studies suggest that PLWD might be getting more serious infections than previously. COVID-19 has recently focused attention on infection in PLWD and highlighted that people from ethnic minorities are more likely to get severely ill and die. Although there are many explanations for this, for some people this is linked to their diabetes, which is more common in people from some ethnic groups. We will use UK data collected by GPs, data from hospitals and national statistics (death data). Our research team has already worked extensively on diabetes and infections using similar data, however we previously focused mainly on type 2 diabetes. We found that overall, PLWD were about 2-3 times more likely to be treated in hospital for many potentially serious infections, such as skin, bone and joint, respiratory and urinary tract infections, and sepsis (blood poisoning). While we observed potentially higher risks for people with type 1 diabetes, this only included patients aged 40 and over, so we could not provide a comprehensive picture. Our previous work was also unable to consider risks by different ethnic groups, but recent data recording improvements now make this possible. For people with type 2 diabetes, both high longer-term blood sugar levels (HbA1c) and changes in HbA1c levels over time were found to increase the chances of getting serious infections. We are now planning to examine the links between living with diabetes, high HbA1c, and changes over time in HbA1c, and infection risk for all PLWD and in different ethnic groups. Diabetes UK have identified this as a priority research area. We have started involving PLWD and we will develop this involvement further including a patient advisory group to inform the project throughout its timeline and help with dissemination. Our work has important clinical implications; we previously showed that less stable levels of blood sugars may be more important than higher sugar levels in increasing risks of infections and other complications and premature death in people with type 2 diabetes, yet targets for control focus most on HbA1c levels, not on reducing instability. Our work could also help development of future interventions specifically to reduce infections in PLWD. Finally, better knowledge of infection risks and their links with diabetes and ethnicity would inform the response to any future waves of COVID-19 and similar pandemics.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: METABOLIC AND ENDOCRINE