Hitting the Sweet Spot: The Impact of Elexacaftor/Tezacaftor/Ivacaftor on Glucose Tolerance in Cystic Fibrosis

Cystic fibrosis–related diabetes (CFRD) is a common and serious complication of CF that affects <1% of children <10 years of age, 9.7% of 10–19-year-olds, and as many as 40–50% of adults (1). Onset is often insidious, with progressive dysglycemia detectable from early childhood (2) and deterioration in respiratory and nutritional health preceding the diabetes diagnosis by 2–4 years (3). Treatment with insulin can reverse health decline and improve survival in CFRD, underscoring the importance of early diagnosis and screening for CFRD. Conversely, insulin treatment appears to have limited benefit for those with earlier glycemic abnormalities (4). Diagnosis of CFRD is a sentinel event for patients, associated with increased treatment burden and reduced quality of life (5). Despite effective treatment with insulin, CFRD is associated with worse pulmonary and nutritional outcomes, microvascular complications, and mortality rates approximately 3.5 times higher than in those without CFRD (1, 6). Progressive improvements in survival attributed to screening and early treatment have stalled (6), prompting a call for novel therapies and interventions to tackle the problem of CFRD.

CFTR modulator therapies have led to unprecedented improvements in pulmonary and nutritional outcomes for many people with CF, and comparable improvements in glucose regulation and CFRD have been highly anticipated. Initial studies of ivacaftor therapy among small cohorts of patients showed promising improvements in insulin secretion and glycemic control (7, 8). Furthermore, analysis of data from the United States and United Kingdom national CF registries indicated a significant reduction in the prevalence of CFRD among ivacaftor-treated versus comparator patients (9). These encouraging results were not replicated in studies of lumacaftor/ivacaftor, which did not appear to consistently improve glucose tolerance and had no effect on insulin secretion (7). Combination triple therapy with elexacaftor/tezacaftor/ivacaftor (ETI) was approved by the U.S. Food and Drug Administration in 2019 and is now available for >90% of people with CF aged ≥2 years. The impact of ETI on glucose regulation and CFRD is largely unknown and is an important area of research.

In this issue of the Journal, Durieu and colleagues (pp. 1926–1934) examined the impact of ETI on glucose tolerance among people with CF aged ⩾12 years (10). In this phase 3b open-label study, 69 participants who were heterozygous for F508del/MF mutations and had abnormal glucose tolerance at screening (impaired glucose tolerance, 42%; CFRD, 58%) received 48 weeks of ETI treatment (10). The primary endpoint was the average absolute change versus baseline in 2-hour blood glucose level after an oral glucose tolerance test at Week 36 and Week 48. Secondary outcomes included safety; change in dysglycemic category, hemoglobin A1_c level, and daily insulin dose at 48 weeks compared with baseline; and the proportion of participants with normal glucose tolerance at 48 weeks. Measures were recorded at 24, 36, and 48 weeks. The authors reported a statistically significant decrease in the within-group mean 2-hour blood glucose level of −35 mg/dl (−1.9 mmol/L), and more than one third of the cohort (37.7%) had an improvement in dysglycemic category following 48 weeks of ETI treatment. Normal glucose tolerance was observed in 35.5% of participants at 48 weeks compared with 13% at baseline. Improvements were detectable at Week 24 and sustained through Weeks 36 and 48.

The observations reported in this study lend significant weight to the existing data that report a positive effect of ETI on glucose regulation (11). The strengths of this study include the cohort size, which is the largest to date; the duration of observation; and repeated measures that demonstrate sustained improvements in glucose regulation during the 48-week period. Although sustained improvements support the efficacy of ETI in glucose regulation, the lack of a control group and patients with normal glucose tolerance at screening means we cannot determine causality or whether the observed changes reflect the common perturbations in glucose tolerance seen in the course of CF disease. The findings of this study, combined with a growing body of evidence (11), highlights the potential for ETI to reduce the burden of CFRD through improvements in glucose tolerance in the CF population. However, the investigators did not observe statistically significant changes in insulin doses, and the impact of ETI on the daily burden of care among patients with established CFRD may fall short of expectations for some.

Durieu and colleagues contribute to our understanding of the impact of ETI in individuals with abnormal glucose homeostasis and CFRD, but the answers to several key questions demand further research. What are the mechanisms for improved glycemic control seen with ETI and other CFTR modulators? Is there a direct effect of CFTR restoration within pancreatic β-cells leading to improved insulin secretion, and of reduced intra–islet cell inflammation ultimately preserving β-cell mass (12, 13)? In this scenario, treatment with ETI in early life, when β-cell mass is greatest, will be crucial to prevent or delay the onset of dysglycemia. Are the main effects of ETI on glucose metabolism secondary to reduced systemic inflammation (14), improved nutrition, and better gastrointestinal function, leading to improved insulin sensitivity and secretion? In this setting, sustained benefits in glucose regulation over the lifespan will depend on individual responses to ETI therapy and ongoing treatment adherence. The impact of ETI and other modulators on glucose metabolism is undoubtedly multifactorial and requires ongoing research in larger, well-designed mechanistic and cohort studies. Finally, we need to understand the experiences of individuals with CFRD and the long-term impact of ETI on diabetes-related treatment burden and quality of life. Then, we will have truly found the sweet spot.