Precision therapy reduces the risk of diabetes in people with cystic fibrosis-related diabetes

Diabetes is a highly prevalent complication of cystic fibrosis (CF), affecting 50% of adults with CF and over 80% of those with exocrine pancreatic insufficiency (PI) by age 50 years. Development of cystic fibrosis-related diabetes (CFRD) is associated with increased morbidity and mortality mostly due to advancement of chronic obstructive lung disease. Highly effective modulator therapy (HEMT), using precision medications targeting the cystic fibrosis transmembrane conductance regulator (CFTR), improves CFTR function and CF lung disease, but its impact on diabetes pathogenesis remains uncertain. We sought to determine whether two types of HEMT, ivacaftor and elexacaftor/tezacaftor/ivacaftor (ETI), alter diabetes prevalence in two large cohorts of individuals with CF and exocrine PI. For comparison, a non-highly-effective modulator, lumacaftor/ivacaftor (LUM/IVA), was also assessed. Data were provided by the CFTR2 project, a multinational CF registry (for ivacaftor and LUM-IVA), and by the CF Genome Project (CFGP), a predominantly US-based CF cohort (for ETI). Among 32,753 individuals with CF (2,803 treated), ivacaftor was associated with reduced diabetes prevalence (age-adjusted OR=0.55). In contrast, lumacaftor/ivacaftor (not highly effective) was not associated with diabetes prevalence (n=32,749). Among 2,854 individuals with CF (2,458 treated), ETI was associated with reduced diabetes prevalence (age-adjusted OR=0.47). Overall, HEMT (ivacaftor and ETI) was associated with a 25-39% reduction in diabetes prevalence in CF, while a non-highly-effective modulator (lumacaftor/ivacaftor) showed no difference. Precision targeted amelioration of CFTR dysfunction can delay onset of diabetes in a high-risk CF population.