From Pathophysiology to Treatment: Contemporary Approaches to CFRD in the Pediatric and Adolescent Population

Cystic fibrosis-related diabetes (CFRD) is the most prevalent nonrespiratory complication of cystic fibrosis (CF), with its prominence growing as survival rates improve due to advances in CFTR modulator therapies. Its prevalence increases with age, affecting nearly 50% of patients with CF (PwCF) over 30 years old. CFRD primarily results from progressive pancreatic fibrosis leading to insulin deficiency, further compounded by intermittent insulin resistance during pulmonary exacerbations and systemic inflammation. Key risk factors include pancreatic insufficiency, female sex, severe CFTR genotypes (such as p.F508del homozygosity), CF-related liver disease, and family history of type 2 diabetes. The early stages of CFRD are often asymptomatic, necessitating proactive screening. Annual oral glucose tolerance tests (OGTT) beginning at age 10 are challenging to perform but remain the gold standard for early detection, while continuous glucose monitoring (CGM) is increasingly recognized as a valuable complementary tool. Diagnosis is based on standard OGTT criteria, with indeterminate glycemia (INDET) and impaired glucose tolerance (IGT) recognized as prediabetic stages requiring close monitoring. Even early abnormalities in glucose metabolism may be associated with declines in pulmonary function and nutritional status, underscoring the need for rigorous surveillance and timely therapeutic intervention. Early initiation of insulin treatment can substantially mitigate these complications and improve clinical outcomes. Insulin remains the cornerstone of CFRD management, is recommended as the primary treatment for patients with CFRD (PwCFRD) rather than dietary modification alone. While pilot studies and observational cohorts have suggested potential benefits of early insulin treatment in individuals with early glycemic abnormalities such as INDET or IGT, findings from randomized controlled trials do not provide evidence to justify initiating insulin before CFRD is established. Management strategies should be individualized, with personalized glycemic targets. Insulin dosing aims to achieve the maximum tolerable dose to maintain a low HbA1c, control postprandial hyperglycemia without inducing hypoglycemia, minimize catabolism, and preserve optimal nutrition and pulmonary health without restricting carbohydrate intake. Regular glucose monitoring, quarterly HbA1c measurements, and annual screening for microvascular complications starting 5 years after diagnosis are essential to optimize outcomes. The advent of CFTR modulator therapies has revolutionized CF care, significantly improving outcomes and quality of life for PwCF. These therapies also show promise in improving glucose regulation and may impact the prevalence, onset, and course of CFRD. However, current data remain inconclusive, and the long-term effects are still being elucidated. Future directions in CFRD research include refining screening protocols, exploring adjunctive noninsulin therapies, and developing predictive biomarkers. This review summarizes the current understanding of CFRD pathophysiology, diagnosis, and management strategies, emphasizing the importance of early intervention and personalized care in the context of evolving CF treatment approaches and their potential to improve prognosis for PwCF.