Division of Endocrinology, Diabetes & Metabolism, Department of Medicine and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
J Clin Endocrinol Metab. 2023 Dec 21;109(1):151-160. doi: 10.1210/clinem/dgad443.
Elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta) enhances aberrant cystic fibrosis transmembrane conductance regulator function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF).
This longitudinal case-control study assessed changes in β-cell function and secretory capacity measures over 2 visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and (1) restudied between 2019 and 2021 (ETI group) vs (2) those restudied between 2015 and 2018 and not yet treated with cystic fibrosis transmembrane conductance regulator modulator therapy (controls).
Nine ETI participants (mean ± SD age, 25 ± 5 years) and 8 matched controls were followed up after a median (interquartile range) 5 (4-7) and 3 (2-3) years, respectively (P < .01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine, and mixed-meal tolerance test measures were assessed with comparisons of within- and between-group change by nonparametric testing.
Glucose-potentiated insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls but not in the ETI group, with C-peptide changes different between groups (P < .05). Deterioration in basal proinsulin secretory ratio was observed in controls but improved, as did the maximal arginine-induced proinsulin secretory ratio, in the ETI group (P < .05 for all comparisons). During mixed-meal tolerance testing, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics.
ETI preserves β-cell function in CF through effects on glucose-dependent insulin secretion, proinsulin processing, and meal-related insulin secretion. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF.
依伐卡托/泰它卡托/艾美卡替（ETI；Trikafta）增强了异常的囊性纤维化跨膜电导调节因子功能，并可能改善与胰腺功能不全型囊性纤维化（PI-CF）临床结局恶化相关的胰岛素分泌缺陷。
本项纵向病例对照研究评估了在基线访视（2012-2018 年）后开始 ETI 的 PI-CF 个体在 2 次访视中β细胞功能和分泌能力测量值的变化：（1）在 2019 年至 2021 年期间重新研究（ETI 组）与（2）在 2015 年至 2018 年期间重新研究且尚未接受囊性纤维化跨膜电导调节剂治疗的个体（对照组）。
9 名 ETI 参与者（平均年龄±标准差，25±5 岁）和 8 名匹配的对照者分别随访中位数（四分位间距）5（4-7）和 3（2-3）年（P＜0.01），ETI 启动时间中位数为随访前 1 年。通过非参数检验比较组内和组间变化，评估临床结局、葡萄糖增强精氨酸和混合餐耐量试验测量值。
葡萄糖增强精氨酸时胰岛素和 C 肽反应在对照组中恶化，但在 ETI 组中未恶化，且两组间 C 肽变化不同（P＜0.05）。对照组中基础胰岛素原分泌比值恶化，但 ETI 组中改善，最大精氨酸诱导的胰岛素原分泌比值也改善（所有比较 P＜0.05）。在混合餐耐量试验期间，胰岛素分泌早期更快，表明早期胰岛素分泌改善。
ETI 通过对葡萄糖依赖性胰岛素分泌、胰岛素原加工和与进餐相关的胰岛素分泌的影响，维持 CF 中的β细胞功能。进一步的研究应确定早期干预 ETI 是否可以预防 PI-CF 中葡萄糖耐量恶化。
