Therapeutic inertia for glycaemic and cardiovascular risk factor control in patients with type 2 diabetes: a real-world electronic medical records based study

People living with type 2 diabetes (T2DM) are known to have higher risk of developing atherosclerotic cardiovascular disease (ASCVD) as compared to the general population. In people with T2DM, ASCVD is a primary cause of mortality and incur significantly higher healthcare resource utilization as compared to those without ASCVD. Emerging evidence shows that cardiometabolic risk factor burden is growing in the global population; and those with early-onset T2DM have been associated with greater cardiometabolic risk factor burden. Guidelines advocate early initiation and intensification of antidiabetic medication for blood glucose control as a strategy to reduce the risk of developing ASCVD shown from high quality evidence. Additionally, adequate control of blood pressure and blood lipid risk factors are known to reduce ASCVD risk. However, there is often a delay in therapy initiation and intensification (therapeutic inertia) as opposed to guideline recommended timelines. The association of delay in pharmacological therapeutic management, cardiometabolic risk factor burden control and the risk of developing ASCVD is unclear, as well as how this differs among those with early- versus usual-onset T2DM and by baseline ASCVD risk. With a central focus on individual and simultaneous management of blood pressure, blood lipid and blood glucose risk factors, this thesis aimed to explore i) the temporal patterns of multimorbidity and cardiovascular risk factors at diagnosis of T2DM in adults of different age groups; ii) evaluate the therapeutic inertia in the management of hypertension and dyslipidaemia and the associated risk factor burden (blood pressure and blood lipids) from diagnosis of T2DM in different age groups and by baseline ASCVD risk; and iii) evaluate the association of therapeutic inertia and risk factor burden with long-term ASCVD risk in different age groups and by baseline ASCVD risk. Therapeutic inertia can only be ethically addressed through observational studies. Using a large primary care database from The Health Improvement Network (THIN) of the United Kingdom, 3 pharmaco-epidemiological studies and 2 methodological studies were conducted. Findings were reported in high impact journals including Diabetes, Obesity and Metabolism and the Journal of Healthcare Informatics Research. One study was reported in a news article in conjunction with a poster presentation at the European Association for the Study of Diabetes Conference 2020. The first methodological study extended current frameworks for extracting diabetes-related codes from diagnosis, prescription, laboratory, and care management data fields as well as formulated a clinically relevant algorithm to identify people with T2DM as appropriate for this project. The second methodological study investigated multiple imputation (MI) for missing risk factor data. MI by chained equations, two-fold MI, and MI with Monte Carlo Markov Chain were shown to produce similar clinical inferences based on imputed data when compared to complete case analyses for observational studies using EMRs. The first clinical study of 254,925 patients with incident T2DM showed stable ASCVD prevalence among all age groups from 2005-2016. Among 254,925 patients with incident T2DM from 2005-2016 in the second study, the prevalence of dsylipidaemia increased by 10% in those aged <60 years while hypertension prevalence remained stable in all age groups. Among sub-cohorts of those with high ASCVD risk at T2DM diagnosis and comorbid dyslipidemia (N = 168,365) or hypertension (N = 167,896), therapeutic inertia was highest in those aged 18-39 years and significantly lower among those aged 40+ years. Compared to those who initiated lipid-lowering and/or anti-hypertensive therapy within one year of T2DM diagnosis, those who initiated therapies after one year had 50-85% higher risk of continued risk factor control consistently over two years.   Understanding the persistence of therapeutic inertia and cardiometabolic risk-factor burden, the real-world evidence of therapeutic inertia and its possible association with atherosclerotic cardiovascular disease (ASCVD) outcomes and the changing practices in blood pressure, lipids and glycaemic control were simultaneously evaluated in incident young- and usual-onset type 2 diabetes (T2DM).  This third study among 113,529 people with incident T2DM, comorbid dyslipidaemia or hypertension, and no history of ASCVD within 2 years of T2DM diagnosis, showed that failure to control lipid, blood pressure and HbA1c over two years was associated with higher ASCVD hazard at all levels of risk-factor burden compared with usual-onset. Those with young-onset T2DM had consistently higher hazard of ASCVD at all levels of risk-factor burden compared with usual-onset T2DM. In people with newly diagnosed T2DM and no prior history of ASCVD, failure of multifactorial cardiometabolic risk factor control from early in the diagnosis significantly increases the ASCVD risk with lipid control failure associated with the highest ASCVD risk, particularly in young-onset T2DM. Multifactorial and simultaneous control need to be promoted in patients with diabetes to ensure shorter-term microvascular and longer-term macrovascular risk is managed well. Addressing other risk factors are as important as addressing diabetes itself for reducing ASCVD risk. The results of this study suggest the need for revisiting the guidelines for lipid and hypertension control in young-onset T2DM population irrespective of baseline risk.