Diabetes remission in adults with cystic fibrosis commenced on Elexacaftor/Tezacaftor/Ivacaftor: A single center case‐series

The introduction of cystic fibrosis transmembrane regulator (CFTR) modulator therapies has revolutionized pulmonary health for people living with cystic fibrosis (CF). In Australia, adults with at least one F508del mutation have been eligible for subsidized Elexacaftor/Tezacaftor/Ivacaftor (ETI) since April 2022. This therapy has been linked to extrapulmonary benefits with emerging evidence of restoration of exocrine pancreatic function1 and improvements in glycaemic profiles and insulin-sparing.2 Here we present a case series of four adults with CF commenced on ETI who achieved diabetes remission. Our adult cystic fibrosis center at The Prince Charles Hospital, uses the 75 gram oral glucose tolerance test (OGTT) for the diagnosis of CF-related diabetes.3 Insulin is used as first line therapy for treatment of hyperglycemia. Following diabetes diagnosis, HbA1c is used for monitoring of glycaemic control. For the purposes of this study, we defined diabetes remission as achievement of (i) plasma HbA1c or glycaemic management indicator on continuous glucose monitoring of ≤6.0% or (ii) normal glucose tolerance on OGTT at least 3-months after insulin cessation. Using a prospective clinical database (ethics exemption granted by Metro North EX/2024/MNHB/111401, quality activity with informed consent waived) we identified (a) all individuals with a confirmed diagnosis of CF-related diabetes, (b) delineated those who had ceased insulin following ETI initiation, and (c) comprehensively evaluated clinical, biochemical, and/or continuous glucose monitoring data to corroborate diabetes remission. We identified four adults (one female), median age 18.5 years (IQR 16.5–25), 50% homozygous for F508del who met diabetes remission criterion. All adults were diagnosed with CF-related diabetes on an OGTT greater than 12 months before ETI initiation and were using basal and/or rapid acting insulin (median dose 6.8 units, range 2–17) for glycaemic optimization. Since starting ETI, none required hospitalization for pulmonary exacerbations. Indication for insulin cessation was new onset hypoglycemia in all cases. One case received Tezacaftor/Ivacaftor for 1-year before transitioning to ETI and was able to completely cease basal insulin (total daily dose of 17 units) at time of ETI commencement. Time to insulin cessation for the remaining cases following ETI initiation was 13.5 months (±5.1) (see Table 1). None of the adults experienced diabetes ketoacidosis following insulin cessation. To-date all cases described in this series continue on ETI and have not required insulin and/or anti-hyperglycaemic therapies to maintain normoglycaemia. In our single center case-series, we present a detailed report of four adults with pre-existing CF-related diabetes who ceased insulin following ETI initiation due to hypoglycemia and achieved diabetes remission. Previous reports of diabetes remission with ETI include an adult post-lung transplant recipient4 and four children.5 A case report of an adult with CF achieving diabetes remission following ivacaftor therapy shared features with our cases, including of younger age and a 1-year time-frame to insulin cessation.6 Based on our findings, we hypothesize predictors of diabetes remission might include younger age, suggesting less time-dependent pancreatic damage due to CFTR dysregulation, and higher likelihood of salvageable pancreatic beta-cells. Pre-ETI modulator use may have provided further beta cell protection and opportunities for salvage as noted in one of our cases who used Tezacaftor/Ivacaftor for 12-months before transitioning to ETI. He was able to immediately cease insulin upon ETI initiation. Insulin cessation instigated by hypoglycemia in our cases suggests improved endogenous insulin production, which may be attributable to a direct CFTR role in beta-cell function. Another hypothesis is improvements in incretin effects, which has been shown to be deranged in people with CF.7 This hypothesis aligns somewhat with the OGTT profile of our case series, which showed only slightly elevated 2-h plasma glucose levels, with a mean of 2.3 mmol/L ± 0.5 above the upper limit of normal (11.1 mmol/L) and no evidence of fasting hyperglycemia. However, the borderline criterion for diabetes being met on OGTT in a younger cohort might also reflect transient early glucose abnormalities. Nevertheless, the risk of diabetes in CF increases with age, which makes diabetes remission in our adult cohort unique. Our cases also demonstrated low-normal body mass index and minimal insulin requirements to maintain normoglycaemia. This perhaps indicates a high degree of insulin sensitivity, endogenous insulin production and/or reduced risk of insulin resistance from type 2 diabetes phenotype. The mean time to insulin cessation was 13.5 months. This prolonged timeframe suggests that reduction in inflammation is perhaps less likely to be the key driver of insulin sparing. Instead, we hypothesize that a regenerative process might be contributing to improved endogenous insulin production. This is further supported by emerging literature on pancreatic exocrine function being restored with ETI over a similar time-frame,8 perhaps highlighting the regenerative potential of the pancreas. Whether ETI can lead to classical regeneration and/or redifferentiation of acinar cells which can impact beta-cell function through complex exocrine-endocrine signaling remains to be elucidated. Ongoing observation is also needed to ascertain whether long-term use of ETI can further restore and/or maintain physiological function of the pancreas in our described cases. Another consideration is whether early insulin administration reduced beta cell stress and slowed loss, leading to the outcomes seen in our cases. Findings from the CF-IDEA trial will be useful to clarify this.9 Finally, limited exercise data was collected for this group, and its contributions to diabetes remission remain unclear. Detailing diabetes remission has prompted our center to undertake a comprehensive review and identify adults on ETI with similar clinical characteristics to the described cases. We plan to work closely together with this group to monitor and repeat discretionary testing with a view to reduce treatment burden in the post-ETI era. Shanal Kumar: Conceptualization; investigation; writing—original draft; methodology; formal analysis; supervision. Angela G. Matson: Conceptualization; data curation; writing—review and editing. Dr Shanal Kumar is supported by Queensland Health through a Clinical Research Fellowship. The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.