Comparative Effectiveness of Oral Antihyperglycemic Agents in Patients with Diabetes and Chronic Kidney Disease by Reid H. Whitlock A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba in partial fulfillment of the requirements of the degree of MASTER OF SCIENCE Department of Community Health Sciences University of Manitoba Winnipeg, Manitoba, Canada Copyright © 2018 by Reid H. Whitlock i Abstract We sought to compare the safety of sulfonylureas to other oral antihyperglycemic agents (OHAs) in patients with type 2 diabetes (T2DM) and examine whether chronic kidney disease (CKD) is an effect modifier. Using Manitoba Center for Health Policy data, we identified adults with an incident OHA prescription between 2006 and 2016 (monotherapy; add-on to metformin [combotherapy]), and a serum creatinine test. We conducted comparisons with Cox models in propensity score matched cohorts. In 1,777 matched monotherapy pairs, sulfonylureas were associated with all-cause mortality (HR 1.44; 95% CI 1.05 – 1.97) vs. metformin where CKD was an effect modifier (p<0.001) as sulfonylureas performed worse in patients without CKD. In 1,266 matched combotherapy pairs, sulfonylureas were associated with all-cause mortality (HR 2.40; 95% CI 1.15 – 5.02) vs. other OHAs. CKD was not an effect modifier for other comparisons. Our evidence supports metformin as monotherapy, and discourages sulfonylureas as add-on therapy for glycemic control. ii Acknowledgements I would like to extend gratitude to everyone who assisted me with my studies and who contributed to the completion of this thesis project: Dr. Navdeep Tangri, Dr. Kristin Clemens, Dr. Paul Komenda, Dr. Nathan Nickel, Dr. Marshall Pitz, Farzana Quddus, Heather Prior, Manitoba Centre for Health Policy, Nicole Askin, Health Information Privacy Committee at Manitoba Health, Winnipeg Regional Health Authority, Vital Statistics Manitoba, Diagnostic Services of Manitoba, and the Research Team at the Chronic Disease Innovation Centre at Seven Oaks Hospital. Furthermore, I would like to acknowledge the financial assistance that I have received throughout completion of my graduate studies in Community Health Sciences, which include the Canadian Frailty Network through the Interdisciplinary Fellowship Program, and the support of the Chronic Disease Innovation Centre at Seven Oaks Hospital. The results and conclusions are those of the authors and no official endorsement by Manitoba Health and Healthy Living was intended or should be inferred. iii Table of Contents Abstract .......................................................................................................................................... ii Acknowledgements ...................................................................................................................... iii Table of Contents ......................................................................................................................... iv List of Tables and Figures .......................................................................................................... vii Glossary of Acronyms.................................................................................................................. ix 1. Chapter 1: Introduction ............................................................................................................1 1.1 Pathophysiology of Type 2 Diabetes Mellitus .......................................................................1 1.2 Diagnosis and Treatment of Type 2 Diabetes Mellitus ..........................................................1 1.3 Epidemiology and Economic Impact of Type 2 Diabetes Mellitus ......................................2 1.4 Pathophysiology of Chronic Kidney Disease .........................................................................3 1.5 Diagnosis and Treatment of Chronic Kidney Disease ...........................................................4 1.6 Epidemiology and Economic Impact of Chronic Kidney Disease .........................................4 1.7 Concomitant Type 2 Diabetes Mellitus and Chronic Kidney Disease ...................................5 1.8 Study Objectives and Thesis Statement .................................................................................6 2. Chapter 2: Literature Review ...................................................................................................8 2.1 Metformin ...............................................................................................................................8 2.2 Sulfonylureas ........................................................................................................................10 2.3 Thiazolidinediones ...............................................................................................................12 iv 2.4 Dipeptidyl Peptidase-4 Inhibitors .........................................................................................14 2.5 Meglitinides ..........................................................................................................................16 2.6 Alpha-glucosidase Inhibitors ................................................................................................17 2.7 Glucagon-like Peptide-1 Receptor Agonists ........................................................................18 2.8 Sodium Glucose Cotransporter-2 Inhibitors ........................................................................20 2.9 Secular Trends and Prescribing Patterns for Oral Antihyperglycemic Agents ....................22 3. Chapter 3: Materials and Methods ........................................................................................24 3.1 Data Sources and Study Design ...........................................................................................24 3.2 Study Population ..................................................................................................................25 3.3 Cohort Design ......................................................................................................................26 3.4 Exposures .............................................................................................................................27 3.5 Outcomes ..............................................................................................................................29 3.6 Sample Size Considerations .................................................................................................30 3.7 Covariates .............................................................................................................................31 3.8 Statistical Analysis ...............................................................................................................32 4. Chapter 4: Results....................................................................................................................36 4.1 Baseline Characteristics .......................................................................................................36 4.2 Propensity Matching ............................................................................................................40 4.3 Outcomes ..............................................................................................................................42 v 4.4 Chronic Kidney Disease as an Effect Modifier ....................................................................46 5. Chapter 5: Discussion ..............................................................................................................48 5.1 Summary of Findings ...........................................................................................................48 5.2 Comparison with Previous Studies ......................................................................................48 5.3 Implications ..........................................................................................................................53 5.4 Strengths and Limitations .....................................................................................................57 5.5 Conclusions ..........................................................................................................................59 Tables and Figures .......................................................................................................................61 References .....................................................................................................................................91 vi List of Tables and Figures Figure 1. Classification of chronic kidney disease ....................................................................61 Table 1. Databases .......................................................................................................................62 Table 2. Exposures .......................................................................................................................63 Table 3. Safety outcomes .............................................................................................................64 Table 4. Baseline comorbidities ..................................................................................................65 Table 5. Baseline medications .....................................................................................................66 Figure 2. Study flow diagram for monotherapy cohort ...........................................................67 Figure 3. Study flow diagram