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Olga Montvida, Msc Student Number: 9341625

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Olga Montvida, Msc Student Number: 9341625 EVALUATION OF CARDIO-METABOLIC EFFECTS OF TREATMENT WITH INCRETIN-BASED THERAPIES IN PATIENTS WITH TYPE 2 DIABETES Olga Montvida, MSc Student number: 9341625 Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy School of Biomedical Sciences Institute of Health and Biomedical Innovation Faculty of Health Queensland University of Technology 2018 ABSTRACT Type 2 diabetes (T2DM) is a chronic and progressive metabolic disorder with a complex and multifactorial pathophysiology. As patients with T2DM are at increased risk of cardiovascular (CV) complications and mortality, efficient disease management requires a holistic multi- faceted approach to control blood glucose, blood pressure, lipids, and body weight. While metformin has been suggested as the first-line anti-diabetic drug (ADD), given the progressive nature of the disease, many patients eventually require intensification. International guidelines suggest multiple options for second- and third-line ADDs, including incretin-based therapies: dipeptidyl peptidase 4 inhibitor (DPP-4i) and glucagon-like peptide-1 receptor agonist (GLP- 1RA). While current disease management guidelines are primarily based on results from randomised controlled trials that are conducted on a protocol-driven selective patient population, the population-level evaluation of the effectiveness and safety of such therapies in the real-world practice would guide the patients and their carer’s in terms of choosing the right therapies for optimum disease management. Clinical studies have evaluated the possible beneficial association of treatment with novel anti-diabetic therapies with CV risk factors, however the real-world evidence on such aspects is scarce. With a central focus on incretin-based therapies, the aims of this thesis were to explore the real- world patterns of (1) longitudinal changes in ADD choices, (2) population-level glycaemic control and its sustainability, and (3) the long-term cardio-metabolic risk factor burden. Using a large database of Electronic Medical Records (EMRs) of the United States, six pharmaco-epidemiological and three methodological studies were conducted. A number of important findings were reported in high impact journals including Diabetes Care and Diabetes, Obesity, and Metabolism, with one publication receiving a dedicated review in the Nature Reviews journal. Extensive methodological and data mining studies were performed to extract reliable data from voluminous EMRs and to develop efficient study designs and analysis approaches. One study was devoted to the data management of medication prescriptions, specifically to the estimation of treatment duration at individual patient-level accounting for intensifications and alterations with multiple therapies. Methodological challenges associated with robust identification of the patients with T2DM were addressed in another separate study. An exploratory analysis to 3 investigate the mechanisms and patterns of longitudinal missing risk factor data along with a comparative study of multiple imputation techniques for such data were conducted to account for the uncertainty due to missing values and to ensure the generalisability of study findings. Advanced statistical methodologies, such as “treatment effects modelling”, were performed throughout the thesis to ensure robust inferences drawn in the individual studies. It was observed that the use of incretin-based drugs has increased since their approval in 2005, in particular the use of DPP-4i as a second-line choice. Patient profiles significantly varied by the class of chosen ADD, for instance GLP-1RA users were younger, had lower HbA1c level, and were more likely to be female, compared to other major ADD users. It was observed that around half of the patients with T2DM do not reach glycaemic targets and clear evidence of therapeutic inertia persists at population-level. Patients who intensified metformin with incretin-based drugs or thiazolidinedione were more likely to achieve and sustain glycaemic control over 24 months of continuous treatment, compared to those treated with sulfonylurea – the most popular intensification choice. A separate study investigated the outcomes of intensifying GLP-1RA with insulin and reported beneficial cardio-metabolic effects of combining these therapies. Even though the popularity of newer therapeutic classes as second-line options was notably increasing, the longitudinal rates of intensification with a third-line ADD was not reduced significantly at the population level. Neither glycaemic nor CV risk factor burden significantly improved over the last decade in patients with T2DM, even though most patients were using multiple drugs for glucose, blood