Glucagon Like Peptide-1 Medicine Outcomes in Real World Patients with Type 1 Diabetes - PROJECT SUMMARY/ABSTRACT Glucagon like-peptide-1 (GLP-1) medicines, including GLP-1 agonists and GLP-1/gastric inhibitory peptide dual agonists, reduce weight, kidney and cardiovascular disease events for people with type 2 diabetes and overweight/obesity. People with type 1 diabetes (T1D) have excess cardiovascular disease and kidney disease, and overweight/obesity prevalence is growing in this population. The detrimental milieu of obesity and insulin resistance further exaggerates risk of diabetes-related complications. In people with T1D, limited studies have examined weight response to GLP-1 medicines and other frequently prescribed weight loss medicines. Further, there is a major knowledge gap about whether GLP-1 medicines prevent kidney disease progression, reduce cardiovascular disease, and cause rare, severe adverse events in this population. The objective of this study is to assess clinically significant: weight loss, kidney disease, and major adverse events in response to GLP-1 medicines in T1D. This project will test the hypothesis that GLP-1 medicines have clinical benefits relevant to cardiorenal disease protection and are safe in a population with T1D. It will leverage existing real world electronic healthcare data from Epic Cosmos, a database of over 300 million people of whom over 943,000 have a T1D diagnosis. Using longitudinal, harmonized data from this cutting-edge platform, this project will compare patients with T1D treated with a cardioprotective GLP-1 medicine (liraglutide, semaglutide, dulaglutide, tirzepatide) to active comparators (phentermine and metformin) using propensity score-based methods to account for bias due to non-random treatment. The project will examine the impact of these drugs on: cardioprotective weight loss (≥10%) (Aim 1); composite kidney outcomes including persistent incidence: urine albumin to creatine ratio [UACR] ≥30 mg/g or UACR ≥300 mg/g, ≥40% eGFR decline, end stage kidney disease, and all-cause mortality (Aim 2); and safety events including major adverse cardiovascular events, all-cause mortality, and incidence rates of emergency department/hospital admissions along with associated diagnoses (Aim 3). This project is a logical extension of the principal investigator’s interventional K23 research project which examines GLP-1 medicine impact on surrogate cardiovascular outcome measures in adults with T1D. The current research proposal focuses on improving health for people with T1D through innovative use of a cutting-edge research platform combined with advanced causal inference methods. To accomplish these goals, this project assembles a team of complementary and well-suited experts, including an endocrinologist with T1D and GLP-1 medicine research expertise, clinical informatician, pharmaco-epidemiologist, data scientist, and biostatistician all with large-scale, secondary data analytic experience. This research is significant because it addresses major knowledge gaps in clinical efficacy of GLP- 1 medicines, and most frequently prescribed comparators, in the T1D population, and it will inform evidence- based guidelines and future methodology for interventional kidney and cardiovascular outcome trials in T1D.
