Real-world gegevens over diabetestechnologie in type 1 diabetes: naar klinisch relevante, persoonsgerichte en voor de gezondheidszorg informatieve inzichten

Type 1 diabetes (T1D) is caused by a cellular-mediated autoimmune destruction of the insulin producing β-cells of the islets of Langerhans in the pancreas, leading to absolute endogenous insulin deficiency. People with T1D therefore require lifelong intensive insulin therapy to manage their blood glucose and minimize the risk of acute (severe hypoglycemia, diabetic ketoacidosis) and chronic diabetes complications (retinopathy, nephropathy, neuropathy and cardiovascular disease). Insulin can be administered via multiple daily injections (MDI) or an insulin pump, both requiring regular self monitoring of blood glucose levels to adjust insulin doses accurately. This can be done via capillary finger pricks or continuous glucose monitoring (CGM) systems, which use a subcutaneous sensor to provide real-time glucose readings. Since the landmark Diabetes Control and Complications Trial established that high hemoglobin A1c (HbA1c; a marker for average blood glucose over the past 2-3 months) is strongly associated with an increased risk of developing chronic diabetes complications, monitoring HbA1c became the gold standard to evaluate glycemic management and guide therapeutic decisions in people with T1D, with international guidelines recommending a target value of <7% for HbA1c. The wealth of data generated by CGM has led to the implementation of additional parameters beyond HbA1c, including the time in range parameters (time in range [TIR; glucose 70-180 mg/dL], time in hypoglycemia [glucose <70 mg/dL and <54 mg/dL] and time in hyperglycemia [glucose >180 mg/dL and >250 mg/dL]). These measures of short-term glycemic management complement HbA1c by providing a more comprehensive assessment of an individual's glycemic profile, addressing the limitations of relying solely on HbA1c. More recently, time in tight range (TITR; glucose 70-140 mg/dL) has been introduced as a marker of near-normal glycemic levels. The introduction of hybrid closed-loop (HCL) insulin delivery systems have fundamentally transformed diabetes management. By using a control algorithm, these pumps automatically adapt insulin delivery in response to real-time glucose readings from a CGM system, with the goal of reaching a predetermined glucose target or target range. However, current HCL systems still require users to manually enter carbohydrate intake and accept a generated bolus advice at moments of meals. Several randomized controlled trials (RCTs) have consistently demonstrated superiority of HCL systems over other intensive insulin regimes in improving glycemic management, minimizing hypoglycemia, and enhancing person-reported outcomes (PROs) for people with T1D across all age groups. While RCTs are the gold standard for evaluating efficacy and safety of novel interventions, they often include highly selected populations and operate under controlled conditions, restricting the generalizability of findings to routine clinical practice. In contrast, real-world studies capture data from broad and heterogeneous populations in everyday settings, better reflecting variations in demographics, comorbidities, behavior, and adherence. In the context of T1D care, technologies such as CGM, insulin pumps, and HCL systems are particularly powerful sources of real-world data, systematically generating detailed, high frequency information on glucose levels, insulin delivery patterns, and user behavior. The overall aim of this PhD thesis was to leverage real-world data from diabetes technology to generate clinically meaningful, person-centered, and policy-informing evidence for people with T1D. The first aim was to validate the clinical relevance of TITR and TIR as key measures of glycemic management alongside HbA1c. In Chapter 3, we conducted a cross-sectional analysis with data from 808 adults with T1D who participated in the RESCUE and FUTURE real-world studies at the University Hospitals of Leuven to evaluate the association of CGM-measured TITR and TIR with the presence of various micro- and macrovascular complications. Both TITR and TIR were found to be inversely associated with the presence of microvascular complications and a cerebrovascular accident, supporting their use as complementary endpoints of HbA1c in future clinical trials and regulatory frameworks. The second aim was to evaluate the real-world effectiveness, safety and usability of HCL therapy (Tandem Control-IQ and the Medtronic 780G specifically) over a period of one year across different age groups. We extended the multicenter, prospective, observational INRANGE study to assess real-world changes in glycemic management and PROs after initiation of Tandem Control-IQ in both adults (Chapter 4) as well as children and adolescents (Chapter 5) with T1D. One year use of the system in routine clinical care resulted in improved glycemic outcomes, more diabetes-related quality of life, higher treatment satisfaction, reduced parental fear of hypoglycemia, fewer severe hypoglycemic events, and less work/school absenteeism days. In an extension of the INRANGE study to young children aged 2-6 years with T1D, in which the Medtronic 780G was evaluated off-label at the time of analysis (Chapter 6), the system was found to be safe and to improve glycemic outcomes and parental burden, although its impact on hypoglycemia and related parental fear was limited. Finally, Chapter 7 assessed the cost-utility of Tandem Control-IQ relative to conventional insulin therapy in adults with T1D in Belgium, using data collected in the INRANGE study. Despite the higher upfront costs of the system compared with MDI and CSII with CGM, the analysis demonstrated that the clinical and person-reported benefits of Tandem Control-IQ translated into meaningful long-term economic value. This PhD thesis highlights the power of real-world data generated by diabetes technologies to provide clinically relevant, person-centered, and policy-informing insights into T1D care. By validating novel glycemic metrics, confirming the real-world benefits of HCL systems across different age groups, and establishing their economic value, this research bridges the gap between evidence from controlled clinical trials and routine practice. Collectively, the findings underscore the importance of integrating real-world evidence into clinical and policy decisionmaking, with the ultimate goal of optimizing individualized diabetes management and improving long-term outcomes for people living with T1D.