pressure and lipid control. The long-term glycaemic burden consistently increased over time, and more than half of the patients with a history of CV disease continued to have uncontrolled blood pressure and lipids post-therapy initiation. Three out of five patients who are already receiving multiple anti-diabetic and cardio-protective drugs were failing to simultaneously control glucose and at least one CV risk factor. Compared to those who initiated second-line ADD with sulfonylurea and insulin, patients who intensified metformin with incretin-based therapies or thiazolidinedione were more likely to achieve simultaneous glucose and CV risk factor control. Treatment with GLP-1RA was associated with lower rates of major adverse macrovascular events, compared to other ADDs. To conclude, this dissertation provides a detailed exploration and valuable insights of T2DM management in the real-world setting and highlights alarming rates of the existing cardio- 4 metabolic burden at the population level. Incretin-based therapies and thiazolidinedione were found to provide higher chances of sustainable glycaemic and CV risk factor control, and treatment with GLP-1RA appears to have a beneficial association with CV risk, compared to other anti-diabetic treatment options. Nonetheless, proper control in terms of timely intensification with anti-hyperglycaemic, anti-hypertensive, and anti-dyslipidemic therapies when needed, remains a key aspect to improve long-term outcomes in patients with T2DM. 5 KEYWORDS Glucagon-like peptide-1 receptor agonist, dipeptidyl peptidase 4 inhibitor, incretin-based therapy, glycaemic control, cardiovascular risk, macrovascular event, type 2 diabetes mellitus, electronic medical records, longitudinal cohort study. 6 LIST OF PUBLICATIONS The following is a list of published or submitted manuscripts that have been incorporated into this thesis, thereby producing a thesis by publication. Chapter 4: Olga Montvida, Ognjen Arandjelović, Edward Reiner, and Sanjoy K. Paul. Data Mining Approach to Estimate the Duration of Drug Therapy from Longitudinal Electronic Medical Records. Open Bioinformatics, 2017, 10:1-15. DOI: 10.2174/1875036201709010001.x. Chapter 6: Mayukh Samanta, Olga Montvida, Joanne Tropea, and Sanjoy K. Paul. A comparison of imputation methods for missing risk factor data from large real-world electronic medical records for comparative effectiveness studies. (Submitted) Chapter 7: Olga Montvida, Jonathan Shaw, John J Atherton, Francis Stringer, Sanjoy K Paul. Long-term Trends in Antidiabetes Drug Usage in the US: Real-world Evidence in Patients Newly Diagnosed With Type 2 Diabetes. Diabetes Care. 2017 Nov 6:dc171414. DOI: 10.2337/dc17-1414.x. Chapter 8: Olga Montvida, Jonathan Shaw, Lawrence Blonde, Sanjoy K Paul. Long-term sustainability of glycaemic achievements with second-line anti-diabetic therapies in patients with type 2 diabetes: A real-world study. Diabetes, Obesity, and Metabolism. 2018;20:1722– 1731. DOI: 10.1111/dom.13288.x. Chapter: 9: Olga Montvida, Sanjoy K Paul. Cardiovascular risk factor burden and safety in patients with type 2 diabetes receiving intensified anti-diabetic and cardio-protective therapies. (Submitted) The following is a list of accepted and submitted manuscripts that are highly relevant to the work performed in this thesis and were developed throughout candidature. Appendix A: Olga Montvida, Kerenaftali Klein, Sudhesh Kumar, Kamplesh Khunti, Sanjoy K. Paul. Addition of or switch to insulin therapy in people treated with glucagon‐like peptide‐ 1 receptor agonists: A real‐world study in 66 583 patients. Diabetes, Obesity and Metabolism. 2017 Jan 1;19(1):108-17. DOI: 10.1111/dom.12790.x. 7 Appendix B: Ebenezer S. Owusu Adjah*, Olga Montvida*, Julius Agbeve, Sanjoy K. Paul. Data Mining Approach to Identify Disease Cohorts from Primary Care Electronic Medical Records: A Case of Diabetes Mellitus. The Open Bioinformatics Journal, 2017, 10: 16-27. DOI: 10.2174/1875036201710010016.x. *Joint first authorship. Appendix C: Sanjoy K Paul, Jonathan Shaw, Olga Montvida, Kerenaftali Klein. Weight gain in insulin treated patients by BMI categories at treatment initiation: New evidence from real- world data in patients with type 2 diabetes. Diabetes, Obesity and Metabolism. 2016 Dec 1;18(12):1244-52. DOI:10.111/dom.12761.x. Appendix D: Olga Montvida, Jennifer B Green, John Atherton, Sanjoy K Paul. Risk of Pancreatic Diseases by Second-line Drug Class: Real World Evidence in 225,898 Type 2 Diabetes Patients. Diabet Med. 2018 Oct 10. doi: 10.1111/dme.13835. The following is a list of presentations and papers in refereed conference proceedings throughout candidature. 1. Olga Montvida, Sanjoy Paul. Cardiovascular risk factor burden and safety in patients with type 2 diabetes receiving intensified anti-diabetic and cardio-protective
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